The application of nanomaterials in tumor therapy based on the regulation of mechanical properties.

Mechanical properties, as crucial physical properties, have a significant impact on the occurrence, development, and metastasis of tumors. Regulating the mechanical properties of tumors to enhance their sensitivity to radiotherapy and chemotherapy has become an important strategy in the field of cancer treatment. Over the past few decades, nanomaterials have made remarkable progress in cancer therapy, either based on their intrinsic properties or as drug delivery carriers. However, the investigation of nanomaterials of mechanical regulation in tumor therapy is currently in its initial stages. The mechanical properties of nanomaterials themselves, drug carrier targeting, and regulation of the mechanical environment of tumor tissue have far-reaching effects on the efficient uptake of drugs and clinical tumor treatment. Therefore, this review aims to comprehensively summarize the applications and research progress of nanomaterials in tumor therapy based on the regulation of mechanical properties, in order to provide strong support for further research and the development of treatment strategies in this field.

Immune Regulation Patterns in Response to Environmental Pollutant Chromate Exposure-Related Genetic Damage: A Cross-Sectional Study Applying Machine Learning Methods.

Exposure to hexavalent chromium damages genetic materials like DNA and chromosomes, further elevating cancer risk, yet research rarely focuses on related immunological mechanisms, which play an important role in the occurrence and development of cancer. We investigated the association between blood chromium (Cr) levels and genetic damage biomarkers as well as the immune regulatory mechanism involved, such as costimulatory molecules, in 120 workers exposed to chromates. Higher blood Cr levels were linearly correlated with higher genetic damage, reflected by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and blood micronucleus frequency (MNF). Exploratory factor analysis revealed that both positive and negative immune regulation patterns were positively associated with blood Cr. Specifically, higher levels of programmed cell death protein 1 (PD-1; mediated proportion: 4.12%), programmed cell death ligand 1 (PD-L1; 5.22%), lymphocyte activation gene 3 (LAG-3; 2.11%), and their constitutive positive immune regulation pattern (5.86%) indirectly positively influenced the relationship between blood Cr and urinary 8-OHdG. NOD-like receptor family pyrin domain containing 3 (NLRP3) positively affected the association between blood Cr levels and inflammatory immunity. This study, using machine learning, investigated immune regulation and its potential role in chromate-induced genetic damage, providing insights into complex relationships and emphasizing the need for further research.

Relationships between blood chromium exposure and liver injury: Exploring the mediating role of systemic inflammation in a chromate-exposed population.

Hexavalent chromium and its compounds are prevalent pollutants, especially in the work environment, pose a significant risk for multisystem toxicity and cancers. While it is known that chromium accumulation in the liver can cause damage, the dose-response relationship between blood chromium (Cr) and liver injury, as well as the possible potential toxic mechanisms involved, remains poorly understood. To address this, we conducted a follow-up study of 590 visits from 305 participants to investigate the associations of blood Cr with biomarkers for liver injury, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL), and to evaluate the mediating effects of systemic inflammation. Platelet (PLT) and the platelet-to-lymphocyte ratio (PLR) were utilized as biomarkers of systemic inflammation. In the linear mixed-effects analyses, each 1-unit increase in blood Cr level was associated with estimated effect percentage increases of 0.82% (0.11%, 1.53%) in TBIL, 1.67% (0.06%, 3.28%) in DBIL, 0.73% (0.04%, 1.43%) in ALT and 2.08% (0.29%, 3.87%) in AST, respectively. Furthermore, PLT mediated 10.04%, 11.35%, and 10.77% increases in TBIL, DBIL, and ALT levels induced by chromate, respectively. In addition, PLR mediated 8.26% and 15.58% of the association between blood Cr and TBIL or ALT. These findings shed light on the mechanisms underlying blood Cr-induced liver injury, which is partly due to worsening systemic inflammation.

Potential mechanisms of lung injury and repair after hexavalent chromium [Cr(VI)] aerosol whole-body dynamic exposure.

