OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Objective To investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) for radiation-induced lung injury (RILI) and the underlying mechanism. Methods Forty-five healthy adult male C57BL/6 mice were randomly divided into control, model, and BMSCs groups. The model and BMSCs groups received a single irradiation dose of 20 Gy to the chest, while the control group did not receive X-ray irradiation. For the BMSCs group, an injection of 1 × 10⁶ BMSCs cells was administered via the tail vein within 6 h after irradiation. In the 5th week, the lung tissue was taken to observe pathological changes with HE staining; examine the expression of the inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) with immunohistochemical staining; observe the polarization of macrophages with immunofluorescence staining; and measure the expression of the epithelial-mesenchymal transition markers E-cadherin, N-cadherin, and vimentin proteins by Western blot. Results After radiation, the model group developed pulmonary vasodilation and congestion with septal thickening and inflammatory cell infiltration, and these changes were markedly reduced in the BMSCs group. The model group showed significantly down-regulated expression of IL-6 and TNF-α compared with significantly increased levels in the model group (P < 0.01, P < 0.05). Treatment with BMSCs significantly increased the polarization of lung macrophages towards the M2 type, while significantly decreasing the abnormally increased N-cadherin and vimentin levels in RILI mice (P < 0.05, P < 0.01). Conclusion BMSCs have therapeutic effects for RILI mice, which may be through promoting macrophage polarization from M1 to M2.

Objective:To discuss the effect of curcumin on the proliferation,migration,and invasion of the human prostate cancer C4-2 and LNCaP cells,and to clarify its possible mechanism.Methods:The lentiviral transfection system was used to transfect the C4-2 and LNCaP cells,regarded as shCD147-C4-2 group and shCD147-LNCaP group.RNA interference technology was used to prepare the CD147-silenced cells;the cells transfected with an empty vector were regarded as negative control and divided into shNC-C4-2 group(shNC-C4-2 cells)and shNC-LNCaP group(shNC-LNCaP cells).The C4-2 and LNCaP cells at logarithmic growth phase,as well as shCD147-C4-2 and shCD147-LNCaP cells,were treated with 20 μmol·L-1 curcumin.The morphology of the cells in various groups was observed under microscope at 0 and 24 h of treatment;MTT method was used to detect the proliferation activities of the cells in various groups;cell scratch assay was used to detect the migration rates of the cells in various groups;Western blotting method was used to detect the expression levels of apoptosis,invasion,and migration-related proteins in the cells in various groups.Results:Compared with C4-2 group,the expression of CD147 protein in the cells in shCD147-C4-2 group was significantly decreased after CD147 gene silenting.Compared with LNCaP group,the expression level of CD147 protein in the cells in shCD147-LNCaP group was significantly decreased after CD147 gene silenting.Compared with 0 h of treatment,some cells in C4-2 and LNCaP groups after 24 h of treatment with 20 μmol·L-1 curcumin,showed apoptosis signs with the presence of typical apoptotic bodies.The apoptotic phenomena in shCD147-C4-2 and shCD147-LNCaP groups was reduced.The MTT assay results showed that compared with C4-2+0 μmol·L-1 curcumin group,the proliferation activities of the cells in C4-2+20 μmol·L-1 curcumin group,C4-2+40 μmol·L-1 curcumin group,C4-2+60 μmol·L-1 curcumin group,and C4-2+80 μmol·L-1 curcumin group were decreased(P<0.01).Compared with LNCaP+0 μmol·L-1 curcumin group,the proliferation activity of the cells in LNCaP+20 μ mol·L-1 curcumin group,LNCaP+40 μmol·L-1 curcumin group,LNCaP+60 μmol·L-1 curcumin group,and LNCaP+80 μmol·L-1 curcumin group were decreased(P<0.01).Compared with shNC-C4-2 group,the proliferation activity of the cells in shNC-C4-2+20 μmol·L-1 curcumin group was decreased(P<0.01).Compared with shNC-C4-2+20 μmol·L-1 curcumin group,the proliferation activity of the cells in shCD147-C4-2+20 μmol·L-1 curcumin group was increased(P<0.01).Compared with shNC-LNCaP group,the proliferation