Search

Background: A precise model for predicting outcomes is needed to guide perioperative management. With the developments of liver transplantation (LT) discipline, previous models may become inappropriate or noncomprehensive. Thus, we aimed to develop a novel model integrating variables from donors and recipients for quick assessment of transplant outcomes., Methods: The risk model was based on Cox regression in a randomly selected derivation cohort and verified in a validation cohort. Perioperative data and overall survival were compared between stratifications grouped by X-tile. Receiver operating characteristic curve and decision curve analysis were used to compare the models. Violin and raincloud plots were generated to present post-LT complications distributed in different stratifications., Results: Overall, 528 patients receiving LT from 2 centers were included with 2/3 in the derivation cohort and 1/3 in the validation cohort. Cox regression analysis showed that cold ischemia time (CIT) (P=0.012) and the Model for End-Stage Liver Disease (MELD) (P=0.007) score were predictors of survival. After comparison with the logarithmic models, the primitive algorithms of CIT and MELD were defined as the CIT-MELD Index (CMI). CMI was stratified by X-tile (grade 1 ≤1.06, 1.06< grade 2 ≤1.87, grade 3 >1.87). In both cohorts, CMI performed better in calculating transplant outcomes than the balance of risk score, including perioperative incidents and prevalence of complications., Conclusions: Model integrating variables from graft and recipient made the prediction more accurate and available. CMI provided new sight in outcome evaluation and risk factor management of LT., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

The influence of water-soluble selenium-containing proteins (WSSeP) in chicken on ulcerative colitis (UC) is not known. This work aims to investigate the effect of two WSSeP including h-Se with 1.78 μg Se/g and l-Se with 1.04 μg Se/g on mice UC induced by dextran sodium sulfate (DSS) versus 5-aminosalicylic acid (5-ASA). Seventy C57BL/6 mice were randomly divided into seven groups: groups 1 and 7 were given normal saline. Group 2 to group 4 were administrated orally 500, 1500, and 3000 mg/kg/day h-Se, respectively. Group 5 was given 1500 mg/kg/day l-Se as the control of group 3. From day 14 to day 21, groups 2 to 7 were fed with 3% DSS. Synchronously, group 6 was fed with 150 mg/kg/day 5-ASA. On day 21, the disease activity index, colon length, the histopathological changes, the expressions of claudin-1, occludin, ZO-1, TLR4, and MyD88 in colons, the levels of inflammatory cytokines (IFN-γ, IL-1β, IL-6, TNF-α), and antioxidant markers (LPS, GSH-Px, SOD, MDA) in serum were determined. WSSeP can effectively improve the damages of DSS to the colon, thymus, and spleen, which present protein and Se dose-dependent. 1.50 g h-Se dose can significantly promote the expression levels of claudin-1, occludin, and ZO-1, to surround crypt gland and goblet and epithelial cells and inhibit the attack of DSS, suppress TLR4/MyD88 pathway, decrease the levels of IL-1β, IL-6, TNF-α, IFN-γ, LPS, and MDA, and increase the activities of GSH-Px and SOD, which are better than those of 5-ASA. Therefore, WSSeP would be a natural and potential anti-inflammatory agent for UC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: This study aimed to explore using peripheral blood mononuclear cell (PBMC)-derived chimeric antigen receptor (CAR) NK cells targeting ROBO1 as a personalized medicine approach for ovarian cancer. Methods: A two-step strategy generated ROBO1-targeted CAR NK cells from PBMCs of ovarian cancer patients. Efficacy was evaluated using xCELLigence RTCA, CCK-8 and Live/Dead fluorescence assays. Results: ROBO1-NK cells exhibited higher efficiency in eradicating primary ovarian cancer cells and lysing ovarian tumor organoids compared with primary NK cells without ROBO1-CAR modification. Conclusion: These findings highlight the potential of developing ROBO1-targeted CAR-NK cells from patients' PBMCs as a personalized treatment option for ovarian cancer.

Photoacoustic imaging (PAI) is an emerging modality in biomedical imaging with superior imaging depth and specificity. However, PAI still has significant limitations, such as the background noise from endogenous chromophores. To overcome these limitations, we developed a covalent activity-based PAI probe, NOx-JS013, targeting NCEH1. NCEH1, a highly expressed and activated serine hydrolase in aggressive cancers, has the potential to be employed for the diagnosis of cancers. We show that NOx-JS013 labels active NCEH1 in live cells with high selectivity relative to other serine hydrolases. NOx-JS013 also presents its efficacy as a hypoxia-responsive imaging probe in live cells. Finally, NOx-JS013 successfully visualizes aggressive prostate cancer tumors in mouse models of PC3, while being negligibly detected in tumors of non-aggressive LNCaP mouse models. These findings show that NOx-JS013 has the potential to be used to develop precision PAI reagents for detecting metastatic progression in various cancers., (© 2024 Wiley-VCH GmbH.)

Background: Additional resection for invasive cancer at perihilar cholangiocarcinoma (pCCA) resection margins has become a consensus. However, controversy still exists regarding whether additional resection is necessary for residual biliary intraepithelial neoplasia (BilIN)., Method: Consecutive patients with pCCA from two hospitals were enrolled. The incidence and pattern of resection margin BilIN were summarized. Prognosis between patients with negative margins (R0) and BilIN margins were analyzed. Cox regression with a forest plot was used to identify independent risk factors associated with overall survival (OS) and recurrence-free survival (RFS). Subgroup analysis was performed based on BilIN features and tumor characteristics., Results: 306 pCCA patients receiving curative resection were included. 255 had R0 margins and 51 had BilIN margins. There was no significant difference in OS (P = 0.264) or RFS (P = 0.149) between the two group. Specifically, 19 patients with BilIN at distal bile ducts and 32 at proximal bile ducts. 42 patients showed low-grade BilIN, and 9 showed high-grade. Further analysis revealed no significant difference in long-term survival between different locations (P = 0.354), or between different grades (P = 0.772). Portal vein invasion, poor differentiation and lymph node metastasis were considered independent risk factors for OS and RFS, while BilIN was not. Subgroup analysis showed no significant difference in long-term survival between the lymph node metastasis subgroup, or between the portal vein invasion subgroup., Conclusion: For pCCA patients underwent curative resection, residual BilIN at resection margin is acceptable. Additional resection is not necessary for such patients to achieve absolute R0 margin., (© 2024. The Author(s).)

Background: Recent epidemiological studies and animal experiments have highlighted the significant role of oxidative stress in the development of osteoporosis (OP). The provision of antioxidants is widely considered a fundamental strategy to combat free radical-induced stress, inhibit oxidative damage, and potentially reverse the adverse effects of oxidative stress on bone health. However, there is no consensus in the scientific literature regarding the practical effectiveness of antioxidants in OP prevention and treatment. Some studies have not shown a clear connection between antioxidant supplementation and decreased OP risk. Therefore, it is essential to clarify the potential causal relationship between antioxidants and the development of OP., Methods: The study utilized the inverse variance weighted (IVW) approach as the primary analytical method in the Mendelian Randomization (MR) framework to investigate the causal effects of five exogenous and six endogenous antioxidants on the risk of OP. To thoroughly assess potential pleiotropic effects and heterogeneity among the data analyzed, the MR-Egger intercept test was employed, and Cochran's Q statistic was calculated., Results: In the evaluation of exogenous antioxidants, single-directional two-sample MR analyses did not reveal any statistically significant relationship between these agents and the risk of OP. Regarding endogenous antioxidants, bidirectional two-sample MR analyses were conducted, which generally indicated that most genetically regulated endogenous antioxidants had no significant association with the onset risk of OP. A significant causal relationship was found between OP and serum albumin levels ( β : -0.0552, 95%CI: -0.0879 to -0.0225, p < 0.0011 after Bonferroni adjustment, power = 100%)., Conclusion: The research uncovers OP as a possible determinant contributing to a decrement in serum albumin levels, and further suggests a potentially intimate relationship between the downward trajectory of serum albumin concentrations and the advancement of the OP disease process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Qi, Huang, Lu and Pan.)

