A Prognostic Model Based on Nutritional Indexes for Patients With Pan-Cancer: A Real-World Cohort Study.

BACKGROUND: The aim was to identify the nutritional indexes, construct a prognostic model, and develop a nomogram for predicting individual survival probability in pan-cancers. METHODS: Nutritional indicators, clinicopathological characteristics, and previous major treatment details of the patients were collected. The enrolled patients were randomly divided into training and validation cohorts. Least absolute shrinkage and selection operator (Lasso) regression cross-validation was used to determine the variables to include in the cox regression model. The training cohort was used to build the prediction model, and the validation cohort was used to further verify the discrimination, calibration, and clinical effectiveness of the model. RESULTS: A total of 2020 patients were included. The median OS was 56.50 months (95% CI, 50.36-62.65 months). In the training cohort of 1425 patients, through Lasso regression cross-validation, 13 characteristics were included in the model. Cox proportional hazards model was developed and visualized as a nomogram. The C-indexes of the model for predicting 1-, 3-, 5-, and 10-year OS were 0.848, 0.826, 0.814, and 0.799 in the training cohort and 0.851, 0.819, 0.814, and 0.801 in the validation cohort. The model showed great calibration in the two cohorts. Patients with a score of less than 274.29 had a better prognosis (training cohort: HR, 6.932; 95% CI, 5.723-8.397; log-rank p < 0.001; validation cohort: HR, 8.429; 95% CI, 6.180-11.497; log-rank p < 0.001). CONCLUSION: The prognostic model based on the nutritional indexes of pan-cancer can divide patients into different survival risk groups and performed well in the validation cohort.

Causal relationships between modifiable risk factors and polycystic ovary syndrome: a comprehensive Mendelian randomization study.

Background: Polycystic Ovary Syndrome (PCOS) is a heritable condition with an as yet unclear etiology. Various factors, such as genetics, lifestyle, environment, inflammation, insulin resistance, hyperandrogenism, iron metabolism, and gut microbiota, have been proposed as potential contributors to PCOS. Nevertheless, a systematic assessment of modifiable risk factors and their causal effects on PCOS is lacking. This study aims to establish a comprehensive profile of modifiable risk factors for PCOS by utilizing a two-sample Mendelian Randomization (MR) framework. Methods: After identifying over 400 modifiable risk factors, we employed a two-sample MR approach, including the Inverse Variance Weighted (IVW) method, Weighted Median method, and MR-Egger, to investigate their causal associations with PCOS. The reliability of our estimates underwent rigorous examination through sensitivity analyses, encompassing Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Results: We discovered that factors such as smoking per day, smoking initiation, body mass index, basal metabolic rate, waist-to-hip ratio, whole body fat mass, trunk fat mass, overall health rating, docosahexaenoic acid (DHA) (22:6n-3) in blood, monounsaturated fatty acids, other polyunsaturated fatty acids apart from 18:2 in blood, omega-3 fatty acids, ratio of bisallylic groups to double bonds, omega-9 and saturated fatty acids, total lipids in medium VLDL, phospholipids in medium VLDL, phospholipids in very large HDL, triglycerides in very large HDL, the genus Oscillibacter, the genus Alistipes, the genus Ruminiclostridium 9, the class Mollicutes, and the phylum Tenericutes, showed a significant effect on heightening genetic susceptibility of PCOS. In contrast, factors including fasting insulin interaction with body mass index, sex hormone-binding globulin, iron, ferritin, SDF1a, college or university degree, years of schooling, household income, the genus Enterorhabdus, the family Bifidobacteriaceae, the order Bifidobacteriales, the class Actinobacteria, and the phylum Actinobacteria were determined to reduce risk of PCOS. Conclusion: This study innovatively employs the MR method to assess causal relationships between 400 modifiable risk factors and the susceptibility of PCOS risk. It supports causal links between factors like smoking, BMI, and various blood lipid levels and PCOS. These findings offer novel insights into potential strategies for the management and treatment of PCOS.

Predicting radiation pneumonitis in lung cancer: a EUD-based machine learning approach for volumetric modulated arc therapy patients.