activity of the cells in shNC-LNCaP+20 μmol·L-1 curcumin group was decreased(P<0.01);compared with shNC-LNCaP+20 μmol·L-1 curcumin group,the proliferation activity of the cells in shCD147-LNCaP+20 μmol·L-1 curcumin group was significantly increased(P<0.01).The cell scratch healing assay results showed that compared with C4-2 group,the migration rates of the cells in C4-2+20 μmol·L-1 curcumin group and C4-2+40 μmol·L-1 curcumin group after 24 h of treatment were decreased(P<0.01);compared with LNCaP group,the migration rates of the cells in LNCaP+20 μmol·L-1 curcumin group and LNCaP+40 μmol·L-1 curcumin group were increased(P<0.01);compared with shNC-C4-2 group,the migration rate of the cells in shNC-C4-2+20 μmol·L-1 curcumin group was decreased(P<0.01);compared with shNC-C4-2+20 μmol·L-1 curcumin group,the migration rate of the cells in shCD147-C4-2+20 μmol·L-1 curcumin group was significantly increased(P<0.05);compared with shNC-LNCaP group,the migration rate of the cells in shNC-LNCaP+20 μmol·L-1 curcumin group was decreased(P<0.01);compared with shNC-LNCaP+20 μmol·L-1 curcumin group,the garation rate of the cells in shCD147-LNCaP+20 μmol·L-1 curcumin group was significantly increased(P<0.05).The Western blotting results showed that compared with C4-2 group,the expression levels of Bcl-2-associated X protein(Bax),cleaved Caspase-3,and poly ADP-ribose polymerase 1(PARP1)proteins in the cells in C4-2+20 μmol·L-1 curcumin group and C4-2+40 μmol·L-1 curcumin group were significantly increased(P<0.01),and the expression levels of Bcl-2 protein was significantly decreased(P<0.05 or P<0.01);compared with LNCaP group,the expression levels of Bax,cleaved Caspase-3,and PARP1 proteins in the cells in LNCaP+20 μmol·L-1 curcumin group and LNCaP+40 μmol·L-1 curcumin group were significantly increased(P<0.01),and the expression level of Bcl-2 protein in the cells in LNCaP+40 μmol·L-1 curcumin group was decreased(P<0.01);compared with shNC-C4-2 group,the expression levels of Bax,cleaved Caspase-3,and PARP1 proteins in the cells in shNC-C4-2+20 μmol·L-1 curcumin group were significantly increased(P<0.05 or P<0.01),and the expression level of Bcl-2 protein was significantly decreased(P<0.05);compared with shNC-C4-2+20 μmol·L-1 curcumin group,the expression levels of Bax and cleaved Caspase-3 proteins in the cells in shCD147-C4-2+20 μmol·L-1 curcumin group were significantly decreased(P<0.01);compared with shNC-LNCaP group,the expression levels of Bax,cleaved Caspase-3,and PARP1 proteins in the cells in shNC-LNCaP+20 μmol·L-1 curcumin group were significantly increased(P<0.05 or P<0.01),and the expression level of Bcl-2 protein was significantly decreased(P<0.05);compared with shNC-LNCaP+20 μmol·L-1 curcumin group,the expression levels of Bax,cleaved Caspase-3,and PARP1 proteins in the cells in shCD147-LNCaP+20 μmol·L-1 curcumin group were significantly decreased(P<0.05 or P<0.01),and the expression level of Bcl-2 protein was significantly increased(P<0.05).Compared with C4-2 group,the expression levels of E-cadherin protein in the cells in C4-2+20 μmol·L-1 curcumin group and C4-2+40 μ mol·L-1 curcumin group were significantly increased(P<0.01),and the expression levels of N-cadherin and Vimentin proteins were significantly decreased(P<0.01);compared with LNCaP group,the expression levels of E-cadherin protein in the cells in LNCaP+20 μmol·L-1 curcumin group and LNCaP+40 μmol·L-1 curcumin group were significantly increased(P<0.01),and the expression levels of N-cadherin and Vimentin proteins in the cells in LNCaP+40 μmol·L-1 curcumin group were significantly decreased(P<0.01);compared with shNC-C4-2 group,the expression levels of N-cadherin and Vimentin proteins in the cells in shNC-C4-2+20 μmol·L-1 curcumin group were significantly decreased(P<0.01);compared with shNC-C4-2+20 μmol·L-1 curcumin group,the expression level of E-cadherin protein in the cells in shCD147-C4-2+20 μmol·L-1 curcumin group was significantly decreased(P<0.01),and the expression levels of N-cadherin and Vimentin proteins were significantly increased(P<0.01);compared with shNC-LNCaP group,the expression level of E-cadherin protein in the cells in shNC-LNCaP+20 μmol·L-1 curcumin group was significantly increased(P<0.01),and the expression levels of N-cadherin and Vimentin proteins were significantly decreased(P<0.01);compared with shNC-LNCaP+20 μmol·L-1 curcumin group,the expression level of E-cadherin protein in the cells in shCD147-LNCaP+20 μmol·L-1 curcumin group was significantly decreased(P<0.01),and the expression level of N-cadherin was significantly increased(P<0.05).Conclusion:Curcumin inhibits the proliferation,migration,and invasion of the prostate cancer cells in vitro and induces the apoptosis;silencing the CD147 gene partially reduces its inhibitory effect and its ability to induce the apoptosis.

