Dynamic Hybrid Module-Driven NK Cell Stimulation and Release for Tumor Immunotherapy.

Natural killer (NK) cells have become a powerful candidate for adoptive tumor immunotherapy, while their therapeutic efficacy in solid tumors remains unsatisfactory. Here, we developed a hybrid module with an injectable hydrogel and hydroxyapatite (HAp) nanobelts for the controlled delivery of NK cells to enhance the therapy of solid tumors. Surface-functionalized HAp nanobelts modified with agonistic antibodies against NKG2D and 4-1BB and cytokines IL-2 and IL-21 support survival and dynamic activation. Thus, the HAp-modified chitosan (CS) thermos-sensitive hydrogel not only improved the retention of NK cells for more than 20 days in vivo but also increased NK cell function by more than one-fold. The unique architecture of this biomaterial complex protects NK cells from the hostile tumor environment and improves antitumor efficacy. The generation of a transient inflammatory niche for NK cells through a biocompatible hydrogel reservoir may be a conversion pathway to prevent cancer recurrence of resectable tumors.

Frailty and risk of metabolic dysfunction-associated steatotic liver disease and other chronic liver diseases.

BACKGROUND & AIMS: Frailty is associated with multiple morbidities. However, its effect on chronic liver diseases remains largely unexplored. This study evaluated the association of frailty with the risk of incident metabolic dysfunction-associated steatotic liver disease (MASLD), cirrhosis, liver cancer, and liver-related mortality. METHODS: A total of 339,298 participants without prior liver diseases from the UK Biobank were included. Baseline frailty was assessed by physical frailty and the frailty index, categorizing participants as non-frail, prefrail, or frail. The primary outcome was MASLD, with secondary outcomes, including cirrhosis, liver cancer, and liver-related mortality, confirmed through hospital admission records and death registries. RESULTS: During a median follow-up of 11.6 years, 4,667 MASLD, 1,636 cirrhosis, 257 liver cancer, and 646 liver-related mortality cases were identified. After multivariable adjustment, the risk of MASLD was found to be higher in participants with prefrailty (physical frailty: hazard ratio [HR] 1.66, 95% CI 1.40-1.97; frailty index: HR 2.01, 95% CI 1.67-2.42) and frailty (physical frailty: HR 3.32, 95% CI 2.54-4.34; frailty index: HR 4.54, 95% CI 3.65-5.66) than in those with non-frailty. Similar results were also observed for cirrhosis, liver cancer, and liver-related mortality. Additionally, the frail groups had a higher risk of MASLD, which was defined as MRI-derived liver proton density fat fraction >5%, than the non-frail group (physical frailty: odds ratio 1.64, 95% CI 1.32-2.04; frailty index: odds ratio 1.48, 95% CI 1.30-1.68). CONCLUSIONS: Frailty was associated with an increased risk of chronic liver diseases. Public health strategies should target reducing chronic liver disease risk in frail individuals. IMPACT AND IMPLICATIONS: While frailty is common and associated with a poor prognosis in people with MASLD (metabolic dysfunction-associated steatotic liver disease) and advanced chronic liver diseases, its impact on the subsequent risk of these outcomes remains largely unexplored. Our study showed that frailty was associated with increased risks of MASLD, cirrhosis, liver cancer, and liver-related mortality. This finding suggests that assessing frailty may help identify a high-risk population vulnerable to developing chronic liver diseases. Implementing strategies that target frailty could have major public health benefits for liver-related disease prevention.

PTBP1-mediated repression of neuron-specific CDC42 splicing constitutes a genomic alteration-independent, developmentally conserved vulnerability in IDH-wildtype glioblastoma.

