Curcumin suppresses colorectal cancer by induction of ferroptosis via regulation of p53 and solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 signaling axis.

Driven by iron-dependent lipid peroxidation, ferroptosis is regulated by p53 and solute carrier family 7 member 11 (SLC7A11)/glutathione/glutathione peroxidase 4 (GPX4) axis in colorectal cancer (CRC). This study aimed to investigate the influence of curcumin (CUR) on ferroptosis in CRC. The efficacies of CUR on the malignant phenotype of CRC cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, wound healing, and clonogenic assays. The effects of CUR on ferroptosis of CRC cells were evaluated by transmission electron microscopy, lactate dehydrogenase release assay, Fe2+ staining, and analyses of reactive oxygen species, lipid peroxide, malondialdehyde, and glutathione levels. CUR's targets in ferroptosis were predicted by network pharmacological study and molecular docking. With SW620 xenograft tumors, the efficacy of CUR on CRC was investigated, and the effects of CUR on ferroptosis were assessed by detection of Fe2+, malondialdehyde, and glutathione levels. The effects of CUR on expressions of p53, SLC7A11, and GPX4 in CRC cells and tumors were analyzed by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. CUR suppressed the proliferation, migration, and clonogenesis of CRC cells and xenograft tumor growth by causing ferroptosis, with enhanced lactate dehydrogenase release and Fe2+, reactive oxygen species, lipid peroxide, and malondialdehyde levels, but attenuated glutathione level in CRC. In silico study indicated that CUR may bind p53, SLC7A11, and GPX4, consolidated by that CUR heightened p53 but attenuated SLC7A11 and GPX4 mRNA and protein levels in CRC. CUR may exert an inhibitory effect on CRC by inducing ferroptosis via regulation of p53 and SLC7A11/glutathione/GPX4 axis.

A comparative study of Chinese medicine quality of life assessment scale (CQ-11D) and EQ-5D-5L and SF-6D scales based on Chinese population.

PURPOSE: To measure health-related quality of life in the Chinese population using three universal health utility scales (CQ-11D, EQ-5D-5L, and SF-6D) and to compare the differences in the results obtained by the different scales to provide a reference for future utility on health-related quality of life in the Chinese population. METHODS: According to the Chinese population's distribution area, gender, and age, quota sampling was conducted. Three scales, CQ-11D, EQ-5D-5L, and SF-6D, whose results were self-reported, were collected in succession after collecting respondents' demographic information. The health utility value and floor/ceiling effect were explained. Bland-Altman was used to evaluate the consistency, the intraclass correlation coefficient was used to evaluate the correlation, and the receiver operating characteristic curve was used to evaluate the discriminative validity of the scale. RESULTS: The mean utility values of the CQ-11D, EQ-5D-5L, and SF-6D scales, respectively, were 0.891, 0.927, and 0.841. The floor effect did not appear in any of the three scales, but the ceiling effect did, and the EQ-5D-5L ceiling effect was the most severe. The limits of the agreement interval for CQ-11D versus EQ-5D-5L in the total sample population were (-0.245,0.172); for CQ-11D versus SF-6D, they were (- 0.256,0.354); and for EQ-5D-5L versus SF-6D, they were (-0.199,0.371). The consistency of the three scales is satisfactory overall. In the total population, the intraclass correlation coefficient between CQ-11D and EQ-5D-5L was 0.709, while EQ-5D-5L and SF-6D were 0.0.565 and that between EQ-5D-5L and SF-6D was 0.472. According to the subject operation curve results, the area under the curve for the total sample population of CQ-11D was 0.746, EQ-5D-5L was 0.669, and SF-6D was 0.734. CONCLUSION: The CQ-11D is inferior to the EQ-5D-5L, but superior to the SF-6D. There is a strong correlation between the health utility values of the total population as measured by the three scales and those of the healthy population. The CQ-11D scale is the most sensitive to differences between populations and diseases.

A novel nomogram based on cell cycle-related genes for predicting overall survival in early-onset colorectal cancer.