Hexavalent chromium [Cr(VI)], known as "Top Hazardous Substances", poses a significant threat to the respiratory system. Nevertheless, the potential mechanisms of toxicity and the lung's repair ability after injury remain incompletely understood. In this study, Cr(VI) aerosol whole-body dynamic exposure system simulating real exposure scenarios of chromate workers was constructed to evaluate the lung injury and repair effects. Subsequently, miRNA sequencing, mRNA sequencing and metabolomics analyses on lung tissue were performed to explore the underlying mechanisms. Our results revealed that Cr(VI) exposure led to an increase in lactic dehydrogenase activity and a time-dependent decline in lung function. Notably, after 13 w of Cr(VI) exposure, alveolar hemorrhage, thickening of alveolar walls, emphysema-like changes, mitochondrial damage of alveolar epithelial cells and macrophage polarization changes were observed. Remarkably, a two-week repair intervention effectively ameliorated lung function decline and pulmonary injury. Furthermore, significant disruptions in the expressions of miRNAs and mRNAs involved in oxidative phosphorylation, glycerophospholipid metabolism and inflammatory signaling pathways were found. The two-week repair period resulted in the reversal of expression of oxidative phosphorylation related genes, and inhibited the inflammatory signaling pathways. This study concluded that the inhibition of the mitochondrial oxidative phosphorylation pathway and the subsequent enhancement of inflammatory response might be key mechanisms underlying Cr(VI) pulmonary toxicity, and timely cessation of exposure could effectively alleviate the pulmonary injury. These findings shed light on the potential mechanisms of Cr(VI) toxicity and provide crucial insights into the health protection for occupational populations exposed to Cr(VI).

A CaCO3-based nanoplatform with sonodynamic and tumor microenvironment activated for combined in vitro cancer therapy.

INTRODUCTION: Sonodynamic therapy (SDT) has potential clinical applications for cancer therapy, and is yet restricted by complex tumor microenvironmental (TME) factors. Thus, the research problem of TME modulation as well as efficient tumor treatment still needs to be clarified. METHOD: In this study, a calcium carbonate (CaCO3) nanoplatform was designed for ultrasound (US) and TME response-triggered, which encapsulated Ag2S and loaded with l-Arg, and further wrapped with RBC/Platelet membrane, named as QD@Ca/ML-Arg. RESULTS: Non-invasive US-triggered SDT by Ag2S and acidic environment-responsive drug release were achieved. In vitro experiments validated the efficacy of SDT, Ca-ion interference and nitric oxide (NO) gas therapy as combined therapy for cancer treatment. By means of RNA sequencing, the cancer therapeutic mechanism of SDT in redox-related pathways was elucidated. The immunosuppressive TME was simulated with a M2-macrophage/cancer cell co-culture system to confirm the immune activating effect of immunogenic cell death (ICD). CONCLUSION: Accordingly, the potential of QD@Ca/ML-Arg-was demonstrated for in vitro TME modulation, cancer therapeutic efficacy and clinical translation.

Effect of cadmium stress on the bacterial community in the rhizosphere of mulberry (Morus alba L.).

