Optimizing predictions: improved performance of preoperative gadobenate-enhanced MRI hepatobiliary phase features in predicting vessels encapsulating tumor clusters in hepatocellular carcinoma-a multicenter study.

BACKGROUND: Vessels Encapsulating Tumor Clusters (VETC) are now recognized as independent indicators of recurrence and overall survival in hepatocellular carcinoma (HCC) patients. However, there has been limited investigation into predicting the VETC pattern using hepatobiliary phase (HBP) features from preoperative gadobenate-enhanced MRI. METHODS: This study involved 252 HCC patients with confirmed VETC status from three different hospitals (Hospital 1: training set with 142 patients; Hospital 2: test set with 64 patients; Hospital 3: validation set with 46 patients). Independent predictive factors for VETC status were determined through univariate and multivariate logistic analyses. Subsequently, these factors were used to construct two distinct VETC prediction models. Model 1 included all independent predictive factors, while Model 2 excluded HBP features. The performance of both models was assessed using the Area Under the Curve (AUC), Decision Curve Analysis, and Calibration Curve. Prediction accuracy between the two models was compared using Net Reclassification Improvement (NRI) and Integrated Discriminant Improvement (IDI). RESULTS: CA199, IBIL, shape, peritumoral hyperintensity on HBP, and arterial peritumoral enhancement were independent predictors of VETC. Model 1 showed robust predictive performance, with AUCs of 0.836 (training), 0.811 (test), and 0.802 (validation). Model 2 exhibited moderate performance, with AUCs of 0.813, 0.773, and 0.783 in the respective sets. Calibration and decision curves for both models indicated consistent predictions between predicted and actual VETC, benefiting HCC patients. NRI showed Model 1 increased by 0.326, 0.389, and 0.478 in the training, test, and validation sets compared to Model 2. IDI indicated Model 1 increased by 0.036, 0.028, and 0.025 in the training, test, and validation sets compared to Model 2. CONCLUSION: HBP features from preoperative gadobenate-enhanced MRI can enhance the predictive performance of VETC in HCC.

Nomogram prediction of vessels encapsulating tumor clusters in small hepatocellular carcinoma ≤ 3 cm based on enhanced magnetic resonance imaging.

BACKGROUND: Vessels encapsulating tumor clusters (VETC) represent a recently discovered vascular pattern associated with novel metastasis mechanisms in hepatocellular carcinoma (HCC). However, it seems that no one have focused on predicting VETC status in small HCC (sHCC). This study aimed to develop a new nomogram for predicting VETC positivity using preoperative clinical data and image features in sHCC (≤ 3 cm) patients. AIM: To construct a nomogram that combines preoperative clinical parameters and image features to predict patterns of VETC and evaluate the prognosis of sHCC patients. METHODS: A total of 309 patients with sHCC, who underwent segmental resection and had their VETC status confirmed, were included in the study. These patients were recruited from three different hospitals: Hospital 1 contributed 177 patients for the training set, Hospital 2 provided 78 patients for the test set, and Hospital 3 provided 54 patients for the validation set. Independent predictors of VETC were identified through univariate and multivariate logistic analyses. These independent predictors were then used to construct a VETC prediction model for sHCC. The model's performance was evaluated using the area under the curve (AUC), calibration curve, and clinical decision curve. Additionally, Kaplan-Meier survival analysis was performed to confirm whether the predicted VETC status by the model is associated with early recurrence, just as it is with the actual VETC status and early recurrence. RESULTS: Alpha-fetoprotein_lg10, carbohydrate antigen 199, irregular shape, non-smooth margin, and arterial peritumoral enhancement were identified as independent predictors of VETC. The model incorporating these predictors demonstrated strong predictive performance. The AUC was 0.811 for the training set, 0.800 for the test set, and 0.791 for the validation set. The calibration curve indicated that the predicted probability was consistent with the actual VETC status in all three sets. Furthermore, the decision curve analysis demonstrated the clinical benefits of our model for patients with sHCC. Finally, early recurrence was more likely to occur in the VETC-positive group compared to the VETC-negative group, regardless of whether considering the actual or predicted VETC status. CONCLUSION: Our novel prediction model demonstrates strong performance in predicting VETC positivity in sHCC (≤ 3 cm) patients, and it holds potential for predicting early recurrence. This model equips clinicians with valuable information to make informed clinical treatment decisions.

Body mass index influences age-related cataracts: an updated meta-analysis and systemic review.