To investigate the risk factors for early colorectal cancer in patients with dyslipidemia and the possible role of statins, data of 266 patients with colorectal mass and dyslipidemia who received endoscopic treatment in Beijing Friendship Hospital from February 2018 to February 2021 were collected. The patients were divided into the colorectal adenoma group ( n=174) and the early colorectal cancer group ( n=92) according to colonoscopic and pathological results. Clinical data of the two groups were analyzed. Logistic regression analysis was used to evaluate the risk factors for early colorectal cancer in patients with dyslipidemia. The results showed compared with the colorectal adenoma group, the early colorectal cancer group had a higher proportion of males (64.1% VS 25.9%), smoking (41.3% VS 14.4%) and drinking (37.0% VS 17.2%) and higher low density lipoprotein cholesterol (LDL-C) (3.06±0.81 mmol/L VS 2.60±0.74 mmol/L) and total cholesterol (TC) values (5.27±1.22 mmol/L VS 4.61±1.06 mmol/L), while the proportion of statin use was lower (27.2% VS 52.9%). There were significant differences in the above indices (all P<0.05). Multivariate logistic regression analysis showed that male ( OR=3.641, 95% CI:1.694-7.826), smoking ( OR=2.920, 95% CI:1.159-7.356), higher LDL-C ( OR=2.203,95% CI:1.481-3.277) and higher TC level ( OR=1.744,95% CI:1.329-2.289) were risk factors for early colorectal cancer in patients with hyperlipidemia, while the history of statin use ( OR =0.469, 95% CI: 0.236-0.932) had a protective effect. Smoking cessation education, early screening of LDL-C, TC level, statin use if necessary to reach the standard lipids and screening of early colorectal cancer should be actively carried out in patients with dyslipidemia.

Objective To explore the predictive value of CT image texture analysis for early enlargement of hypertensive intracerebral hemorrhage.Methods One hundred and eight patients with hypertensive intracerebral hemorrhage were divided into enlarged hematoma group (positive group)and non-enlarged hematoma group (negative group),according to whether the volume of hematoma on 24 h follow up CT scan was more than 30% or 6 mL of the baseline CT.Phillis Radiomics Tool V93 software was used to segment the hematoma on CT plain scan images of two groups,four features of first-order and three of gray-level co-occurrence matrix (GLCM),thirteen of gray-level size zone matricx (GLSZM)and eleven of gray-level run-length matricx (GLRLM)were obtained.The differences of thirty-one texture features between the two groups were compared.The ROC curves of the features with statistical differences were analyzed.The independent predictors of early enlargement of intracerebral hemorrhage were screened by Logistic multivariate regression model.Results Among the one hundred and eight patients,twenty-eight were positive group and eighty were negative group.Skewness and long run low gray-level emphasis (LRLGE)in positive group were significantly higher than those in negative group (P＜0.05).There was no significant difference in the remaining twenty-nine features between the two groups (P＞0.05).ROC curve analysis showed that the AUC of Skewness,LRLGE and their combined diagnosis were 0.634,0.814 and 0.828,respectively.The independent variables were screened by stepwise regression analysis.The LRLGE (OR＝1.238,95%CI＝1.009－1.51 9,P＜0.05)was selected as the regression model, suggesting that LRLGE was an independent predictor of the early enlargement of intracerebral hemorrhage.Conclusion Texture analysis of CT images is helpful to predict the early enlargement of hypertensive intracerebral hemorrhage,and LRLGE based on GLRLM algorithm can be used as an independent predictor.