Gene co-expression networks may encode hitherto inadequately recognized vulnerabilities for adult gliomas. By identifying evolutionally conserved gene co-expression modules around EGFR (EM) or PDGFRA (PM), we recently proposed an EM/PM classification scheme, which assigns IDH-wildtype glioblastomas (GBM) into the EM subtype committed in neural stem cell compartment, IDH-mutant astrocytomas and oligodendrogliomas into the PM subtype committed in early oligodendrocyte lineage. Here, we report the identification of EM/PM subtype-specific gene co-expression networks and the characterization of hub gene polypyrimidine tract-binding protein 1 (PTBP1) as a genomic alteration-independent vulnerability in IDH-wildtype GBM. Supervised by the EM/PM classification scheme, we applied weighted gene co-expression network analysis to identify subtype-specific global gene co-expression modules. These gene co-expression modules were characterized for their clinical relevance, cellular origin and conserved expression pattern during brain development. Using lentiviral vector-mediated constitutive or inducible knockdown, we characterized the effects of PTBP1 on the survival of IDH-wildtype GBM cells, which was complemented with the analysis of PTBP1-depedent splicing pattern and overexpression of splicing target neuron-specific CDC42 (CDC42-N) isoform.  Transcriptomes of adult gliomas can be robustly assigned into 4 large gene co-expression modules that are prognostically relevant and are derived from either malignant cells of the EM/PM subtypes or tumor microenvironment. The EM subtype is associated with a malignant cell-intrinsic gene module involved in pre-mRNA splicing, DNA replication and damage response, and chromosome segregation, and a microenvironment-derived gene module predominantly involved in extracellular matrix organization and infiltrating immune cells. The PM subtype is associated with two malignant cell-intrinsic gene modules predominantly involved in transcriptional regulation and mRNA translation, respectively. Expression levels of these gene modules are independent prognostic factors and malignant cell-intrinsic gene modules are conserved during brain development. Focusing on the EM subtype, we identified PTBP1 as the most significant hub for the malignant cell-intrinsic gene module. PTBP1 is not altered in most glioma genomes. PTBP1 represses the conserved splicing of CDC42-N. PTBP1 knockdown or CDC42-N overexpression disrupts actin cytoskeleton dynamics, causing accumulation of reactive oxygen species and cell apoptosis. PTBP1-mediated repression of CDC42-N splicing represents a potential genomic alteration-independent, developmentally conserved vulnerability in IDH-wildtype GBM.

Combined associations of visceral adipose tissue and adherence to a Mediterranean lifestyle with T2D and diabetic microvascular complications among individuals with prediabetes.

BACKGROUND: It's unclear if excess visceral adipose tissue (VAT) mass in individuals with prediabetes can be countered by adherence to a Mediterranean lifestyle (MEDLIFE). We aimed to examine VAT mass, MEDLIFE adherence, and their impact on type 2 diabetes (T2D) and diabetic microvascular complications (DMC) in individuals with prediabetes. METHODS: 11,267 individuals with prediabetes from the UK Biobank cohort were included. VAT mass was predicted using a non-linear model, and adherence to the MEDLIFE was evaluated using the 25-item MEDLIFE index, encompassing categories such as "Mediterranean food consumption," "Mediterranean dietary habits," and "Physical activity, rest, social habits, and conviviality." Both VAT and MEDLIFE were categorized into quartiles, resulting in 16 combinations. Incident cases of T2D and related DMC were identified through clinical records. Cox proportional-hazards regression models were employed to examine associations, adjusting for potential confounding factors. RESULTS: Over a median follow-up of 13.77 years, we observed 1408 incident cases of T2D and 714 cases of any DMC. High adherence to the MEDLIFE, compared to the lowest quartile, reduced a 16% risk of incident T2D (HR: 0.84, 95% CI: 0.71-0.98) and 31% for incident DMC (0.69, 0.56-0.86). Conversely, compared to the lowest quartile of VAT, the highest quartile increased the risk of T2D (5.95, 4.72-7.49) and incident any DMC (1.79, 1.36-2.35). We observed an inverse dose-response relationship between MEDLIFE and T2D/DMC, and a dose-response relationship between VAT and all outcomes (P for trend < 0.05). Restricted cubic spline analysis confirmed a nearly linear dose-response pattern across all associations. Compared to individuals with the lowest MEDLIFE quartile and highest VAT quartile, those with the lowest T2D risk had the lowest VAT and highest MEDLIFE (0.12, 0.08-0.19). High MEDLIFE was linked to reduced T2D risk across all VAT categories, except in those with the highest VAT quartile. Similar trends were seen for DMC. CONCLUSION: High adherence to MEDLIFE reduced T2D and MDC risk in individuals with prediabetes, while high VAT mass increases it, but MEDLIFE adherence may offset VAT's risk partly. The Mediterranean lifestyle's adaptability to diverse populations suggests promise for preventing T2D.

