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Abstract Purpose Immune checkpoint blockades (ICBs) are promising, however they do not fit all types of tumor, such as those lack of tumor antigens. Induction of potent anti-tumor T cell immunity is critical for cancer therapy. In this study, we investigated the efficacy of immunotherapy via the immunogenic cell death (ICD) dying tumor cells in mouse models of lung metastasis and tumorigenesis. Methods ICD was induced by short exposure to lethal dose of chemotherapeutic drug doxorubicin (Dox), which initiated an irreversible ICD program in tumor cells. We immunized mice with ICD dying tumor cells in prevention, therapy in lung metastasis models, and Gprc5a-knockout (ko) model of lung tumorigenesis. T cells and macrophages isolated from lymph nodes or tumor tissues were analyzed by flow cytometry. Cytokines were analyzed by ELISA or Q-PCR analysis. Results Immunization with these live but ICD dying tumor cells induced potent tumor-specific anti-tumor T cell immunity, which not only protected host from challenge by these tumor cells in prevention and therapy in mouse model of lung metastasis, but also prevented tumors development in Gprc5a-ko mouse model of lung tumorigenesis. The lymphocytes from lymph nodes and tumor tissues exhibited greatly enhanced activities of Th1 cells and M1 macrophages. Conclusion Immunization with the ICD dying tumor cells evokes potent tumor-specific T cell immunity, which provides a novel approach for cancer immunotherapy.

Abstract This research explores the potential of multimodal fusion for the differential diagnosis of early-stage lung adenocarcinoma (LUAD) (tumor sizes < 2 cm). It combines liquid biopsy biomarkers, specifically extracellular vesicle long RNA (evlRNA) and the computed tomography (CT) attributes. The fusion model achieves an impressive area under receiver operating characteristic curve (AUC) of 91.9% for the four-classification of adenocarcinoma, along with a benign-malignant AUC of 94.8% (sensitivity: 89.1%, specificity: 94.3%). These outcomes outperform the diagnostic capabilities of the single-modal models and human experts. A comprehensive SHapley Additive exPlanations (SHAP) is provided to offer deep insights into model predictions. Our findings reveal the complementary interplay between evlRNA and image-based characteristics, underscoring the significance of integrating diverse modalities in diagnosing early-stage LUAD.

Potassium-ion batteries (PIBs) have been widely studied owing to the abundant reserves, widespread distribution, and easy extraction of potassium (K) resources. Molybdenum disulfide (MoS2) has received a great deal of attention as a key anode material for PIBs owing to its two-dimensional diffusion channels for K+ ions. However, due to its poor electronic conductivity and the huge influence of embedded K+ ions (with a large ionic radius of 3.6 Å) on MoS2 layer, MoS2 anodes exhibit a poor rate performance and easily collapsed structure. To address these issues, the common strategies are enlarging the interlayer spacing to reduce the mechanical strain and increasing the electronic conductivity by adding conductive agents. However, simultaneous implementation of the above strategies by simple methods is currently still a challenge. Herein, MoS2 anodes on reduced graphene oxide (MoS2/rGO) composite were prepared using one-step hydrothermal methods. Owing to the presence of rGO in the synthesis process, MoS2 possesses a unique scaled structure with large layer spacing, and the intrinsic conductivity of MoS2 is proved. As a result, MoS2/rGO composite anodes exhibit a larger rate performance and better cycle stability than that of anodes based on pure MoS2, and the direct mixtures of MoS2 and graphene oxide (MoS2-GO). This work suggests that the composite material of MoS2/rGO has infinite possibilities as a high-quality anode material for PIBs.

BackgroundClonorchis sinensis (C. sinensis) is a epidemiologically significant food-borne parasite, causing several hepatobiliary diseases. Biliary microbiota community structure might be influenced by infection with pathogens. However, the biliary microbiome of biliary obstruction patients infected with C. sinensis is still an unexplored aspect.MethodsA total of 50 biliary obstruction patients were enrolled, including 24 infected with C. sinensis and 26 non-infected subjects. The bile samples were collected by Endoscopic Retrograde Cholangiopancretography. Biliary microbiota alteration was analyzed through high-throughput 16S ribosomal RNA (rRNA) gene sequencing.ResultsOur findings revealed that there was significant increase in both richness and diversity, as well as changes in the taxonomic composition of the biliary microbiota of C. sinensis infected patients. At the phylum level, C. sinensis infection induced Proteobacteria increased and Firmicutes reduced. At the genus level, the relative abundance of Pseudomonas and Staphylococcus increased significantly, while Enterococcus decreased prominently in infected groups (P < 0.05). The PICRUSt analysis further showed remarkably different metabolic pathways between the two groups.ConclusionC. sinensis infection could modify the biliary microbiota, increasing the abundance and changing the phylogenetic composition of bacterial in biliary obstruction patients. This study may help deepen the understanding of the host-biliary microbiota interplay with C. sinensis infection on the background of biliary obstruction and provide new insights into understanding the pathogenesis of clonorchiasis.