Mulberry has a good tolerance to cadmium (Cd) and is considered a candidate plant for phytoremediation. The rhizosphere microbial community plays an important role in phytoremediation. Nevertheless, little information on the rhizosphere microbial community mechanisms in mulberry during the phytoremediation of Cd-contaminated soil is available. In this study, the remediation efficiency of mulberry in pots subjected to three simulated Cd pollution levels and their rhizosphere bacterial communities during the remediation process were analyzed. "Yuesang 11" was used as the test mulberry variety, and three simulated Cd pollution levels were set by adding three concentrations of Cd (Cd5, 5 mg kg-1; Cd3, 3 mg kg-1; Cd2, 2 mg kg-1). The results showed that the elimination rates of Cd in the rhizosphere soil were 81.7%, 85.3%, and 57.9% under the stress of the Cd2, Cd3, and Cd5 conditions, respectively. Meanwhile, 3,082,583 high-quality sequence reads and 976 operational taxonomic units were successfully obtained from the mulberry rhizosphere soil by high-throughput absolute quantification sequencing and further assigned to 11 bacterial phyla and 26 families. Of these, decreased abundances of 19 bacteria at the family level and increased abundances of seven bacteria under Cd stress were revealed by comparative analysis. Based on the alpha diversity indices (Chaol, Shannon and Simpson) and principal component analysis, the rhizosphere bacterial diversity of the Cd5 condition was significantly decreased, but that of the Cd2 and Cd3 conditions was not different from that of soil without Cd (CK). Likewise, redundancy analysis showed that the abundances of Acidobacteria Gp2, Acidobacteria Gp13, and Sphingobacteria were significantly positively associated with the elimination rates of Cd. This study suggested that the mulberry rhizosphere contains a relatively stable bacterial community consisting of diverse Cd-resistant bacteria, providing a scientific basis for remediating heavy-metal polluted soils using mulberry.

From WSI-level to patch-level: Structure prior-guided binuclear cell fine-grained detection.

Accurate and quick binuclear cell (BC) detection plays a significant role in predicting the risk of leukemia and other malignant tumors. However, manual counting of BCs using microscope images is time consuming and subjective. Moreover, traditional image processing approaches perform poorly due to the limitations in staining quality and the diversity of morphological features in binuclear cell (BC) microscopy whole-slide images (WSIs). To overcome this challenge, we propose a multi-task method inspired by the structure prior of BCs based on deep learning, which cascades to implement BC coarse detection at the WSI level and fine-grained classification at the patch level. The coarse detection network is a multitask detection framework based on circular bounding boxes for cell detection and central key points for nucleus detection. Circle representation reduces the degrees of freedom, mitigates the effect of surrounding impurities compared to usual rectangular boxes and can be rotation invariant in WSIs. Detecting key points in the nucleus can assist in network perception and be used for unsupervised color layer segmentation in later fine-grained classification. The fine classification network consists of a background region suppression module based on color layer mask supervision and a key region selection module based on a transformer due to its global modeling capability. Additionally, an unsupervised and unpaired cytoplasm generator network is first proposed to expand the long-tailed distribution dataset. Finally, experiments are performed on BC multicenter datasets. The proposed BC fine detection method outperforms other benchmarks in almost all evaluation criteria, providing clarification and support for tasks such as cancer screenings.

Evaluation of surgical placement accuracy of customized CAD/CAM titanium mesh using screws-position-guided template: A retrospective comparative study.

BACKGROUND: Customized computer-aided-design/computer-aided-manufacturing (CAD/CAM) titanium meshes have been adopted for alveolar bone augmentation. But the inaccuracies between planned and created bone volume/contour are quite common, and the surgical placement of the customized mesh was considered as the first critical factor. However, the evaluation of surgical placement accuracy of customized mesh is currently lacking. PURPOSE: The aim of this study was to evaluate the accuracy of the surgical placement of customized meshes. METHODS: A total of 30 cases, 20 without the screws-position-guided template and 10 with the screws-position-guided template, were included in this study. The cone beam CT (CBCT) data sets of pre- and postoperative were converted into 3D models and digitally aligned. Then the actual placement of customized mesh and retainer titanium screws was compared to the virtual one to assess the surgical placement accuracy of customized mesh. At least 6 months after surgery, a new CBCT was taken and converted into 3D models. Planned bone volume, created bone volume, vertical bone augmentation, healing complications rate, pseudo-periosteum rate, exposure rate, and infection rate were all evaluated. RESULTS: The 3D digital reconstruction/registration analysis showed that the average difference between actual placement and planned one of customized mesh in positive and negative directions was 2.69 ± 0.70 mm and -1.41 ± 0.90 mm, respectively, without the screws-position-guided template. And the mean difference values between the actual and planned placement of the screws on the X and Y axes were 0.74 ± 0.85 mm and 0.89 ± 0.84 mm. In contrast, with the screws-position-guided template, the results were 2.38 ± 0.69 mm and -1.30 ± 1.13 mm. Accordingly, the mean difference values of screws were 0.76 ± 0.84 mm and 0.94 ± 0.72 mm. There was no statistical difference between the two groups, and the noninferiority of the control group compared to the test group was also confirmed by the comparative analysis. CONCLUSION: It can be concluded that there is a certain deviation between the planned surgical placement and actual one of customized mesh, and using screws-position-guided template is of limited help for its accurate placement. Further research is needed to achieve precise surgical placement of the customized mesh to achieve precise alveolar bone augmentation.

