Hepatocyte-specific Selenoi deficiency predisposes mice to hepatic steatosis and obesity.

Selenoprotein I (Selenoi) is highly expressed in liver and plays a key role in lipid metabolism as a phosphatidylethanolamine (PE) synthase. However, the precise function of Selenoi in the liver remains elusive. In the study, we generated hepatocyte-specific Selenoi conditional knockout (cKO) mice on a high-fat diet to identify the physiological function of Selenoi. The cKO group exhibited a significant increase in body weight, with a 15.6% and 13.7% increase in fat accumulation in white adipose tissue (WAT) and the liver, respectively. Downregulation of the lipolysis-related protein (p-Hsl) and upregulation of the adipogenesis-related protein (Fasn) were observed in the liver of cKO mice. The cKO group also showed decreased oxygen consumption (VO2), carbon dioxide production (VCO2), and energy expenditure (p < .05). Moreover, various metabolites of the steroid hormone synthesis pathway were affected in the liver of cKO mice. A potential cascade of Selenoi-phosphatidylethanolamine-steroid hormone synthesis might serve as a core mechanism that links hepatocyte-specific Selenoi cKO to biochemical and molecular reactions. In conclusion, we revealed that Selenoi inhibits body fat accumulation and hepatic steatosis and elevates energy consumption; this protein could also be considered a therapeutic target for such related diseases.

Risk model and factors for prediction of response to neoadjuvant chemotherapy in patients with advanced gastric cancer-a two-center cohort study.

OBJECTIVE: Due to inconsistency in neoadjuvant chemotherapy (NACT) response in advanced gastric cancer (GC), the indications remain the source of controversy. This study focused on identifying factors related to NACT chemosensitivity and providing the best treatment for GC cases. METHODS: Clinical data in 867 GC cases treated with neoadjuvant chemotherapy were downloaded from two medical centers between January 2014 and December 2020, and analyzed by logistic regression and the least absolute shrinkage and selection operator (LASSO) for identifying potential factors that predicted NACT response and might be incorporated in constructing the prediction nomogram. RESULTS: After the inclusion and exclusion criteria were applied, totally 460 cases were enrolled, among which, 307 were males (66.74%) whereas 153 were females (33.26%), with the age of 24-77 (average, 59.37 ± 10.60) years. Consistent with RECIST standard, 242 patients were classified into effective group (PR or CR) while 218 were into ineffective group (PD or SD), with the effective rate of 52.61%. In training set, LASSO and logistic regression analysis showed that five risk factors were significantly associated with NACT effectiveness, including tumor location, Smoking history, T and N stages, and differentiation. In terms of our prediction model, its C-index was 0.842. Moreover, calibration curve showed that the model-predicted results were in good consistence with actual results. Validation based on internal and external validation sets exhibited consistency between training set results and ours. CONCLUSIONS: This study identified five risk factors which were significantly associated with NACT response, including smoking history, clinical T stage, clinical N stage, tumor location and differentiation. The prediction model that exhibited satisfying ability to predict NACT effectiveness was constructed, which may be adopted for identifying the best therapeutic strategy for advanced GC by gastrointestinal surgeons.

Dietary Selenium Regulates microRNAs in Metabolic Disease: Recent Progress.

Selenium (Se) is an essential element for the maintenance of a healthy physiological state. However, due to environmental and dietary factors and the narrow safety range of Se, diseases caused by Se deficiency or excess have gained considerable traction in recent years. In particular, links have been identified between low Se status, cognitive decline, immune disorders, and increased mortality, whereas excess Se increases metabolic risk. Considerable evidence has suggested microRNAs (miRNAs) regulate interactions between the environment (including the diet) and genes, and play important roles in several diseases, including cancer. MiRNAs target messenger RNAs to induce changes in proteins including selenoprotein expression, ultimately generating disease. While a plethora of data exists on the epigenetic regulation of other dietary factors, nutrient Se epigenetics and especially miRNA regulated mechanisms remain unclear. Thus, this review mainly focuses on Se metabolism, pathogenic mechanisms, and miRNAs as key regulatory factors in Se-related diseases. Finally, we attempt to clarify the regulatory mechanisms underpinning Se, miRNAs, selenoproteins, and Se-related diseases.