PURPOSE: Visual impairment and blindness caused by cataracts are major public health problems. Several factors are associated with an increased risk of age-related cataracts, such as age, smoking, alcohol consumption, and ultraviolet radiation. This meta-analysis aimed to assess the association between body mass index and age-related cataracts. METHODS: Studies on weight and age-related cataracts published from January 2011 to July 2020 were reviewed by searching PubMed, Medline, and Web of Science databases. The random-effects and fixed-effects models were used for the meta-analysis, and the results were reported as odd ratios. RESULTS: A total of nine studies were included in the meta-analysis. No correlation was found between underweight and nuclear cataracts (OR=1.31, 95% CI [-0.50 to 3.12], p=0.156). The results of the random-effects model showed that overweight was significantly associated with age-related cataracts and reduced the risk of age-related cataracts (OR=0.91, 95% CI [0.80-1.02], p<0.0001; I2=62.3%, p<0.0001). Significant correlations were found between overweight and cortical, nuclear, and posterior subcapsular cataracts (OR=0.95, 95% CI [0.66-1.24], p<0.0001; OR=0.92, 95% CI (0.76-1.08), p<0.0001; OR=0.87, 95% CI [0.38-1.02], p<0.0001). Significant correlations were found between obesity and cortical, nuclear, and posterior subcapsular cataracts (OR=1.00, 95% CI [0.82-1.17], p<0.0001; OR=1.07, 95% CI [0.92-1.22], p<0.0001; OR=1.14, 95% CI [0.91-1.37], p<0.0001). CONCLUSION: This finding suggested a significant correlation between body mass index and age-related cataracts, with overweight and obesity reducing or increasing the risk of age-related cataracts, respectively.

Total iridoid glycoside extract of Lamiophlomis rotata (Benth) Kudo accelerates diabetic wound healing by the NRF2/COX2 axis.

BACKGROUND: Lamiophlomis rotata (Benth.) Kudo (L. rotata), the oral Traditional Tibetan herbal medicine, is adopted for treating knife and gun wounds for a long time. As previously demonstrated, total iridoid glycoside extract of L. rotata (IGLR) induced polarization of M2 macrophage to speed up wound healing. In diabetic wounds, high levels inflammatory and chemotactic factors are usually related to high reactive oxygen species (ROS) levels. As a ROS target gene, nuclear factor erythroid 2-related factor 2 (NRF2), influences the differentiation of monocytes to M1/M2 macrophages. Fortunately, iridoid glycosides are naturally occurring active compounds that can be used as the oxygen radical scavenger. Nevertheless, the influence of IGLR in diabetic wound healing and its associated mechanism is largely unclear. MATERIALS AND METHODS: With macrophages and dermal fibroblasts in vitro, as well as a thickness excision model of db/db mouse in vivo, the role of IGLR in diabetic wound healing and the probable mechanism of the action were investigated. RESULTS: Our results showed that IGLR suppressed oxidative distress and inflammation partly through the NRF2/cyclooxygenase2 (COX2) signaling pathway in vitro. The intercellular communication between macrophages and dermal fibroblasts was investigated by the conditioned medium (CM) of IGLR treatment cells. The CM increased the transcription and translation of collagen I (COL1A1) and alpha smooth muscle actin (α-SMA) within fibroblasts. With diabetic wound mice, the data demonstrated IGLR activated the NRF2/KEAP1 signaling and the downstream targets of the pathway, inhibited COX2/PEG2 signaling and decreased the interaction inflammatory targets of the axis, like interleukin-1beta (IL-1ß), interleukin 6 (IL-6), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase1 (caspase1) and NOD-like receptor-containing protein 3 (NLRP3).In addition, the deposition of COL1A1, and the level of α-SMA, and Transforming growth factor-ß1 (TGF-ß1) obviously elevated, whereas that of pro-inflammatory factors reduced in the diabetic wound tissue with IGLR treatment. CONCLUSION: IGLR suppressed oxidative distress and inflammation mainly through NRF2/COX2 axis, thus promoting paracrine and accelerating wound healing in diabetes mice.

Tobacco smoking, second-hand smoking exposure in relation to psychotic-like experiences in adolescents.

BACKGROUND: Previous literature supports that tobacco smoking and second-hand smoking (SHS) exposure were strongly associated with poor mental health in the general population. However, there is a lack of empirical data on the relationship between tobacco smoking, SHS exposure and psychotic-like experiences (PLEs). This study conducted a cross-sectional survey to explore PLEs and the associations of PLEs with tobacco smoking and SHS exposure among adolescents in China. METHODS: A total sample of 67 182 Chinese adolescents were recruited from Guangdong province in China (53.7% boys, mean age = 12.79 years) from December 17 to 26, 2021. All adolescents have completed self-reported questionnaires on demographic characteristics, smoking status, SHS exposure and PLEs. RESULTS: Within the sample, only 1.2% of participants had an experience of tobacco smoking while approximately three-fifths reported being exposed to SHS. 10.7% of adolescents reported frequent PLEs over the past month. Adolescents who smoked showed a higher prevalence of PLEs than in non-smoking samples. After controlling for confounders, SHS exposure was a robust risk factor for PLEs with or without the effect of tobacco smoking. DISCUSSION: These findings support the importance of smoke-free legislation, and anti-smoking measures in educational settings directed at both adolescents and their caregiver, which may decrease occurring rates of PLEs among adolescents.