This work aimed to propose a rapid method to screen the bioactive peptides with anti-α-glucosidase activity instead of traditional multiple laborious purification and identification procedures. 242 peptides binding to α-glycosidase were quickly screened and identified by bio-affinity ultrafiltration combined with LC-MS/MS from the double enzymatic hydrolysate of black beans. Top three peptides with notable anti-α-glucosidase activity, NNNPFKF, RADLPGVK and FLKEAFGV were further rapidly screened and ranked by the three artificial intelligence tools (three-AI-tool) BIOPEP database, PeptideRanker and molecular docking from the 242 peptides. Their IC 50 values were in order as 4.20 ± 0.11 mg/mL, 2.83 ± 0.03 mg/mL, 1.32 ± 0.09 mg/mL, which was opposite to AI ranking, for the hydrophobicity index of the peptides was not included in the screening criteria. According to the kinetics, FT-IR, CD and ITC analyses, the binding of the three peptides to α-glucosidase is a spontaneous and irreversible endothermic reaction that results from hydrogen bonds and hydrophobic interactions, which mainly changes the α-helix structure of α-glucosidase. The peptide-activity can be evaluated vividly by AFM in vitro. In vivo, the screened FLKEAFGV and RADLPGVK can lower blood sugar levels as effectively as acarbose, they are expected to be an alternative to synthetic drugs for the treatment of Type 2 diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fly ash from municipal solid waste incineration (MSWIFA) contains leachable heavy metals (HMs), and the environmental risk of contained HMs is an important concern for its safe treatment and disposal. This paper presents a dynamic leaching test of fly ash-based cementitious materials containing arsenic (FCAC) in three particle sizes based on an innovative simulation of two acid rainfall conditions to investigate the long-term stability of FCAC under acid rain conditions. As well as semi-dynamic leaching test by simulating FCAC in three scenarios. Furthermore, the long-term stability risk of FCAC is evaluated using a sequential extraction procedure (SEP) and the potential risk assessment index. Results showed that the Al 3+ in the FCAC dissolved and reacted with the OH - in solution to form Al(OH) 3 colloids as the leaching time increased. Moreover, the oxidation of sulfide minerals in the slag produced oxidants, such as H 2 SO 4 and Fe 2 (SO 4 ) 3 , which further aggravated the oxidative dissolution of sulfides, thereby resulting in an overall decreasing pH value of the leachate. In addition, due to the varying particle sizes of the FCAC, surface area size, and adsorption site changes, the arsenic leaching process showed three stages of leaching characteristics, namely, initial, rapid, and slow release, with a maximum leaching concentration of 2.42 mg/L, the cumulative release of 133.78 mg/kg, and the cumulative release rate of 2.32%. The SEP test revealed that the reduced state of HMs in the raw slag was lowered substantially, and the acid extractable state and residual state of HMs were increased, which was conducive to lessening the risk of FCAC. Overall, the geological polymerization reaction of MSWIFA is a viable and promising solution to stabilize mining and industrial wastes and repurpose the wastes into construction materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Some Polycyclic Aromatic Compounds (PACs) such as nitrated-PAHs (NPAHs), oxygenated-PAHs (OPAHs) and methyl-PAHs (MPAHs) have attracted significant concern due to derivatives have greater potential to be more toxic at low environmental concentrations compared to their PPAHs, particularly in petrochemical industrial region and its surrounding areas surface soils in China. Hence, this article provides an insight into the fate, sources, impacts, and relevance to the external environment of PAH-derivatives based on important emissions source. Moreover, prospective health risk due to their exposure has also been discussed. In this study, the concentration (10 -3  ng/g) of Ʃ18PPAHs, Ʃ11MPAHs, Ʃ12NPAHs, and Ʃ4OPAHs in the park were 9.67 ± 1.40, 3.24 ± 0.54, 0.03 ± 0.02 and 0.19 ± 0.65, respectively, which were 4.47, 3.89, 2.04 and 1.17 times than of them surrounding the region. A decreasing trend of the low molecular weight (2-4Rings) contribution to the total amount of PAHs, while the fraction of high molecular weight (5-6Rings) species showed the opposite trend. According to the principal component analysis (PCA) and diagnostic ratios indicated PAHs in the soil samples have mixed sources from industrial activities, solid fuel combustion, and heavy traffic. Despite the high concentrations of MPAHs and OPAHs, the toxicity equivalency quotients (TEQs) of them were not calculated due to the lack of toxic equivalent factors (TEF), thus current studies on PAH and derivatives could have underestimated their exposure risks. The quality and sustainable management of soils are crucial for human health and sustainable development, while there is lack of public awareness of the severe issue of soil pollution. It is recommended to conduct more intensive monitoring and regional assessments in the future., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells preferentially in the bone marrow. Currently, emerging chemotherapy drugs with improved biosafety profiles, such as immunomodulatory agents and protease inhibitors, have been used in clinics to treat MM in both initial therapy or maintenance therapy post autologous hematopoietic stem cell transplantation (ASCT). We previously discovered that caffeic acid phenethyl ester (CAPE), a water-insoluble natural compound, inhibited the growth of MM cells by inducing oxidative stress. As part of our continuous effort to pursue a less toxic yet more effective therapeutic approach for MM, the objective of this study is to investigate the potential of CAPE for in vivo applications by using magnetic resonance imaging (MRI)-capable superparamagnetic iron oxide nanoparticles (IONP) as carriers. Cyclo (Arg-Gly-Asp-D-Phe-Cys) (RGD) is conjugated to IONP (RGD-IONP/CAPE) to target the overexpressed α v β 3 integrin on MM cells for receptor-mediated internalization and intracellular delivery of CAPE. A stable loading of CAPE on IONP can be achieved with a loading efficiency of 48.7% ± 3.3% (wt%). The drug-release studies indicate RGD-IONP/CAPE is stable at physiological (pH 7.4) and basic pH (pH 9.5) and subject to release of CAPE at acidic pH (pH 5.5) mimicking the tumor and lysosomal condition. RGD-IONP/CAPE causes cytotoxicity specific to human MM RPMI8226, U266, and NCI-H929 cells, but not to normal peripheral blood mononuclear cells (PBMCs), with IC50s of 7.97 ± 1.39, 16.75 ± 1.62, and 24.38 ± 1.71 μM after 72-h treatment, respectively. Apoptosis assays indicate RGD-IONP/CAPE induces apoptosis of RPMI8226 cells through a caspase-9 mediated intrinsic pathway, the same as applying CAPE alone. The apoptogenic effect of RGD-IONP/CAPE was also confirmed on the RPMI8226 cells co-cultured with human bone marrow stromal cells HS-5 in a Transwell model to mimic the MM microenvironment in the bone marrow. In conclusion, we demonstrate that water-insoluble CAPE can be loaded to RGD-IONP to greatly improve the biocompatibility and significantly inhibit the growth of MM cells in vitro through the induction of apoptosis. This study paves the way for investigating the MRI-trackable delivery of CAPE for MM treatment in animal models in the future., Competing Interests: Author YL is an employee of 5M Biomed. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Smith, Li, Fields, Tucker, Staskiewicz, Wong, Ma, Mao and Wang.)

Coke production is an important source of environmental polycyclic aromatic compounds (PACs), including parent polycyclic aromatic hydrocarbons (PAHs) and their derivatives. The focus near coking plants has primarily been on parent-PAH contamination, with less attention given to highly toxic derivatives. In this study, soil samples were collected from both within and outside of a coking plant. The concentrations of parent-PAHs and their derivatives, including methylated-PAHs, oxygenated-PAHs, and nitrated-PAHs, were examined. Spatial interpolation was employed to determine their spatial distribution patterns. Methods for identifying potential sources and conducting incremental lifetime cancer risk analysis were used. This could achieve a comprehensive understanding of the status of PAC pollution and the associated health risks caused by coke production. The concentrations of total PACs inside the plant ranged from 7.4 to 115.8 mg/kg, higher than those outside (in the range of 0.2 to 65.7 mg/kg). The spatial distribution of parent-PAH concentration and their derivatives consistently decreased with increasing distance from the plant. A significant positive correlation ( p < 0.05) among parent-PAHs and their derivatives was observed, indicating relatively consistent sources. Based on diagnostic ratios, the potential emission sources of soil PACs could be attributed to coal combustion and vehicle emissions, while principal component analysis-multiple linear regression further indicated that primary emissions and secondary formation jointly influenced the PAC content, accounting for 60.4% and 39.6%, respectively. The exposure risk of soil PACs was dominated by 16 priority control PAHs; the non-priority PAHs' contribution to the exposure risk was only 6.4%.

