Prenatal triphenyl phosphate exposure impairs placentation and induces preeclampsia-like symptoms in mice.

Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.

Effects of dietary arsenic exposure on liver metabolism in mice.

Arsenic, a ubiquitous environmental toxicant with various forms and complex food matrix interactions, can reportedly exert differential effects on the liver compared to drinking water exposure. To examine its specific liver-related harms, we targeted the liver in C57BL/6 J mice (n=48, 8-week-old) fed with arsenic-contaminated food (30 mg/kg) for 60 days, mimicking the rice arsenic composition observed in real-world scenarios (iAsV: 7.3%, iAsIII: 72.7%, MMA: 1.0%, DMA: 19.0%). We then comprehensively evaluated liver histopathology, metabolic changes, and the potential role of the gut-liver axis using human hepatocellular carcinoma cells (HepG2) and microbiota/metabolite analyses. Rice arsenic exposure significantly altered hepatic lipid (fatty acids, glycerol lipids, phospholipids, sphingolipids) and metabolite (glutathione, thioneine, spermidine, inosine, indole-derivatives, etc.) profiles, disrupting 33 metabolic pathways (bile secretion, unsaturated fatty acid biosynthesis, glutathione metabolism, ferroptosis, etc.). Pathological examination revealed liver cell necrosis/apoptosis, further confirmed by ferroptosis induction in HepG2 cells. Gut microbiome analysis showed enrichment of pathogenic bacteria linked to liver diseases and depletion of beneficial strains. Fecal primary and secondary bile acids, short-chain fatty acids, and branched-chain amino acids were also elevated. Importantly, mediation analysis revealed significant correlations between gut microbiota, fecal metabolites, and liver metabolic alterations, suggesting fecal metabolites may mediate the impact of gut microbiota and liver metabolic disorders. Gut microbiota and its metabolites may play significant roles in arsenic-induced gut-liver injuries. Overall, our findings demonstrate that rice arsenic exposure triggers oxidative stress, disrupts liver metabolism, and induces ferroptosis.

Design of a Robust Synchronization-Based Topology Observer for Complex Delayed Networks with Fixed and Adaptive Coupling Strength.

Network topology plays a key role in determining the characteristics and dynamical behaviors of a network. But in practice, network topology is sometimes hidden or uncertain ahead of time because of network complexity. In this paper, a robust-synchronization-based topology observer (STO) is proposed and applied to solve the problem of identifying the topology of complex delayed networks (TICDNs). In comparison to the existing literature, the proposed STO does not require any prior knowledge about the range of topological parameters and does not have strict limits on topology type. Furthermore, the proposed STO is suitable not only for networks with fixed coupling strength, but also for networks with adaptive coupling strength. Finally, a few comparison examples for TICDNs are used to verify the feasibility and efficiency of the proposed STO, and the results show that the proposed STO outperforms the other methods.

Cip2a induces arginine biosynthesis and promotes tumor progression in non-small cell lung cancer.

Cancerous inhibitor of protein phosphatase 2A (Cip2a) is an oncoprotein, playing important roles in tumor progression. However, the underlying mechanisms by which Cip2a promotes tumor aggressiveness in NSCLC remain to be further investigated. In this study, we found that Cip2a expression is elevated in NSCLC and correlates with poor prognosis. Knockdown of Cip2a significantly reduced the ability of cell proliferation, invasion, and metastasis of NSCLC both in vitro and in vivo. Furthermore, we found that Cip2a promotes tumor progression partly by inducing arginine biosynthesis, and knockdown of Cip2a exhibited a significantly increased sensitivity to arginine deprivation and mTOR inhibition. In addition, we found that p53 mutants in NSCLC cells increased Cip2a expression by inhibiting the activity of wild-type p53. Our findings provide new insights into the mechanisms of Cip2a in promoting tumor progression and suggest that Cip2a represents a potential therapeutic target for treating NSCLC.

An Experimental Study on [125I]I-pHLIP (Var7) for SPECT/CT Imaging of an MDA-MB-231 Triple-Negative Breast Cancer Mouse Model by Targeting the Tumor Microenvironment.

