Early-onset colorectal cancer (EOCRC) shows a different epidemiological trend compared to later-onset colorectal cancer, with its incidence rising in most regions and countries worldwide. However, the reasons behind this trend remain unclear. The etiology of EOCRC is complex and could involve both genetic and environmental factors. Apart from Lynch syndrome and Familial Adenomatous Polyposis, sporadic EOCRC exhibits a broad spectrum of pathogenic germline mutations, genetic polymorphisms, methylation changes, and chromosomal instability. Early-life exposures and environmental risk factors, including lifestyle and dietary risk factors, have been found to be associated with EOCRC risk. Meanwhile, specific chronic diseases, such as inflammatory bowel disease, diabetes, and metabolic syndrome, have been associated with EOCRC. Interactions between genetic and environmental risk factors in EOCRC have also been explored. Here we present findings from a narrative review of epidemiological studies on the assessment of early-life exposures, of EOCRC-specific environmental factors, and their interactions with susceptible loci. We also present results from EOCRC-specific genome-wide association studies that could be used to perform Mendelian randomization analyses to ascertain potential causal links between environmental factors and EOCRC.
Humans ; Colorectal Neoplasms/etiology* ; Risk Factors ; Genome-Wide Association Study ; Genetic Predisposition to Disease/genetics*

AIM:This study aimed to investigate the mechanisms by which treadmill exercise ameliorates de-pressive-like behaviors and hippocampal neuronal damage in chronic restraint stress(CRS)mice by regulating mitophagy via the Sirt1/PGC-1α signaling axis.METHODS:Forty C57BL/6J mice were randomly assigned to control,CRS,CRS+exercise(EXE)and EXE groups(n=10).The mice in CRS and CRS+EXE groups underwent 4 h of daily restraint for 28 consecutive days to establish a depression model.The mice in CRS+EXE and EXE groups received 8 weeks of treadmill training(6 sessions per week).Depressive-like behaviors were evaluated using the open field test,sucrose preference test,and tail suspension test.Hippocampal neuronal morphology and pathological changes were examined using hematoxy-lin-eosin and Nissl staining,while neuronal apoptosis was assessed through TUNEL staining.Mitochondrial ultrastructure was examined via transmission electron microscopy.Mitochondrial membrane potential and ATP content were measured using JC-1 assay and ATP assay kits,respectively.The expression levels of silent information regulator 1(Sirt1),peroxi-some proliferator-activated receptor γ coactivator-1α(PGC-1α),PTEN-induced kinase 1(PINK1)and parkin were as-sessed at both mRNA and protein levels by RT-qPCR and Western blot assays,as well as key markers of mitophagy[mi-crotubule-associated protein 1 light chain 3(LC3)and P62]and apoptosis(cleaved caspase-9 and cleaved caspase-3).RESULTS:Compared with control group,CRS mice exhibited significantly reduced central zone entries and time(P<0.01),decreased sucrose preference(P<0.01),increased immobility time(P<0.01),severe hippocampal neuronal damage,elevated apoptosis rate(P<0.01),mitochondrial deterioration;reduced membrane potential and ATP content(P<0.01),decreased mRNA expressions of Sirt1,PGC-1α,PINK1,and parkin(P<0.01),reduced protein levels of Sirt1,PGC-1α,PINK1,parkin and LC3(P<0.01),and increased expression of P62,cleaved caspase-9,and cleaved caspase-3(P<0.01).The mice in CRS+EXE group showed significant improvements in all these parameters compared to CRS group(P<0.05 or P<0.01).CONCLUSION:Treadmill exercise mitigates CRS-induced depressive-like behaviors,mi-tochondrial dysfunction,and neuronal apoptosis in mice by activating the hippocampal Sirt1/PGC-1α/mitophagy axis.