Background: Nonearly biliary complications (BCs) after liver transplantation (LT) are highly associated with immunological status. Tacrolimus is the main immunosuppressant. Whether and how tacrolimus bioavailability affects BCs is unclear., Methods: LT recipients receiving tacrolimus-free immunosuppressants or developing BCs within 3 months after LT were excluded. Tacrolimus-related variables included trough concentration (C0), variability and cumulative exposure to tacrolimus (CET). Receiver operating characteristic (ROC) curves defined cutoff values of CET and variability. The values divided patients into adequate and low CET groups, also high and low-variability groups. Inverse probability of treatment weighting (IPTW) was used to reduce bias. Logistic regression identified risk factors. Kaplan-Meier curves were generated for survival comparison., Results: 409 patients were enrolled, and 39 (9.5 %) suffered from BCs. The mean C0 values were 6.9 and 7.2 ng/mL in the BCs and BCs-free groups, respectively. CET within 3 postoperative months was 550.0 and 608.6 ng.day/mL, while the tacrolimus variability was 0.4 and 0.3, respectively. The cutoff values for CET within 3 months and variability predicting BCs were 660.5 and 0.54, respectively. Multivariable logistic regression revealed that low CET within 3 months (p = 0.005, p = 0.002) and high variability (p < 0.001, p < 0.001) were associated with BCs before and after IPTW. Appropriate CET and low variability were associated with better overall survival (p = 0.009 and 0.029). Subgroup analysis indicated that long cold ischemia time (CIT), high bilirubin and low CET had a higher relative risk and raised the incidence of BCs., Conclusions: Adequate CET and low variability of tacrolimus ameliorated nonearly BCs incidence and improved survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polycystic ovary syndrome (PCOS) is a set of endocrine disorder syndrome characterized by ovulation disorder. Increased insulin resistance (IR) and compensatory hyperinsulinemia play a vital role in the pathogenesis of PCOS. Therefore, insulin sensitizing agents have been studied in the treatment of PCOS. Berberine (BBR) has been proved to alleviate IR in patients with PCOS, but the mechanism remained unclear. This study was aimed to verify the regulatory mechanism of BBR on PCOS-IR rats. Firstly, we established a female rat PCOS-IR model induced by dehydroepiandrosterone (DHEA) and found that estrus cycle was disrupted in the PCOS-IR group, serum fasting insulin (FINS) level and the homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly higher than normal control group. BBR treatment could recover estrous cycle, reduce abnormal serum hormone levels like luteotropic hormone (LH) and testosterone (T). Most importantly, BBR could concentration-dependently reduce serum FINS level in PCOS-IR rat model. Meanwhile, BBR may improve the abnormal lipid metabolism levels in PCOS-IR group by decreasing low density lipoprotein (LDL), total cholesterol (TC) and triglyceride (TG). Histological results showed that BBR can also protect normal histological structures of ovaries in PCOS-IR rats. Our results indicated that BBR plays a protective role in PCOS-IR, increasing insulin sensitivity, improving hyperandrogens and recovering abnormal blood lipids. Therefore, Our research provides novel insights for therapeutic treatment of BBR in patients with glucolipid metabolic disturbances., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Network attacks pose a significant challenge for smart grid networks, mainly due to the existence of several multi-directional communication devices coupling consumers to the grid. One of the network attacks that can affect the smart grid is the distributed denial of service (DDoS), where numerous compromised communication devices/nodes of the grid flood the smart grid network with false data and requests, leading to disruptions in smart meters, data servers, and the state estimator, ultimately effecting the services for end-users. Machine learning-based strategies show distinctive benefits in resolving the challenge of securing the network from DDoS attacks. Regardless, a notable hindrance in deploying machine learning-based techniques is the requirement of model retraining whenever new attack classes arise. Practically, disrupting the normal operations of smart grid is really discouraged. To handle this challenge effectively and detect DDoS attacks without major disruptions, we propose the deployment of reconstructive deep learning techniques. A primary benefit of our proposed technique is the minimum disruption during the introduction of a new attack class, even after complete deployment. We trained several deep and shallow reconstructive models to get representations for each attack type separately, and we performed attack detection by class-specific reconstruction error-based classification. Our technique experienced rigid evaluation via multiple experiments using two well-acknowledged standard databases exclusively for DDoS attacks, including their subsets. Later, we performed a comparative estimation of our outcomes against six methods prevalent within the same domain. Our outcomes reveal that our technique attained higher accuracy, and notably eliminates the requirement of a complete model retraining in the event of the introduction of new attack classes. This method will not only boost the security of smart grid networks but also ensure the stability and reliability of normal operations, protecting the critical infrastructure from ever-evolving network attacks. As smart grid is advancing rapidly, our approach proposes a robust and adaptive way to overcome the continuous challenges posed by network attacks., Competing Interests: The authors declare there are no competing interests., (©2024 Naqvi et al.)

Background: The Cangshan National Nature Reserve of Dali City was adopted as the research object to clarify the vertical distribution characteristics of soil organic carbon (SOC) and vegetation types at different elevations in western Yunnan., Methods: The contents of SOC, light fraction organic carbon (LFOC), heavy fraction organic carbon (HFOC), and water-soluble organic carbon (WSOC) in the 0-30 cm soil layer at different elevations (2,400, 2,600, 2,800, 3,000, 3,200, 3,400, and 3,600 m) were determined, and the above-ground vegetation types at different elevations were investigated., Results: Results showed that the SOC content was the highest in 0-20 cm surface soil and gradually decreased with the deepening of the soil layer. It increased then decreased with the increase in elevation, and it peaked at 3,000 m. The LFOC content was between 1.28 and 7.3515 g kg -1 . It exhibited a decreasing trend and little change in profile distribution. The HFOC content ranged between 12.9727 and 23.3708 g kg -1 ; it increased then decreased with the increase in profile depth. The WSOC content was between 235.5783 and 392.3925 mg kg -1 , and the response sensitivity to elevation change was weak. With the increase in elevation, WSOC/SOC and LFOC/SOC showed a similar trend, whereas HFOC presented an opposite trend. This observation indicates that the active organic carbon content at 3,600 m was lower than that at 2,400 m, and the middle elevation was conducive to the storage of active organic carbon. Meanwhile, the physical and chemical properties of soil affected the distribution of organic carbon to a certain extent. The vegetation type survey showed that the above-ground dominant species within 2,400-2,800 m were Pinus yunnanensis and Pinus armandii . Many evergreen and mixed coniferous broadleaf forests were distributed from 3,000 m to 3,200 m. Species of Abies delavayi were mainly distributed from 3,400 m to 3,600 m. This research serves as a reference for the study of forest soil carbon stability in high-elevation areas and plays an important role in formulating reasonable land use management policies, protecting forest soil, reducing organic carbon loss, and investigating the carbon sequestration stability of forest ecosystems., Competing Interests: The authors declare there are no competing interests., (©2024 Yang et al.)

Introduction: In cancer treatment, every minute counts. Due to the unpredictable behavior of cancer cells caused by continuous mutations, each cancer patient has a unique situation and may or may not respond to a specific drug or treatment. The process of finding an effective therapy can be time-consuming, but cancer patients do not have the luxury of time for trial and error. Therefore, a novel technology to fast generate a patient relevant organoid for the therapies selecting is urgently needed., Methods: Utilizing the new organoid technology by specially dissolving the mesenchyme in tumor tissues acquired from cancer patients, we realized the work of creating patient-specific organoids (PSO) within one day., Results: PSO properties reflect those of its respective original in vivo tumor tissue and can be utilized to perform various in vitro drug sensitivity tests to identify the most effective clinical treatment for patients. Additionally, PSO can aid in assessing the efficacy of immune cell therapies., Discussion: Organoid technology has advanced significantly in recent years. However, current cancer organoid methods involve creating 3D tumor tissue from 2D cancer cells or cell clusters, primarily for cancer research purposes aimed at investigating related molecular and cellular mechanisms of tumor development. These methods are research-driven, not tailored towards clinical applications, and cannot provide personalized information for individual patients. PSO filled the gap of clinic-driven and time-saving method for the personalized therapies selecting to the cancer patients., Competing Interests: Authors ZD, DC, YY, JH, YL, YaL, TG and HZ were employed by Guangdong Procapzoom Biosciences, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Ding, Wang, Wu, Chen, Wang, Li, Yao, Huang, Li, Wang, Lin, Guan, Zeng and Li.)