Relationship between systemic inflammation and lung injury induced by chromate exposure: A cross-sectional study in workers.

Hexavalent chromium [Cr(VI)] compounds, known as "Group I Human Carcinogen" and "Category I Respiratory Sensitizer", posed great challenges to the respiratory system. A cross-sectional study was undertaken among chromate workers. Serum club cell protein 16 (CC16) and soluble urokinase-type plasminogen activator receptor (suPAR) were measured using ELISA. Thirteen macrophage-related mediators were tested using cytometric bead array. After controlling for sex, age, smoking status, drinking status and BMI, each increase of one-unit of Ln-transformed blood Cr was related to the increase of IL-1beta [Beta (95% CI), 7.22(1.14, 13.29)%, P = 0.021], IL-23 [8.5(1.15, 15.85)%, P = 0.021], IFN-gamma [3.14(0.15, 6.13)%, P = 0.040], and suPAR [9.31(2.5, 16.12) %, P = 0.008], as well as the increase of CC16 by 3.88(0.42, 7.34) % (P = 0.029). Moreover, these inflammatory mediators played an mediation role in the rise of CC16 caused by Cr(VI). The exposure-response curve analysis revealed a substantial nonlinear association of IFN-gamma and suPAR with CC16, thus the mediation effect of INF-gamma and suPAR required cautious interpretation. The positive connection between macrophage-related mediators was stronger in the high exposure group than in the low exposure group, suggesting that high concentration of chromate might promote a complex interplay within the immune system.

Two-week repair alleviates hexavalent chromium-induced hepatotoxicity, hepatic metabolic and gut microbial changes: A dynamic inhalation exposure model in male mice.

Hexavalent chromium [Cr(VI)] has been identified as a "Group I human carcinogen" with multisystem and multiorgan toxicity. A dynamic inhalation exposure model in male mice, coupled with the hepatic metabolome and gut microbiome, was used to explore hepatotoxicity, and hepatic metabolic and gut microbial changes under the exposure scenarios in the workspace and general environment. The present study set up an exposure group (EXP) that inhaled 150 µg Cr/m3 for 13 weeks, a control group (CONT) that inhaled purified air, as well as a two-week repair group (REXP) after 13 weeks of exposure and the corresponding control group (RCONT). Cr(VI) induced elevation of hepatic Cr accumulation, the ratio of ALT and AST, and folate in serum. Inflammatory infiltration in the liver and abnormal mitochondria in hepatocytes were also induced by Cr(VI). Glutathione, ascorbate, folic acid, pantetheine, 3'-dephospho-CoA and citraconic acid were the key metabolites affected by Cr(VI) that were associated with significant pathways such as pantothenate and CoA biosynthesis, hypoxia-inducible factor-1 signaling pathway, antifolate resistance, alpha-linolenic acid metabolism and one carbon pool by folate. g_Allobaculum was identified as a sensitive biomarker of Cr(VI) exposure because g_Allobaculum decreased under Cr(VI) exposure but increased after repair. The gut microbiota might be involved in the compensation of hepatotoxicity by increasing short-chain fatty acid-producing bacteria, including g_Lachnospiraceae_NK4A136_group, g_Blautia, and f_Muribaculaceae. After the two-week repair, the differential metabolites between the exposed and control groups were reduced from 73 to 29, and the KEGG enrichment pathways and differential microbiota also decreased. The mechanism for repair was associated with reversion of lipid peroxidation and energy metabolism, as well as activation of protective metabolic pathways, such as the AMPK signaling pathway, longevity regulating pathway, and oxidative phosphorylation. These findings might have theoretical and practical implications for better health risk assessment and management.