AIM:This study aimed to investigate the mechanisms by which treadmill exercise ameliorates de-pressive-like behaviors and hippocampal neuronal damage in chronic restraint stress(CRS)mice by regulating mitophagy via the Sirt1/PGC-1α signaling axis.METHODS:Forty C57BL/6J mice were randomly assigned to control,CRS,CRS+exercise(EXE)and EXE groups(n=10).The mice in CRS and CRS+EXE groups underwent 4 h of daily restraint for 28 consecutive days to establish a depression model.The mice in CRS+EXE and EXE groups received 8 weeks of treadmill training(6 sessions per week).Depressive-like behaviors were evaluated using the open field test,sucrose preference test,and tail suspension test.Hippocampal neuronal morphology and pathological changes were examined using hematoxy-lin-eosin and Nissl staining,while neuronal apoptosis was assessed through TUNEL staining.Mitochondrial ultrastructure was examined via transmission electron microscopy.Mitochondrial membrane potential and ATP content were measured using JC-1 assay and ATP assay kits,respectively.The expression levels of silent information regulator 1(Sirt1),peroxi-some proliferator-activated receptor γ coactivator-1α(PGC-1α),PTEN-induced kinase 1(PINK1)and parkin were as-sessed at both mRNA and protein levels by RT-qPCR and Western blot assays,as well as key markers of mitophagy[mi-crotubule-associated protein 1 light chain 3(LC3)and P62]and apoptosis(cleaved caspase-9 and cleaved caspase-3).RESULTS:Compared with control group,CRS mice exhibited significantly reduced central zone entries and time(P<0.01),decreased sucrose preference(P<0.01),increased immobility time(P<0.01),severe hippocampal neuronal damage,elevated apoptosis rate(P<0.01),mitochondrial deterioration;reduced membrane potential and ATP content(P<0.01),decreased mRNA expressions of Sirt1,PGC-1α,PINK1,and parkin(P<0.01),reduced protein levels of Sirt1,PGC-1α,PINK1,parkin and LC3(P<0.01),and increased expression of P62,cleaved caspase-9,and cleaved caspase-3(P<0.01).The mice in CRS+EXE group showed significant improvements in all these parameters compared to CRS group(P<0.05 or P<0.01).CONCLUSION:Treadmill exercise mitigates CRS-induced depressive-like behaviors,mi-tochondrial dysfunction,and neuronal apoptosis in mice by activating the hippocampal Sirt1/PGC-1α/mitophagy axis.

Objective:To investigate the efficacy and mechanism of modified Yinjia formula in the treatment of persistent genital tract chlamydia trachomatis infections based on the targeted regulation of CD8+T cell autophagy pathway.Methods:Thirty-six BALB/c mice,except for the blank group,were inoculated intravaginally with chlamydia to establish a model of persistent chlamydia trachomatis infection.After successful modeling,patients were divided into groups and given low,medium and high doses of Yinjia modifiedformula and azithromycin by continuous gavage for 4 weeks,respectively.HE staining was used to observe the histomorphologic changes of uterus and fallopian tube tissues of the mice.Real-time fluorescence quantitative polymerase chain reaction was used to detect the expression level of chlamydia trachomatis genes in the low reproductive tract.Proportion of OX40 and LAG-3 positive cells in mouse lymph nodes was detected by flow cytometry.Immunoblotting was used to detect the expression of autophagy-related protein Beclin-1,Atg5,LC3Ⅱ/LC3Ⅰ,p62,and Ras/Raf/MEK/ERK pathway protein in mouse splenic CD8+T cells.Results:Compared with the model group,the inflammatory cell infiltration was reduced to different degrees in all treatment groups.Among them,only a very small amount of in-flammatory cell infiltration was observed in the uterus and fallopian tubes in the high-dose group of traditional Chi-nese medicine,and no significant inflammatory exudation and thickening was observed in the fallopian tubes.Compared with the model group,the expression of Beclin-1,Atg5,LC3Ⅱ/LC3Ⅰ was decreased in all treatment groups(P＜0.01),while the protein expression of p62,Ras,P-Raf,P-MEK and P-ERK was up-regulated(P＜0.01).Additionally,the proportion of OX40 and LAG-3 positive cells in lymphocytes was decreased(P＜0.01).A-mong them,Beclin-1,Atg5,LC3Ⅱ/LC3Ⅰ protein expression as well as the percentage of OX40 and LAG-3 positive cells were the lowest in the high-dose group of traditional Chinese medicine(P＜0.01).Conclusions:The modi-fied Yinjia formula may inhibit the autophagic activity of CD8+T cells through the Ras/Raf/MEK/ERK signaling pathway,thereby enhancing the targeted clearance function of chlamydia trachomatis inclusion bodies by CD8+T cells and delaying the process of persistent chlamydia trachomatis infection in the reproductive tract.