Objective: To investigate the role of exosome (EXO) transporting Let-7a to regulate MYC gene in the malignant biological behaviors of triple negative breast cancer (TNBC) cell, and to explore the underlying mechanism. Methods: After the completion of cell culture, the gene and protein expressions of MYC and Let-7a in TNBC MDA-MB-231cells were detected by qPCR and WB, respectively. Recombinant lenti-virus vector carrying Let-7a and Crisper/Cas-9 system with MYC knockdown were transfected into MDA-MB-231 cells; MTT assay, Transwell assay and Scratch healing assay were performed to examine the proliferation, invasion and migration of MDA-MB-231 cells. Luciferase activity assay was performed to validate the binding between MYC and Let-7a. EXO was isolated and identified by transmission electron microscopy and WB assay in wild-type and Let-7a over-expressed MDA-MB-231 cells, respectively. After co-incubation of two types of EXO and MDA-MB-231 cells, the effects of Let-7a on biological behaviors of MDAMB-231 cells via EXO were detected by qPCR, WB, MTT and Transwell etc. Results: Let-7a was negatively correlated with MYC in breast cancer tissues and cell lines (all P<0.05); MYC promoted while Let-7a inhibited the proliferation, migration and invasion of breast cancer cells (all P<0.01); Let-7a silenced MYC by acting on 3'UTR of MYC gene, thereby reducing the expression of MYC protein (P<0.05); Let-7a was enveloped by EXO and transported to cancer cells, there by inhibiting the proliferation, migration and invasion of MDA-MB-231 cells. Conclusion: EXO some mediated Let-7a silences MYC gene by acting on its 3'UTR region, thus inhibiting the proliferation, migration and invasion of MDA-MB-231 cells.

Objective ToassessthevalueofGdGEOBGDTPAenhancedT1ρimaginginevaluatingtheseverityandinflammation gradeinnonalcoholicsteatohepatitis(NASH)rabbitsmodel.Methods NASH modelswereestablishedin26adultrabbitsbyfeeding withthehighGfat,highGcholesteroldietinavarieddurations (0,4,8,12 weeks).T1ρ,T1ρinthehepatobiliaryphase (HBP)and changeofT1ρ(Δ%)werecomparedamongthedifferentgroupswhichweredeterminedbydifferentnonGalcoholicfattyliverdisease activityscore(NAS)andinflammationgrades.SpearmancorrelationanalysiswasusedtoassessthecorrelationsofT1ρ,T1ρ(HBP) withNASscoresandinflammationgrades.ROCcurvewasperformedtoevaluatethediagnosticvalueofT1ρ,T1ρ(HBP)inpredicting NASHandadvancedinflammation.Results T1ρandT1ρ(HBP)werepositivelyassociatedwithNASandinflammationscores.The differencesofT1ρ(HBP)amongNASH,nonalcoholicfattyliver(NAFL)andnormalliverwerestatisticallysignificant(P＜0.05). T1ρ(HBP)wassignificantlydifferentintherabbitswithgrade3inflammationfromintherabbitswithgrade0,grade1andgrade2 inflammation (P＜0.05).AUCsofT1ρandT1ρ(HBP)fordifferentiatingNASH were0.849and0.949,respectively.AUCofT1ρand T1ρGHBPfordiagnosinggrade2andgrade3inflammationwere0.925and0.922,respectively.Fibrosisandinflammationwerethe mainindependentfactorsaffectingT1(HBP).Conclusion GdGEOBGDTPAenhancedT1ρimagingcanreflecttheseverityofNASH anddegreeofinflammation.T1ρ(HBP)mightbeamoresuperiornoninvasiveimagingbiomarkerthannonGenhancedT1ρforassessmentof NASHactivityandinflammationgrading.