Genetic damage and potential mechanism exploration under different air pollution patterns by multi-omics.

Ambient air pollution was classified as carcinogenic to humans (Group 1) for lung cancer. DNA damage was an important first step in the process of carcinogenesis, and could also be induced by air pollution. In this study, intratracheal instillation and real-time air exposure system were combined to establish SHP (short-term high-level PM2.5) and LLPO (long-term low-level PM2.5 and O3) exposure patterns, respectively. Hierarchical levels of genetic biomarkers were analyzed to explore DNA damage effects in rats. Representative DNA repair genes from different repair pathways were selected to explore the relative expression levels. The methylation level of differentially expressed repair genes were also determined. Besides, miRNA sequencing and non-targeted metabolomic analysis were performed in rat lungs. KEGG and multi-omics analysis were used to explore the potential mechanism of genetic damage under different air pollution patterns. We found that LLPO exposure induced DSBs and chromosome damage. SHP exposure could induce DSBs and DNA oxidative damage, and the effects of genetic damage under this pollution pattern could be repaired by natural repair. Repair genes involved in two pattern were different. SHP exposure could induce higher methylation levels of RAD51, which might be a potential epigenetic mechanism for high-level PM2.5 induced down-regulated expression of RAD51 and DSBs. Besides, 29 overlapped alterations in metabolic pathways were identified by metabolomic and miRNA sequencing, including purine metabolism and pyrimidine metabolism after LLPO exposure. Differential miRNAs expression in lung tissue were associated with apoptosis, DNA damage and damage repair. We concluded that under different air pollution patterns, DNA damage biomarkers and activated targets of DNA damage repair network were both different. The genetic damage effects caused by high-level short-term PM2.5 can be alleviated by natural repair. We provided possible mechanisms by multi-omics which could explain the increased carcinogenic risk caused by air pollution.

DNA damage, serum metabolomic alteration and carcinogenic risk associated with low-level air pollution.

Outdoor air pollution has been classified as carcinogenic to humans (Group 1) for lung cancer, but the underlying mechanism and key toxic components remain incompletely understood. Since DNA damage and metabolite alterations are associated with cancer progression, exploring potential mechanisms linking air pollution and cancer might be meaningful. In this study, a real-time ambient air exposure system was established to simulate the real-world environment of adult male SD rats in Beijing from June 13th, 2018, to October 8th, 2018. 8-OHdG in the urine, γ-H2AX in the lungs and mtDNA copy number in the peripheral blood were analyzed to explore DNA damage at different levels. Serum non-targeted metabolomics analysis was performed. Pair-wise spearman was used to explore the correlation between DNA damage biomarkers and serum differential metabolites. Carcinogenic risks of heavy metals and PAHs via inhalation were assessed according to US EPA guidelines. Results showed that PM2.5 and O3 were the major air pollutants in the exposure group and not detected in the control group. Compared with control group, higher levels of 8-OHdG, mtDNA copy number, γ-H2AX and PCNA-positive nuclei cells were observed in the exposure group. Histopathological evaluation suggested ambient air induced alveolar wall thickening and inflammatory cell infiltration in lungs. Perturbed metabolic pathways identified included glycolysis/gluconeogenesis metabolism, purine and pyrimidine metabolism, etc. γ-H2AX was positively correlated with serum ADP, 3-phospho-D-glyceroyl phosphate and N-acetyl-D-glucosamine. The BaPeq was 0.120 ng/m3. Risks of Cr(VI), As, V, BaP, BaA and BbF were above 1 × 10-6. We concluded that low-level air pollution was associated with DNA damage and serum metabolomic alterations in rats. Cr(VI) and BaP were identified as key carcinogenic components in PM2.5. Our results provided experimental evidence for hazard identification and risk assessment of low-level air pollution.