Field Testing Integrated Interventions for Schistosomiasis Elimination in the People's Republic of China: Outcomes of a Multifactorial Cluster-Randomized Controlled Trial.

Despite significant progress, China faces the challenge of re-emerging schistosomiasis transmission in currently controlled areas due, in part, to the presence of a range of animal reservoirs, notably water buffalo and cattle, which can harbor Schistosoma japonicum infections. Environmental, ecological and social-demographic changes in China, shown to affect the distribution of oncomelanid snails, can also impact future schistosomiasis transmission. In light of their importance in the S. japonicum, lifecycle, vaccination has been proposed as a means to reduce the excretion of egg from cattle and buffalo, thereby interrupting transmission from these reservoir hosts to snails. A DNA-based vaccine (SjCTPI) our team developed showed encouraging efficacy against S. japonicum in Chinese water buffaloes. Here we report the results of a double-blind cluster randomized trial aimed at determining the impact of a combination of the SjCTPI bovine vaccine (given as a prime-boost regimen), human mass chemotherapy and snail control on the transmission of S. japonicum in 12 selected administrative villages around the Dongting Lake in Hunan province. The trial confirmed human praziquantel treatment is an effective intervention at the population level. Further, mollusciciding had an indirect ~50% efficacy in reducing human infection rates. Serology showed that the SjCTPI vaccine produced an effective antibody response in vaccinated bovines, resulting in a negative correlation with bovine egg counts observed at all post-vaccination time points. Despite these encouraging outcomes, the effect of the vaccine in preventing human infection was inconclusive. This was likely due to activities undertaken by the China National Schistosomiasis Control Program, notably the treatment, sacrifice or removal of bovines from trial villages, over which we had no control; as a result, the trial design was compromised, reducing power and contaminating outcome measures. This highlights the difficulties in undertaking field trials of this nature and magnitude, particularly over a long period, and emphasizes the importance of mathematical modeling in predicting the potential impact of control intervention measures. A transmission blocking vaccine targeting bovines for the prevention of S. japonicum with the required protective efficacy would be invaluable in tandem with other preventive intervention measures if the goal of eliminating schistosomiasis from China is to become a reality.

The role of pleomorphic adenoma gene-like 2 in gastrointestinal cancer development, progression, and prognosis.

Numerous previous studies have revealed that pleomorphic adenoma gene-like 2 (PLAGL2) is a transcription factor that is active in cancer progression. The aim of this study was to investigate the role of PLAGL2 in the development, progression and prognosis of gastrointestinal cancer. Immunohistochemical analysis revealed that PLAGL2 was expressed in gastrointestinal tumors and adjacent normal tissues. The expression of PLAGL2 was significantly higher in 225 colorectal cancer tissues than in 66 adjacent non-tumor tissues (P = 0.037). However, expression was not significantly different between 286 gastric tumors and 57 adjacent non-tumor tissues (P = 0.352). Moreover, the PLAGL2 expression level significantly correlated with the depth of tumor invasion in colorectal cancer (P = 0.030). However, the PLAGL2 expression level significantly correlated with tumor size in gastric cancer (P = 0.046). Furthermore, we performed survival analyses and found that neither higher nor lower PLAGL2 expression was a prognostic factor in gastrointestinal cancer. Our findings indicate that PALGL2 serves as a tumor oncoprotein in the development and progression of colorectal cancer. However, the role of this protein in the development, progression and prognosis of gastric cancer is uncertain. Further investigation into the molecular mechanisms of PLAGL2 activity in gastrointestinal cancer is warranted.

A multi-component integrated approach for the elimination of schistosomiasis in the People's Republic of China: design and baseline results of a 4-year cluster-randomised intervention trial.

