Shape-dependent cellular uptake of iron oxide nanorods: mechanisms of endocytosis and implications on cell labeling and cellular delivery.

The effects of nanoparticle morphology, especially size and shape, on their interactions with cells are of great interest in understanding the fate of nanoparticles in biological systems and designing them for biomedical applications. While size and shape-dependent cell behavior, endocytosis mechanism, and subcellular distribution of nanoparticles have been investigated extensively with gold and other nanoparticles, studies on iron oxide nanoparticles (IONP), one of the most promising and well-thought-of nanomaterials in biomedical applications, were limited. In this study, we synthesized oligosaccharide-coated water-soluble iron oxide nanorods (IONR) with different core sizes (nm) and different aspect ratios (i.e., length/width), such as IONR(L) at 140/6 nm and IONR(S) at 50/7 nm as well as spherical IONP (20 nm). We investigated how their sizes and shapes affect uptake mechanisms, localization, and cell viability in different cell lines. The results of transmission electron microscopy (TEM) and confocal fluorescence microscopic imaging confirmed the internalization of these nanoparticles in different types of cells and subsequent accumulation in the subcellular compartments, such as the endosomes, and into the cytosol. Specifically, IONR(L) exhibited the highest cellular uptake compared to IONR(S) and spherical IONP, 1.36-fold and 1.17-fold higher than that of spherical IONP in macrophages and pediatric brain tumor medulloblastoma cells, respectively. To examine the cellular uptake mechanisms preferred by the different IONR and IONP, we used different endocytosis inhibitors to block specific cellular internalization pathways when cells were treated with different nanoparticles. The results from these blocking experiments showed that IONR(L) enter macrophages and normal kidney cells through clathrin-mediated, dynamin-dependent, and macropinocytosis/phagocytosis pathways, while they are internalized in cancer cells primarily via clathrin/caveolae-mediated and phagocytosis mechanisms. Overall, our findings provide new insights into further development of magnetic IONR-based imaging probes and drug delivery systems for biomedical applications.

Ferrostatin-1 alleviates skin inflammation and inhibits ferroptosis of neutrophils and CD8+ T cells in allergic contact dermatitis.

BACKGROUND: Ferroptosis is considered as an immunogenic type of regulated cell death and associated with the pathogenesis of inflammatory skin diseases. However, the involvement and function of ferroptosis in allergic contact dermatitis (ACD) remains unknown. OBJECTIVE: To explore the role of ferroptosis in ACD. To reveal which type of cells develops ferroptosis in ACD. METHODS: We detected the key markers of ferroptosis in 1-Chloro-2,4-dinitrochlorobenzene (DNCB)-induced ACD mice model. We applicated ferrostatin-1 (Fer-1) to restrain ferroptosis in ACD mice and then compared the severity of dermatitis and the level of inflammation and ferroptosis in dermis and epidermis, respectively. Keratinocyte-specific Gpx4 conditional knockout (cKO) mice were used to investigate the function of keratinocyte ferroptosis in the development of ACD. Single-cell RNA sequencing was conducted to analyze the affection of Fer-1 on different type of cells in ACD. RESULTS: Ferroptosis was involved in DNCB-induced ACD mice. Ferroptosis activation was more remarkable in dermis rather than in epidermis. Gpx4 cKO mice showed similar severity of skin dermatitis as control mice. Fer-1 alleviated skin inflammation in mice and reduced ferroptosis in neutrophils and CD8+ T cells both of which contribute to development of ACD. CONCLUSION: Ferroptosis was activated in immune cells, especially neutrophils and CD8+ T cells in DNCB-induced ACD mice. Fer-1 treatment inhibited ferroptosis of neutrophils and CD8+ T cells and relieved skin damage in ACD mice.

Joint effects of sleep disturbance and renal function impairment on incident new-onset severe metabolic dysfunction-associated steatotic liver disease.