Body mass index influences age-related cataracts: an updated meta-analysis and systemic review / O índice de massa corporal é o fator de influência da catarata relacionada à idade: uma meta-análise atualizada e revisão sistêmica

ABSTRACT Purpose: Visual impairment and blindness caused by cataracts are major public health problems. Several factors are associated with an increased risk of age-related cataracts, such as age, smoking, alcohol consumption, and ultraviolet radiation. This meta-analysis aimed to assess the association between body mass index and age-related cataracts. Methods: Studies on weight and age-related cataracts published from January 2011 to July 2020 were reviewed by searching PubMed, Medline, and Web of Science databases. The random-effects and fixed-effects models were used for the meta-analysis, and the results were reported as odd ratios. Results: A total of nine studies were included in the meta-analysis. No correlation was found between underweight and nuclear cataracts (OR=1.31, 95% CI [-0.50 to 3.12], p=0.156). The results of the random-effects model showed that overweight was significantly associated with age-related cataracts and reduced the risk of age-related cataracts (OR=0.91, 95% CI [0.80-1.02], p<0.0001; I2=62.3%, p<0.0001). Significant correlations were found between overweight and cortical, nuclear, and posterior subcapsular cataracts (OR=0.95, 95% CI [0.66-1.24], p<0.0001; OR=0.92, 95% CI (0.76-1.08), p<0.0001; OR=0.87, 95% CI [0.38-1.02], p<0.0001). Significant correlations were found between obesity and cortical, nuclear, and posterior subcapsular cataracts (OR=1.00, 95% CI [0.82-1.17], p<0.0001; OR=1.07, 95% CI [0.92-1.22], p<0.0001; OR=1.14, 95% CI [0.91-1.37], p<0.0001). Conclusion: This finding suggested a significant correlation between body mass index and age-related cataracts, with overweight and obesity reducing or increasing the risk of age-related cataracts, respectively.

RESUMO Objetivo: A deficiência visual e a cegueira causadas pela catarata são um grande problema de saúde pública. Há vários fatores associados a um risco maior de catarata relacionada à idade na população mundial, tais como idade, tabagismo, consumo de álcool e radiação ultravioleta. Esta meta-análise foi realizada para avaliar a associação entre o índice de massa corporal e a catarata relacionada à idade. Métodos: Foi revisada a literatura sobre catarata relacionada a peso e idade publicada de janeiro de 2011 a julho de 2020, através de buscas nos bancos de dados PubMed, Medline e Web of Science. Na meta-análise, foram utilizados modelos de efeito aleatórios e de efeitos fixos e os resultados foram apresentados como razões de chances (OR). Resultados: Um total de 9 estudos foi incluído na meta-análise. Não houve correlação entre ausência de sobrepeso e cataratas nucleares (OR=1,31, IC 95%: -0,50-3,12, p=0,156). Os resultados do modelo de efeitos aleatórios mostraram que o excesso de peso estava significativamente associado a uma redução do risco de catarata relacionada à idade (OR=0,91, IC 95%: 0,80-1,02, p<0,0001, I2=62,3%, p<0,0001). Houve correlações significativas entre o excesso de peso e cataratas corticais (OR=0,95, IC 95%: 0,66-1,24, p<0,0001), nucleares (OR=0,92, IC 95%: 0,76-1,08, p<0,0001) e subcapsulares posteriores (OR=0,87, IC 95%: 0,38-1,02, p<0,0001) relacionadas à idade. Houve correlações significativas entre obesidade e cataratas corticais (OR=1,00, IC 95%: 0,82-1,17, p<0,0001), nucleares (OR=1,07, IC 95%: 0,92-1,22, p<0,0001) e subcapsulares posteriores (OR=1,14, IC 95%: 0,91-1,37, p<0,0001) relacionadas à idade. Conclusão: Estes achados sugeriram uma correlação significativa entre o índice de massa corporal e a catarata relacionada à idade, com o excesso de peso e a obesidade reduzindo e aumentando o risco de catarata relacionada à idade, respectivamente.

Garlic consumption and colorectal cancer risk in US adults: a large prospective cohort study.