Objective To study the thalamic metabolic alterations and its correlation with cognitive impairment in patients with cerebral small vessel disease(CSVD).Methods The cognitive function of 34 patients with CSVD and 26 matched volunteers were evaluated by Montreal cognitive assessment(MoCA), and received single voxel 1H-MRS examination to detect the content of NAA,Cho and Cr,and record the ratio of NAA/Cr and Cho/Cr on bilateral thalami.The differences of NAA/Cr, Cho/Cr on bilateral thalami between the two groups were compared, and the correlation between NAA/Cr,Cho/Cr and MoCA total score and its sub-items score in CSVD group were analyzed.Results ①The MoCA of total score as well as its sub-items such as visual space and executive ability,memory,attention and language for CSVD group were significantly lower than that for the control group(P<0.05);②NAA/Cr on bilateral thalami in CSVD group were both lower than that in the control group(left 1.57±0.18,1.68±0.17,t=2.46,P=0.02;right 1.66±0.21,1.78±0.19,t=2.23,P=0.03), the differences were statistically significant (P<0.05);there were no significantly differences in the ratio of Cho/Cr between the two groups(P>0.05);③In CSVD group, the ratio of NAA/Cr on both bilateral thalami were significantly positively correlated with MoCA score (left r=0.83,right r=0.79,P<0.05)as well as visual space and executive ability(left r=0.65,right r=0.46,P<0.05), memory(left r=0.59, right r=0.50, P<0.05), attention(left r=0.42, right r=0.52, P<0.05),language(left r=0.52, right r=0.41, P<0.05), abstraction(left r=0.47, right r=0.40, P<0.05), orientation(left r=0.48,right r=0.42, P<0.05),Cho/Cr were not significantly correlated with MoCA total score and its sub-items(P>0.05).Conclusion The thalamic neuron has been damaged and dysfunctioned in patients with CSVD,and this metabolic abnormality may be related to a wide range of cognitive impairment in CSVD patients.

Based on untermolecular splut G-quardruplex-hemun DNAzymes, a buosensor for detectuon of sulver uons and cysteune was developed wuth magnetuc nanopartucles ( MNPs ) as carruer to ummobuluze the DNA probes. Sunce Ag+ chelates guanune bases at the bundung sutes whuch are unvolved un G-quadruplex formatuon, the presence of Ag+ may unhubut G-quartets connected by Hoogsteen-type base paurung and dusrupt G-quadruplexes structures, whuch decreases the peroxudase actuvuty of G-quadruplex-hemun DNAzymes that effucuently catalyze H2 O2-meduated reactuons, such as the oxudatuon of ABTS ( 2, 2'-azunobus ( 3-ethylbenzothuozolune)-6-sulfonuc acud) by H2 O2 . Moreover, un the presence of L-cysteune, ut was used as a competutor by the strongly Ag-S to release Ag+ from G-ruch olugonucleotudes, promotung the reformatuon of G-quadruplexes and uncreasung the peroxudase actuvuty, whuch catalyzes the ABTS-H2 O2 reactuon system. In thus experument, the effucuent separatuon from real sample was achueved usung magnetuc nanopartucles as a solud phase carruer to effectuvely uncrease the detectuon sensutuvuty and decrease the background sugnal. Under the optumum condutuons, a hugh lunear relatuonshup between the UV absorbance and the Ag+ concentratuon was establushed un the range of 0. 5-100 nmol/L wuth a detectuon lumut of 0. 2 nmol/L. The calubratuon curve of cysteune was udentufued un the range from 0. 1 to 80 nmol/L and the detectuon lumut was as low as 0. 04 nmol/L.