AIM: To elucidate the effects of sleep parameters and renal function on the risk of developing new-onset severe metabolic dysfunction-associated steatotic liver disease (MASLD). MATERIALS AND METHODS: The primary analysis involved a cohort of 305 257 participants. Multivariable Cox models were employed to calculate hazard ratios and 95% confidence intervals. Traditional mediation and two-step Mendelian randomization (MR) analyses were conducted to assess the associations and mediating roles of renal function indicators between sleep and new-onset severe MASLD. RESULTS: Poor sleep score and renal function biomarker score (RFS) were associated with an increased risk of new-onset severe MASLD (all ptrend <0.001). Participants with poor sleep patterns and the highest RFS had a 5.45-fold higher risk of new-onset severe MASLD, compared to those with healthy sleep patterns and the lowest RFS (p < 0.001). The RFS could explain 10.08% of the correlations between poor sleep score and risk of new-onset severe MASLD. Additionally, MR analyses supported a causal link between insomnia and new-onset severe MASLD and revealed a mediating role of chronic kidney disease in the connection between insomnia and new-onset severe MASLD risk. CONCLUSIONS: This study highlights the independent and combined associations of sleep parameters and renal function indicators with new-onset severe MASLD, underscoring the bidirectional communication of the liver-kidney axis and providing modifiable strategies for preventing MASLD.

A brief model evaluated outcomes after liver transplantation based on the matching of donor graft and recipient.

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.

Promising approach for targeting ROBO1 with CAR NK cells to combat ovarian cancer primary tumor cells and organoids.

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.

Ovarian cancer represents a formidable clinical challenge necessitating the urgent exploration of novel therapeutic approaches. In this study, the focus was directed toward ROBO1, a molecule known to play a pivotal role in cancer angiogenesis and metastasis, while limited investigation in the context of ovarian cancer. Leveraging this knowledge, we sought to construct ROBO1-targeting chimeric antigen receptor natural killer (CAR-NK) cells utilizing peripheral blood mononuclear cells derived from the patients themselves. The overarching goal of this investigation was to harness the potential of immunotherapy using autologous resources to realize personalized treatment strategies for ovarian cancer in clinical settings.

Development of a Dual-Factor Activatable Covalent Targeted Photoacoustic Imaging Probe for Tumor Imaging.

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.

Vascular reconstruction provides short-term and long-term survival benefits for patients with hilar cholangiocarcinoma: A retrospective, multicenter study.

BACKGROUND: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively. METHODS: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared. RESULTS: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups. CONCLUSIONS: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection.

Residual biliary intraepithelial neoplasia without malignant transformation at resection margin for perihilar cholangiocarcinoma does not require expanded resection: a dual center retrospective study.

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.

Exogenous and endogenous antioxidants in osteoporosis risk: causal associations unveiled by Mendelian Randomization analysis.

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 (ß: -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.

Rapid screening of the novel bioactive peptides with notable α-glucosidase inhibitory activity by UF-LC-MS/MS combined with three-AI-tool from black beans.

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 IC50 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.

Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities.

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 αvß3 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.

Polycyclic aromatic compounds (PACs) in industrial soils from northwestern of China: occurrence, distribution, exposure risk, and implications on risk-based controls.

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 Æ©18PPAHs, Æ©11MPAHs, Æ©12NPAHs, and Æ©4OPAHs 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.

Pollution Characteristics and Health Risks of Polycyclic Aromatic Compounds (PACs) in Soils of a Coking Plant.

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%.

DDoS attack detection in smart grid network using reconstructive machine learning models.

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.

Effects of Berberine on glucolipid metabolism among dehydroepiandrosterone-induced rats of polycystic ovary syndrome with insulin-resistance.

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.

Adequate cumulative exposure to tacrolimus and low tacrolimus variability decrease the incidence of biliary complications after liver transplantation.

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.

Risk assessment for the long-term stability of fly ash-based cementitious material containing arsenic: Dynamic and semidynamic leaching.

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 Al3+ 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 H2SO4 and Fe2(SO4)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.

Vertical distribution characteristics of soil organic carbon and vegetation types under different elevation gradients in Cangshan, Dali.

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.

DJ-1: A Potential Biomarker Related to Prognosis, Chemoresistance, and Expression of Microenvironmental Chemokine in HR-Positive Breast Cancer.

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.

Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

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 endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. 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.