Objective: To clarify the inconsistent findings of epidemiological studies on the association between dietary garlic consumption and colorectal cancer (CRC) incidence, by prospectively assessing the association in a large US population. Methods: Data of 58,508 participants (aged 55-74) from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were analyzed. Dietary data were collected using a validated questionnaire. Multivariable Cox regression analysis determined hazard ratio (HR) and 95% confidence interval (CI). Restricted cubic spline regression was used to investigate the non-linear relationship, and subgroup analysis was conducted to examine potential effect modifiers. Results: During a median follow-up of 12.05 years, 782 CRC cases were documented, including 456 proximal colon cancer cases, 322 distal CRC cases, and 4 CRC cases with an unknown site. Moderate dietary garlic consumption was significantly associated with a reduced risk of overall CRC (HRquintile 3vs. 1: 0.70, 95% CI: 0.54 to 0.91, p = 0.007, P for trend: 0.434), exhibiting a U-shaped dose-response pattern, and also with overall CRC in males in the stratified Cox regression model (Model 2: HRquintile 3vs. 1: 0.57, 95% CI: 0.40 to 0.81, p = 0.002), but not in females. The protective association was more pronounced in men, Caucasian, and those with lower alcohol consumption. Notably, these protective effects were observed for overall distal CRC (HRquintile 3vs. 1: 0.62, 95% CI: 0.42 to 0.93, p = 0.021; and HRquintile 4vs. 1: 0.63, 95% CI: 0.43 to 0.92, p = 0.018, P for trend: 0.208); and for distal CRC in males (HRquintile 3vs. 1: 0.40, 95% CI: 0.22 to 0.71, p = 0.002, P for trend: 0.696), but not for proximal CRC. Conclusion: Moderate consumption of dietary garlic is associated with a decreased CRC risk in the US population, with variations based on CRC anatomic subsites. Further in-depth prospective studies are needed to validate these findings in different populations and to explore subsites-specific associations.

Associations between colorectal cancer risk and dietary intake of tomato, tomato products, and lycopene: evidence from a prospective study of 101,680 US adults.

Background: Previous epidemiological studies have yielded inconsistent results regarding the effects of dietary tomato, tomato products, and lycopene on the incidence of colorectal cancer (CRC), possibly due to variations in sample sizes and study designs. Methods: The current study used multivariable Cox regression, subgroup analyses, and restricted cubic spline functions to investigate correlations between CRC incidence and mortality and raw tomato, tomato salsa, tomato juice, tomato catsup, and lycopene intake, as well as effect modifiers and nonlinear dose-response relationships in 101,680 US adults from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Results: During follow-up 1100 CRC cases and 443 CRC-specific deaths occurred. After adjustment for confounding variables, high consumption of tomato salsa was significantly associated with a reduced risk of CRC incidence (hazard ratio comparing the highest category with the lowest category 0.8, 95% confidence interval 0.65-0.99, p for trend = 0.039), but not with a reduced risk of CRC mortality. Raw tomatoes, tomato juice, tomato catsup, and lycopene consumption were not significantly associated with CRC incidence or CRC mortality. No potential effect modifiers or nonlinear associations were detected, indicating the robustness of the results. Conclusion: In the general US population a higher intake of tomato salsa is associated with a lower CRC incidence, suggesting that tomato salsa consumption has beneficial effects in terms of cancer prevention, but caution is warranted when interpreting these findings. Further prospective studies are needed to evaluate its potential effects in other populations.

Differences in Gut Microbiota between Healthy Individuals and Patients with Perianal Abscess before and after Surgery.

Surgery is the most important treatment for perianal abscesses. However, the gut microbiota of patients with perianal abscess and the effects of perianal abscess on the gut microbiota after surgery are unknown. In this study, significant changes in interleukin 6 and tumor necrosis factor-α in the blood of healthy subjects, patients with perianal abscesses, and patients after perianal abscess surgery were identified. 16S rRNA gene sequencing technology was used to detect the changes in the gut microbiota among 30 healthy individuals and 30 patients with perianal abscess before and after surgery. Venn diagrams and alpha diversity analyses indicated differences in the abundance and uniformity of gut microbiota between the healthy individuals and patients with perianal abscesses before and after surgery. Beta diversity analysis indicated that the grouping effects among the control, abscess, and surgery groups were good. The classification and compositional analysis showed significant differences in the gut microbiota between healthy individuals and patients with perianal abscesses before and after surgery. LEfSe analysis, random forest analysis, and ROC curve analysis showed that Klebsiella (AUC = 0.7467) and Bilophila (AUC = 0.72) could be potential biomarkers for the diagnosis of perianal abscess. The functional prediction results showed that the differential microbiota is significantly enriched in the pathways related to nutrition and drug metabolism. This study may have important implications for the clinical management and prognostic assessment of patients with perianal abscesses.