Blood chromium exposure, immune inflammation and genetic damage: Exploring associations and mediation effects in chromate exposed population.

Both genetic damage and inappropriate immune function are relevant to cancer of hexavalent chromium [Cr(VI)]. However, its associations with immune response and genetic damage development are poorly understood. To explore their associations and mediating effects, 1249 participants were included from the Occupational Chromate Exposure Dynamic Cohort, and their blood Cr concentrations were measured as internal exposure. A set of biomarkers including urinary 8-hydroxy-2' - deoxyguanosine (8-OHdG), micronucleus frequency (MNF) and mitochondrial DNA copy number (mtCN) was developed to evaluate the landscape of genetic damage of Cr(VI). Serum C-reactive protein (CRP) and first component of complement q (C1q) were measured to reflect immune inflammation. Multivariate linear regression and mediation analyses were applied to assess the potential associations and mediation effects. It was found that blood Cr level showed significant dose-dependent relationships with increasing of MNF and urinary 8-OHdG, while negative association with CRP and C1q. Furthermore, a 1-unit increase in CRP was associated with decreases of - 0.765 to - 0.254 in MNF, - 0.400 to - 0.051 in urinary 8-OHdG. 4.97% of the association between blood Cr level and the increased MNF was mediated by CRP. 11.58% of the relationship between concentration of blood Cr and urinary 8-OHdG was mediated by C1q. These findings suggested that Cr(VI) exposures might prompt genetic damage, possibly partial via worsening immune inflammation.

Analysis of serum metabolome of workers occupationally exposed to hexavalent chromium: A preliminary study.

Hexavalent chromium (Cr(VI)) compound is considered as a common environmental and occupational pollutant due to widespread application in industry and agriculture. Cr(VI) as a carcinogen poses a serious threat to human health and the underlying mechanisms need further investigation. Previous studies had demonstrated the characteristic expression profiling after Cr(VI) treatment in vitro and in vivo at the levels of gene and protein. The comprehensive metabolic signatures were also conducive to discover potential biomarkers for effects assessment of Cr(VI) toxicity. In the current study, Ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) non-targeted metabolomics was applied to analyze serum metabolic changes in 77 chromate exposure workers and 62 controls. Thirteen metabolites were found significantly decreased and 41 metabolites were increased, which were involved in arginine and proline metabolism, and glycerophospholipid metabolism by bioinformatic analysis. Furthermore, there were significant negative correlations between blood Cr level and Arginine, PC(18:2/24:4) and PC(14:0/16:0), subgroup analyses indicated that these correlations were observed in male-only subgroups, and were not found among chromate workers and controls separately. Diet could be a potential confounder which was not controlled rigorously in this study. These findings provided preliminary clues to investigate the underlying mechanisms of Cr(VI)-induced toxicity and were required to be further verified in future researches.

The Effect of Global DNA Methylation on PDCD5 Expression in the PBMC of Occupational Chromate Exposed Workers.

OBJECTIVES: To evaluate the alteration of protein of programmed cell death 5 (PDCD5) in peripheral blood mononuclear cells (PBMC) and DNA methylation caused by hexavalent chromium exposure. METHODS: There were 112 workers and 56 controls in this study. The chromium in RBC and urine, PBMC with PDCD5+, DNA methylation, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and score of DNA damage were measured. RESULTS: In chromate exposed workers, the percent of PBMC with PDCD5+, urine 8-OHdG, and score of DNA damage were significantly higher, whereas global DNA methylation was significantly lower. The binary logistic regression and generalized linear mixed model analysis showed that the percent of PBMC with PDCD5+ was significantly associated with global DNA hypomethylation. CONCLUSIONS: The aberrant DNA hypomethylation plays an important role in PBMC apoptosis of occupational hexavalent chromium exposure.