Objective:To investigate the efficacy and mechanism of modified Yinjia formula in the treatment of persistent genital tract chlamydia trachomatis infections based on the targeted regulation of CD8+T cell autophagy pathway.Methods:Thirty-six BALB/c mice,except for the blank group,were inoculated intravaginally with chlamydia to establish a model of persistent chlamydia trachomatis infection.After successful modeling,patients were divided into groups and given low,medium and high doses of Yinjia modifiedformula and azithromycin by continuous gavage for 4 weeks,respectively.HE staining was used to observe the histomorphologic changes of uterus and fallopian tube tissues of the mice.Real-time fluorescence quantitative polymerase chain reaction was used to detect the expression level of chlamydia trachomatis genes in the low reproductive tract.Proportion of OX40 and LAG-3 positive cells in mouse lymph nodes was detected by flow cytometry.Immunoblotting was used to detect the expression of autophagy-related protein Beclin-1,Atg5,LC3Ⅱ/LC3Ⅰ,p62,and Ras/Raf/MEK/ERK pathway protein in mouse splenic CD8+T cells.Results:Compared with the model group,the inflammatory cell infiltration was reduced to different degrees in all treatment groups.Among them,only a very small amount of in-flammatory cell infiltration was observed in the uterus and fallopian tubes in the high-dose group of traditional Chi-nese medicine,and no significant inflammatory exudation and thickening was observed in the fallopian tubes.Compared with the model group,the expression of Beclin-1,Atg5,LC3Ⅱ/LC3Ⅰ was decreased in all treatment groups(P＜0.01),while the protein expression of p62,Ras,P-Raf,P-MEK and P-ERK was up-regulated(P＜0.01).Additionally,the proportion of OX40 and LAG-3 positive cells in lymphocytes was decreased(P＜0.01).A-mong them,Beclin-1,Atg5,LC3Ⅱ/LC3Ⅰ protein expression as well as the percentage of OX40 and LAG-3 positive cells were the lowest in the high-dose group of traditional Chinese medicine(P＜0.01).Conclusions:The modi-fied Yinjia formula may inhibit the autophagic activity of CD8+T cells through the Ras/Raf/MEK/ERK signaling pathway,thereby enhancing the targeted clearance function of chlamydia trachomatis inclusion bodies by CD8+T cells and delaying the process of persistent chlamydia trachomatis infection in the reproductive tract.

Objective:To explore the classification performance of combined model constructed from CT signs combined with radiomics for discriminating COVID-19 pneumonia and other viral pneumonia.Methods:The clinical and CT imaging data of 181 patients with viral pneumonia confirmed by reverse transcription-polymerase chain reaction in 15 hospitals of Yunnan Province from March 2015 to March 2020 were analyzed retrospectively. The 181 patients were divided into COVID-19 group (89 cases) and non-COVID-19 group (92 cases), which were further divided into training cohort (126 cases) and test cohort (55 cases) at a ratio of 7∶3 using random stratified sampling. The CT signs of pneumonia were determined and the radiomics features were extracted from the initial unenhanced chest CT images to build independent and combined models for predicting COVID-19 pneumonia. The diagnostic performance of the models were evaluated using receiver operating characteristic (ROC) analysis, continuous net reclassification index (NRI) calibration curve and decision curve analysis.Results:The combined models consisted of 3 significant CT signs and 14 selected radiomics features. For the radiomics model alone, the area under the ROC curve (AUC) were 0.904 (sensitivity was 85.5%, specificity was 84.4%, accuracy was 84.9%) in the training cohort and 0.866 (sensitivity was 77.8%, specificity was 78.6%, accuracy 78.2%) in the test cohort. After combining CT signs and radiomics features, AUC of the combined model for the training cohort was 0.956 (sensitivity was 91.9%, specificity was 85.9%, accuracy was 88.9%), while that for the test cohort was 0.943 (sensitivity was 88.9%, specificity was 85.7%, accuracy was 87.3%). The AUC values of the combined model and the radiomics model in the differentiation of COVID-19 group and the non-COVID-19 group were significantly different in the training cohort ( Z=-2.43, P=0.015), but difference had no statistical significance in the test cohort ( Z=-1.73, P=0.083), and further analysis using the NRI showed that the combined model in both the training cohort and the test cohort had a positive improvement ability compared with radiomics model alone (training cohort: continuous NRI 1.077, 95 %CI 0.783-1.370; test cohort: continuous NRI 1.421, 95 %CI 1.051-1.790). The calibration curve showed that the prediction probability of COVID-19 predicted by the combined model was in good agreement with the observed value in the training and test cohorts; the decision curve showed that a net benefit greater than 0.6 could be obtained when the threshold probability of the combined model was 0-0.75. Conclusion:The combination of CT signs and radiomics might be a potential method for distinguishing COVID-19 and other viral pneumonia with good performance.

Inflammatory bowel disease (IBD) mainly includes Crohn′s disease (CD) and ulcerative colitis (UC) . The imaging diagnosis of CD is difficult because of its complex disease and varied imaging manifestations. Standardizations of imaging techniques and reports are helpful to improve the imaging diagnosis level of CD. This article aims to provide guideline for the imaging technique selection, scanning scheme formulation, imaging features interpretation and imaging report writing of CD in China.