Objective: To evaluate the diagnostic efficacy of MDA-MB-231 triple-negative breast cancer with 125I-labeled pHLIP (Var7) by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. Methods: The binding fraction of [125I]I-pHLIP (Var7) and MDA-MB-231 cells was measured at pH 7.4 and pH 6.0, and tumor-bearing mice were subjected to small-animal SPECT/CT imaging studies. Results: At pH = 6.0, the binding fractions of [125I]I-pHLIP (Var7) and MDA-MB-231 cells at 10 min, 40 min, 1 h, and 2 h were 1.9 ± 0.1%, 3.5 ± 0.1%, 6.3 ± 0.8%, and 6.6 ± 0.3%, respectively. At pH = 7.4, there was no measured binding between [125I]I-pHLIP (Var7) and MDA-MB-231 cells. Small-animal SPECT/CT imaging showed clearly visible tumors at 1 and 2 h after injection. Conclusions: [125I]I-pHLIP (Var7) could bind to MDA-MB-231 cells in an acidic environment, and small-animal SPECT/CT imaging showed clear tumors at 1 and 2 h after probe injection.

Additional value of metabolic parameters to PET/CT-based radiomics nomogram in predicting lymphovascular invasion and outcome in lung adenocarcinoma.

PURPOSE: Lymphovascular invasion (LVI) impairs surgical outcomes in lung adenocarcinoma (LAC) patients. Preoperative prediction of LVI is challenging by using traditional clinical and imaging parameters. The purpose of this study was to investigate the value of the radiomics nomogram integrating clinical factors, CT features, and maximum standardized uptake value (SUVmax) to predict LVI and outcome in LAC and to evaluate the additional value of the SUVmax to the PET/CT-based radiomics nomogram. METHODS: A total of 272 LAC patients (87 LVI-present LACs and 185 LVI-absent LACs) with PET/CT scans were retrospectively enrolled, and 160 patients with SUVmax ≥ 2.5 of them were used for PET radiomics analysis. Clinical data and CT features were analyzed to select independent LVI predictors. The performance of the independent LVI predictors and SUVmax was evaluated. Two-dimensional (2D) and three-dimensional (3D) CT radiomics signatures (RSs) and PET-RS were constructed with the least absolute shrinkage and selection operator algorithm and radiomics scores (Rad-scores) were calculated. The radiomics nomograms, incorporating Rad-score and independent clinical and CT factors, with SUVmax (RNWS) or without SUVmax (RNWOS) were built. The performance of the models was assessed with respect to calibration, discrimination, and clinical usefulness. All the clinical, PET/CT, pathologic, therapeutic, and radiomics parameters were assessed to identify independent predictors of progression-free survival (PFS). RESULTS: CT morphology was the independent LVI predictor. SUVmax provided better discrimination capability compared with CT morphology in the training set (P < 0.001) and test set (P = 0.042). A total of 1409 CT and PET radiomics features were extracted and reduced to 8, 8, and 10 features to build the 2D CT-RS, 3D CT-RS, and the PET-RS, respectively. There was no significant difference in AUC between the 2D-RS and 3D-RS (P > 0.05), and 2D CT-RS showed a relatively higher AUC than 3D CT-RS. The CT-RS, the CT-RNWOS, and the CT-RNWS showed good discrimination in the training set (AUC [area under the curve], 0.799, 0.796, and 0.851, respectively) and the test set (AUC, 0.818, 0.822, and 0.838, respectively). There was significant difference in AUC between the CT-RNWS and CT-RNWOS (P = 0.044) in the training set. Decision curve analysis (DCA) demonstrated the CT-RNWS outperformed the CT-RS and the CT-RNWOS in terms of clinical usefulness. Furthermore, DCA showed the PETCT-RNWS provided the highest net benefit compared with the PET-RNWS and CT-RNWS. PFS was significantly different between the pathologic and RNWS-predicted LVI-present and LVI-absent patients (P < 0.001). Carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), pathologic LVI, histologic subtype, and SUVmax were independent predictors of PFS in the 244 CT-RNWS-predicted cohort; and CA125, NSE, pathologic LVI, and SUVmax were the independent predictors of PFS in the 141 PETCT-RNWS-predicted cohort. CONCLUSIONS: The radiomics nomogram, incorporating Rad-score, clinical and PET/CT parameters, shows favorable predictive efficacy for LVI status in LAC. Pathologic LVI and SUVmax are associated with LAC prognosis.