Despite major successes in its control over the past 50years, schistosomiasis japonica continues to be a public health problem in the People's Republic of China (P.R. China). Historically, the major endemic foci occur in the lakes and marshlands along the Yangtze River, areas where transmission interruption has proven difficult. The current endemic situation may alter due to the closure of the Three Gorges Dam. Considerable environmental and ecological changes are anticipated that may result in new habitats for the oncomelanid intermediate snail host of Schistosoma japonicum (Sj), thereby increasing the risk of transmission. The current national control program for P.R. China involves a multi-component integrated strategy but, despite targeting multiple transmission pathways, certain challenges remain. As the Chinese government pushes towards elimination, there is a requirement for additional tools, such as vaccination, for long-term prevention. Whereas the zoonotic nature of schistosomiasis japonica adds to the complexity of control, it provides a unique opportunity to develop a transmission blocking vaccine targeting bovines to assist in the prevention of human infection and disease. Mathematical modelling has shown that control options targeting the various transmission pathways of schistosomiasis japonica and incorporating bovine vaccination, mass human chemotherapy and mollusciciding could lead to its elimination from P.R. China. Here we present the study design and baseline results of a four-year cluster randomised intervention trial we are undertaking around the schistosomiasis-endemic Dongting Lake in Hunan Province aimed at determining the impact on schistosome transmission of the multi-component integrated control strategy, including bovine vaccination using a heterologous "prime-boost" delivery platform based on the previously tested SjCTPI vaccine.

ILEI: a novel marker for epithelial-mesenchymal transition and poor prognosis in colorectal cancer.

AIMS: Accumulating evidence over the past decade has shown that abnormal activation of epithelial to mesenchymal transition (EMT) contributes to tumour progression and metastasis in colorectal cancer (CRC). In this study, we investigated the expression of interleukin-like EMT inducer (ILEI) and EMT-associated markers (E-cadherin, vimentin) in CRC tissues and determined the correlations between ILEI expression and clinicopathological characteristics, prognosis and EMT in CRC. METHODS AND RESULTS: In total, 194 patients diagnosed with CRC based on histopathological evaluation and those subjected to surgical resection at the First Hospital of China Medical University between 2003 and 2005 were examined. Immunohistochemical staining for ILEI, vimentin and E-cadherin was performed for each specimen. Cytoplasmic overexpression of ILEI usually accompanied down-regulation of E-cadherin and positive expression of vimentin. Conversely, ILEI was simultaneously down-regulated with overexpression of E-cadherin and negative expression of vimentin. ILEI overexpression was associated significantly with T-stage, N-stage, TNM stage and EMT phenotype (P = 0.024, <0.001, <0.001 and <0.001, respectively). Multivariate analysis revealed that ILEI expression was an independent prognostic factor for patient survival. CONCLUSIONS: Our findings indicate that cytoplasmic ILEI expression is a potential marker of EMT and tumour progression in CRC. ILEI is an independent predictive factor associated with poor prognosis in CRC.

The clinical significance of mesenchyme forkhead 1 (FoxC2) in gastric carcinoma.

AIMS: Mesenchyme forkhead 1 (FoxC2) is an epithelial-mesenchymal transition (EMT)-inducing factor. Previous studies have demonstrated that FoxC2 binds directly to the promoter region of p120-catenin (p120ctn). The aim of this study was to investigate the clinical significance of FoxC2 expression and the inter-relationship between FoxC2 and p120ctn, in gastric cancer. METHODS AND RESULTS: Immunohistochemistry was used to examine the expression of FoxC2 and p120ctn proteins in 325 gastric cancer samples. Staining for FoxC2 in cancer tissues was markedly stronger than in normal tissues. High FoxC2 expression was associated significantly with differentiation, invasion depth, lymph node metastasis and tumour stage. Patients with high FoxC2 expression or low p120ctn expression had a poor prognosis. In the high p120ctn expression group, the prognosis for patients with low FoxC2 expression was better than for the high FoxC2 group. Moreover, stepwise Cox regression showed that p120ctn was an independent prognostic factor, but FoxC2 in combination with p120ctn was not correlated significantly with survival. CONCLUSIONS: We found that FoxC2 and p120ctn play important roles in the progression and prognosis of gastric cancer. Moreover, FoxC2 and p120ctn should be evaluated further as novel biomarkers and therapeutic targets for gastric cancer treatment.

Can the tumor deposits be counted as metastatic lymph nodes in the UICC TNM staging system for colorectal cancer?