BACKGROUND: Although the incidence of late-onset colorectal cancer (LOCRC) has decreased, the incidence of early-onset colorectal cancer (EOCRC) is still rising dramatically. Heterogeneity in the genomic, biological, and clinicopathological characteristics between EOCRC and LOCRC has been revealed. Therefore, the previous prognostic models based on the total CRC patient population might not be suitable for EOCRC patients. Here, we constructed a prognostic classifier to enhance the precision of individualized treatment and management of EOCRC patients. METHODS: EOCRC expression data were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The regulatory pathways were explored by gene set enrichment analysis (GSEA). The prognostic model was developed by univariate Cox-LASSO-multivariate Cox regression analyses of GEO samples. TCGA samples were used to verify the model. The expression and mutation profiles and immune landscape of the high-risk and low-risk cohorts were analyzed and compared. Finally, the expression and prognostic value of the model genes were verified by immunohistochemistry and qRT‒PCR analysis. RESULTS: The cell cycle was identified as the most significantly enriched oncological signature of EOCRC. Then, a 4-gene prognostic signature comprising MCM2, INHBA, CGREF1, and KLF9 was constructed. The risk score was an independent predictor of overall survival. The area under the curve values of the classifier for 1-, 3-, and 5-year survival were 0.856, 0.893, and 0.826, respectively, in the training set and 0.749, 0.858, and 0.865, respectively, in the validation set. Impaired DNA damage repair capability (p < 0.05) and frequent PIK3CA mutations (p < 0.05) were found in the high-risk cohort. CD8 T cells (p < 0.05), activated memory CD4 T cells (p < 0.01), and activated dendritic cells (p < 0.05) were clustered in the low-risk group. Finally, we verified the expression of MCM2, INHBA, CGREF1, and KLF9. Their prognostic value was closely related to age. CONCLUSION: In this study, a robust prognostic classifier for EOCRC was established and validated. The findings may provide a reference for individualized treatment and medical decision-making for patients with EOCRC.

How Work Pattern Transformation May Affect the Mental Health of Older Workers Faced With Unmet Health Care Needs During the Pandemic? A Comparative Investigation of Different Work Models.

PURPOSE: This study compares the relation between unmet health care needs and mental health of older people with different work patterns. METHODS: This study uses data of Survey of Health, Aging and Retirement in Europe Corona survey (n = 51,632 to 51,731). RESULTS: The unmet health care need results in depression/sadness during the pandemic (0.304, P < 0.01). Besides, such problem is more salient in workers than the nonemployed population (0.066, P < 0.01 for workers; 0.058, P < 0.01 for the nonemployed) and more outstanding in those working on site and with hybrid work model compared with the telecommuters (0.264, P < 0.01 for telecommuters; 0.378, P < 0.01 for on-site workers; 0.437, P < 0.01 for hybrid work model). CONCLUSIONS: Policymakers should focus on mental health of older people especially for those fully or partially involved in on-site work, when common health care need can be crowded out for limited health care resources during the pandemic.

Metformin induces myeloma cells necrosis and apoptosis and it is considered for therapeutic use.

Accumulating evidence, especially in solid tumor, indicated that metformin possessed the potential ability in the proliferation of cancer cells. However, its effects on myeloma cells were relatively rarely clarified. To evaluate the anti-cancer effects of metformin against dexamethasone-resistant and -sensitive myeloma cells. The effects of metformin on myeloma cell lines, including dexamethasone-resistant U266, H929, RPMI 8226 and dexamethasone-sensitive MM.1s, were investigated using the cell counting kit-8 assay for cell proliferation. Apoptosis, necrosis, cell cycle arrest, and cell death mechanisms were explored via flow cytometry (FCM) and Western blot. In addition, the anti-myeloma activity was evaluated in vivo via non-obese diabetic/severe combined immunodeficiency xenograft mouse models. Metformin inhibited proliferation in a dose and time-dependent manner in all the cell lines, while dexamethasone only affected the viability of MM1.s cells. The FCM detection displayed that metformin induced apoptosis in H929, RPMI8226 and MM.1s cells, while for U266 cells, it induced necrosis with Annexin V-/Propidium iodide+. The cell cycle assays showed that metformin arrested G0/G1 phase of H929 and MM.1s cells, or G2/M phase of RPMI8226 cells, but showed no effect on U226 cells. Western blotting analyses demonstrated that the apoptosis-related protein of cleaved caspase 3 was activated; the expressions of Mcl-1, IGF-1R, PI3K, pAKT, and pmTOR proteins were inhibited by metformin in H929, RPMI8226, and MM.1s cells. The necrosis-related protein of iNOS increased in U266 cells while metformin treated. In vivo assay indicated metformin decreased U266 and H929 growth in bone marrow, and thus prolonged mice survival. These data suggested that metformin inhibited the proliferation of myeloma cells via inducing necrosis and apoptosis. This finding indicated that metformin may be served as a potent adjuvant in treating multiple myeloma.