Abstract Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has shown durable clinical benefits in lung cancer. However, many patients respond poorly to ICB treatment, underscoring an incomplete understanding of PD-L1 regulation and therapy resistance. Here, we find that MTSS1 is downregulated in lung adenocarcinoma, leading to PD-L1 upregulation, impairment of CD8+ lymphocyte function, and enhanced tumor progression. MTSS1 downregulation correlates with improved ICB efficacy in patients. Mechanistically, MTSS1 interacts with the E3 ligase AIP4 for PD-L1 monoubiquitination at Lysine 263, leading to PD-L1 endocytic sorting and lysosomal degradation. In addition, EGFR-KRAS signaling in lung adenocarcinoma suppresses MTSS1 and upregulates PD-L1. More importantly, combining AIP4-targeting via the clinical antidepressant drug clomipramine and ICB treatment improves therapy response and effectively suppresses the growth of ICB-resistant tumors in immunocompetent mice and humanized mice. Overall, our study discovers an MTSS1-AIP4 axis for PD-L1 monoubiquitination and reveals a potential combinatory therapy with antidepressants and ICB.

Conductive polymer polypyrrole (PPy)-coated lithium-rich manganese-based Li1.2Mn0.54Ni0.13Co0.13O2 (LMNCO) nanotube cathode materials were synthesized by electrospinning and subsequently subjected to low-temperature vapor-phase polymerization. X-ray diffraction (XRD), scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM) results confirm that the successful coating of the PPy layer (~2 nm) on the surface of LMNCO nanotubes did not destroy their morphologies or structures. Electrochemical tests indicate that the electrochemical performance of PPy-coated LMNCO nanotubes has been significantly enhanced. At a rate of 1 C, the discharge capacity of the PPy-coated LMNCO cell is 200.1 mAh g−1, and the capacity retention is 99% after 120 cycles. This excellent stability is attributed to the inhibition of side reactions and the protective function of the tubular structure due to the PPy coating layer. Additionally, the rate capability is also improved at a high current density due to the higher electronic and ionic conductivity.

Fine particulate matter (PM2.5) is the primary environmental stressor and a significant threat to public health. However, the effect of PM2.5 exposure on human nasal microbiota and its pathophysiological implication remain less understood. This study aimed to explore the associations of PM2.5 exposure with indices of nasal microbiota and biomarkers of nasal inflammation and oxidative stress. We conducted a panel study with 75 students in Xinxiang, Henan Province, China, from September to December 2017. Biomarkers of nasal inflammation and oxidative stress including interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), 8-epi-prostaglandin F2 alpha (8-epi-PGF2α) and indices of nasal microbiota diversity and phenotypes were measured. Linear mixed-effect models and bioinformatic analyses were performed to assess the association of PM2.5 concentrations with the abovementioned biomarkers and indices. It was found that per 1 μg/m3 increase in PM2.5 was associated with increments of 13.15% (95 % CI: 5.53–20.76 %) and 78.98 % (95 % CI: 21.61–136.36 %) in TNF-α on lag2 and lag02. Indices of microbial diversity and phenotypes including equitability, Shannon index, biofilm forming, and oxidative stress tolerant decreased to different extent with the increment in PM2.5. Notably, thirteen differential microbes in Clostridia, Bacilli, and Gammaproteobacteria classes were recognized as keystone taxa and eight of them were associated with TNF-α, IL-6, or 8-epi-PGF2α. Moreover, environmental adaptation was the most critical functional pathway of nasal microbiota associated with PM2.5 exposure. In summary, short-term exposure to PM2.5 is associated with nasal inflammation, microbiota diversity reduction, and the microbiota phenotype alterations.

BackgroundClonorchiasis is an important foodborne parasitic disease. However, eggs of Clonorchis sinensis (C. sinensis) cannot be detected in feces during biliary obstruction. Moreover, many diseases can cause biliary obstruction, such as gallstones, adenocarcinoma, cholangiocarcinoma and Ascaris lumbricoides infection. Therefore, it is of great significance to distinguish between patients of biliary obstruction and biliary obstruction with C. sinensis infection.MethodsA total of 48 biliary obstruction patients were enrolled, including 23 infected with C. sinensis (C. sinensis) (OB+C.s) and 25 non-infected subjects (OB). The bile samples were collected by endoscopic retrograde cholangiopancreatography and analyzed using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Additionally, multivariate statistical analysis methods were employed to identify differential metabolites. Next, bile amino acid levels were determined by targeted metabolomics analysis.ResultA total of 146 and 132 significant metabolites were identified in electrospray ionization (ESI)+ and ESI− modes, respectively. The levels of amino acids (asparagine, glutamate, ornithine) and polyamines (spermidine and spermine) were significantly changed. Targeted analysis showed that the levels of amino acids (such as L-arginine, L-glutamine, L-lysine, L-propionic, and L-tyrosine) were lower in OB+C.s patients compared to those in OB patients. Marked metabolic pathways were involved in “Glutathione metabolism”, “Caffeine metabolism”, “Alanine, aspartate and glutamate metabolism”, “Arginine and proline metabolism”, “Purine metabolism”, “Beta-Alanine metabolism”, and “D-glutamine and D-glutamate metabolism”.ConclusionThese results show that there were significant differences between OB+C.s and OB patients, especially in amino acids. The metabolic signature and perturbations in metabolic pathways may help to better distinguish OB+C.s and OB patients.