OBJECTIVE: The 7th edition of AJCC staging manual implicitly states that only T1 and T2 lesions that lack regional lymph node metastasis but have tumor deposit(s) will be classified in addition as N1c, though it is not consistent in that pN1c is also an option for pT3/T4a tumors in the staging table. Nevertheless, in this TNM classification, how to classify tumor deposits (TDs) in colorectal cancer patients with lymph node metastasis (LNM) and TDs simultaneously is still not clear. The aim of this study is to investigate the possibility of counting TDs as metastatic lymph nodes in TNM classification and to identify its prognostic value for colorectal cancer patients. METHODS AND RESULTS: In this retrospective study, 513 cases of colorectal cancer with LNM were reviewed. We proposed a novel pN (npN) category in which TDs were counted as metastatic lymph nodes in the TNM classification. Cancer-specific survival according to the npN or pN category was analyzed using Kaplan-Meier survival curves. Univariate and multivariate analyses were performed to identify significant prognostic factors. Harrell's C statistic was used to test the predictive capacity of the prognostic models. The results revealed that the TD was a significant prognostic factor in colorectal cancer. Univariate and multivariate analyses uniformly indicated that the npN category was significantly correlated with prognosis. The results of Harrell's C statistical analysis demonstrated that the npN category exhibited a superior predictive capacity compared to the pN category of the 7th edition TNM classification. Moreover, we also found no significant prognostic differences in patients with or without TD in the same npN categories. CONCLUSIONS: The counting of TDs as metastatic lymph nodes in the TNM classification system is potentially superior to the classification in the 7th edition of the TNM staging system to assess prognosis and survival for colorectal cancer patients.

The integration of macroscopic tumor invasion of adjacent organs into TNM staging system for colorectal cancer.

OBJECTIVE: In addition to pathological TNM (pTNM) staging, the macroscopic staging (surgical TNM, sTNM) is another method used to stage and assess tumors, and it also potentially influences patient treatment guidelines. However, for the same patient, surgeons and pathologists might assess tumor depth differently. We aimed to evaluate the prognosis of patients who exhibit unconformity of intraoperative and postoperative results and propose a revised pT category (r-pT category) to predict survival in colorectal cancer. METHODS AND RESULTS: In our study, 948 colorectal cancer patients were reviewed. We proposed a novel r-pT category in which surgical macroscopic T4b (sT4b) is incorporated into the pT category, namely, patients in the pT3 category with sT4b cancers are reclassified as being in the r-pT4a category; patients in the pT4a category with sT4b cancers are reclassified as being in the r-pT4b category. Cancer-specific survival according to the r-pT category was analyzed using Kaplan-Meier survival curves. A two-step multivariate analysis was used to determine correlations between the r-pT category and the prognosis. Harrell's C statistic was utilized to test the predictive capacity. There were significant prognostic differences among the r-pT subcategories. We substituted the r-pT category for the pT category in current TNM staging in a 2-step multivariate analysis. The Harrell's C statistical analysis results demonstrated that the r-pT category had superior predictive capacity compared to the pT category (Harrell' C: 0.668 vs. 0.636; P = 0.002). CONCLUSIONS: Patients in the pT3 category with sT4b cancers, and patients in the pT4a category with sT4b cancers, are potentially under-staged, reclassification into higher categories could potentially benefit these patients. The results indicate that the r-pT category we proposed is potentially superior to the pT category in the assessment of prognosis for colorectal cancer.

[Endothelial cell proliferation stimulated by basic fibroblast growth factor].

OBJECTIVE: To determine the influence of basic fibroblast growth factor (bFGF) on endothelial cell (EC) proliferation in vitro and its possible mechanisms, and to examine the effect of both TNP-470 and dexamethasone (Dex) on the EC proliferation induced by bFGF. METHODS: Human umbilical vein endothelial cells were cultured and the proliferation of EC was quantified by a colorimetric assay using MTT reagent. The expression of nuclear factor-kappa B (NF-kappa B) and ki-67 was detected with SABC immunohistochemical method. RESULTS: bFGF stimulated the EC proliferation and enhanced the expression of NF-kappa B and ki-67 in nucleus; TNP-470 and Dex suppressed EC proliferation induced by bFGF, and reduced the expression of NF-kappa B and ki-67 in nucleus. CONCLUSION: The above results indicate that the possible mechanisms of EC proliferation stimulated by bFGF come from that bFGF can activate NF-kappa B to promote the synthesis of DNA and EC mitosis. TNP-470 and Dex inhibited EC proliferation stimulated by bFGF by inhibiting NF-kappa B.