Perspectives of Genetic Damage and Epigenetic Alterations by Hexavalent Chromium: Time Evolution Based on a Bibliometric Analysis.

Compounds containing hexavalent chromium [Cr(VI)] have been classified as Group I human carcinogens in 1990 by the International Agency for Research on Cancer, known to induce human lung cancers. To determine the nature of Cr(VI) carcinogenesis, much has been learned about genetic damage and epigenetic alterations. On the basis of bibliometric analysis of the available literature found between 1966 and 2020, the present study investigated the evolution of author keywords; provided a summary of relevant studies focused on populations, animals/plants, or cells; and depicted the co-operation among countries or institutions and research group development. Additionally, multiomics technology and bioinformatics analysis can be a valuable tool for figuring out new biomarkers from different molecular levels like gene, RNA, protein, and metabolite and ascertaining the mechanism pathways of Cr(VI) genotoxicity and carcinogenesis.

A Novel Transcriptome Integrated Network Approach Identifies the Key Driver lncRNA Involved in Cell Cycle With Chromium (VI)-Treated BEAS-2B Cells.

Hexavalent chromium [Cr(VI)] is a well-known occupational carcinogen, but the mechanisms contributing to DNA damage and cell cycle alternation have not been fully characterized. To study the dose-response effects of Cr(VI) on transcription, we exposed BEAS-2B cells to Cr(VI) at concentrations of 0.2, 0.6, and 1.8 µmol/L for 24 h. Here, we identified 1,484 differentially expressed genes (DEGs) in our transcript profiling data, with the majority of differentially expressed transcripts being downregulated. Our results also showed that these DEGs were enriched in pathways associated with the cell cycle, including DNA replication, chromatin assembly, and DNA repair. Using the differential expressed genes related to cell cycle, a weighted gene co-expression network was constructed and a key mRNA-lncRNA regulation module was identified under a scale-free network with topological properties. Additionally, key driver analysis (KDA) was applied to the mRNA-lncRNA regulation module to identify the driver genes. The KDA revealed that ARD3 (FDR = 1.46 × 10-22), SND1 (FDR = 5.24 × 10-8), and lnc-DHX32-2:1 (FDR = 1.43 × 10-17) were particularly highlighted in the category of G2/M, G1/S, and M phases. Moreover, several genes we identified exhibited great connectivity in our causal gene network with every key driver gene, including CDK14, POLA1, lnc-NCS1-2:1, and lnc-FOXK1-4:1 (all FDR < 0.05 in those phases). Together, these results obtained using mathematical approaches and bioinformatics algorithmics might provide potential new mechanisms involved in the cytotoxicity induced by Cr.

U-Shaped Association of Serum Uric Acid With All-Cause and Cause-Specific Mortality in US Adults: A Cohort Study.

BACKGROUND: In addition to the controversy regarding the association of hyperuricemia with mortality, uncertainty also remains regarding the association between low serum uric acid (SUA) and mortality. We aimed to assess the relationship between SUA and all-cause and cause-specific mortality. METHODS: This cohort study included 9118 US adults from the National Health and Nutrition Examination Survey (1999-2002). Multivariable Cox proportional hazards models were used to evaluate the relationship between SUA and mortality. Our analysis included the use of a generalized additive model and smooth curve fitting (penalized spline method), and 2-piecewise Cox proportional hazards models, to address the nonlinearity between SUA and mortality. RESULTS: During a median follow-up of 5.83 years, 448 all-cause deaths occurred, with 100 cardiovascular disease (CVD) deaths, 118 cancer deaths, and 37 respiratory disease deaths. Compared with the reference group, there was an increased risk of all-cause, CVD, cancer, and respiratory disease mortality for participants in the first and third tertiles of SUA. We further found a nonlinear and U-shaped association between SUA and mortality. The inflection point for the curve was found at a SUA level of 5.7 mg/dL. The hazard ratios (95% confidence intervals) for all-cause mortality were 0.80 (0.65-0.97) and 1.24 (1.10-1.40) to the left and right of the inflection point, respectively. This U-shaped association was observed in both sexes; the inflection point for SUA was 6 mg/dL in males and 4 mg/dL in females. CONCLUSION: Both low and high SUA levels were associated with increased all-cause and cause-specific mortality, supporting a U-shaped association between SUA and mortality.