The EMT-related transcription factor snail up-regulates FAPα in malignant melanoma cells.

FAPα is a cell surface serine protease, mainly expressed in tumor stromal fibroblasts in more than 90% of human epithelial carcinomas. Due to its almost no expression in normal tissues and its tumor-promoting effects, FAPα has been studied as a novel potential target for antitumor therapy. However, the regulation mechanism on FAPα expression is poorly understood. In this study, we found that overexpression of snail significantly increased the mRNA and protein expression levels of FAPα in malignant melanoma B16 and SK-MEL-28 cells. Overexpression of snail increased FAPα promoter activity remarkably. Snail could directly bind to FAPα promoter to regulate FAPα expression. Moreover, snail expression was positively correlated to FAPα expression in human cutaneous malignant melanoma. Furthermore, knockdown of FAPα markedly reduced snail-induced cell migration. Overall, our findings provide a novel regulation mechanism on FAPα expression and highlight the role of snail/FAPα axis as a novel target for melanoma treatment.

Characterization of CSF2A fusion gene and its effect on Epstein-Barr virus-positive tumor cells.

We build the latent membrane protein gene latent membrane protein 2A (LMP2A) and the granulocyte-macrophase colony-stimulating factor (GM-CSF) gene fusion gene (CSF2A) and discuss how the CSF2A fusion protein influenced the proliferation and apoptosis of Epstein-Barr virus-positive (EBV+ ) tumor cells. Reverse-transcription polymerase chain reaction (RT-PCR) method was used to amplify the LMP2A gene and GM-CSF gene fragments, respectively, according to the principle of overlap extension in the coding (Gly4Ser)3 polypeptide gene fragments of DNA restructured under the connection. The CSF2A gene could be connected with the pIRES2-enhanced green fluorescent protein vector by recombinant DNA technology and identified by enzyme electrophoresis analysis and DNA sequencing. Then, the recombinant vector was transfected into dendritic cells (DCs); RT-PCR and Western blot analysis were used for testing the CSF2A gene messenger RNA and protein expression. The impacts of CSF2A on the proliferation and apoptosis of EBV+ tumor cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Hochest 33342 staining. We successfully obtained the recombinant vector named pIRES2-CSF2A. The expression of CSF2A could be detected by transfecting pIRES2-CSF2A into DCs. The DCs were cocultured with T lymphocytes and then acted on the EBV+ CNE2 nasopharyngeal carcinoma cells. MTT assay showed that the inhibiting effect of CSF2A obviously increased and the time dependency (**P < 0.01, *P < 0.05) also existed. Hochest 33342 staining showed apoptosis morphological changes of cells in nucleus staining and generated the apoptotic body. Apoptosis cells of the pIRES2-CSF2A group increased significantly at 48 hours. The results showed that the pIRES2-CSF2A recombinant vector was effectively transfected into DCs and the fusion gene CSF2A could promote EBV+ CNE2 cell apoptosis, laying the foundation for the specificity of EBV+ tumor targeting immune gene therapy in the future.

LncRNA HOTTIP-Mediated HOXA11 Expression Promotes Cell Growth, Migration and Inhibits Cell Apoptosis in Breast Cancer.

As the most common cause of cancer death in women, the pathogenesis of breast cancer still remains unclear. Here, we reported a long non-coding RNA (lncRNA), HOTTIP (HOXA transcript at the distal tip), that may play an important role in the pathogenesis of breast cancer. Using gain-and-loss-of experiments in vitro and in vivo, we observed the marked upregulation of HOTTIP/HOXA11 in the breast cancer cell line, MCF-7, and the downregulation of HOTTIP or HOXA11, which might inhibit cell proliferation and migration but promote cell apoptosis in breast cancer MCF-7 cells. In addition, by further rescue experiments with HOXA11 overexpression, we uncovered a novel potential regulatory mechanism between HOTTIP and one of its physical HOXA clusters, HOXA11. Hence, HOTTIP may mediate, at least partly, HOXA11 expression involved in cell growth, migration, and apoptosis of breast cancer MCF-7 cells.