DJ-1 is significantly elevated in various malignancies. However, the clinical significance of DJ-1 in hormone receptor (HR)-positive (HR+) breast cancer remains unclear. We evaluated DJ-1 expression in different databases and validated in vitro assay by RT-PCR and western blot among HR+ breast cancer. The correlations between DJ-1 level and tumor-immune were calculated. Mutational landscape, enriched signaling pathways, and drug sensitivity analyses were also assessed between DJ-1 high and low-expression groups. DJ-1 was upregulated in HR+ breast cancer, and high DJ-1 expression was significantly linked with poor prognosis. DJ-1 was correlated with the expression and function of different immune cells. The low DJ-1 group showed sensitivity to paclitaxel and docetaxel, while the high-expression group showed sensitivity to doxorubicin. CTLA4 and PD-L1 were more sensitive in high- DJ-1 group. It is involved in a range of pathways and might behave as a novel biomarker of prognostic value for the immune environment and drug sensitivity in HR+ breast cancer., Competing Interests: The authors have declared that no conflicts of interest exist., (Copyright © 2023 Yinghong Xie et al.)

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8 + T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously 1 . Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter 2,3 , but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively 4,5 . Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands 6-8 . TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8 + T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8 + T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours., (© 2023. The Author(s).)

Glucose-6-phosphate isomerase (GPI) is a highly conserved glycolytic enzyme in nature, and less information was available for GPI from hens. In this study a newly discovered selenocysteine (Sec)-containing GPI in common chicken breast meat was first isolated, purified and identified. Data about LC-MS/MS, FTIR and Se species analyses show that the molecular weight of the enzyme is 62,091 Da and only one Sec is inserted at the 403rd position in the highly conserved primary domain SIS&#95;PGI with sugar conversion function. The enzyme shows excellent activity against hydroxyl radicals as vitamin C (Vc) in vitro. It is deduced that the Sec-containing GPI in the chicken meat may depend on Sec in its molecular structure to resist reactive oxygen species (ROS) stress produced by the accompanying biochemical reactions in cells, to protect its stability and maintain its efficient function that catalyzes the conversion of glucose-6-phosphate to fructose-6-phosphate in the critical glycolytic pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The widespread distribution of nanoplastics and dissolved organic matter (DOM) in sewage raises concerns about the potential impact of DOM on the bioavailability of nanoplastics. In this study, the effects of different sizes (100 nm and 350 nm) of polystyrene nanoplastics (PS-NPs, 50 mg/L) and combined with 10 mg/L or 50 mg/L DOMs (fulvic acid, humic acid and sodium alginate) on the growth and denitrification ability of Thiobacillus denitrificans were investigated. Results showed that 100 nm PS-NPs (50 mg/L) cause a longer delay in the nitrate reduction (3 days) of T. denitrificans than 350 nm PS-NPs (2 days). Furthermore, the presence of DOM exacerbated the adverse effect of 100 nm PS-NPs on denitrification, resulting in a delay of 1-4 days to complete denitrification. Fulvic acid (50 mg/L) and humic acid (50 mg/L) had the most significant adverse effect on increasing 100 nm PS-NPs (50 mg/L), causing a reduction of 20 mmol/L nitrate by T. denitrificans in nearly 7 days. It is noteworthy that the presence of DOM did not modify the adverse effect of 350 nm PS-NPs on denitrification. Further analysis of toxicity mechanism of PS-NPs revealed that they could induce reactive oxygen species (ROS) and suppressed denitrification gene expression. The results suggested that DOM may assist in the cellular internalization of PS-NPs by inhibiting PS-NPs aggregation, leading to the increased ROS levels and accelerated T. denitrificans death. This study highlights the potential risk of nanoplastics to autotrophic denitrifying bacteria in the presence of DOM and provides new insights for the treatment of nitrogen-containing wastewater by T. denitrificans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Efficient remedies for living organisms including bacteria to counteract cadmium (Cd 2+ ) toxicity are still highly needed. Plant toxicity studies have showed that exogenous S(-II) (including hydrogen sulfide and its ionic forms, i.e., H 2 S, HS - , and S 2- ) application can effectively alleviate adverse effects of Cd stress, but whether S(-II) could mitigate bacterial Cd toxicity remains unclear. In this study, S(-II) was applied exogenously to Cd-stressed Shewanella oneidensis MR-1 and the results showed that S(-II) can significantly reactivate impaired physiological processes including growth arrest and enzymatic ferric (Fe(III) reduction inhibition. The efficacy of S(-II) treatment is negatively correlated with the concentration and time length of Cd exposure. Energy-dispersive X-ray (EDX) analysis suggested the presence of cadmium sulfide inside cells treated with S(-II). Both compared proteomic analysis and RT-qPCR showed that enzymes associated with sulfate transport, sulfur assimilation, methionine, and glutathione biosynthesis were up-regulated in both mRNA and protein levels after the treatment, indicating S(-II) may induce the biosynthesis of functional low-molecular-weight (LMW) thiols to counteract Cd toxicity. Meanwhile, the antioxidant enzymes were positively modulated by S(-II) and thus the activity of intracellular reactive oxygen species was attenuated. The study demonstrated that exogenous S(-II) can effectively alleviate Cd stress for S. oneidensis likely through inducing intracellular trapping mechanisms and modulating cellular redox status. It suggested that S(-II) may be a highly effective remedy for bacteria such as S. oneidensis under Cd-polluted environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Herein, we innovatively propose a mucin 1 and azoreductase dual-responsive DNA tetrahedral nanoprobe for two-step lighting imaging-guided photodynamic therapy of tumors. We hope that this highly specific, responsive and well biocompatible drug delivery system can be effectively used for the performance of cancer therapy in the hypoxia-related biomedical field.

Viral hepatitis is a major worldwide public health issue, affecting hundreds of millions of people and causing substantial morbidity and mortality. The majority of the worldwide burden of viral hepatitis is caused by five biologically unrelated hepatotropic viruses: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Metabolomics is an emerging technology that uses qualitative and quantitative analysis of easily accessible samples to provide information of the metabolic levels of biological systems and changes in metabolic and related regulatory pathways. Alterations in glucose, lipid, and amino acid levels are involved in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, and amino acid metabolism. These changes in metabolites and metabolic pathways are associated with the pathogenesis and medication mechanism of viral hepatitis and related diseases. Additionally, differential metabolites can be utilized as biomarkers for diagnosis, prognosis, and therapeutic responses. In this review, we present a thorough overview of developments in metabolomics for viral hepatitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Wang, Li, Wang, Hu and Wang.)