Distinct pathway activities are associated with prognosis and response to bortezomib-containing treatment in MCL1-M based molecular subtypes of multiple myeloma.

Multiple myeloma (MM) is the second most prevalent hematological malignancy and remains incurable with remarkable heterogeneity in prognosis and treatment response across the patients. Clinical diagnosis and the existing molecular classification systems are inadequate for predicting treatment responses. Based on the convergence between plasma cell development and MM pathogenesis, we identified a gene co-expression module centered on the plasma cell survival regulator MCL1 (MCL1 module, MCL1-M) in the transcriptomes of pre-treated MM, which enabled stratification of MM patients into MCL1-M high and MCL1-M low molecular subtypes with subtype-specific prognosis and response to bortezomib-containing treatment. Here, we aimed to examine the mechanism underlying the disparate prognosis and treatment responses between the two molecular subtypes. Our findings reveal that MCL1-M high MM displays significant activation of pathways associated with cell proliferation, while MCL1-M low MM exhibits activation of immune-related signaling pathways. The relative enrichment of immune cells within the bone marrow microenvironment of MCL1-M low MM, particularly plasmacytoid dendritic cells, likely contributes to the activation of immune-related signaling pathways in this subset of myeloma cells. Using phase III trial data, we show that responses to bortezomib-containing treatment are associated with the extent of unfolded protein response (UPR) signaling activity. Further, bortezomib-mediated killing of MM cells could be enhanced or inhibited by in vitro manipulation of UPR activities in representative cell lines. In conclusion, MCL1-M based molecular subtypes of MM are characterized by distinct signaling activities from both malignant cells and bone marrow microenvironment, which may drive distinct prognosis and treatment responses.

Helicobacter pylori disrupts gastric mucosal homeostasis by stimulating macrophages to secrete CCL3.

BACKGROUND: Helicobacter pylori (H. pylori) is the predominant etiological agent of gastritis and disrupts the integrity of the gastric mucosal barrier through various pathogenic mechanisms. After H. pylori invades the gastric mucosa, it interacts with immune cells in the lamina propria. Macrophages are central players in the inflammatory response, and H. pylori stimulates them to secrete a variety of inflammatory factors, leading to the chronic damage of the gastric mucosa. Therefore, the study aims to explore the mechanism of gastric mucosal injury caused by inflammatory factors secreted by macrophages, which may provide a new mechanism for the development of H. pylori-related gastritis. METHODS: The expression and secretion of CCL3 from H. pylori infected macrophages were detected by RT-qPCR, Western blot and ELISA. The effect of H. pylori-infected macrophage culture medium and CCL3 on gastric epithelial cells tight junctions were analyzed by Western blot, immunofluorescence and transepithelial electrical resistance. EdU and apoptotic flow cytometry assays were used to detect cell proliferation and apoptosis levels. Dual-luciferase reporter assays and chromatin immunoprecipitation assays were used to study CCL3 transcription factors. Finally, gastric mucosal tissue inflammation and CCL3 expression were analyzed by hematoxylin and eosin staining and immunohistochemistry. RESULTS: After H. pylori infection, CCL3 expressed and secreted from macrophages were increased. H. pylori-infected macrophage culture medium and CCL3 disrupted gastric epithelial cells tight junctions, while CCL3 neutralizing antibody and receptor inhibitor of CCL3 improved the disruption of tight junctions between cells. In addition, H. pylori-infected macrophage culture medium and CCL3 recombinant proteins stimulated P38 phosphorylation, and P38 phosphorylation inhibitor improved the disruption of tight junctions between cells. Besides, it was identified that STAT1 was a transcription factor of CCL3 and H. pylori stimulated macrophage to secret CCL3 through the JAK1-STAT1 pathway. Finally, after mice were injected with murine CCL3 recombinant protein, the gastric mucosal injury and inflammation were aggravated, and the phosphorylation level of P38 was increased. CONCLUSIONS: In summary, our findings demonstrate that H. pylori infection stimulates macrophages to secrete CCL3 via the JAK1-STAT1 pathway. Subsequently, CCL3 damages gastric epithelial tight junctions through the phosphorylation of P38. This may be a novel mechanism of gastric mucosal injury in H. pylori-associated gastritis.