Inflammatory bowel disease (IBD) mainly includes Crohn′s disease (CD) and ulcerative colitis (UC) . The imaging diagnosis of CD is difficult because of its complex disease and varied imaging manifestations. Standardizations of imaging techniques and reports are helpful to improve the imaging diagnosis level of CD. This article aims to provide guideline for the imaging technique selection, scanning scheme formulation, imaging features interpretation and imaging report writing of CD in China.

Objective To elucidate whether metformin could regulate the mRNA expression level of estrogen synthetase and ER in human uterine leiomyoma tissues. Methods (1) Seventeen pairs of uterine leiomyoma tissues and adjacent myometrium (>2 cm) were collected from patients underwent hysterectomy in Peking University First Hospital between December 2016 and January 2017. Real-time PCR was used to measure the mRNA expression level of estrogen synthetase [including cytochrome P450 cholesterol side chain cleavage enzyme (P450scc), cytochrome P450 17 α-hydroxylase (P450c17), 3-beta-hydroxysteroid dehydrogenase type 2 (3β-HSD-2), 17-beta-hydroxysteroid dehydrogenase type 1 (17β-HSD-1) and aromatase cytochrome P450 (P450arom)] and ER (including ERα and ERβ) in the uterine leiomyoma tissues and adjacent myometrium. (2) Uterine leiomyoma cells derived from uterine leiomyoma tissues were identified by immunocytochemistry method and cultured to the third generation. The treatment groups were cultured with different concentrations of metformin (10, 50 and 100 μmol/L) for 48 hours, and the control group was cultured with deionized water for 48 hours. The mRNA expression level of estrogen synthetase and estrogen receptor subtypes were measured by real-time PCR. Results (1) P450scc, P450c17, 3β-HSD-2, 17β-HSD-1, P450arom mRNA median expression levels were 112, 4, 13, 42 and 194 in the uterine leiomyoma tissues, and were respectively 114, 5, 11, 32 and 6 in the myometrium. Compared to those of the myometrium, 3β-HSD-2 and P450arom mRNA expression levels in the uterine leiomyoma tissue were significantly higher (P<0.05), while there were no significant change of mRNA expression levels among P450scc, P450c17 and 17β-HSD-1 (P>0.05). ERα and ERβ mRNA median expression levels were 208 and 116 in the uterine leiomyoma tissues, and were 24 and 95 in the myometrium. Compared to that of the myometrium, ERα mRNA level in the uterine leiomyoma tissue was significantly higher (P=0.001), while there were no significant change of ERβ mRNA level (P=0.193). (2) After cultured with different concentrations of metformin (10, 50 and 100 μmol/L), the P450arom mRNA levels in the uterine leiomyoma tissues were 9 ± 4, 8 ± 5 and 8 ± 3 respectively in the treatment groups and was 16 ± 5 in the control group. Compared to that of the control group, P450arom mRNA expression levels in the treatment groups were significantly declined (P<0.05). There were no significant different change of mRNA expression levels among 3β-HSD-2, ERα and ERβ between the treatment groups and the control group (P>0.05). Conclusions Metformin could down-regulate the mRNA expression level of aromatase in the uterine leiomyoma cells. These results indicate that metformin may inhibit the local estrogen synthesis and therefore suppress the development of uterine leiomyoma.

Objective To investigate surgical treatments for hepatolithiasis complicated with biliary cirrhosis and portal hypertension. Methods Clinical data of 31 patients with hepatolithiasis complicated with biliary cirrhosis and portal hypertension receiving surgical treatments in Nanfang Hospital, Southern Medical University from June 2004 to June 2013 were analyzed retrospectively. There were 21 males and 8 females with the mean age of (49±8) years old. The informed consents of all patients were obtained and local ethical committee approval had been received. The surgical treatments included one-stage cholangiolithotomy (n=26), two-stage cholangiolithotomy (n=5). The perioperative situation and the treatment efifcacy were observed. Results The median intraoperative blood loss was 537 (300-1 800) ml for the 26 cases undergoing one-stage cholangiolithotomy. Postoperative bleeding was observed in 2 cases. Pericardial fundus devascularization and transjugular intrahepatic portosystem shunt (TIPS) were performed emergently in the patients respectively and then the bleeding was ceased. The intraoperative blood loss was 350 (300-450) ml for the left 5 cases undergoing two-stage cholangiolithotomy. The liver function of the patients recovered well and no liver failure, hepatic encephalopathy were observed. The postoperative choledochoscope residual rate of calculus was 16%(5/31) and the ultrasound residual rate of calculus was 26% (8/31). Good efficacy was observed in 14 cases and fine in 17 cases. Conclusions The surgical operation for hepatolithiasis complicated with biliary cirrhosis and portal hypertension is with high dififculty and risk. It is necessary to design personalized surgical plan and to perform multiple surgical procedures.