Exploring the role of sphingolipid-related genes in clinical outcomes of breast cancer.

Background: Despite tremendous advances in cancer research, breast cancer (BC) remains a major health concern and is the most common cancer affecting women worldwide. Breast cancer is a highly heterogeneous cancer with potentially aggressive and complex biology, and precision treatment for specific subtypes may improve survival in breast cancer patients. Sphingolipids are important components of lipids that play a key role in the growth and death of tumor cells and are increasingly the subject of new anti-cancer therapies. Key enzymes and intermediates of sphingolipid metabolism (SM) play an important role in regulating tumor cells and further influencing clinical prognosis. Methods: We downloaded BC data from the TCGA database and GEO database, on which we performed in depth single-cell sequencing analysis (scRNA-seq), weighted co-expression network analysis, and transcriptome differential expression analysis. Then seven sphingolipid-related genes (SRGs) were identified using Cox regression, least absolute shrinkage, and selection operator (Lasso) regression analysis to construct a prognostic model for BC patients. Finally, the expression and function of the key gene PGK1 in the model were verified by in vitro experiments. Results: This prognostic model allows for the classification of BC patients into high-risk and low-risk groups, with a statistically significant difference in survival time between the two groups. The model is also able to show high prediction accuracy in both internal and external validation sets. After further analysis of the immune microenvironment and immunotherapy, it was found that this risk grouping could be used as a guide for the immunotherapy of BC. The proliferation, migration, and invasive ability of MDA-MB-231 and MCF-7 cell lines were dramatically reduced after knocking down the key gene PGK1 in the model through cellular experiments. Conclusion: This study suggests that prognostic features based on genes related to SM are associated with clinical outcomes, tumor progression, and immune alterations in BC patients. Our findings may provide insights for the development of new strategies for early intervention and prognostic prediction in BC.

Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer.

Background: Although breast cancer (BC) treatment has entered the era of precision therapy, the prognosis is good in the case of comprehensive multimodal treatment such as neoadjuvant, endocrine, and targeted therapy. However, due to its high heterogeneity, some patients still cannot benefit from conventional treatment and have poor survival prognoses. Amino acids and their metabolites affect tumor development, alter the tumor microenvironment, play an increasingly obvious role in immune response and regulation of immune cell function, and are involved in acquired and innate immune regulation; therefore, amino acid metabolism is receiving increasing attention. Methods: Based on public datasets, we carried out a comprehensive transcriptome and single-cell sequencing investigation. Then we used 2.5 Weighted Co-Expression Network Analysis (WGCNA) and Cox to evaluate glutamine metabolism-related genes (GRGs) in BC and constructed a prognostic model for BC patients. Finally, the expression and function of the signature key gene SNX3 were examined by in vitro experiments. Results: In this study, we constituted a risk signature to predict overall survival (OS) in BC patients by glutamine-related genes. According to our risk signature, BC patients can obtain a Prognostic Risk Signature (PRS), and the response to immunotherapy can be further stratified according to PRS. Compared with traditional clinicopathological features, PRS demonstrated robust prognostic power and accurate survival prediction. In addition, altered pathways and mutational patterns were analyzed in PRS subgroups. Our study sheds some light on the immune status of BC. In in vitro experiments, the knockdown of SNX3, an essential gene in the signature, resulted in a dramatic reduction in proliferation, invasion, and migration of MDA-MB-231 and MCF-7 cell lines. Conclusion: We established a brand-new PRS consisting of genes associated with glutamine metabolism. It expands unique ideas for the diagnosis, treatment, and prognosis of BC.

The Nord Stream pipeline gas leaks released approximately 220,000 tonnes of methane into the atmosphere.

Sudden mega natural gas leaks of two Nord Stream pipelines in the Baltic Sea (Denmark) occurred from late September to early October 2022, releasing large amounts of methane into the atmosphere. We inferred the methane emissions of this event based on surface in situ observations using two inversion methods and two meteorological reanalysis datasets, supplemented with satellite-based observations. We conclude that approximately 220 ± 30 Gg of methane was released from September 26 to October 1, 2022.

PD-1/PD-L1 inhibitors for advanced or metastatic cervical cancer: From bench to bed.