Association between plasma and dietary trace elements and obesity in a rural Chinese population.

Trace elements may play an important role in obesity. This study aimed to assess the plasma and dietary intake levels of four trace elements, Mn, Cu, Zn and Se in a rural Chinese population, and analyse the relationship between trace elements and obesity. A cross-sectional study involving 2587 participants was conducted. Logistic regression models were used to analyse the association between trace elements and obesity; restricted cubic spline (RCS) models were used to assess the dose-response relationship between trace elements and obesity; the weighted quantile sum (WQS) model was used to examine the potential interaction of four plasma trace elements on obesity. Logistic regression analysis showed that plasma Se concentrations in the fourth quartile (Q4) exhibited a lower risk of developing obesity than the first quartile (Q1) (central obesity: OR = 0·634, P = 0·002; general obesity: OR = 0·525, P = 0·005). Plasma Zn concentration in the third quartile (Q3) showed a lower risk of developing obesity in general obesity compared with the first quartile (Q1) (OR = 0·625, P = 0·036). In general obesity, the risk of morbidity was 1·727 and 1·923 times higher for the second and third (Q2, Q3) quartiles of dietary Mn intake than for Q1, respectively. RCS indicated an inverse U-shaped correlation between plasma Se and obesity. WQS revealed the combined effects of four trace elements were negatively associated with central obesity. Plasma Zn and Se were negatively associated with obesity, and dietary Mn was positively associated with obesity. The combined action of the four plasma trace elements had a negative effect on obesity.

Current research on the interaction between Helicobacter pylori and macrophages.

Helicobacter pylori (H. pylori) is a gram-negative bacteria with a worldwide infection rate of 50%, known to induce gastritis, ulcers and gastric cancer. The interplay between H. pylori and immune cells within the gastric mucosa is pivotal in the pathogenesis of H. pylori-related disease. Following H. pylori infection, there is an observed increase in gastric mucosal macrophages, which are associated with the progression of gastritis. H. pylori elicits macrophage polarization, releases cytokines, reactive oxygen species (ROS) and nitric oxide (NO) to promote inflammatory response and eliminate H. pylori. Meanwhile, H. pylori has developed mechanisms to evade the host immune response in order to maintain the persistent infection, including interference with macrophage phagocytosis and antigen presentation, as well as induction of macrophage apoptosis. Consequently, the interaction between H. pylori and macrophages can significantly impact the progression, pathogenesis, and resolution of H. pylori infection. Moreover, macrophages are emerging as potential therapeutic targets for H. pylori-associated gastritis. Therefore, elucidating the involvement of macrophages in H. pylori infection may provide novel insights into the pathogenesis, progression, and management of H. pylori-related disease.

Association between multiple-heavy-metal exposures and systemic immune inflammation in a middle-aged and elderly Chinese general population.