Threshold Effects of Serum Uric Acid on Chronic Kidney Disease in US Women without Hypertension and Diabetes: A Cross-Sectional Study.

BACKGROUND: Serum uric acid (SUA) has been associated with increased risk of chronic kidney disease (CKD) in observational studies; however, data in women without hypertension and diabetes are sparse. PURPOSE: To examine the association between SUA and CKD among women without hypertension and diabetes. METHODS: In this cross-sectional study of 6,776 US women without hypertension and diabetes from the National Health and Nutrition Examination Survey (1999-2006), we investigated the relationship between SUA and CKD using multivariable logistic regression models. Moreover, a generalized additive model and smooth curve fitting (penalized spline method) and a 2 piecewise logistic regression models were conducted to address for nonlinearity. RESULTS: The prevalence of CKD was 8.3%. Multiple logistic analyses showed that per 1 mg/dL increase in SUA was associated with 39% increased prevalence of CKD. Analyses using restricted cubic spline confirmed that the association between SUA and CKD was nonlinear. Further, threshold and saturation effect analysis showed that the inflection point of SUA was 4.5 mg/dL. The ORs (95% CIs) were 0.84 (0.66-1.08) on the left side of inflection point and 1.87 (1.56-2.24) on the right side of inflection point, respectively. Subgroup analysis showed that the stronger association between SUA and CKD was observed in elder women with never/former smoking and higher fasting blood glucose levels (all p values for interaction <0.05). CONCLUSION: Our study suggested threshold effects of SUA on the prevalence of CKD among US women without hypertension and diabetes. SUA levels >4.5 mg/dL were positively and independently associated with CKD.

Nonlinear relationship between triglyceride/high-density lipoprotein cholesterol ratio and chronic kidney disease in US adults: a National Health and Nutrition Examination Survey investigation.

PURPOSE: Published data on the association between triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) ratio and chronic kidney disease (CKD) in US populations are limited. We examined the association between TG/HDL-C ratio and the prevalence of CKD using US National Health and Nutrition Examination Survey (NHANES) database. METHODS: This cross-sectional study included 13,780 US adults from NHANES (1999-2006). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 or albuminuria. Multivariable logistic regression models were used to examine the relationship between TG/HDL-C ratio and CKD. A generalized additive model (GAM) and smooth curve fitting (penalized spline method) and a two-piecewise logistic regression models were also conducted to address for nonlinearity between TG/HDL-C ratio and CKD. RESULTS: The prevalence of CKD was 15.8%. Multiple logistic analyses showed that showed that TG/HDL-C ratio was associated with 5% increased prevalence of CKD. Analyses using restricted cubic spline showed a saturation and nonlinear association between TG/HDL-C ratio and CKD. The inflection point for the curve was found at a TG/HDL-C ratio level of 6.68. The ORs (95% CIs) for CKD were 1.08 (1.04, 1.13) and 0.97 (0.89, 1.05) to the left and right of the inflection point, respectively. None of all stratified variables showed significant effect modification on the association between TG/HDL-C ratio and CKD (P-interaction > 0.05). CONCLUSIONS: Our study suggested saturated effects of TG/HDL-C ratio on the prevalence of CKD among US adults. TG/HDL-C ratio less than 6.68 was positively and independently associated with CKD.