Advanced or metastatic cervical cancer has a poor prognosis, and the 5-year overall survival is <5% with conventional radiotherapy and chemotherapy. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), achieved initial success in advanced solid tumors, while their efficacy and safety in advanced or metastatic cervical cancer remains to be explored. Previous studies found high-risk HPV infection and elevated PD-L1 expression in cervical precancerous lesions and squamous cell carcinoma. Meanwhile, elevated PD-L1 expression, high cytotoxic T lymphocyte infiltration, and abnormal cytotoxic T lymphocyte function might benefit inflammation infiltration for ICIs in the tumor microenvironment. Patients with HPV infection, squamous cell carcinoma, advanced stage, large tumor size, poor differentiation, metastatic disease, history of multiple childbirth and abortion, or a previous history of receiving chemotherapy might be associated with positive PD-L1 expression. Although there is no correlation between PD-L1 expression and prognosis using conventional radiotherapy, patients with high PD-L1 expression have a poorer prognosis. Several clinical studies demonstrate preliminary safety and efficacy for PD-1/PD-L1 inhibitors, and the exploration of combination strategies such as immunotherapy combined with chemotherapy, radiotherapy, anti-angiogenesis therapy, or dual ICIs is ongoing. This paper systematically reviews PD-L1 expression patterns and their relationship with prognosis, along with reported and ongoing clinical trials of PD-1/PD-L1 inhibitors in cervical cancer to clarify the prospect of ICIs for cervical cancer from bench to bed.

Association of Dietary Carrot/Carotene Intakes With Colorectal Cancer Incidence and Mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Background: The evidence of dietary carrot/carotene intake's effect on the association with colorectal cancer (CRC) risk is conflicted. We sought to examine the association of carrot/carotene intake with CRC incidence and mortality in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening cohort. Methods: In all, 101,680 participants were enrolled between November 1993 and July 2001 from the PLCO cohort. We employed the multivariable Cox regression analyses to estimate the hazard ratios and 95% confidence interval. Subgroup analyses and interaction tests were performed to examine the potential effect modifiers. We further applied the generalized additive model to explore the non-linear trend of the exposure to cancer-related outcomes. Results: A total of 1,100 CRC cases and 443 cancer-related deaths were documented. We noted that the 4th quintile of dietary carrot intakes was associated with a 21% lower risk of CRC incidence, compared with the lowest quintile group (full-adjusted HRquintile4vs.quintile1 = 0.79, 95%CI = 0.65-0.97, p for trend = 0.05), while the adjusted-HR was 0.95 (95%CI = 0.89-1.02) with per SD increment of carrot intakes, and no statistically significant associations were detected between dietary α-, and ß-carotene intake and CRC incidence. There were no statistically significant associations observed between carrot/carotene intakes and CRC mortality. Furthermore, there were no non-linear dose-response relationships between dietary carrot, α-, and ß-carotene intake and CRC incidence and mortality (all p nonlinearity > 0.05). Of note, smoking status as a modifier on the association of dietary carrot intakes with CRC incidence but not mortality was observed. Conclusions: In summary, this large U.S. prospective cohort study indicated that a moderate consumption of carrots was associated with a lower CRC incidence, which suggested that a certain dose-range of carrots consumed might contribute to a potential cancer-prevention effect, not the more the better.

Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction.

PURPOSE: Progressive corneal edema and endothelial cell loss represent the major corneal complications observed in diabetic patients after intraocular surgery. However, the underlying pathogenesis and potential treatment remain incompletely understood. METHODS: We used streptozotocin-induced type 1 diabetic mice and db/db type 2 diabetic mice as diabetic animal models. These mice were treated with the endoplasmic reticulum (ER) stress agonist thapsigargin; 60-mmHg intraocular pressure (IOP) with the ER stress antagonist 4-phenylbutyric acid (4-PBA); mitochondria-targeted antioxidant SkQ1; or reactive oxygen species scavenger N-acetyl-l-cysteine (NAC). Corneal thickness and endothelial cell density were measured before and after treatment. Human corneal endothelial cells were treated with high glucose with or without 4-PBA. The expression of corneal endothelial- and ER stress-related genes was detected by western blot and immunofluorescence staining. Mitochondrial bioenergetics were measured with an Agilent Seahorse XFp Analyzer. RESULTS: In diabetic mice, the appearance of ER stress preceded morphological changes in the corneal endothelium. The persistent ER stress directly caused corneal edema and endothelial cell loss in normal mice. Pharmacological inhibition of ER stress was sufficient to mitigate corneal edema and endothelial cell loss in both diabetic mice after high IOP treatment. Mechanistically, inhibiting ER stress ameliorated the hyperglycemia-induced mitochondrial bioenergetic deficits and improved the barrier and pump functional recovery of the corneal endothelium. When compared with NAC, 4-PBA and SkQ1 exhibited better improvement of corneal edema and endothelial cell loss in diabetic mice. CONCLUSIONS: Hyperglycemia-induced ER stress contributes to the dysfunction of diabetic corneal endothelium, and inhibiting ER stress may offer therapeutic potential by improving mitochondrial bioenergetics.