BACKGROUND: Exposure to heavy metals alone or in combination can promote systemic inflammation. The aim of this study was to investigate potential associations between multiple plasma heavy metals and markers of systemic immune inflammation. METHODS: Using a cross-sectional study, routine blood tests were performed on 3355 participants in Guangxi, China. Eight heavy metal elements in plasma were determined by inductively coupled plasma mass spectrometry. Immunoinflammatory markers were calculated based on peripheral blood WBC and its subtype counts. A generalised linear regression model was used to analyse the association of each metal with the immunoinflammatory markers, and the association of the metal mixtures with the immunoinflammatory markers was further assessed using weighted quantile sum (WQS) regression. RESULTS: In the single-metal model, plasma metal Fe (log10) was significantly negatively correlated with the levels of immune-inflammatory markers SII, NLR and PLR, and plasma metal Cu (log10) was significantly positively correlated with the levels of immune-inflammatory markers SII and PLR. In addition, plasma metal Mn (log10 conversion) was positively correlated with the levels of immune inflammatory markers NLR and PLR. The above associations remained after multiple corrections. In the mixed-metal model, after WQS regression analysis, plasma metal Cu was found to have the greatest weight in the positive effects of metal mixtures on SII and PLR, while plasma metals Mn and Fe had the greatest weight in the positive effects of metal mixtures on NLR and LMR, respectively. In addition, blood Fe had the greatest weight in the negative effects of the metal mixtures for SII, PLR and NLR. CONCLUSION: Plasma metals Cu and Mn were positively correlated with immunoinflammatory markers SII, NLR and PLR. While plasma metal Fe was negatively correlated with immunoinflammatory markers SII, NLR, and PLR.

[Effects of plumbagin on proliferation and apoptosis of human hepatocellular carcinoma cells based on CKB/p53 signaling pathway].

To investigate the effects of plumbagin on the proliferation and apoptosis of human hepatoma Huh-7 cells and its mechanism based on the creatine kinase B(CKB)/p53 signaling pathway. Huh-7 cells were treated with plumbagin from 1 to 12 µmol·L~(-1) for cell counting kit-8(CCK-8) assay, and 1, 3, and 6 µmol·L~(-1) were determined as low, medium, and high concentrations of plumbagin for subsequent experiments. CKB gene was knocked out in Huh-7 cells by clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated proteins(Cas)-9 gene editing technology. CKB overexpression lentivirus was transfected into Huh-7 cells to up-regulate the expression of CKB. Cell proliferation and apoptosis were detected by plate cloning assay and flow cytometry. The mRNA expression of CKB was detected by quantitative real-time PCR(qRT-PCR). CKB, p53, mouse double minute 2 homolog(MDM2), B-cell lymphoma 2(Bcl-2), Bcl-2 associated X protein(Bax), and caspase-3 protein were detected by Western blot(WB). The results showed that plumbagin significantly inhibited the proliferation of Huh-7 cells and induced cell apoptosis. Compared with the control group, the apoptosis level was significantly increased in the plumbagin group, while the apoptosis level was significantly decreased in the plumbagin combined with the apoptosis inhibitor group. Plumbagin significantly down-regulated the protein expression levels of CKB, Bcl-2, and MDM2 and up-regulated the protein expression levels of p53, Bax, and caspase-3. Knockdown of the CKB gene decreased the proliferative ability of Huh-7 cells, increased the apoptotic rate, decreased the expression levels of Bcl-2 and MDM2 proteins, and increased the expression levels of p53, Bax, and caspase-3 proteins. After up-regulation of CKB expression, the proliferation ability of Huh-7 cells was enhanced, and the protein expression levels of Bcl-2 and MDM2 were elevated. The protein expression levels of p53, Bax, and caspase-3 were decreased. In addition, plumbagin reversed the effect of overexpression of CKB on the proliferation and apoptosis of Huh-7 cells. In conclusion, plumbagin significantly inhibited the proliferative ability of Huh-7 cells, and the mechanism may be related to the inhibition of CKB expression, activation of the p53 signaling pathway, and regulation of the expression of mitochondrial-associated apoptotic proteins, ultimately inducing cell apoptosis.

Leveraging a disulfidptosis­related lncRNAs signature for predicting the prognosis and immunotherapy of glioma.