Purpose: This study aims to develop an optimal machine learning model that uses lung equivalent uniform dose (lung EUD to predict radiation pneumonitis (RP) occurrence in lung cancer patients treated with volumetric modulated arc therapy (VMAT). Methods: We analyzed a cohort of 77 patients diagnosed with locally advanced squamous cell lung cancer (LASCLC) receiving concurrent chemoradiotherapy with VMAT. Patients were categorized based on the onset of grade II or higher radiation pneumonitis (RP 2+). Dose volume histogram data, extracted from the treatment planning system, were used to compute the lung EUD values for both groups using a specialized numerical analysis code. We identified the parameter α, representing the most significant relative difference in lung EUD between the two groups. The predictive potential of variables for RP2+, including physical dose metrics, lung EUD, normal tissue complication probability (NTCP) from the Lyman-Kutcher-Burman (LKB) model, and lung EUD-calibrated NTCP for affected and whole lung, underwent both univariate and multivariate analyses. Relevant variables were then employed as inputs for machine learning models: multiple logistic regression (MLR), support vector machine (SVM), decision tree (DT), and K-nearest neighbor (KNN). Each model's performance was gauged using the area under the curve (AUC), determining the best-performing model. Results: The optimal α-value for lung EUD was 0.3, maximizing the relative lung EUD difference between the RP 2+ and non-RP 2+ groups. A strong correlation coefficient of 0.929 (P< 0.01) was observed between lung EUD (α = 0.3) and physical dose metrics. When examining predictive capabilities, lung EUD-based NTCP for the affected lung (AUC: 0.862) and whole lung (AUC: 0.815) surpassed LKB-based NTCP for the respective lungs. The decision tree (DT) model using lung EUD-based predictors emerged as the superior model, achieving an AUC of 0.98 in both training and validation datasets. Discussions: The likelihood of developing RP 2+ has shown a significant correlation with the advancements in RT technology. From traditional 3-D conformal RT, lung cancer treatment methodologies have transitioned to sophisticated techniques like static IMRT. Accurately deriving such a dose-effect relationship through NTCP modeling of RP incidence is statistically challenging due to the increased number of degrees-of-freedom. To the best of our knowledge, many studies have not clarified the rationale behind setting the α-value to 0.99 or 1, despite the closely aligned calculated lung EUD and lung mean dose MLD. Perfect independence among variables is rarely achievable in real-world scenarios. Four prominent machine learning algorithms were used to devise our prediction models. The inclusion of lung EUD-based factors substantially enhanced their predictive performance for RP 2+. Our results advocate for the decision tree model with lung EUD-based predictors as the optimal prediction tool for VMAT-treated lung cancer patients. Which could replace conventional dosimetric parameters, potentially simplifying complex neural network structures in prediction models.

Cancer-associated fibroblasts facilitate DNA damage repair by promoting the glycolysis in non-small cell lung cancer.

Radiotherapy is an essential treatment modality for the management of non-small cell lung cancer (NSCLC) patients. Tumor radioresistance is the major factor limiting the efficacy of radiotherapy in NSCLC patients. Our study aimed to reveal whether cancer-associated fibroblasts (CAFs), one main component of the tumor microenvironment, regulated DNA damage response of NSCLC cells following irradiation and clarify the involved mechanisms. We found CAFs inhibited irradiation-induced DNA damage while promoted DNA repair of NSCLC cells and caused cell cycle arrest in the radioresistant S phase. CAFs have the ability of up-regulating and stabilizing c-Myc, leading to the transcription activation of HK2 kinase, a key rate-limiting enzyme in glycolysis by activating Wnt/ß-catenin pathway. Attenuation of glycolysis significantly reversed the effect of CAFs on DNA damage response of NSCLC cells. By high-throughput screening of human cytokines/chemokines array, we found CAFs-secreted midkine led to the promotion of glycolysis by activating Wnt/ß-catenin pathway in NSCLC cells. In vivo, CAFs caused the radioresistance of NSCLC cells also by promoting the glycolysis in a ß-catenin signaling-dependent manner. These findings may provide novel strategies for reversing the radioresistance of NSCLC cells.

Prediction of radiation-induced acute skin toxicity in breast cancer patients using data encapsulation screening and dose-gradient-based multi-region radiomics technique: A multicenter study.