Abstract Severe eosinophilic asthma (SEA) is a therapy-resistant respiratory condition with poor clinical control. Treatment efficacy and patient compliance of current therapies remain unsatisfactory. Here, inspired by the remarkable success of chimeric antigen receptor-based cellular adoptive immunotherapies demonstrated for the treatment of a variety of malignant tumors, we engineered a cytokine-anchored chimeric antigen receptor T (CCAR-T) cell system using a chimeric IL-5-CD28-CD3ζ receptor to trigger T-cell-mediated killing of eosinophils that are elevated during severe asthma attacks. IL-5-anchored CCAR-T cells exhibited selective and effective killing capacity in vitro and restricted eosinophil differentiation with apparent protection against allergic airway inflammation in two mouse models of asthma. Notably, a single dose of IL-5-anchored CCAR-T cells resulted in persistent protection against asthma-related conditions over three months, significantly exceeding the typical therapeutic window of current mAb-based treatments in the clinics. This study presents a cell-based treatment strategy for SEA and could set the stage for a new era of precision therapies against a variety of intractable allergic diseases in the future.

Abstract When participating in demand response, the industrial adjustable load has the advantages of large capacity, high benefit, and easy management compared with commercial and residential loads. However, the stage of the production process is strongly coupled with the power consumption process, especially in the steel industry. Here, a multi‐objective optimization model for the optimal scheduling of hot rolling load considering the actual production operation conditions was proposed, the model was abstracted into a vehicle routing problem (VRP) ,which is a typical combinatorial optimization problem .To minimize the cost of electricity and the risk of delivery order default, this paper considered the jump penalty value between adjacent slabs simultaneously, constructed an integrated scheduling model of hot rolling shop scheduling and power demand response, and designed a multi‐objective production scheduling algorithm based on NSGA‐II to solve the problem. The results showed that the proposed method can realize the reasonable distribution of production load under the constraints of electricity price and production.

BackgroundEmerging evidence has shown the damage of air pollution and the benefits of physical activity to human health, and the effects of air pollution and physical activity on the nervous system need more research.ObjectiveTo explore the effects of short-term air pollution exposure and physical activity on neural damage biomarkers in healthy elderly.MethodsUsing a design of panel study, physically and mentally healthy retired employees were recruited from Xinxiang Medical University, and were followed up five times regularly from December 2018 to April 2019. The demographic characteristics and physical activity information were obtained by questionnaire, and the weekly physical activity level was calculated according to intensity and duration of physical activity. Biomarkers of neural damage in serum were measured, including brain-derived neurotrophic factor (BDNF), neurofilament light chain (NF-L), neuron specific enolase (NSE), protein gene product 9.5 (PGP9.5), and S100 calcium-binding protein B (S100B). Air pollution data (including PM2.5, PM10, O3, SO2, CO, and NO2) of the follow-up period were collected. Generalized estimation equation was used to analyze the association of air pollution concentration and physical activity level with the concentration of neural damage biomarkers.ResultsA total of 29 volunteers were included in the study, with an average age of (63.5±5.9) years; there were 11 men accounting for 37.93%; more than half of them (62.07%) received above junior middle school education; the mean physical activity level was (80.23±54.51) MET-h·week−1. The daily average concentrations of PM2.5, PM10, O3, SO2, CO, and NO2 during the study period were (68.27±60.98) μg·m−3, (130.57±58.71) μg·m−3, (36.86±13.89) μg·m−3, (17.86±10.59) μg·m−3, (4.94±1.34) mg·m−3, and (50.83±8.03) μg·m−3, respectively. The average serum concentrations of BDNF, NF-L, NSE, PGP9.5, and S100B were (139.12±46.71) μg·L−1, (402.60±183.31) ng·L−1, (11.26±10.32) ng·L−1, (14.32±13.57) ng·L−1, and (127.57±41.74) ng·L−1, respectively. The results of generalized estimation equation showed that a higher concentration of PM2.5 or O3 was associated with increased serum NSE (OR=1.359, 95%CI: 1.224-1.509, P0.05).ConclusionAcute exposure to air pollution and high-level physical activity might affect the neural damage of elderly populations. Specifically, particulate matter (PM2.5) could increase NSE, while gaseous pollutants (O3, NO2, and SO2) could decrease NF-L and PGP9.5.