BACKGROUND: Gliomas, a prevalent form of primary brain tumors, are linked with a high mortality rate and unfavorable prognoses. Disulfidptosis, an innovative form of programmed cell death, has received scant attention concerning disulfidptosis-related lncRNAs (DRLs). The objective of this investigation was to ascertain a prognostic signature utilizing DRLs to forecast the prognosis and treatment targets of glioma patients. METHODS: RNA-seq data were procured from The Cancer Genome Atlas database. Disulfidptosis-related genes were compiled from prior research. An analysis of multivariate Cox regression and the least absolute selection operator was used to construct a risk model using six DRLs. The risk signature's performance was evaluated via Kaplan-Meier survival curves and receiver operating characteristic curves. Additionally, functional analysis was carried out using GO, KEGG, and single-sample GSEA to investigate the biological functions and immune infiltration. The research also evaluated tumor mutational burden, therapeutic drug sensitivity, and consensus cluster analysis. Reverse transcription quantitative PCR was conducted to validate the expression level of DRLs. RESULTS: A prognostic signature comprising six DRLs was developed to predict the prognosis of glioma patients. High-risk patients had significantly shorter overall survival than low-risk patients. The robustness of the risk model was validated by receiver operating characteristic curves and subgroup survival analysis. Risk model was used independently as a prognostic indicator for the glioma patients. Notably, the low-risk patients displayed a substantial decrease in the immune checkpoints, the proportion of immune cells, ESTIMATE and immune score. IC50 values from the different risk groups allowed us to discern three drugs for the treatment of glioma patients. Lastly, the potential clinical significance of six DRLs was determined. CONCLUSIONS: A novel six DRLs signature was developed to predict prognosis and may provide valuable insights for patients with glioma seeking novel immunotherapy and targeted therapy.

Plumbagin Exhibits Genotoxicity and Induces G2/M Cell Cycle Arrest via ROS-Mediated Oxidative Stress and Activation of ATM-p53 Signaling Pathway in Hepatocellular Cells.

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone, PLB), a naturally occurring naphthoquinone mainly isolated from the plant Plumbago zeylanica L., has been proven to possess anticancer activities towards multiple types of cancer. Although there has been an increasing amount of research regarding its anticancer effects, the association between oxidative stress, genotoxicity and the cell cycle arrest induced by PLB still remains unclear. Therefore, it is important to investigate their potential connections and the involvement of DNA damage and the ataxia telangiectasia mutated protein (ATM)-p53 signaling pathway in PLB's anticancer mechanism. The present study showed that PLB exposure significantly reduced HCC cell viability and colony formation. In addition, PLB-induced G2/M cell cycle arrest, oxidative stress, and DNA damage was detected, which could be almost blocked by NAC pretreatment. PLB could trigger a DNA damage response by activating cell cycle checkpoints such as ATM, checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2) and p53. Meanwhile, the key modulator of the G2/M transition factor, Cell Division Cycle 25C (cdc25C), was significantly downregulated in an ROS-dependent manner. Furthermore, pretreatment with ATM and p53 inhibitors (KU55933 and Pifithrin-α) could reduce the occurrence of G2/M cell cycle arrest by inhibiting the activation of the ATM-p53 pathway. Taken together, these results indicate that ROS-mediated oxidative stress plays a key role in PLB-induced G2/M cell cycle arrest mediated by the ATM-p53 pathway.

Increased expression of pathological markers in Parkinson's disease dementia post-mortem brains compared to dementia with Lewy bodies.

BACKGROUND: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking. METHODS: Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls. RESULTS: We found that p-APPT668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aß42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB. CONCLUSIONS: Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level.

Association between combined exposure to plasma heavy metals and dyslipidemia in a chinese population.