A long non-coding RNA HOTTIP expression is associated with disease progression and predicts outcome in small cell lung cancer patients.

BACKGROUND: Despite progress in treatment of small cell lung cancer (SCLC), the biology of the tumor still remains poorly understood. Recently, we globally investigated the contributions of lncRNA in SCLC with a special focus on sponge regulatory network. Here we report lncRNA HOTTIP, which is specifically amplified in SCLC, is associated with SCLC proliferation and poor prognosis of patients. METHODS: RT-qPCR was used to investigate the expression of HOTTIP in SCLC tissues and cell lines. The role of HOTTIP in SCLC cell proliferation was demonstrated by CCK8 assay, colony formation assay, flow cytometry analysis and in vivo SCLC xenograft model in nude mice through HOTTIP loss- and gain-of-function effects. Western blot assay was used to evaluate gene expression in cell lines at protein level. RNA pull-down, Mass spectrometry and RNA binding protein immunoprecipitation (RIP) were performed to confirm the molecular mechanism of HOTTIP involved in SCLC progression. RESULTS: We found that HOTTIP was overexpressed in SCLC tissues, and its expression was correlated with the clinical stage and the shorter survival time of SCLC patients. Moreover, HOTTIP knockdown could impair cell proliferation, affect the cell cycle and inhibit tumor growth of mice, while HOTTIP overexpression might enhance cell proliferation and cell cycle in vitro and in vivo. Mechanistic investigations showed that HOTTIP functions as an oncogene in SCLC progression by sponging miR-574-5p and affecting the expression of polycomb group protein EZH1. CONCLUSIONS: Overall, we identified that HOTTIP was involved in SCLC tumorigenesis through the ceRNA network "HOTTIP/miR-574-5p/EZH1". Our findings not only illuminate how HOTTIP confers an oncogenic function in SCLC pathogenesis, but also underscore a novel gene expression governing hallmarks in the disease.

TSPAN12 promotes chemoresistance and proliferation of SCLC under the regulation of miR-495.

Studies have shown that TSPAN12 serves as an oncogenic gene or tumor suppressor depending on the types of cancer. However, its role in the drug resistance of small cell lung cancer (SCLC) is still unknown. In this study, we investigated whether TSPAN12 regulates chemoresistance, proliferation and tumor growth of SCLC under the regulation of miR-495 using two drug resistant cell lines. The results showed that down-regulation of TSPAN12 inhibited cells chemoresistance, proliferation and tumor growth. Besides, TSPAN12 elevation in SCLC specimens correlated with poor pathologic stage and shorter survival time. In addition, the dual luciferase assay indicated that TSPAN12 was one of the directly targeted genes of miR-495. Our study revealed that TSPAN12 promoted chemoresistance of SCLC under the regulation of miR-495. TSPAN12 depletion is a promising strategy for inhibiting the chemoresistance in SCLC.

Small animal PET imaging with the 68Ga-labeled pH (low) insertion peptide-like peptide YJL-4 in a triple-negative breast cancer mouse model.