Purpose: Radiation-induced dermatitis is one of the most common side effects for breast cancer patients treated with radiation therapy (RT). Acute complications can have a considerable impact on tumor control and quality of life for breast cancer patients. In this study, we aimed to develop a novel quantitative high-accuracy machine learning tool for prediction of radiation-induced dermatitis (grade ≥ 2) (RD 2+) before RT by using data encapsulation screening and multi-region dose-gradient-based radiomics techniques, based on the pre-treatment planning computed tomography (CT) images, clinical and dosimetric information of breast cancer patients. Methods and Materials: 214 patients with breast cancer who underwent RT between 2018 and 2021 were retrospectively collected from 3 cancer centers in China. The CT images, as well as the clinical and dosimetric information of patients were retrieved from the medical records. 3 PTV dose related ROIs, including irradiation volume covered by 100%, 105%, and 108% of prescribed dose, combined with 3 skin dose-related ROIs, including irradiation volume covered by 20-Gy, 30-Gy, 40-Gy isodose lines within skin, were contoured for radiomics feature extraction. A total of 4280 radiomics features were extracted from all 6 ROIs. Meanwhile, 29 clinical and dosimetric characteristics were included in the data analysis. A data encapsulation screening algorithm was applied for data cleaning. Multiple-variable logistic regression and 5-fold-cross-validation gradient boosting decision tree (GBDT) were employed for modeling training and validation, which was evaluated by using receiver operating characteristic analysis. Results: The best predictors for symptomatic RD 2+ were the combination of 20 radiomics features, 8 clinical and dosimetric variables, achieving an area under the curve (AUC) of 0.998 [95% CI: 0.996-1.0] and an AUC of 0.911 [95% CI: 0.838-0.983] in the training and validation dataset, respectively, in the 5-fold-cross-validation GBDT model. Meanwhile, the top 12 most important characteristics as well as their corresponding importance measures for RD 2+ prediction in the GBDT machine learning process were identified and calculated. Conclusions: A novel multi-region dose-gradient-based GBDT machine learning framework with a random forest based data encapsulation screening method integrated can achieve a high-accuracy prediction of acute RD 2+ in breast cancer patients.

Capilliposide from Lysimachia capillipes promotes terminal differentiations and reverses paclitaxel resistance in A2780T cells of human ovarian cancer by regulating Fos/Jun pathway.

Objective: To investigate the potential effect of Lysimachia capillipes capilliposide (LCC) on the chemo sensitivity and the stemness of human ovarian cancer cells. Methods: Cell Counting Kit-8 (CCK8) was used to measure the IC50 values. The apoptosis of cells was measured through flow cytometry. Evaluation of the stemness and differentiation markers was performed by the immunoblotting and the immunostaining assays. RNA-seq was performed through the Illumina HiSeq PE150 platform and differentially expressed genes (DEGs) were screened out through the bioinformation analysis. Overexpression or knockdown of Fos gene was achieved by shRNA transfection. Results: Pre-exposure of A2780T cells with 10 µg/mL LCC sensitized them to paclitaxel, of which the IC50 value reduced from 8.644 µmol/L (95%CI: 7.315-10.082 µmol/L) to 2.5 µmol/L (95%CI: 2.233-2.7882 µmol/L). Exposure with LCC enhanced the paclitaxel-induced apoptosis and inhibited the colony formation of A2780T cells. LCC exposure reduced the expression of cancer stemness markers, ALDH1, Myd88 and CD44, while promoting that of terminal differentiation markers, NFATc1, Cathepsin K and MMP9. RNA-seq analysis revealed that the expressions of FOS and JUN were upregulated in LCC-treated A2780T cells. A2780T cells overexpressing Fos gene displayed increased paclitaxel-sensitivity and reduced cell stemness, and shared common phenotypes with LCC-treated A2780T cells. Conclusion: These findings suggested that LCC promoted terminal differentiations of ovarian cancer cells and sensitized them to paclitaxel through activating the Fos/Jun pathway. LCC might become a novel therapy that targets at cancer stem cells and enhances the chemotherapeutic effect of ovarian cancer treatments.

Dexamethasone enhances glucose uptake by SGLT1 and GLUT1 and boosts ATP generation through the PPP-TCA cycle in bovine neutrophils.

BACKGROUND: Clinical dexamethasone (DEX) treatment or stress in bovines results in extensive physiological changes with prominent hyperglycemia and neutrophils dysfunction. OBJECTIVES: To elucidate the effects of DEX treatment in vivo on cellular energy status and the underlying mechanism in circulating neutrophils. METHODS: We selected eight-month-old male bovines and injected DEX for 3 consecutive days (1 time/d). The levels of glucose, total protein (TP), total cholesterol (TC), and the proinflammatory cytokines interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α in blood were examined, and we then detected glycogen and adenosine triphosphate (ATP) content, phosphofructosekinase-1 (PFK1) and glucose-6-phosphate dehydrogenase (G6PDH) activity, glucose transporter (GLUT)1, GLUT4, sodium/glucose cotransporter (SGLT)1 and citrate synthase (CS) protein expression and autophagy levels in circulating neutrophils. RESULTS: DEX injection markedly increased blood glucose, TP and TC levels, the Ca2+/P5+ ratio and the neutrophil/lymphocyte ratio and significantly decreased blood IL-1ß, IL-6 and TNF-α levels. Particularly in neutrophils, DEX injection inhibited p65-NFκB activation and elevated glycogen and ATP contents and SGLT1, GLUT1 and GR expression while inhibiting PFK1 activity, enhancing G6PDH activity and CS expression and lowering cell autophagy levels. CONCLUSIONS: DEX induced neutrophils glucose uptake by enhancing SGLT1 and GLUT1 expression and the transformation of energy metabolism from glycolysis to pentose phosphate pathway (PPP)-tricarboxylic acid (TCA) cycle. This finding gives us a new perspective on deeper understanding of clinical anti-inflammatory effects of DEX on bovine.