BACKGROUND: Exposure to heavy metals in the environment is widespread, while the relationship between combined exposure to heavy metals and dyslipidemia is unclear. METHODS: A cross-sectional study was performed, and 3544 participants aged 30 years or older were included in the analyses. Heavy metal concentrations in plasma were based on inductively coupled plasma‒mass spectrometry. The relationship between heavy metals and dyslipidemia was estimated by logistic regression. BKMR was used to evaluate metal mixtures and their potential interactions. RESULTS: In logistic regression analysis, participants in the fourth quartile of Fe and Zn (Fe > 1352.38 µg/L; Zn > 4401.42 µg/L) had a relatively higher risk of dyslipidemia (Fe, OR = 1.13, 95% CI: 0.92,1.38; Zn, OR = 1.30, 95% CI: 1.03,1.64). After sex stratification, females in the third quartile of plasma Zn (1062.05-4401.42 µg/L) had a higher relative risk of dyslipidemia (OR = 1.75, 95% CI: 1.28, 2.38). In BKMR analysis, metal mixtures were negatively associated with dyslipidemia in females when all metal concentrations were above the 50th percentile. In the total population (estimated from 0.030 to 0.031), As was positively associated with dyslipidemia when other metals were controlled at the 25th, 50th, or 75th percentile, respectively, and As was below the 75th percentile. In females (estimated from - 0.037 to -0.031), Zn was negatively associated with dyslipidemia when it was above the 50th percentile. CONCLUSION: This study indicated that As was positively associated with dyslipidemia and that Zn may be negatively associated with dyslipidemia in females. Combined metal exposure was negatively associated with dyslipidemia in females. Females with low plasma Zn levels are more likely to develop dyslipidemia and should receive more clinical attention in this population.

Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma.

Genomic instability (GI) drives tumor heterogeneity and promotes tumor progression and therapy resistance. However, causative factors underlying GI and means for clinical detection of GI in glioma are inadequately identified. We describe here that elevated expression of a gene module coexpressed with CDC20 (CDC20-M), the activator of the anaphase-promoting complex in the cell cycle, marks GI in glioma. The CDC20-M, containing 139 members involved in cell proliferation, DNA damage response, and chromosome segregation, was found to be consistently coexpressed in glioma transcriptomes. The coexpression of these genes was conserved across multiple species and organ systems, particularly in human neural stem and progenitor cells. CDC20-M expression was not correlated with the morphological subtypes, nor with the recently defined molecular subtypes of glioma. CDC20-M signature was an independent and robust predictor for poorer prognosis in over 1,000 patients from four large databases. Elevated CDC20-M signature enabled the identification of individual glioma samples with severe chromosome instability and mutation burden and of primary glioma cell lines with extensive mitotic errors leading to chromosome mis-segregation. AURKA, a core member of CDC20-M, was amplified in one-third of CDC20-M-high gliomas with gene-dosage-dependent expression. MLN8237, a Food and Drug Administration-approved AURKA inhibitor, selectively killed temozolomide-resistant primary glioma cells in vitro and prolonged the survival of a patient-derived xenograft mouse model with a high-CDC20-M signature. Our findings suggest that application of the CDC20-M signature may permit more selective use of adjuvant therapies for glioma patients and that dysregulated CDC20-M members may provide a therapeutic vulnerability in glioma.

Modeling of High-Power Tonpilz Terfenol-D Transducer Using Complex Material Parameters.

The loss effect in smart materials, the active part of a transducer, is of significant importance to acoustic transducer designers, as it directly affects the important characteristics of the transducer, such as the impedance spectra, frequency response, and the amount of heat generated. It is therefore beneficial to be able to incorporate energy losses in the design phase. For high-power low-frequency transducers requiring more smart materials, losses become even more appreciable. In this paper, similar to piezoelectric materials, three losses in Terfenol-D are considered by introducing complex quantities, representing the elastic loss, piezomagnetic loss, and magnetic loss. The frequency-dependent eddy current loss is also considered and incorporated into the complex permeability of giant magnetostrictive materials. These complex material parameters are then successfully applied to improve the popular plane-wave method (PWM) circuit model and finite element method (FEM) model. To verify the accuracy and effectiveness of the proposed methods, a high-power Tonpilz Terfenol-D transducer with a resonance frequency of around 1 kHz and a maximum transmitting current response (TCR) of 187 dB/1A/µPa is manufactured and tested. The good agreement between the simulation and experimental results validates the improved PWM circuit model and FEA model, which may shed light on the more predictable design of high-power giant magnetostrictive transducers in the future.

Correlation between urinary contents of some metals and fasting plasma glucose levels: A cross-sectional study in China.