ABSTRACT: Lung cancer has the highest incidence and mortality rate worldwide. Immunotherapy is a universal treatment for lung cancer, but its overall treatment remains a challenge. Tumor immunoediting is a process in which the immune system restricts or promotes tumor development through elimination, equilibrium, and escape to change tumor immunogenicity and obtain an immunosuppressive mechanism to promote disease progression. An increasing number of immunotherapy drugs, including monoclonal antibody-targeting drugs and chimeric antigen (Ag) receptor-modified T cells (CAR-T cells), have been used in clinical therapy. Additionally, cancer vaccine development and new clustered regularly spaced short palindromes (CRISPR)- based combination therapies against cancer open up new avenues for immunotherapy. However, these immunotherapies cause autoimmune induction and non-specific inflammation, with many limitations. The development and study of nanoparticle systems have shown the possibility of localization, pharmacokinetic programming, and immunomodulator co-delivery. Rapid advances in nanotechnology over the past decade have provided a strategic impetus for cancer immunotherapy improvements. Nanotechnology advancements in various aspects, such as virus-like size, high surface-volume ratio, and surface modifications to precisely target specific cell types, can be investigated through cancer vaccine and immunomodulator delivery system development. This review presents the current immunotherapy approaches for lung cancer and emphasizes the current process and prospects of the fusion of cancer immunotherapy, nanotechnology, bioengineering, and drug delivery.

Ambient nitrogen dioxide (NO2)-induced adverse health effects have been studied, but documented evidence on neural systems is limited. This study aimed to determine the acute effect of NO2 exposure on nervous system damage biomarker levels in healthy older adults. Five rounds of follow-up among 34 healthy retired people were scheduled from December 2018 to April 2019 in Xinxiang, China. The real-time NO2 concentrations were measured using a fixed site monitor. Serum samples were acquired during each round to measure nervous system damage biomarker levels: brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), neuron-specific enolase (NSE), protein gene product 9.5 (PGP9.5), and S100 calcium-binding protein B (S100B). A linear mixed-effect model was incorporated to analyze the association between short-term NO2 exposure and serum concentrations of the above-mentioned biomarkers. Stratification analysis based on sex, educational attainment, glutathione S-transferase theta 1 gene (GSTT1) polymorphism, and physical activity intensity was conducted to explore their potential modification effect. The NO2 concentration ranged from 34.7 to 59.0 µg/m3 during the study period. Acute exposure to ambient NO2 was significantly associated with elevated serum levels of NfL, PGP9.5, and BDNF. In response to a 10 µg/m3 increase in NO2 concentration, NfL and PGP9.5 levels increased by 76 % (95 % confidence interval [CI]: 12–140 %) and 54 % (95 % CI: 1–107 %) on the lag0 day, respectively, while BDNF levels increased by 49 % (95 % CI: 2–96 %) at lag4 day. The estimated effect of NO2 on NSE levels in GSTT1-sufficient participants was significantly higher than that in GSTT1-null participants. Intriguingly, the estimation of NO2 on PGP9.5 levels in females was significantly higher than that in males. Most two-pollutant models showed robust results, except for O3, which might have had confounding effects on NO2-induced BDNF stimulation. In summary, acute exposure to NO2 was associated with increased levels of serum nervous system damage biomarker levels including NFL, PGP9.5, and BDNF. The present study provided insights into NO2 exposure-induced adverse neural effects.

CO2 + O2in situ leaching has been extensively applied in uranium recovery in sandstone-type uranium deposits of China. The geochemical processes impact and constrain the leaching reaction and leaching solution migration; thus, it is necessary to study the CO2 + O2–water–rock geochemical reaction process and its influence on the physical properties of uranium-bearing reservoirs. In this work, a CO2 + O2–water–rock geochemical reaction simulation experiment was carried out, and the mineralogical and multiscale pore characteristics of typical samples before and after this simulation experiment were compared by X-ray diffraction and high-pressure mercury intrusion porosimetry (HPMIP). The results show that the CO2 + O2–water–rock geochemical reaction has complicated effects on the mineral compositions due to the various reaction modes and types. After the CO2 + O2–water–rock geochemical reaction, the femic minerals decrease and the clay minerals in the coarse sandstone, medium sandstone, fine sandstone, and siltstone increase, while the femic minerals and clay minerals in sandy mudstone show a contrary changing trend. The CO2 + O2–water–rock geochemical reaction decreases the total pore volume of uranium-bearing reservoirs and then promotes pore transformation from small scale to large scale. The fractal dimensions of macropores are decreased, and the fractal dimensions of mesopores, transition pores, and micropores are increased. The effects of felsic mineral and carbonate dissolution, secondary mineral precipitate, clay mineral swelling, and mineral particle migration are simultaneously present in the CO2 + O2in situ leaching process, which exhibit the positive transformation and the negative transformation for the uranium-bearing reservoirs. The mineral dissolution may improve reservoir permeability to a certain degree, while the siltation effect will gradually reveal with the extension of CO2 + O2in situ leaching. This research will provide a deep understanding of the physical property response of uranium-bearing reservoirs during CO2 + O2in situ leaching and indicate the direction for the efficient recovery of uranium resources.