Background: Cervical cancer is still present a major public health problem, especially in developing countries. In International Federation of Gynaecology and Obstetrics 2018, allowing assessment of retroperitoneal lymph nodes by imaging and/or pathological findings and, if deemed metastatic, the case is designated as stage IIIC (with r and p notations). Patients with lymph node metastases have lower overall survival (OS), progression free survival (PFS), and survival after recurrence, especially those who have unresectable macroscopical positive lymph nodes. Retrospective analysis suggests that there may be a benefit to debulking macroscopic nodes that would be otherwise difficult to sterilize with standard doses of radiation therapy. However, there are no prospective study reporting that resecting macroscopic nodes before concurrent chemoradiation therapy (CCRT) would improve PFS or OS of cervical cancer and no guidelines for surgical resection of bulky lymph nodes. The CQGOG0103 study is a prospective, multicenter and randomized controlled trial (RCT) evaluating lymph node dissection on stage IIICr of cervical cancer., Methods: Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by computed tomography [CT]/magnetic resonance imaging/positron emission tomography/CT) and the short diameter of image-positive lymph node ≥15 mm. 452 patients will be equally randomized to receive either CCRT (pelvic external-beam radiotherapy [EBRT]/extended-field EBRT + cisplatin [40 mg/m²] or carboplatin [the area under curve=2] every week for 5 cycles + brachytherapy) or open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The primary endpoint is PFS. Secondary endpoints are OS and surgical complications. A total of 452 patients will be enrolled from multiple hospitals in China within 4 years and followed up for 5 years., Trial Registration: ClinicalTrials.gov Identifier: NCT04555226., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Cervical cancer (CC) is a gynecological malignant tumor worldwide. Astragaloside IV (AS-IV) has been found to exert antitumor effects on CC. In addition, M2-polarized macrophages, known as tumor-associated macrophages (TAMs), play an important role in promoting cancer cell growth and angiogenesis. Thus, we explored the association between the antitumor effect of AS-IV and macrophage polarization in CC. Flow cytometry, ELISA, and RT‒qPCR assays were applied to detect the levels of CD163, IL-10, TGFβ, and CD206 in M2 macrophages with or without AS-IV treatment. In addition, conditioned medium (CM) was collected from these M2 macrophages, and CC cells were then cultured in various CMs. Wound healing and transwell assays were used to assess the migratory ability of CC cells. In this study, we found that AS-IV significantly inhibited M2 polarization of macrophages, as shown by decreased CD163, IL-10, TGFβ, and CD206 expression. In addition, compared with CM from M2 macrophages, CM from AS-IV-treated M2 macrophages notably inhibited angiogenesis, migration, and epithelial-mesenchymal transition (EMT) in CC cells. Furthermore, compared with CM from M2 macrophages, CM from AS-IV-treated M2 macrophages markedly reduced p-Smad2 and p-Smad3 protein expression in CC cells, and these changes were reversed by TGF-β treatment. Collectively, suppression of M2-like polarization of macrophages by AS-IV could prevent the migration and EMT of CC cells by inactivating TGF-β/Smad2/3 signaling. These findings might provide some theoretical support for exploring novel treatments for CC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fluorescence molecular probes have been regarded as a valuable tool for RNA detection and imaging. However, the pivotal challenge is how to develop an efficient fluorescence imaging platform for accurate identification of RNA molecules with low expression in complicated physiological environments. Herein, we construct the DNA nanoparticles to glutathione (GSH)-responsive controllable release of hairpin reactants for catalytic hairpin assembly (CHA)-hybridization chain reaction (HCR) cascade circuits, which enables the analysis and imaging of low-abundance target mRNA in living cells. The aptamer-tethered DNA nanoparticles are constructed via the self-assembly of single-stranded DNAs (ssDNAs), exhibiting sufficient stability, cell-specific penetration, and precise controllability. Moreover, the in-depth integration of different DNA cascade circuits shows the improved sensing performance of DNA nanoparticles in live cell analysis. Therefore, through the combination of multi-amplifiers and programmable DNA nanostructure, the developed strategy enables accurately triggered release of hairpin reactants and further achieves sensitive imaging and quantitative evaluation of survivin mRNA in carcinoma cells, which provides a potential platform to facilitate RNA fluorescence imaging applications in early clinical cancer theranostics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Schwertmannite (Sch) is an iron-hydroxysulfate mineral commonly found in acid mine drainage contaminated environment. The transformation mechanism of Sch mediated by pure cultured iron-reducing bacteria (FeRB) or sulfate-reducing bacteria (SRB) has been studied. However, FeRB and SRB widely coexist in the environment, the mechanism of Sch transformation by the consortia of FeRB and SRB is still unclear. This study investigated the Sch reduction by co-cultured Shewanella oneidensis (FeRB) and Desulfosporosinus meridiei (SRB). The results showed that co-culture of FeRB and SRB could accelerate the reductive dissolution of Sch, but not synergistically, and there were two distinct phases in the reduction of Sch mediated by FeRB and SRB: an initial phase in which FeRB predominated and Fe 3+ in Sch was reduced, accompanied with the release of SO 4 2- , and the detected secondary minerals were mainly vivianite; the second phase in which SRB predominated and mediated the reduction of SO 4 2- , producing minerals including mackinawite and siderite in addition to vivianite. Compared to pure culture, the abundance of FeRB and SRB in the consortia decreased, and more minerals aggregated inside and outside the cell; correspondingly, the transcription levels of genes (cymA, omcA, and mtrCBA) related to Fe 3+ reduction in co-culture was down-regulated, while the transcription levels of SO 4 2- -reducing genes (sat, aprAB, dsr(C)) was generally up-regulated. These phenomena suggested that secondary minerals produced in co-culture limited but did not inhibit bacterial growth, and the presence of SRB was detrimental to dissimilatory Fe 3+ reduction, while existed FeRB was in favor of dissimilatory SO 4 2- reduction. SRB mediated SO 4 2- reduction by up-regulating the expression of SO 4 2- reduction-related genes when its abundance was limited, which may be a strategy to cope with external coercion. These findings allow for a better understanding of the process and mechanism of microbial mediated reduction of Sch in the environment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Polycystic ovary syndrome (PCOS) not only increases fertility challenges for women of reproductive age, but also leads to increased complications during pregnancy and even affects the birth weight of newborns. Also, hyperandrogenemia is associated with lower pregnancy rates and lower live birth rates and may even play a role in preterm delivery and pre-eclampsia in patients with PCOS. However, it is still controversial whether PCOS patients are treated with androgen-lowering therapy before pregnancy., Objective: To assess the effect of anti-androgen therapy prior to ovulation induction on maternal and infant pregnancy outcomes in patients with PCOS., Methods: Prospective cohort study., Results: A total of 296 patients with PCOS were enrolled in the study. The prevalence of adverse pregnancy outcomes, and neonatal complications was lower in DRSP(with drospirenone ethinyl estradiol tablets (II) pretreatment) group than in NO-DRSP(without drospirenone ethinyl estradiol tablets (II) pretreatment) groups (DRSP vs . NO-DRSP: adverse pregnancy outcomes, 12.16% vs . 27.03%, P =0.001; neonatal complications, 17.16% vs . 36.67%, P <0.001). No significant difference was found in maternal complications. Further subgroup analysis revealed that PCOS with pretreatment decreased the risk of preterm delivery (2.99% vs . 10.00%; Adjusted RR, 3.80; 95% CI, 1.19-12.13), pregnancy loss (9.46% vs . 18.92%; Adjusted RR, 2.07; 95% CI, 1.08-3.96), low birth weight (0.75% vs 7.50%; Adjusted RR, 12.08; 95% CI, 1.50-97.31), fetal malformations(1.49% vs . 8.33%; Adjusted RR, 5.63; 95% CI, 1.20-26.33).There were no significant differences in the incidence of DM and PIH as pregnancy complications between the two groups ( P >0.05)., Conclusion: Our findings suggest that preconception androgen-lowering therapy in patients with PCOS improves pregnancy outcomes and reduces neonatal complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Miao, Zhou, Chen, Ou, Song, Peng, Li and Li.)

The real-time imaging of low-abundance tumor-related microRNAs (miRNAs) in living cells holds great potential for early clinical diagnosis of cancers. However, the relatively low detection sensitivity and possible false-positive signals of a probe in complex cellular matrices remain critical challenges for accurate RNA detection. Herein, we developed a novel aptamer-functionalized cruciate DNA probe that enabled amplified multiple miRNA imaging in living cells via catalytic hairpin assembly (CHA). The cross-shaped design of the cruciate DNA probe improved the stability against nucleases and acted as a modular scaffold for CHA circuits for efficient delivery into tumor cells. The cruciate DNA probe allowed self-assembly through thermal annealing and displayed excellent performance for sensitive miRNA detection in vitro . The cruciate DNA probe could be internalized into nucleolin-overexpressed cells specifically via cell-targeting of the AS1411 aptamer, achieving amplified fluorescence imaging and quantitative evaluation of the expression of miRNAs in living cells. Through the simultaneous detection of intracellular multiple miRNAs, the developed cruciate DNA probe could provide more accurate information and reduce the chances of false positive signals for cancer diagnosis. This approach offers a new opportunity for promoting the development of miRNA-related biomedical research and tumor diagnostic applications.

How to generate the path planning of mobile robots quickly is a problem in the field of robotics. The Q-learning(QL) algorithm has recently become increasingly used in the field of mobile robot path planning. However, its selection policy is blind in most cases in the early search process, which slows down the convergence of optimal solutions, especially in a complex environment. Therefore, in this paper, we propose a continuous local search Q-Learning (CLSQL) algorithm to solve these problems and ensure the quality of the planned path. First, the global environment is gradually divided into independent local environments. Then, the intermediate points are searched in each local environment with prior knowledge. After that, the search between each intermediate point is realized to reach the destination point. At last, by comparing other RL-based algorithms, the proposed method improves the convergence speed and computation time while ensuring the optimal path.