Many metals are involved in the pathogenesis of diabetes, but most of existing studies focused on single metals. The study of mixtures represents real-life exposure scenarios and deserves attention. This study aimed to explore the potential relationship of urinary copper (Cu), zinc (Zn), arsenic (As), selenium (Se), and strontium (Sr) contents with fasting plasma glucose (FPG) levels in 2766 participants. The levels of metals in urine were determined by inductively coupled plasma-mass spectrometry. We used linear regression models and the Bayesian kernel machine regression (BKMR) to evaluate the association between metals and FPG levels. In the multiple metals linear regression, Zn (ß = 0.434), Se (ß = 0.172), and Sr (ß = -0.143) showed significant association with FPG levels (all P < 0.05). The BKMR model analysis showed that the results of single metal association were consistent with the multiple metals linear regression. The mixture of five metals had a positive over-all effect on FPG levels, and Zn (PIP = 1.000) contributed the most to the FPG levels. Cu and As were negatively correlated with FPG levels in women. The potential interaction effect between Cu and Sr was observed in participants aged ≥ 60 years old (Pinteraction = 0.035). In summary, our results suggested that multiple metals in urine are associated with FPG levels. Further studies are needed to confirm these findings and clarify the underlying mechanisms.

Plumbagin induces autophagy and apoptosis of SMMC-7721 cells in vitro and in vivo.

Plumbagin (PL), an active naphthoquinone compound, has been demonstrated to be a potential anticancer agent. However, the underlying anticancer mechanism is not fully understood. In this study, the human hepatocellular carcinoma (HCC) SMMC-7721 cell line was studied in an in vitro model. The cell proliferation was inhibited by PL in a dose- and time-dependent manner. Electron microscopy, acridine orange staining, and immunofluorescence were used to evaluate autophagosome formation and LC3 protein expression in PL-treated SMMC-7721 cells. Real-time polymerase chain reaction and Western blot showed that PL treatment suppressed the expression of apoptosis and autophagy factors (LC3, Beclin1, Atg7, and Atg5), which are associated with tumor apoptosis and autophagy in SMMC-7721 cells. In the study of in vitro tumor nude mouse models, PL can inhibit tumor growth. Cell apoptosis and autophagy of the transplanted tumors were evaluated by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, and Western blot. In addition, in the in vivo studies of HCC cells, we found that pretreatment with the autophagy inhibitor 3-methyladenine blocked the formation of apoptosis induced by PL. In contrast, administration of the apoptosis inhibitor Z-VAD did not affect PL-induced autophagy. Taken together, our findings strongly suggest that PL is a promising drug with significant antitumor activity in HCC.

Plumbagin Restrains Hepatocellular Carcinoma Angiogenesis by Stromal Cell-Derived Factor (SDF-1)/CXCR4-CXCR7 Axis.

BACKGROUND Anti-angiogenic therapy has recently emerged as a highly promising therapeutic strategy for treating hepatocellular carcinoma (HCC). MATERIAL AND METHODS We assessed cellular proliferation, invasion, and activation of growth factors (VEGF and IL-8) with SDF-1 induced in the hepatocellular carcinoma cell line SMMC-7721, and this progression was limited by plumbagin (PL). The human umbilical vein endothelial cell line HUVEC was co-cultured with SDF-1-induced SMMC-7721, and the expressions of CXCR7, CXCR4, and PI3K/Akt pathways after PL treatment were detected by RT-PCR and Western blot analysis. RESULTS The treatment of the hepatoma cell line SMMC-7721 with SDF-1 resulted in enhanced secretion of the angiogenic factors, IL-8 and VEGF, and shows that these stimulatory effects are abolished by PL. The study further demonstrated that PL not only abolishes SDF-1-induced formation of endothelial tubes, but also inhibits expression of CXCR4 and CXCR7, and partially prevents activation of angiogenic signaling pathways. CONCLUSIONS The effect of PL on the SDF-1-CXCR4/CXCR7 axis has become an attractive target for inhibiting angiogenesis in hepatoma cells. Our results provide more evidence for the clinical application of PL as part of traditional Chinese medicine in modern cancer treatment.