BackgroundClonorchiasis is an important foodborne parasitic disease. The omics-based-techniques could illuminate parasite biology and further make innovations in the research for parasitic diseases. However, knowledge about the serum metabolic profiles and related metabolic pathways in clonorchiasis is very limited.MethodsA untargeted ultra-high performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS) was used to profile the serum metabolites of rats at both 4 and 8 weeks post infection (wpi) with Clonorchis sinensis (C. sinensis). Additionally, multivariate statistical analysis methods were employed to identify differential metabolites. Next, serum amino acids and phosphatidylcholines (PCs) levels were determined by targeted metabolomics analysis.ResultA total of 10530 and 6560 ions were identified in ESI+ and ESI− modes. The levels of phosphatidylcholines, glycerophosphocholine and choline were significantly changed, with the shift in lipid metabolism. Significant changes were also observed in amino acids (isoleucine, valine, leucine, threonine, glutamate and glutamine). Targeted analysis showed that BCAAs (isoleucine, valine, leucine) levels significantly increased at 4 wpi and decreased at 8 wpi; threonine was increased at 8 wpi, whereas glutamate and glutamine showed a decreasing trend at 8 wpi. Additionally, the level of 17 PCs were significantly changed in infected rats. Marked metabolic pathways were involved in clonorchiasis, including glycerophospholipid metabolism, alanine, aspartate and glutamate metabolism, histidine metabolism and pyrimidine metabolism.ConclusionThese results show that C. sinensis infection can cause significant changes in the rat serum metabolism, especially in amino acids and lipids. The metabolic signature together with perturbations in metabolic pathways could provide more in depth understanding of clonorchiasis and further make potential therapeutic interventions.

Chronic inflammation is associated with lung tumorigenesis, in which NF-κB–mediated epigenetic regulation plays a critical role. Lung tumor suppressor G protein–coupled receptor, family C, member 5A (GPRC5A), is repressed in most non–small cell lung cancer (NSCLC); however, the mechanisms remain unclear. Here, we show that NF-κB acts as a transcriptional repressor in suppression of GPRC5A. NF-κB induced GPRC5A repression both in vitro and in vivo. Intriguingly, transactivation of NF-κB downstream targets was not required, but the transactivation domain of RelA/p65 was required for GPRC5A repression. NF-κB did not bind to any potential cis-element in the GPRC5A promoter. Instead, p65 was complexed with retinoic acid receptor α/β (RARα/β) and recruited to the RA response element site at the GPRC5A promoter, resulting in disrupted RNA polymerase II complexing and suppressed transcription. Notably, phosphorylation on serine 276 of p65 was required for interaction with RARα/β and repression of GPRC5A. Moreover, NF-κB–mediated epigenetic repression was through suppression of acetylated histone H3K9 (H3K9ac), but not DNA methylation of the CpG islands, at the GPRC5A promoter. Consistently, a histone deacetylase inhibitor, but not DNA methylation inhibitor, restored GPRC5A expression in NSCLC cells. Thus, NF-κB induces transcriptional repression of GPRC5A via a complex with RARα/β and mediates epigenetic repression via suppression of H3K9ac.

Girdling is an important means of improving the yield and quality of jujube trees, but this measure can easily cause injury, or even death, to jujube trees. A technology for increasing yield and improving quality, based on local thermal damage of jujube bark, is proposed to address a series of issues in current jujube-tree-girdling technology. First, we measured the thermophysical parameters of jujube bark and established a heat-transfer model for jujube bark. Then, in order to investigate the impact of local thermal damage on jujube-tree yield and fruit quality, local heating experiments were conducted on jujube-tree bark, using the heat-transfer model. The experimental results indicated that heating the jujube bark at a certain temperature for an appropriate time can effectively improve the yield and quality of jujube fruit. Compared with traditional girdling techniques, this method has less impact on the health of jujube trees and does not form permanent wounds on them. The research results provide new ideas for exploring sustainable yield-increase methods for fruit trees.