Cetuximab-decorated and NIR-activated Nanoparticles Based on Platinum(IV)-prodrug: Preparation, Characterization and In-vitro Anticancer Activity in Epidermoid Carcinoma Cells.

Platinum-based drugs are the mainstay of chemotherapy regimens in a clinic, but their use is seriously limited by severe side effects and drug resistance. A cetuximab-decorated drug delivery system can selectively deliver drugs into EGFR-highexpressing cancer cells to prevent the shortcomings of platinum-based chemotherapy. Here, cetuximab-decorated and near-infrared (NIR)-activated nanoparticles based on Pt(IV)-prodrug (abbreviated as Cetuximab-Pt-INPs) was constructed. First, PEGylated Pt(IV)-prodrug was synthesized by a condensation reaction between c,c,t-[Pt(NH3)2Cl2(OOCCH2CH2COOH)(OH)] and MPEG-PLA. Then, Pt(IV)-prodrug and indocyanine green co-encapsulated nanoparticles (Pt-INPs) were prepared through an ultrasonic emulsification method. Finally, Cetuximab-Pt-INPs were obtained by decorating Pt-INPs with cetuximab as a targeting vector. The optimized Cetuximab-Pt-INPs exhibited a spherical core-shell shape of 138.5 ± 0.96 nm. In-vitro cellular uptake and cytotoxicity assays revealed that more Cetuximab-Pt-INPs with NIR irradiation were selectively taken up by A431 cells, thereby leading to higher cytotoxicity. These multifunctional nanoparticles may have promising potential for targeted and effective therapy against EGFR-highexpressing cells of epidermoid carcinoma.

Lactate Dehydrogenase-A (LDH-A) Preserves Cancer Stemness and Recruitment of Tumor-Associated Macrophages to Promote Breast Cancer Progression.

Increasing evidence reveals that breast cancer stem cells (BCSCs) subtypes with distinct properties are regulated by their abnormal metabolic changes; however, the specific molecular mechanism and its relationship with tumor microenvironment (TME) are not clear. In this study, we explored the mechanism of lactate dehydrogenase A (LDHA), a crucial glycolytic enzyme, in maintaining cancer stemness and BCSCs plasticity, and promoting the interaction of BCSCs with tumor associated macrophages (TAMs). Firstly, the expression of LDHA in breast cancer tissues was much higher than that in adjacent tissues and correlated with the clinical progression and prognosis of breast cancer patients based on The Cancer Genome Atlas (TCGA) data set. Moreover, the orthotopic tumor growth and pulmonary metastasis were remarkable inhibited in mice inoculated with 4T1-shLdha cells. Secondly, the properties of cancer stemness were significantly suppressed in MDA-MB-231-shLDHA or A549-shLDHA cancer cells, including the decrease of ALDH+ cells proportion, the repression of sphere formation and cellular migration, and the reduction of stemness genes (SOX2, OCT4, and NANOG) expression. However, the proportion of ALDH+ cells (epithelial-like BCSCs, E-BCSCs) was increased and the proportion of CD44+ CD24- cells (mesenchyme-like BCSCs, M-BCSCs) was decreased after LDHA silencing, suggesting a regulatory role of LDHA in E-BCSCs/M-BCSCs transformation in mouse breast cancer cells. Thirdly, the expression of epithelial marker E-cadherin, proved to interact with LDHA, was obviously increased in LDHA-silencing cancer cells. The recruitment of TAMs and the secretion of CCL2 were dramatically reduced after LDHA was knocked down in vitro and in vivo. Taken together, LDHA mediates a vicious cycle of mutual promotion between BCSCs plasticity and TAMs infiltration, which may provide an effective treatment strategy by targeting LDHA for breast cancer patients.

Association between alcohol consumption and oesophageal microbiota in oesophageal squamous cell carcinoma.