BACKGROUND: The aim of this study was to prepare a novel 68Ga-labeled pH (low) insertion peptide (pHLIP)-like peptide, YJL-4, and determine its value for the early diagnosis of triple-negative breast cancer (TNBC) via in vivo imaging of tumor-bearing nude mice. The novel peptide YJL-4 was designed using a template-assisted method and synthesized by solid-phase peptide synthesis. After modification with the chelator 1,4,7­triazacyclononane-N,N',N″-triacetic acid (NOTA), the peptide was labeled with 68Ga. Then, the biodistribution of 68Ga-YJL-4 in tumor-bearing nude mice was investigated, and the mice were imaged by small animal positron emission tomography (PET). RESULTS: The radiochemical yield and radiochemical purity of 68Ga-YJL-4 were 89.5 ± 0.16% and 97.95 ± 0.06%, respectively. The biodistribution of 68Ga-YJL-4 in tumors (5.94 ± 1.27% ID/g, 6.72 ± 1.69% ID/g and 4.54 ± 0.58% ID/g at 1, 2 and 4 h after injection, respectively) was significantly greater than that of the control peptide in tumors at the corresponding time points (P < 0.01). Of the measured off-target organs, 68Ga-YJL-4 was highly distributed in the liver and blood. The small animal PET imaging results were consistent with the biodistribution results. The tumors were visualized by PET at 2 and 4 h after the injection of 68Ga-YJL-4. No tumors were observed in the control group. CONCLUSIONS: The novel pHLIP family peptide YJL-4 can adopt an α-helical structure for easy insertion into the cell membrane in an acidic environment. 68Ga-YJL-4 was produced in high radiochemical yield with good stability and can target TNBC tissue. Moreover, the strong concentration of radioactive 68Ga-YJL-4 in the abdomen does not hinder the imaging of early TNBC.

Long-term arsenic exposure decreases mice body weight and liver lipid droplets.

Arsenic (As) is a widespread global pollutant, and there is significant controversy surrounding its complex relationship with obesity, primarily focused on short-term exposure. Recognizing the prolonged nature of dietary arsenic exposure, this study involved feeding mice with arsenic-contained food for 14 months. The results showed that mice exposed to arsenic developed a non-alcoholic fatty liver condition, characterized by a light-yellow hue on the liver surface and various pathological alterations in the liver cells, including enlarged nuclei, cellular necrosis, inflammatory infiltration, dysfunctional mitochondria, and endoplasmic reticulum disorganization. There were also disruptions in biochemistry indices, with a significant increase in total cholesterol (TC) level and a decrease in high-density lipoprotein (HDL) level. However, some contradictory observations occurred, such as a significant decrease in body weight, triglyceride (TG) level, and the numbers of lipid droplets. Several genes related to lipid metabolism were tested, and a model was used to explain these discrepancies. Besides, examinations of the colon revealed compromised intestinal barrier function and signs of inflammation. Fecal 16S rRNA sequencing and pseudo-targeted metabolomics revealed disruptions in internal homeostasis, such as modules, nodes, connections, and lipid-related KEGG pathways. Fecal targeted metabolomics analyses of short-chain fatty acids (SCFAs) and bile acids (BAs) demonstrated a significant upregulation in three primary bile acids (CA, CDCA, TCDCA), four secondary bile acids (TUDCA, DCA, LCA, GUDCA), and total SCFAs level. Oxidative stress and inflammation were also evident. Additionally, based on correlation analysis and mediation analysis, it was assumed that changes in the microbiota (e.g., Dubosiella) can impact the liver metabolites (e.g., TGs) through alterations in fecal metabolites (e.g., LPCs). These findings provide a theoretical reference for the long-term effect of arsenic exposure on liver lipid metabolism.

Apoptotic effect of selenium mushroom extract from Qinba on multiple myeloma cells.

Qinba selenium mushroom is a mushroom belonging to the Basidiomycetes family, which is believed to have anti- oxidant, anti-tumoral and anti-mutagenic activities. However, the efficacy of Qinba selenium mushroom against multiple myeloma has not been confirmed. The present study aimed to investigate the apoptotic effect of FA-2-b-ß, the selenium mushroom extract from Qinba on multiple myeloma (MM) cells. The MM RPMI-8226 cells were treated with FA-2-b-ß at different concentrations and time points. MM RPMI-8226 cell proliferation and apoptosis were detected by the Cell Counting Kit-8 (CCK-8) assay and Annexin V/propidium iodide (PI) assay, RT-QPCR and western blotting analyses were performed to determine the proteins and pathways involved. The results of the present study demonstrated that FA-2-b-ß has high anti-proliferative activities and strong pro-apoptotic effects on MM RPMI-8226 cells, and its pharmacological effects on proliferation changes occurred in a dose- and time-dependent manner. In addition, we found that FA-2-b-ß was able to induce cell apoptosis and promote cell cycle arrest at G0/G1 phase. In summary, the results illustrate the involvement of FA-2-b-ß in mediating G0/G1 cell cycle arrest and apoptosis in MM RPMI-8226 cells, which suggested that FA-2-b-ß might have therapeutic potential against multiple myeloma as an effective compound, and may provide useful information for the development of a novel therapeutic target in this area.