Summary: Background: Regional lymph node (LN) acts as a pivotal organ for antitumor immunity. Paradoxically, tumor-draining LNs (TDLNs) are usually the first site of tumor metastasis in lung cancer. It is largely unknown about the association between the status of TDLNs and the response of primary tumor beds to immune checkpoint inhibitors (ICIs) in lung cancer patients. Also, studies characterizing the TDLNs in response to ICIs are scarce. Methods: We characterized and compared the radiological, metabolic (18F-FDG) and pathologic responses between primary tumor beds and paired TDLNs (invaded/non-invaded) from 68 lung cancer patients who underwent neoadjuvant ICIs plus surgery. Additionally, we performed the spatial profiling of immune and non-immune cells within TDLNs using multiplexed immunofluorescence. Therapy responses (e.g., pathologic complete (pCR) or major response (MPR)) of primary lung tumor beds and paired TDLNs were investigated separately. Findings: We observed that responses of TDLNs to ICIs markedly differ from their paired primary lung tumors regarding the radiological, metabolic (18F-FDG uptake), and pathologic alterations. Neoadjuvant ICIs therapy specifically decreased 18F-FDG-reflected metabolic activity in the primary tumor beds with pCR/MPR but not their TDLNs counterparts. Furthermore, the presence of invaded TDLNs was associated with poor pathologic responses in the matched primary tumor beds and predictive of rapid post-treatment tumor relapse. Spatial profiling demonstrated exclusion of T cell infiltrates within the metastatic lesions of invaded TDLNs, and diminished multiple immune and non-immune compositions in non-involved regions surrounding the metastatic lesions. Interpretation: These results provide the first clinically-relevant evidence demonstrating unique response patterns of TDLNs under ICIs treatment and revealing the underappreciated association of TDLNs status with the response of their paired primary tumors to ICIs in lung cancer. Funding: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun), the excellent talent program of Shanghai Chest Hospital (to F.Y), the Basic Foundation Program for Youth of Shanghai Chest Hospital (2021YNJCQ2 to H.Yang), and the Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZLCX20212302 to F. Yao).

Background and Objectives: Non-invasive methods for evaluating liver fibrosis have been a crucial focus of clinical research. The aim of the current study is to assess the accuracy of serum alpha-fetoprotein (AFP) in determining the stage of liver fibrosis in patients with chronic hepatitis B (CHB) who are positive for HBeAg. Materials and Methods: The current study included a total of 276 HBeAg-positive CHB patients who underwent liver biopsy. The levels of serum AFP were measured in these patients using electrochemiluminescence immunoassays. The correlations between serum AFP levels and other laboratory parameters were analyzed using Spearman’s correlation analysis. Binary logistic regression analysis was performed to determine the independent associations between serum AFP levels and liver fibrosis. The diagnostic performance of serum AFP and other non-invasive markers was evaluated using receiver operating characteristic (ROC) curves. Results: A total of 59 (21.4%) patients were found to have elevated levels of serum AFP (>7 ng/mL). These patients displayed a significantly higher proportion of both advanced fibrosis and cirrhosis compared to those with normal serum AFP levels (0–7 ng/mL). The level of serum AFP was positively associated with levels of serum globulin (GLB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL), as well as the AST-to-platelet ratio (APRI), fibrosis-4 (FIB-4), and Scheuer’s classification, and negatively correlated with platelet (PLT) counts. Furthermore, serum AFP was found to be independently associated with significant fibrosis, advanced fibrosis, and cirrhosis. The results of the ROC analysis showed that serum AFP was an effective predictor of significant fibrosis, advanced fibrosis, and cirrhosis, with an area under the receiver operating characteristic curve (AUROC) of 0.773 (95% CI: 0.721–0.821), 0.889 (95% CI: 0.847–0.923), and 0.925 (95% CI: 0.887–0.953), respectively. These values are higher than those of the APRI and FIB-4. Conclusions: Serum AFP could serve as a valuable supplemental biomarker for determining the severity of liver fibrosis in HBeAg-positive patients with chronic hepatitis B.

Background Cows’ milk allergy (CMA) is a hypersensitivity immune reaction brought on by specific immunologic mechanisms to cow’s milk proteins. As one of the most common food allergies in infants, the incidence of CMA during the first year of life is estimated to be nearly 7.5%. Due to the limitation in the knowledge of the pathological mechanism underlying CMA, however, the clinical interventions and therapies remain very unsatisfactory. Aim of the study The transcriptional factor FOXP3 possesses crucial roles in CMA, and increased FOXP3 mRNA expression has a predictive function in faster acquisition of tolerance in infants with CMA. But the exact mechanism remains not fully elucidated. Methods For PAG treatment, PAG (dissolved in saline 30 mg/mL, 0, 5, 10, 20 mg/kg BW) was administered daily intraperitoneally (ip) for one week at the time that 6 weeks after the CMP sensitisation. Results In the present study, we revealed that the expression of FOXP3 is significantly up-regulated in PBMCs from CMA patients and CMA mice on mRNA and protein level. Furthermore, a dramatic reduction in the FOXP3 TSDR methylation and a significant increase in the expression of TET2 are observed in CMA patients and CMA mice. More importantly, we found that propargylglycine (PAG) significantly alleviates symptoms of CMA in mice by suppressing the expression of FOXP3 through restoring TET2 expression. Conclusions Our work revealed a novel function of PAG on CMA, which may provide a deeper insight into the pathomechanism of CMA and a novel therapy target for CMA clinical interventions.