Gastric duplication cyst with ectopic pancreas in a teenager successfully resected by endoscopic submucosal dissection.

BACKGROUND: Gastric duplication cyst associated with ectopic pancreas is rare and we aimed to alert clinician to this congenital anomaly. CASE PRESENTATION: A 15-year-old girl presented with intermittent vomiting. Gastroscopy showed a submucosal tumor with an approximate diameter of 40 mm in the anterior wall of the gastric antrum. The lesion had a central umbilication and was diagnosed preliminarily as gastric ectopic pancreas with pseudocyst formation on the basis of its appearance. However, computed tomographic scan showed a thick-walled cystic lesion with an enhanced outline of the cystic wall in the antrum of stomach, suggestive of duplication cyst. Serum amylase was normal. Endoscopic ultrasonography revealed a solid-cystic lesion; the solid portion were inhomogeneously mixed with echoes, and had indistinct border to muscularis propria; the cystic portion had echogenic internal mucosal layer and distinct border to muscularis propria. Endoscopic submucosal dissection (ESD) was suggested for the patient to relieve symptoms and diagnose the lesion definitely. The operation procedure was uneventful and the solid-cystic lesion was resected completely. Histopathologic examination revealed that the solid portion was ectopic pancreas, and the cystic portion was gastric duplication cyst. After resection, the patient discharged successfully and neither symptoms nor tumors recurred during the 9 months follow-up period. CONCLUSIONS: This is the first case of a solid-cystic lesion with central umbilication in the stomach diagnosed as gastric duplication cyst associated with ectopic pancreas. ESD could be an optional treatment to provide a definitive diagnosis.

Survival Prediction in Home Hospice Care Patients with Lung Cancer Based on LASSO Algorithm.

PURPOSE: The aim of the present study was to develop a nomogram for prognostic prediction of patients with lung cancer in hospice. METHODS: The data was collected from 1106 lung cancer patients in hospice between January 2008 and December 2018. The data were split into a training set, which was used to identify the most important prognostic factors by the least absolute shrinkage and selection operator (LASSO) and to build the nomogram, while the testing set was used to validate the nomogram. The performance of the nomogram was assessed by c-index, calibration curve and the decision curve analysis (DCA). RESULTS: A total of 1106 patients, including 835 (75%) from the training set and 271 (25%) from testing set, were retrospectively analyzed in this study. Using the LASSO regression, 5 most important prognostic predictors that included sex, Karnofsky Performance Scale (KPS), quality-of-life (QOL), edema and anorexia, were selected out of 28 variables. Validated c-indexes of training set at 15, 30, and 90 days were .778 [.737-.818], .776 [.743-.809], and .751 [.713-.790], respectively. Similarly, the validated c-indexes of testing set at 15, 30, and 90 days were .789 [.714-.864], .748 [.685-.811], and .757 [.691-.823], respectively. The nomogram-predicted survival was well calibrated, as the predicted probabilities were close to the expected probabilities. Moreover, the DCA curve showed that nomogram received superior standardized net benefit at a broad threshold. CONCLUSIONS: The study built a non-lab nomogram with important predictor to analyze the clinical parameters using LASSO. It may be a useful tool to allow clinicians to easily estimate the prognosis of the patients with lung cancer in hospice.

A Correlation Study of Prognostic Risk Prediction for Colorectal Cancer Based on Autophagy Signature Genes.

Autophagy plays a complex role in tumors, sometimes promoting cancer cell survival and sometimes inducing apoptosis, and its role in the colorectal tumor microenvironment is controversial. The purpose of this study was to investigate the prognostic value of autophagy-related genes (ARGs) in colorectal cancer. We identified 37 differentially expressed autophagy-related genes by collecting TCGA colorectal tumor transcriptome data. A single-factor COX regression equation was used to identify 11 key prognostic genes, and a prognostic risk prediction model was constructed based on multifactor COX analysis. We classified patients into high and low risk groups according to prognostic risk parameters (p <0.001) and determined the prognostic value they possessed by survival analysis and the receiver operating characteristic (ROC) curve in the training and test sets of internal tests. In a multifactorial independent prognostic analysis, this risk value could be used as an independent prognostic indicator (HR=1.167, 95% CI=1.078-1.264, P<0.001) and was a robust predictor without any staging interference. To make it more applicable to clinical procedures, we constructed nomogram based on risk parameters and parameters of key clinical characteristics. The area under ROC curve for 3-year and 5-year survival rates were 0.735 and 0.718, respectively. These will better enable us to monitor patient prognosis, thus improve patient outcomes.