Super-enhancers (SEs) are important transcriptional regulators in tumorigenesis; however, the functional characterization and clinical significance of SEs in lung adenocarcinoma (LUAD) remain unclear. By using H3K27ac ChIP-seq data of two LUAD cell lines and eight lung tissues, we detected 1045 cancer-specific and 5032 normal-specific SEs. Compared to normal-specific SEs, cancer-specific SEs have different regulatory mechanisms where associated target genes were enriched in critical tumor-related pathways and tended to be regulated by transcription factors of Fos Proto-Oncogene, AP-1 Transcription Factor Subunit and Jun Proto-Oncogene, AP-1 Transcription Factor Subunit families. By using expression data of 513 LUAD and 57 adjacent samples from The Cancer Genome Atlas and 80 tumor-normal paired LUAD samples from the Nanjing Lung Cancer Cohort study, we performed differential expression analysis of target genes for SEs and defined 243 crucial SEs. Unsupervised clustering of crucial SEs revealed two subtypes with different levels of genomic aberrations (i.e., mutation and copy number alteration) and clinical outcomes (progression-free interval: p = 0.030; disease-free interval: p = 0.047). In addition, patients with adverse clinical outcomes were more sensitive to three small molecule inhibitors (bortezomib, doxorubicin, and etoposide), and their targets (PSMB5 and TOP2A) also have elevated expression levels among these patients. Taken together, our findings provided a comprehensive characterization of SEs in LUAD and emphasized their clinical significance in LUAD therapy., (© 2022 Wiley Periodicals LLC.)

As a renewable and sustainable source for energy, environment, and biomedical applications, microalgae and microalgal biodiesel have attracted great attention. However, their applications are confined due to the cost-efficiency of microalgal mass production. One-step strategy and continuous culturing systems could be solutions. However, current studies for optimization throughout microalgae-based biofuel production pipelines are generally derived from the batch culture process. Better tools are needed to study algal growth kinetics in continuous systems. A microfluidic chemostatic bioreactor was presented here, providing low-bioadhesive cultivations for algae in a cooperative environment of gas, nutrition, and temperature (GNT) involved with high throughput. The chip was used to mimic the continuous culture environment of bioreactors. It allowed simultaneously studying of 8 × 8 different chemostatic conditions on algal growth and oil production in parallel on a 7 × 7 cm 2 footprint. On-chip experiments of batch and continuous cultures of Chlorella. sp . were performed to study growth and lipid accumulation under different nitrogen concentrations. The results demonstrated that microalgal cultures can be regulated to grow and accumulate lipids concurrently, thus enhancing lipid productivity in one step. The developed on-chip culturing condition screening, which was more suitable for continuous bioreactor, was achieved at a half shorter time, 64-times higher throughput, and less reagent consumption. It could be used to establish chemostat cultures in continuous bioreactors which can dramatically accelerate the development of renewable and sustainable algal for CO 2 fixation and biosynthesis and related systems for advanced sustainable energy, food, pharmacy, and agriculture with enormous social and ecological benefits., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Effectively delivering therapeutics for treating brain tumors is hindered by the physical and biological barriers in the brain. Even with the compromised blood-brain barrier and highly angiogenic blood-tumor barrier seen in glioblastoma (GBM), most drugs, including nanomaterial-based formulations, hardly reach intracranial tumors. This work investigates sub-5 nm ultrafine iron oxide nanoparticles (uIONP) with 3.5 nm core diameter as a carrier for delivering DNA topoisomerase inhibitor 7-ethyl-10-hydroxyl camptothecin (SN38) to treat GBM. Given a higher surface-to-volume ratio, uIONP shows one- or three-folds higher SN38 loading efficiency (48.3 ± 6.1%, mg/mg Fe) than those with core sizes of 10 or 20 nm. SN38 encapsulated in the coating polymer exhibits pH sensitive release with <10% over 48 h at pH 7.4, but 86% at pH 5, thus being protected from converting to inactive glucuronide by UDP-glucuronosyltransferase 1A1. Conjugating α v β 3 -integrin-targeted cyclo(Arg-Gly-Asp-D-Phe-Cys) (RGD) as ligands, RGD-uIONP/SN38 demonstrates targeted cytotoxicity to α v β 3 -integrin-overexpressed U87MG GBM cells with a half-maximal inhibitory concentration (IC 50 ) of 30.9 ± 2.2 nm. The efficacy study using an orthotopic mouse model of GBM reveals tumor-specific delivery of 11.5% injected RGD-uIONP/SN38 (10 mg Fe kg -1 ), significantly prolonging the survival in mice by 41%, comparing to those treated with SN38 alone (p < 0.001)., (© 2022 Wiley-VCH GmbH.)

The intelligence of energy storage devices has led to a sharp increase in the amount of detection data generated. Data sharing among distributed energy storage networks can realize collaborative control and comprehensive analysis, which effectively improves the clustering and intelligence. However, data security problems have become the main obstacle for energy storage devices to share data for joint modeling and analysis. The security issues caused by information leakage far outweigh property losses. In this article, we first proposed a blockchain-based machine learning scheme for secure data sharing in distributed energy storage networks. Then, we formulated the data sharing problem into a machine-learning problem by incorporating secure federated learning. Innovative verification methods and consensus mechanisms were used to encourage participants to act honestly, and to use well-designed incentive mechanisms to ensure the sustainable and stable operation of the system. We implemented the scheme of SFedChain and experimented on real datasets with different settings. The numerical results show that SFedChain is promising., Competing Interests: The authors declare there are no competing interests., (©2022 meng et al.)