Chemotherapy is still one of the most common ways to treat human glioblastoma in clinic. However, severe side effects limited its clinic application. Design of cancer-targeted drugs with high efficiency and low side effect is urgently needed. Herein, silver nanoparticles (Ag NPs) and nano-selenium (Se NPs) conjugated with RGD peptides (Ag@Se@RGD NPs) to target integrin high-expressed glioma were designed. The results found that Ag@Se@RGD NPs displayed stable particle size and morphology in physiological condition, and induced significant integrin-targeted intracellular uptake. Ag@Se@RGD NPs in vitro dose-dependently inhibited U251 human glioma cells growth by induction of cells apoptosis through triggering the loss of mitochondrial membrane potential, overproduction of reactive oxygen species (ROS), and MAPKs activation. However, ROS inhibition dramatically attenuated Ag@Se@RGD NPs-induced MAPKs activation, indicating the significant role of ROS as an early apoptotic event. Importantly, Ag@Se@RGD NPs administration in vivov effectively inhibited U251 tumor xenografts growth by induction of apoptosis through regulation MAPKs activation. Taken together, our findings validated the rational design that Ag-Se NPs conjugated with RGD peptides was a promising strategy to combat human glioma by induction of apoptosis through triggering mitochondrial dysfunction and ROS-dependent MAPKs activation.

Background: We sought to determine if the morphological and compositional features of chronic internal carotid artery occlusion (CICAO), as assessed by MR vessel wall imaging (MR-VWI), initially predict successful endovascular recanalization. Methods: Consecutive patients with CICAO scheduled for endovascular recanalization were recruited. MR-VWI was performed within 1 week prior to surgery for evaluating the following features: proximal stump morphology, extent of occlusion, occlusion with collapse, arterial tortuosity, the presence of hyperintense signals (HIS) and calcification in the occluded C1 segment. Multivariate logistic regression was used to identify features associated with technical success and construct a prediction model. Results: Eighty-three patients were recruited, of which fifty-seven (68.7%) were recanalized successfully. The morphological and compositional characteristics of CICAO were associated with successful recanalization, including occlusions limited to C1 and extensive HIS, as well as the absence of extensive calcification, absence of high tortuosity, and absence of artery collapse. The MR CICAO score that comprised the five predictors showed a high predictive ability (area under the curve: 0.888, p < 0.001). Conclusion: the MR-VWI characteristics of CICAO predicted the technical success of endovascular recanalization and may be leveraged for identifying patients with a high probability of successful recanalization.

Introduction: Hirschsprung's disease is a common digestive tract malformation in children, and the Soave procedure is one of the classic surgical methods for Hirschsprung's disease (HD). Fecal incontinence is one of the most common postoperative complications that can cause significant distress to the patients and their family, the incidence of which is 20% in a recent series. Biofeedback therapy (BFT) can be an effective treatment for managing anorectal disorders, but there has been little report of the efficacy of BFT for the treatment of fecal incontinence after the Soave procedure, and the main objective of this study is to evaluate it.Methods: We retrospectively analyzed postoperative fecal incontinence in 46 children who received the Soave procedure for HD and who received BFT at our institution from March 2016 to February 2020, which included 38 males and 8 females (mean age 8.1 years, from 3.7 to 14 years). Anal sphincter contraction training was performed using BFT for 10 days per session in the hospital, one time each day, and 20 min each time. BFT was performed by employing visual and verbal feedback techniques using the biofeedback instrument. Long-term functional outcomes were objectively assessed using the Rintala Bowel Function Score (RBFS), and the patients were scored according to the sum total as excellent (18–20 points, 0 case), good (11–16 points, 0 case), fair (9–11 points, 9 cases), or poor (6–9 points, 37 cases). Defecation questionnaires and anorectal manometry were completed pretreatment and after three, six, or nine sessions, and primary outcome measures of anorectal manometry were anal maximal contraction pressure (AMCP), anal longest contraction time (ALCT), rectal rest pressure (RRP), and anal rest pressure (ARP).Results: Followed up from 6 months to 4 years, the symptoms of fecal incontinence disappeared completely in 39 (84.78%) patients. Among them, 14 (30.43%) had complete disappearance of symptoms after 3 sessions of treatment, 25 (54.34%) patients had improved symptoms after 6 sessions of treatment, symptoms completely disappeared after 6 sessions of treatment, and 7 (15.22%) cases still suffered fecal incontinence mildly. The AMCP after three and six sessions in the poor group was significantly increased compared with that before treatment [(85.87 ± 31.75) mmHg vs. (135.33 ± 37.69) mmHg vs. (128.41 ± 33.45) mmHg, P < 0.05]. The ALCT and ARP showed the same trend, while the RRP after three and six sessions were not significant (P > 0.05). The mean (±SD) score of the RBFS increased from 9 to 17.40 ± 0.84 in the fair group, while it increased from 7.22 ± 0.76 to 16.58 ± 1.66 in the poor group after six sessions (P < 0.05).Conclusion: Biofeedback therapy is a safe and effective treatment of fecal incontinence after the Soave procedure of children for Hirschsprung's disease. It is beneficial to design the individualized treatment programs for the children with varying degrees of fecal incontinence.