Nonalcoholic Fatty Liver Disease-Associated Liver Fibrosis Is Linked with the Severity of Coronary Artery Disease Mediated by Systemic Inflammation.

METHODS AND RESULTS: We conducted a retrospective study of 531 patients with ultrasonogram-confirmed NAFLD who underwent percutaneous coronary intervention (PCI). Then, all patients were separated into four categories by Gensini score (0, 0-9, 9-48, and ≥48) for use in ordinal logistic regression analysis to determine whether NAFLD fibrosis was associated with increased Gensini scores. Mediation analysis was used to investigate whether systemic inflammation is a mediating factor in the association between NAFLD fibrosis and CAD severity. FIB - 4 > 2.67 (OR = 5.67, 95% CI 2.59-12.38) and APRI > 1.5 (OR = 14.8, 95% CI 3.24-67.60) remained to be independent risk factors for the severity of CAD after adjusting for conventional risk factors, whereas among the inflammation markers, only neutrophils and neutrophil-to-lymphocyte ratio (NLR) were independently associated with CAD. Multivariable ordinal regression analysis suggested that increasing Gensini score (0, 0-9, 9-48, and ≥48) was associated with advanced NAFLD fibrosis. ROC curve showed that either fibrosis markers or inflammation markers, integrating with traditional risk factors, could increase the predictive capacity for determining CAD. Inflammation markers, especially neutrophils and NLR, were mediators of the relationship between NAFLD fibrosis and CAD severity. CONCLUSIONS: NAFLD patients with advanced fibrosis are at a high risk of severe coronary artery stenosis, and inflammation might mediate the association between NAFLD fibrosis and CAD severity.

A non-lab nomogram of survival prediction in home hospice care patients with gastrointestinal cancer.

BACKGROUND: Patients suffering from gastrointestinal cancer comprise a large group receiving home hospice care in China, however, little is known about the prediction of their survival time. This study aimed to develop a gastrointestinal cancer-specific non-lab nomogram predicting survival time in home-based hospice. METHODS: We retrospectively studied the patients with gastrointestinal cancer from a home-based hospice between 2008 and 2018. General baseline characteristics, disease-related characteristics, and related assessment scale scores were collected from the case records. The data were randomly split into a training set (75%) for developing a predictive nomogram and a testing set (25%) for validation. A non-lab nomogram predicting the 30-day and 60-day survival probability was created using the least absolute shrinkage and selection operator (LASSO) Cox regression. We evaluated the performance of our predictive model by means of the area under receiver operating characteristic curve (AUC) and calibration curve. RESULTS: A total of 1618 patients were included and divided into two sets: 1214 patients (110 censored) as training dataset and 404 patients (33 censored) as testing dataset. The median survival time for overall included patients was 35 days (IQR, 17-66). The 5 most significant prognostic variables were identified to construct the nomogram among all 28 initial variables, including Karnofsky Performance Status (KPS), abdominal distention, edema, quality of life (QOL), and duration of pain. In training dataset validation, the AUC at 30 days and 60 days were 0.723 (95% CI, 0.694-0.753) and 0.733 (95% CI, 0.702-0.763), respectively. Similarly, the AUC value was 0.724 (0.673-0.774) at 30 days and 0.725 (0.672-0.778) at 60 days in the testing dataset validation. Further, the calibration curves revealed good agreement between the nomogram predictions and actual observations in both the training and testing dataset. CONCLUSION: This non-lab nomogram may be a useful clinical tool. It needs prospective multicenter validation as well as testing with Chinese clinicians in charge of hospice patients with gastrointestinal cancer to assess acceptability and usability.

Laparoscopic versus open distal gastrectomy for advanced gastric cancer: A meta-analysis of randomized controlled trials and high-quality nonrandomized comparative studies.