BACKGROUND: Microbiota has been reported to play a role in cancer patients. Nevertheless, little is known about the association between alcohol consumption and resultant changes in the diversity and composition of oesophageal microbiota in oesophageal squamous cell carcinoma (ESCC). METHODS: We performed a hospital-based retrospective study of 120 patients with pathologically diagnosed primary ESCC. The relevant information for all study participants were collected through a detailed questionnaire. The differences in adjacent tissues between non-drinkers and drinkers were explored using 16S rRNA gene sequencing. Raw sequencing data were imported into QIIME 2 to analyse the diversity and abundance of microbiota. Linear discriminant analysis effect size (LEfSe) and unconditional logistic regression were performed to determine the bacterial taxa that were associated with drinking. RESULTS: The Shannon diversity index and Bray-Curtis distance of oesophageal microbiota were significantly different among drinkers(P < 0.05). The alcohol-related bacteria were primarily from the orders Clostridiales, Gemellales and Pasteurellales, family Clostridiaceae, Lanchnospiraceae, Helicobacteraceae, Alcaligenaceae, Bacteroidaceae, Pasteurellaceae and Gemellaceae; genus Clostridium, Helicobacter, Catonella, Bacteroides, Bacillus, Moraxella, and Bulleidia; and species B. moorei and longum (genus Bifidobacterium). In addition, the diversity and abundance of these microbiota were observed to be affected by the age, residential districts of the patients, and sampling seasons. Moreover, the higher the frequency and years of alcohol consumption, the lower was the relative abundance of genus Catonella that was observed. CONCLUSION: Alcohol consumption is associated with alterations in both the diversity and composition the of the oesophageal microbiota in ESCC patients.

MicroRNA-3613-3p functions as a tumor suppressor and represents a novel therapeutic target in breast cancer.

BACKGROUND: MicroRNAs have been reported to participate in tumorigenesis, treatment resistance, and tumor metastasis. Novel microRNAs need to be identified and investigated to guide the clinical prognosis or therapy for breast cancer. METHOD: The copy number variations (CNVs) of MIR3613 from Cancer Genome Atlas (TCGA) or Cancer Cell Line Encyclopedia (CCLE) were analyzed, and its correlation with breast cancer subtypes or prognosis was investigated. The expression level of miR-3613-3p in tumor tissues or serum of breast cancer patients was detected using in situ hybridization and qPCR. Gain-of-function studies were performed to determine the regulatory role of miR-3613-3p on proliferation, apoptosis, and tumor sphere formation of human breast cancer cells MDA-MB-231 or MCF-7. The effects of miR-3613-3p on tumor growth or metastasis in an immunocompromised mouse model of MDA-MB-231-luciferase were explored by intratumor injection of miR-3613-3p analogue. The target genes, interactive lncRNAs, and related signaling pathways of miR-3613-3p were identified by bioinformatic prediction and 3'-UTR assays. RESULTS: We found that MIR3613 was frequently deleted in breast cancer genome and its deletion was correlated with the molecular typing, and an unfavorable prognosis in estrogen receptor-positive patients. MiR-3613-3p level was also dramatically lower in tumor tissues or serum of breast cancer patients. Gain-of-function studies revealed that miR-3613-3p could suppress proliferation and sphere formation and promote apoptosis in vitro and impeded tumor growth and metastasis in vivo. Additionally, miR-3613-3p might regulate cell cycle by targeting SMS, PAFAH1B2, or PDK3 to restrain tumor progression. CONCLUSION: Our findings indicate a suppressive role of miR-3613-3p in breast cancer progression, which may provide an innovative marker or treatment for breast cancer patients.

Upregulated expression of serum exosomal hsa_circ_0026611 is associated with lymph node metastasis and poor prognosis of esophageal squamous cell carcinoma.

Background: To identify the diagnostic and prognostic values of serum exosomal hsa_circ_0026611 in esophageal squamous cell carcinoma (ESCC). Methods: ESCC serum exosome global circRNA expression was detected using a circRNA microarray. The expression levels of candidate serum exosome circRNAs were detected by quantitative polymerase chain reaction (qRT-PCR). A receiver operating characteristic curve (ROC) was generated to confirm the diagnostic value. Survival data and their differences were observed by the Kaplan-Meier method and log-rank tests. The Cox regression analysis was employed to identify prognostic factors. Results: The expression levels of serum exosomal has_circ_0026611 in ESCC with lymph node metastasis were significantly higher than those in ESCC without lymph node metastasis (P =0.001). In addition, serum exosomal hsa_circ_0026611 expression could be used as a significant parameter to discriminate between non-lymph node-metastatic and lymph node-metastatic ESCC with an area under curve (AUC) of 0.724 (95% CI: 0.604~0.865). The multivariate Cox regression analysis indicated that survival was poor in patients with high serum exosomal hsa_circ_0026611 expression levels compared to those with low serum exosomal hsa_circ_0026611 levels (for OS, HR [95% CI]: 3.79 [1.27, 11.29], for DFS, HR [95% CI]: 2.77 [1.06, 7.22]). Conclusion: Serum exosomal hsa_circ_0026611 expression is significantly upregulated in ESCC with lymph node metastasis and is a predictor of ESCC prognosis.