Key genes involved with prognosis were identified in lung adenocarcinoma by integrated bioinformatics analysis.

Objective: By screening the core genes in lung adenocarcinoma (LUAD) with bioinformatics, our study evaluated its prognosis value and role in infiltration process of immune cells. Methods: Using GEO database, we screened 5 gene chips, including GSE11072, GSE32863, GSE43458, GSE115002, and GSE116959. Then, we obtained the corresponding differentially expressed genes by analyzed 5 gene chips online by GEO2R (P < 0.05, |logFC| > 1). Then, through DAVID online platform, Cytoscape 3.6.1 software and PPI network analysis, the network was visualized and obtain the final core genes. Next, we plan to use the GEPIA, UALCAN, Kaplan-Meier plotter and Time 2.0 database for corresponding analysis. The GEPIA database was used to verify the expression of core genes in LUAD and normal lung tissues, and survival analysis was used to evaluate the value of core genes in the prognosis of LUAD patients. UALCAN was used to verify the expression of the LUAD core gene and promoter methylation status, and the predictive value of core genes was evaluated in LUAD patients by the Kaplan-Meier plotter online tool. Then, we used the Time 2.0 database to identify the relationship to immune infiltration in LUAD. Finally, we used the human protein atlas (HPA) database for online immunohistochemical analysis of the expressed proteins. Results: The expression of CCNB2 and CDC20 in LUAD were higher than those in normal lung tissues, their increased expression was negatively correlated with the overall survival rate of LUAD, and they were involved in cell cycle signal transduction, oocyte meiosis signal transduction as well as the infiltration process of immune cells in LUAD. The expression proteins of CCNB2 and CDC20 were also different in lung cancer tissue and normal lung tissue. Therefore, CCNB2 and CDC20 were identified as the vital core genes. Conclusion: CCNB2 and CDC20 are essential genes that may constitute prognostic biomarkers in LUAD, they also participate the immune infiltration process and protein expression process of LUAD, and might provides basis for clinical anti-tumor drug research.

Gestation and lactation triphenyl phosphate exposure disturbs offspring gut microbiota in a sex-dependent pathway.

Triphenyl phosphate (TPhP) is an Organophosphate flame retardant (OPFR) that has been widely used in many commercial products. Following its widely usage, its health risk has been concerned. In this study, mice were exposed to TPhP (1 mg/kg) during pregnancy and lactation (E0-PND21), the effect of TPhP on gut microbiota and its role in TPhP mediated lipid metabolism disturbance of offspring was investigated. Our results showed that TPhP disturbed the gut microbiota in dam or offspring at different extent, with male offspring experiencing major effects. Both the composition, abundance or network of gut microbiome was affected in male offspring. In male offspring, expression of genes along gut-liver axis including FXR, CYP7A1, SREBP-1c and ChREBP was significantly up-regulated, and expression of SHP, FGF15 and ASBT was significantly down-regulated. Consistent with this, lipid accumulation in the liver, and increased level of triglyceride, total cholestrol and total bile acid in the serum was observed. The changed abundance of Ruminococcaceae, Clostridiaceae, and Bacteroidaceae shows strong correlation with disturbed lipid metabolism in male offspring. Our research showed that indirect TPhP exposure during early life stage could affect the gut microbiota and gene expression along gut-liver axis in offspring at sex-dependent pathways, with males experiencing more effects.

Identification of Potential Key Genes and Prognostic Biomarkers of Lung Cancer Based on Bioinformatics.