Phospholipase A2, group VII (PLA2G7) is widely recognized as a secreted, lipoprotein-associated PLA2 in plasma that converts phospholipid platelet-activating factor (PAF) to a biologically inactive product Lyso-PAF during inflammatory response. We report that intracellular PLA2G7 is selectively important for cell proliferation and tumor growth potential of melanoma cells expressing mutant NRAS, but not cells expressing BRAF V600E. Mechanistically, PLA2G7 signals through its product Lyso-PAF to contribute to RAF1 activation by mutant NRAS, which is bypassed by BRAF V600E. Intracellular Lyso-PAF promotes p21-activated kinase 2 (PAK2) activation by binding to its catalytic domain and altering ATP kinetics, while PAK2 significantly contributes to S338-phosphorylation of RAF1 in addition to PAK1. Furthermore, the PLA2G7-PAK2 axis is also required for full activation of RAF1 in cells stimulated by epidermal growth factor (EGF) or cancer cells expressing mutant KRAS. Thus, PLA2G7 and Lyso-PAF exhibit intracellular signaling functions as key elements of RAS-RAF1 signaling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Pancreatic cancer remains one of the most lethal cancers largely due to the inefficient delivery of therapeutics. Nanomaterials have been extensively investigated as drug delivery platforms, showing improved drug pharmacodynamics and pharmacokinetics. However, their applications in pancreatic cancer have not yet been successful due to limited tumor delivery caused by dense tumor stroma and distorted tumor vasculatures. Meanwhile, smaller-sized nanomaterials have shown improved tumor delivery and retention in various tumors, including pancreatic tumors, suggesting their potential in enhancing drug delivery. An ultrafine iron oxide nanoparticle (uIONP) was used to encapsulate 7-ethyl-10-hydroxyl camptothecin (SN38), the water-insoluble active metabolite of pancreatic cancer chemotherapy drug irinotecan. Insulin-like growth factor 1 (IGF-1) was conjugated to uIONP as a ligand for targeting pancreatic cancer cells overexpressing IGF-1 receptor (IGF1R). The SN38 loading and release profile were characterized. The pancreatic cancer cell targeting using IGF1-uIONP/SN38 and subsequently induced cell apoptosis were also investigated. IGF1-uIONP/SN38 demonstrated a stable drug loading in physiological pH with the loading efficiency of 68.2 ± 3.5% (SN38/Fe, wt%) and < 7% release for 24 h. In tumor-interstitial- and lysosomal-mimicking pH (6.5 and 5.5), 52.2 and 91.3% of encapsulated SN38 were released over 24 h. The IGF1-uIONP/SN38 exhibited specific receptor-mediated cell targeting and cytotoxicity Ato MiaPaCa-2 and Panc02 pancreatic cancer cells with IC50 of 11.8 ± 2.3 and 20.8 ± 3.5 nM, respectively, but not to HEK293 human embryonic kidney cells. IGF1-uIONP significantly improved the targeted SN38 delivery to pancreatic cancer cells, holding the potential for in vivo theranostic applications., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ceria (CeO 2 )-based materials are potential catalysts for the removal of the Hg 0 and AsH 3 present in reducing atmospheres. However, theoretical studies investigating the Hg 0 and AsH 3 removal capacity of ceria remain limited. In this study, the adsorption behavior and mechanistic pathways for the catalytic oxidation of Hg 0 and AsH 3 on the CeO 2 (111) surface, including the calculation of optimized adsorption configurations and energies, were investigated using density functional theory calculations. The results suggest that Hg 0 and AsH 3 are favorably adsorbed on the CeO 2 (111) surface, whereas CO is not, which is crucial for selective removal when CO is a desirable gas component. Furthermore, AsH 3 is adsorbed more favorably than Hg 0 . In addition, the calculations revealed that the Hg atom is initially adsorbed on the surface and then oxidized by lattice oxygen to form HgO. Concerning AsH 3 decomposition, the stepwise dehydrogenation of AsH 3 followed by bonding with lattice O atoms to form the As-O bond seems the most plausible. Finally, the adsorbed As-O bond is further forms elemental As and As 2 O 3 . Therefore, CeO 2 can adsorb and remove Hg 0 and AsH 3 , making it a promising catalyst for the simultaneous catalytic oxidation of Hg 0 and AsH 3 in strongly reducing off-gas., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Surgical exploration is widely performed in hilar cholangiocarcinoma (HCCA), but the intraoperative resectability rate is only 60%-80%. Exploration substantially increases pain and mental stress, and the costs and length of hospital stay are considerably increased. Identifying preoperative risk factors associated with unresectability could decrease unnecessary exploration., Materials and Methods: In total, 440 HCCA patients from multiple centers were enrolled. Those receiving surgical exploration were divided into the resected and unresected groups. Morphological variables including Bismuth classification, lymph node metastasis and vessel invasion were obtained from radiological exams. Logistic regression for the training cohort was used to identify risk factors for unresectability, and a nomogram was constructed to calculate the unresectability rate. A calibration curve assessed the power of the nomogram., Results: Among 311 patients receiving surgical exploration, 45 (14.7%) were unresectable by intraoperative judgment. Compared with the resected group, unresected patients had similar costs (p = 0.359) and lengths of hospital stay (p = 0.439). Multivariable logistic regression of the training cohort (235 patients) revealed that CA125, Bismuth-Corlette type IV, lymph node metastasis and hepatic artery invasion were risk factors for unresectability. Liver atrophy (p = 0.374) and portal vein invasion (p = 0.114) were not risk factors. The nomogram was constructed based on the risk factors. The concordance index (C-index) values of the calibration curve for predicting the unresectability rate of the training and validation (76 patients) cohorts were 0.900 (95% CI, 0.835-0.966) and 0.829 (95% CI, 0.546-0.902), respectively., Conclusion: Analysis of preoperative factors could reveal intraoperative unresectability and reduce futile surgical explorations, ultimately benefiting HCCA patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers worldwide and includes cancers arising from the oral cavity, pharynx and larynx. Genome-wide association studies have found several genetic variants related to the risk of SCCHN; however, they could only explain a small fraction of the heritability. Thus, more susceptibility loci associated with SCCHN need to be identified., Methods: An association study was conducted by genotyping 555 patients with SCCHN and 1367 controls in a Chinese population. Single-variant association analysis was conducted on 63 373 SNPs, and the promising variants were then confirmed by a two-stage validation with 1875 SCCHN cases and 4637 controls. Bioinformatics analysis and functional assays were applied to uncover the potential pathogenic mechanism of the promising variants and genes associated with SCCHN., Results: We first identified three novel genetic variants significantly associated with the risk of SCCHN (p=7.45×10 -7 for rs2517611 at 6p22.1, p=1.76×10 -9 for rs2524182 at 6p21.33 and p=2.17×10 -10 for rs3131018 at 6p21.33). Further analysis and biochemical assays showed that rs3094187, which was in a region in high linkage disequilibrium with rs3131018, could modify TCF19 expression by regulating the binding affinity of the transcription factor SREBF1 to the promoter of TCF19 . In addition, experiments revealed that the inhibition of TCF19 may affect several important pathways involved in tumourigenesis and attenuate the cell proliferation and migration of SCCHN., Conclusion: These findings offer important evidence that functional genetic variants could contribute to development of SCCHN and that TCF19 may function as a putative susceptibility gene for SCCHN., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent advances in society have resulted in the emergence of both hyperlipidemia and obesity as life-threatening conditions in people with implications for various types of diseases, such as cardiovascular diseases and cancer. This is further complicated by a global rise in the aging population, especially menopausal women, who mostly suffer from overweight and bone loss simultaneously. Interestingly, clinical observations in these women suggest that osteoarthritis may be linked to a higher body mass index (BMI), which has led many to believe that there may be some degree of bone dysfunction associated with conditions such as obesity. It is also common practice in many outpatient settings to encourage patients to control their BMI and lose weight in an attempt to mitigate mechanical stress and thus reduce bone pain and joint dysfunction. Together, studies show that bone is not only a mechanical organ but also a critical component of metabolism, and various endocrine functions, such as calcium metabolism. Numerous studies have demonstrated a relationship between metabolic dysfunction in bone and abnormal lipid metabolism. Previous studies have also regarded obesity as a metabolic disorder. However, the relationship between lipid metabolism and bone metabolism has not been fully elucidated. In this narrative review, the data describing the close relationship between bone and lipid metabolism was summarized and the impact on both the normal physiology and pathophysiology of these tissues was discussed at both the molecular and cellular levels., (© 2021. The Author(s).)

Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91-0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer., (© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: CircRNAs are critical gene modulators in tumor initiation and progression. However, the expression pattern and molecular pathogenesis of circRNAs in oral squamous cell carcinoma (OSCC) are still poorly characterized., Methods: RNA sequencing with CIRCexplorer2 pipeline was performed to identify circRNAs in 46 tumor-normal paired tissues from OSCC patients. Another set of 48 head and neck squamous cell carcinoma samples from the MiOncoCirc database were utilized as an independent validation., Results: Of the 1276 identified high-confidence circRNAs, 154 were differentially expressed between tumor and normal tissues (log 2 |Fold Change|≥1 and false discovery rate < 0.05). CircRNAs expression was globally down-regulated in tumors compared to normal tissues (P = 9.44 × 10 -14 ). Correlation analysis demonstrated that the global expression of circRNAs was positively related to tumor infiltrating lymphocyte (P = 1.10 × 10 -4 ) and stromal signature (P = 2.70 × 10 -3 ) whereas negatively associated with cell proliferation markers (P = 4.32 × 10 -2 ). CircRNAs-miRNAs-mRNAs regulatory network revealed 6574 interactions, and the target genes were enriched in extracellular matrix and immune-related pathways. Survival analysis were performed on target genes in immune-related pathways, and 20 genes were significantly associated with the prognostic status of OSCC in The Cancer Genome Atlas cohort. The risk model constructed with above 20 genes was associated with the prognosis status of OSCC (HR = 3.28, P = 5.06 × 10 -11 ), and the result was validated in an independent study (GSE41613) (HR = 2.06, P = 1.73 × 10 -2 )., Conclusion: CircRNAs showed a global down-regulation pattern in OSCC tissues, and genes regulated by circRNAs primarily involved in immune and extracellular matrix pathways, which could also affect the OSCC prognosis, indicating that they may serve as potential prognostic biomarkers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: To evaluate the prognostic value of left ventricular (LV) remodelling index (RI) in idiopathic dilated cardiomyopathy (DCM) patients., Methods and Results: We prospectively enrolled 412 idiopathic DCM patients and 130 age- and sex-matched healthy volunteers who underwent cardiovascular magnetic resonance imaging between September 2013 and March 2018. RI was defined as the cubic root of the LV end-diastolic volume divided by the mean LV wall thickness on basal short-axis slice. The primary endpoint included all-cause mortality and heart transplantation. The secondary endpoint included the primary endpoint and heart failure (HF) readmission. During the median follow-up of 28.1 months (interquartile range: 19.3-43.0 months), 62 (15.0%) and 143 (34.7%) patients reached the primary and secondary endpoints, respectively. Stepwise multivariate Cox regression showed that RI [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.11-1.30, P < 0.001], late gadolinium enhancement (LGE) presence and log (N-terminal pro-B-type natriuretic peptide) were independent predictors of the primary endpoint, while RI (HR 1.15, 95% CI 1.08-1.23, P < 0.001) and extracellular volume were independent predictors of the secondary endpoint. The addition of RI to LV ejection fraction (EF) and LGE presence showed significantly improved global χ2 for predicting primary and secondary endpoints (both P < 0.001). Furthermore, RI derived from echocardiography also showed independent prognostic value for primary and secondary endpoints with clinical risk factors., Conclusions: RI is an independent predictor of all-cause mortality, heart transplantation, and HF readmission in DCM patients and provides incremental prognostic value to LVEF and LGE presence., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Mutant isocitrate dehydrogenase (IDH) 1 and 2 play a pathogenic role in cancers, including acute myeloid leukemia (AML), by producing oncometabolite 2-hydroxyglutarate (2-HG). We recently reported that tyrosine phosphorylation activates IDH1 R132H mutant in AML cells. Here, we show that mutant IDH2 (mIDH2) R140Q commonly has K413 acetylation, which negatively regulates mIDH2 activity in human AML cells by attenuating dimerization and blocking binding of substrate (α-ketoglutarate) and cofactor (NADPH). Mechanistically, K413 acetylation of mitochondrial mIDH2 is achieved through a series of hierarchical phosphorylation events mediated by tyrosine kinase FLT3, which phosphorylates mIDH2 to recruit upstream mitochondrial acetyltransferase ACAT1 and simultaneously activates ACAT1 and inhibits upstream mitochondrial deacetylase SIRT3 through tyrosine phosphorylation. Moreover, we found that the intrinsic enzyme activity of mIDH2 is much higher than mIDH1, thus the inhibitory K413 acetylation optimizes leukemogenic ability of mIDH2 in AML cells by both producing sufficient 2-HG for transformation and avoiding cytotoxic accumulation of intracellular 2-HG., Competing Interests: Declaration of interests R.L.L. is on the supervisory board of QIAGEN and is a scientific advisor to Loxo, Imago, C4 Therapeutics, and Isoplexis, each of which includes an equity interest. He receives research support from and consulted for Celgene and Roche, has received research support from Prelude Therapeutics, and has consulted for Incyte, Novartis, Astellas, Morphosys, and Janssen. He has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The creatine transporter (CrT) maintains brain creatine (Cr) levels, but the effects of its deficiency on energetics adaptation under stress remain unclear. There are also no effective treatments for CrT deficiency, the second most common cause of X-linked intellectual disabilities. Herein, we examined the consequences of CrT deficiency in brain energetics and stress-adaptation responses plus the effects of intranasal Cr supplementation. We found that CrT-deficient (CrT-/y) mice harbored dendritic spine and synaptic dysgenesis. Nurtured newborn CrT-/y mice maintained baseline brain ATP levels, with a trend toward signaling imbalance between the p-AMPK/autophagy and mTOR pathways. Starvation elevated the signaling imbalance and reduced brain ATP levels in P3 CrT-/y mice. Similarly, CrT-/y neurons and P10 CrT-/y mice showed an imbalance between autophagy and mTOR signaling pathways and greater susceptibility to cerebral hypoxia-ischemia and ischemic insults. Notably, intranasal administration of Cr after cerebral ischemia increased the brain Cr/N-acetylaspartate ratio, partially averted the signaling imbalance, and reduced infarct size more potently than intraperitoneal Cr injection. These findings suggest important functions for CrT and Cr in preserving the homeostasis of brain energetics in stress conditions. Moreover, intranasal Cr supplementation may be an effective treatment for congenital CrT deficiency and acute brain injury.