Extreme climate change, rapid population growth and economic development drive a growing demand for resources, which lead to energy, food, water and their intertwined nexus becoming increasingly important. Agricultural decisions considering the interconnections among water, energy, and food are critical. The consumption of large amounts groundwater and non-renewable energy by the predominant traditional wheat-maize cropping system has caused a serious water shortage in the North China Plain (NCP), which is a large food production region in China. This situation has strained the relationship between water/energy consumption and food production. It is important to seek synergy in the water-energy-food nexus. This paper proposed a relative index of water-energy-food (WEFRI) based on different values of resource consumption and use efficiency between treatment systems and control system to analyze the synergy between water utilization, energy consumption and food supply in different cropping systems at the field scale. The goal is to seek a sustainable cropping system to balance crop production while reducing energy consumption and water depletion. In this case, different systems including monocropped maize (Zea mays) (MM), intercropped maize and soybean (Glycine max) (MS), relay cropped of maize with pea (Pisum sativum) (MP) and potato (Solanum tuberosum) (MO), rotation of maize with spinach (Spinacia oleracea) (MI) and ryegrass (Secale cereale) (MR), and using traditional wheat-maize (Triticum aestivum) (MW) as a control. MM, MS, MP and MO were the best systems within a particular range of food supply reduction. The WEFRI of the MM/MS system was the highest (2.96/2.78). Compared to the MW system, the groundwater consumption of MM/MS was reduced by 73.84%/73.84%, and non-renewable energy inputs were reduced by 48.01%/48.30%; however, the food supply decreased by 48.05%/51.70%. The WEFRI of the MP system was 1.98. In comparison with the MW system, the groundwater consumption of the MP system was reduced by 28.46%, and the non-renewable energy inputs were reduced by 42.68%. However, the food supply decreased by 37.13%. The WEFRI of MO system was 1.92. Compared to the MW system, the groundwater consumption of MO was reduced by 11.47%, non-renewable energy inputs were reduced by 32.14%, and the food supply only decreased by 26.27%. In conclusion, we theoretically proposed the following references for cropping systems in the NCP: MM and MS are implemented when the areas has extreme water shortages, MO is implemented when a less than 30% reduction in the food supply capacity is acceptable, and MP is recommended if a 30%–40% reduction in the food supply is acceptable.

Potassium-ion batteries (PIBs) have been widely studied owing to the abundant reserves, widespread distribution, and easy extraction of potassium (K) resources. Molybdenum disulfide (MoS2) has received a great deal of attention as a key anode material for PIBs owing to its two-dimensional diffusion channels for K+ ions. However, due to its poor electronic conductivity and the huge influence of embedded K+ ions (with a large ionic radius of 3.6 Å) on MoS2 layer, MoS2 anodes exhibit a poor rate performance and easily collapsed structure. To address these issues, the common strategies are enlarging the interlayer spacing to reduce the mechanical strain and increasing the electronic conductivity by adding conductive agents. However, simultaneous implementation of the above strategies by simple methods is currently still a challenge. Herein, MoS2 anodes on reduced graphene oxide (MoS2/rGO) composite were prepared using one-step hydrothermal methods. Owing to the presence of rGO in the synthesis process, MoS2 possesses a unique scaled structure with large layer spacing, and the intrinsic conductivity of MoS2 is proved. As a result, MoS2/rGO composite anodes exhibit a larger rate performance and better cycle stability than that of anodes based on pure MoS2, and the direct mixtures of MoS2 and graphene oxide (MoS2-GO). This work suggests that the composite material of MoS2/rGO has infinite possibilities as a high-quality anode material for PIBs. [ABSTRACT FROM AUTHOR]

The major role of aldehyde dehydrogenase 2 family (ALDH2) is to detoxify acetaldehyde (ACE) to non-toxic acetic acid. Many evidences suggest that ALDH2 dysfunction contributes to a variety of human diseases including cancer. However, the biological function and molecular mechanism of ALDH2 in tumor progression remain elusive. In this study, we found that ALDH2 repression was associated with poor prognosis in lung adenocarcinoma. Overexpression of ALDH2 inhibited malignant features of lung adenocarcinoma cells, such as proliferation, stemness and migration, whereas ALDH2 knockdown increased these features. Mechanistically, ALDH2 repression led to accumulation of ACE; whereas ACE enhanced the migration features of lung adenocarcinoma cells, which was associated with increased DNA damage. Importantly, accumulated ACE and increased DNA damage were identified in Aldh2-knockout (KO) mouse lung tissues in vivo. Consistent with this concept, treatment of lung adenocarcinoma cells with ALDH2 agonist Alda-1 suppressed the proliferation, stemness and migration features of lung adenocarcinoma cells. Thus, activating ALDH2, such as via its agonist, may provide a novel strategy for treatment of lung cancer.