Objective: To analyze and identify the core genes related to the expression and prognosis of lung cancer including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) by bioinformatics technology, with the aim of providing a reference for clinical treatment. Methods: Five sets of gene chips, GSE7670, GSE151102, GSE33532, GSE43458, and GSE19804, were obtained from the Gene Expression Omnibus (GEO) database. After using GEO2R to analyze the differentially expressed genes (DEGs) between lung cancer and normal tissues online, the common DEGs of the five sets of chips were obtained using a Venn online tool and imported into the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database for Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The protein-protein interaction (PPI) network was constructed by STRING online software for further study, and the core genes were determined by Cytoscape software and KEGG pathway enrichment analysis. The clustering heat map was drawn by Excel software to verify its accuracy. In addition, we used the University of Alabama at Birmingham Cancer (UALCAN) website to analyze the expression of core genes in P53 mutation status, confirmed the expression of crucial core genes in lung cancer tissues with Gene Expression Profiling Interactive Analysis (GEPIA) and GEPIA2 online software, and evaluated their prognostic value in lung cancer patients with the Kaplan-Meier online plotter tool. Results: CHEK1, CCNB1, CCNB2, and CDK1 were selected. The expression levels of these four genes in lung cancer tissues were significantly higher than those in normal tissues. Their increased expression was negatively correlated with lung cancer patients (including LUAD and LUSC) prognosis and survival rate. Conclusion: CHEK1, CCNB1, CCNB2, and CDK1 are the critical core genes of lung cancer and are highly expressed in lung cancer. They are negatively correlated with the prognosis of lung cancer patients (including LUAD and LUSC) and closely related to the formation and prediction of lung cancer. They are valuable predictors and may be predictive biomarkers of lung cancer.

Long-term effects on liver metabolism induced by ceftriaxone sodium pretreatment.

Ceftriaxone is an emerging contaminant due to its potential harm, while its effects on liver are still need to be clarified. In this study, we first pretreated the 8-week-old C57BL/6J mice with high dose ceftriaxone sodium (Cef, 400 mg/mL, 0.2 mL per dose) for 8 days to prepare a gut dysbiosis model, then treated with normal feed for a two-month recovery period, and applied non-targeted metabolomics (including lipidomics) to investigate the variations of fecal and liver metabolome, and coupled with targeted determination of fecal short-chain fatty acids (SCFAs) and bile acids (BAs). Lastly, the correlations and mediation analysis between the liver metabolism and gut metabolism/microbes were carried, and the potential mechanisms of the mal-effects on gut-liver axis induced by Cef pretreatment were accordingly discussed. Compared to the control group, Cef pretreatment reduced the rate of weight gain and hepatosomatic index, induced bile duct epithelial cells proliferated around the central vein and appearance of binucleated hepatocytes, decreased the ratio of total branching chains amino acids (BCAAs) to total aromatic amino acids (AAAs) in liver metabolome. In fecal metabolome, the total fecal SCFAs and BAs did not change significantly while butyric acid decreased and the primary BAs increased after Cef pretreatment. Correlation and mediation analysis revealed one potential mechanism that Cef may first change the intestinal microbiota (such as destroying its normal structure, reducing its abundance and the stability of the microbial network or certain microbe abundance like Alistipes), and then change the intestinal metabolism (such as acetate, caproate, propionate), leading to liver metabolic disorder (such as spermidine, inosine, cinnamaldehyde). This study proved the possibility of Cef-induced liver damage, displayed the overall metabolic profile of the liver following Cef pretreatment and provided a theoretical framework for further research into the mechanism of Cef-induced liver damage.

Asymptomatic chronic suppurative cholecystitis and peritonitis mimicking metastasis by 18F-FDG PET/CT scan during sigmoid colon cancer surveillance.

The study describes an unusual case that a patient with previous history of adenocarcinoma of sigmoid colon who has developed chronic suppurative cholecystitis and peritonitis was misdiagnosed as metastasis. This case is presented to illustrate the importance of considering benign etiologies that may mimic metastatic disease when interpreting positron emmision tomography (PET)/CT scans.