BACKGROUND: Controversy persists about the effects of laparoscopic distal gastrectomy (LDG) versus open distal gastrectomy (ODG) on short-term surgical outcomes and long-term survival within the field of advanced gastric cancer (AGC). METHODS: Studies published from January 1994 to February 2020 that compare LDG and ODG for AGC were identified. All randomized controlled trials (RCTs) were included. The selection of high-quality nonrandomized comparative studies (NRCTs) was based on a validated tool (Methodological Index for Nonrandomized Studies, MINORS). The short- and long-term outcomes of both procedures were compared. RESULTS: Overall, 30 studies were included in this meta-analysis, which comprised of 8 RCTs and 22 NRCTs involving 16,029 patients (7864 LDGs, 8165 ODGs). The recurrence, 3-year disease-free survival (DFS), 3-year overall survival (OS), and 5-year OS rates for LDG and ODG were comparable. LDG was associated with a lower postoperative complication rate (OR 0.79; P < 0.00001), lower estimated volume of blood loss (WMD -102.21 mL; P < 0.00001), shorter postoperative hospital stay (WMD -1.96 days; P < 0.0001), shorter time to first flatus (WMD -0.54 day; P = 0.0007) and shorter time to first liquid diet (WMD -0.66 day; P = 0.001). The number of lymph nodes retrieved, mortality, intraoperative complications, intraoperative blood transfusion, and time to ambulation were similar. However, LDG was associated with a longer surgical time (WMD 33.57 min; P < 0.00001). CONCLUSIONS: LDG with D2 lymphadenectomy is a safe and effective technique for patients with AGC when performed by experienced surgeons at high-volume specialized centers.

High risk of colorectal polyps in men with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND AND AIM: This meta-analysis aims to explore the risk of colorectal polyps among non-alcoholic fatty liver disease (NAFLD) patients. METHODS: We searched PubMed, EMBASE, and Cochrane library databases using predefined search term to identify eligible studies (published up to 7 November 2019). Data from selected studies were extracted by using a standardized information collection form, and meta-analyses were performed using random-effects model. The statistical heterogeneity among studies (I2 ), subgroup analyses, meta-regression analyses, and the possibility of publication bias were assessed. RESULTS: Twenty observational (12 cross-sectional, two case-control, and six cohort) studies met the eligibility criteria, involving 142 387 asymptomatic adults. In cross-sectional/case-control studies, NAFLD was found to be associated with an increased risk of colorectal polyps (odds ratio [OR] = 1.34; 95% confidence interval [CI] = 1.23-1.47) (including unclassified colorectal polyps, hyperplastic polyps, adenomas, and cancers) with statistically significant heterogeneity (I2  = 67.8%; P < 0.001). NAFLD was also associated with a higher risk of incident colorectal polyps (hazard ratio = 1.60; 95% CI = 1.36-1.87) with low heterogeneity (I2  = 21.8%; P = 0.263) in longitudinal studies. The severity of NAFLD was associated with a higher risk of colorectal adenomas (OR = 1.57; 95% CI = 1.30-1.88), but not colorectal cancer (OR = 1.37; 95% CI = 0.92-2.03). The subgroup analysis according to gender showed that NAFLD was significantly associated with a higher risk of colorectal polyps in the male population without significant heterogeneity (OR = 1.47; 95% CI = 1.29-1.67, I2  = 0%), but not in the female population (OR = 0.88; 95% CI = 0.60-1.29, I2  = 34.2%). CONCLUSIONS: NAFLD was associated with an increased risk of colorectal polyps. There was a significant difference of the relationship between genders, which suggested more precise screening colonoscopy recommendation in NAFLD patients according to gender.

MicroRNA-17 promotes cell proliferation and migration in human colorectal cancer by downregulating SIK1.

Purpose: There is mounting evidence to indicate that microRNA-17 (miR-17) is expressed and functionally involved in human cancers. However, the molecular mechanism underlying the role of miR-17 in colorectal cancer (CRC) remains largely unclear. This study aims to reveal the biological function of miR-17 in colorectal cancer. Materials and methods: The expression of miR-17 in CRC cells and tissues was examined using qRT-PCR. Cell proliferation and migration assays were performed after transfection with an miR-17 mimic and inhibitors. The potential gene targets of miR-17 were predicted by bioinformatics analysis and further validated by PCR, Western blot and dual luciferase reporter assays. Results: The expression of miR-17 was significantly upregulated in CRC cell lines and tissues and may imply poor prognosis. miR-17 upregulation promoted cell invasion and migration in CRC cell lines in vitro, while downregulation of miR-17 inhibited tumor progression. SIK1 was identified as a potential direct target of miR-17 by dual luciferase reporter assay, and its downregulation in CRC may suggest poor prognosis. Conclusions: Our study indicated that upregulated miR-17 may promote the progression of CRC and may exert its function as a tumor suppressor miRNA by targeting SIK1.