Objective: To investigate the prognostic significance of T1 mapping using T1 long and short in hypertrophic cardiomyopathy (HCM) patients., Methods: A total of 263 consecutive patients with HCM referred for cardiovascular magnetic resonance (CMR) imaging were enrolled in this study. The imaging protocol consisted of cine, late gadolinium enhancement (LGE), and T1 mapping with T1 long and short. All patients were followed up prospectively. Outcome events were divided into the primary and secondary endpoint events. Primary endpoint events included cardiac death, heart transplant, aborted sudden death, and cardiopulmonary resuscitation after syncope. The secondary endpoint event was defined as unplanned rehospitalization for heart failure., Result: The average follow-up duration was 28.3 ± 12.1 (range: 1-78) months. In all, 17 patients (7.0%) experienced a primary endpoint including 13 cardiovascular deaths, three aborted sudden deaths, and one resuscitation after syncope, and 34 patients experienced a secondary endpoint. Patients with primary endpoints showed a trend towards more extensive LGE (p < 0.001), significantly higher ECV (p < 0.001), and native T1 (p = 0.028) than those without events. In multivariate Cox regression analysis, ECV was independently associated with primary and secondary endpoints (p < 0.001 and p = 0.047, respectively). For every 3% increase, ECV portended a 1.374-fold increase risk of a primary endpoint occurring (p < 0.001). In the Kaplan-Meier survival analysis, the incidence of primary and secondary endpoint events was significantly higher in HCM with increased ECV (p < 0.001 and p = 0.009, respectively)., Conclusion: In patients with HCM, ECV is a strong imaging marker for predicting adverse outcome., Key Points: • ECV is a potent imaging index which has a strong correlation with LVEF and LVEDVI and can evaluate myocardial tissue structure and function. • ECV and LGE can provide a prognostic value in patients with hypertrophic cardiomyopathy. • ECV has stronger predictive effectiveness than LGE; even in the subgroup with LGE, ECV shows independent predictive significance for adverse events.

Background: As a nutritional index, preoperative serum prealbumin highly correlates with surgical complications. However, the correlation between preoperative prealbumin and postoperative complications remains unclear in liver transplantation (LT)., Methods: A total of 191 patients who underwent LT between 2015 and 2019 were included in the retrospective analysis. According to a cut-off value calculated from a receiver operating characteristic (ROC) curve, the patients were divided into normal and low preoperative prealbumin groups. Univariable and multivariable logistic regression analyses were used to identify independent risk factors for postoperative complications. In addition, patients were divided into subgroups by Model for End-stage Liver Disease (MELD) score, and the association between preoperative prealbumin and postoperative complications was also assessed in each group., Results: A total of 111 (58.1%) patients were included in the low prealbumin group based on a cut-off value of 120 mg/L. The area under the ROC curve (AUC) was 0.754 (95% confidence interval [CI] 0.678-0.832). Low prealbumin (95% CI 1.51-12.8, P = 0.007) was identified as a predictor for postoperative complications based on multivariable regression. In the low and normal prealbumin groups, the prevalence rates of postoperative complications were 27.5% and 8.0% (P = 0.003) in the MELD score ≤ 15 subgroup and 53.3% and 20.0% (P = 0.197) in the MELD score > 15 subgroup, respectively., Conclusions: Preoperative prealbumin was associated with postoperative complications in LT, and preoperative nutritional support benefitted postoperative recovery, especially for patients with low MELD scores.

In the V2G network, the release and sharing of real-time data are of great value for data mining. However, publishing these data directly to service providers may reveal the privacy of users. Therefore, it is necessary that the data release model with a privacy protection mechanism protects user privacy in the case of data utility. In this paper, we propose a privacy protection mechanism based on differential privacy to protect the release of data in V2G networks. To improve the utility of the data, we define a variable sliding window, which can dynamically and adaptively adjust the size according to the data. Besides, to allocate the privacy budget reasonably in the variable window, we consider the sampling interval and the proportion of the window. Through experimental analysis on real data sets, and comparison with two representative w event privacy protection methods, we prove that the method in this paper is superior to the existing schemes and improves the utility of the data., Competing Interests: Rixuan Qiu, Fuyong Zheng and Liang Liang are employed by State Grid Jiangxi Information & Telecommunication Company., (©2021 Qiu et al.)

Environmental pollution due to resistance genes from livestock manure has become a serious issue that needs to be resolved. However, little studies focused on the removal of resistance genes in simultaneous processing of livestock feces and urine. This study investigated the fate of antibiotic resistance genes (ARGs), metal resistance genes (MRGs), and class 1 integron-integrase gene (intI1) during thermophilic fermentation of swine manure in an ectopic fermentation system (EFS), which has been regarded as a novel system for efficiently treating both feces and urine. The abundances of MRGs and tetracycline resistance genes were 34.44-97.71% lower in the EFS. The supplementation of heavy metals significantly increased the abundance of intI1, with the enhancement effect of copper being more prominent than that of zinc. The highest abundances of resistance genes and intI1 were observed at high Cu levels (A2), indicating that Cu can increase the spreading of resistance genes through integrons. Network analysis revealed the co-occurrence of ARGs, MRGs, and intI1, and these genes potentially shared the same host bacteria. Redundancy analysis showed that the bacterial community explained most of the variations in ARGs, and environmental factors had influences on ARGs abundances by modulating the bacterial community composition. The decreased Sphingomonas, Comamonas, Acinetobacter, Lactobacillus, Bartonella, Rhizobium, and Bacteroides were mainly responsible for the reduced resistance genes. These results demonstrate that EFS can reduce resistance genes in simultaneous processing of livestock feces and urine., (Copyright © 2021. Published by Elsevier Inc.)

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.