Accelerating Nickel-Based Molecular Construction via DFT Guidance for Advanced Photocatalytic Hydrogen Production.

Understanding the nickel-based molecular catalyst structure and functional relationship is crucial for catalytic hydrogen production in aqueous solutions. Density functional theory (DFT) provides mature theoretical knowledge for efficient catalyst design, significantly reducing catalyst synthesis time and energy consumption. In the present work, three molecular catalysts, Ni(qbz)(pys)2 (qbz = 2-quinoline benzimidazole) (NQP 1), Ni(qbo)(pys)2 (qbo = 2-quinoline benzothiazole) (NQP 2), and Ni(pbz)(pys)2 (pbz = 4-chloro-2,2-pyridylbenzimidazole) (NQP 3) (pys = 2-mercaptopyridine), were designed and synthesized and exhibit a high performance for H2 generation in aqueous solution with a lamp (λ ≥ 400 nm) under visible light irradiation. Under the optimal conditions, a H2 evolution rate as high as 1190 µmol h-1 can be obtained over 25 mg of NQP 1 with the best catalytic performance. DFT has been adopted in this study to unveil the relationship between the ligand qbz and catalyst NQP 1─an efficient step in the design of catalysts with an excellent catalytic performance. We show that, in addition to the presence of the triphenyl ring increasing the overall electron density, rapid electron transfer (ET) from excited fluorescein (Fl) to NQP 1 significantly improves the chance of photogenerated electrons transferring to the active site, ultimately increasing the catalytic activity for H2 production. This work on understanding the correlation between structures and properties of complexes provides a new idea for manufacturing high-performance photocatalysts.

A nanoflower-like polypyrrole-based cobalt-nickel sulfide hybrid heterostructures with electrons migration to boost overall water splitting.

The development of high-efficiency and cost-effective difunctional electrocatalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) are highly attractive to fulfill the practical water electrolysis. Herein, a novel low-cost difunctional cobalt-nickel sulfide (Co3S4/Ni3S2) flower-like heterostructures are purposely loaded on the surface of polypyrrole (PPy) nanosheets on nickel foam (NF) via feasible and efficient electrodeposition and hydrothermal tactics. The unique hierarchical architecture of the PPy nanosheets and strong electron interaction in the Co3S4/Ni3S2 nanohybrid effectively offer sufficient specific surface area and regulate electronic configuration for expediting the electrocatalytic process. The theoretical simulations also provide convincing proof that the interface of the Co3S4/Ni3S2 heterostructures supplies a lower energy pathway for water adsorption and dissociation, and the electrons migration that occurs when heterostructures emerge is probably the root of the result above. Consequently, the as-fabricated Co3S4/Ni3S2@PPy/NF exhibits outstanding electrochemical activity of HER and OER requiring low overpotentials of 63 mV and 207 mV to reach a current density of 10 mA cm-2 in the alkaline electrolyte, respectively. When equipped in a two-electrode electrolyzer, the Co3S4/Ni3S2@PPy/NF electrode couple displays a low voltage of only 1.52 V at 10 mA cm-2, indicating its potential application in the field of the water electrolysis.

CircATL2 enhances paclitaxel resistance of ovarian cancer via impacting miR-506-3p/NFIB axis.

Circular RNAs (circRNAs) play vital regulatory roles in the development of ovarian cancer (OC). However, the functions of circRNA Atlastin GTPase 2 (circATL2) in paclitaxel (PTX) resistance of OC are still unclear. As a result, circATL2 was upregulated in PTX-resistant OC tissues and cells. CircATL2 knockdown reduced IC50 of PTX, inhibited colony formation ability and promoted cell cycle arrest and apoptosis in PTX-resistant OC cells. Silencing of circATL2 restrained PTX resistance in vivo. Furthermore, miR-506-3p could be targeted by circATL2 and miR-506-3p inhibition reversed the impacts of circATL2 knockdown on PTX resistance and cell progression in PTX-resistant OC cells. NFIB was identified as the target of miR-506-3p. MiR-506-3p overexpression suppressed PTX resistance and malignant behaviors of PTX-resistant OC cells, with NFIB elevation rescued the impacts. To summarize, circATL2 promoted the resistance of OC to PTX by sponging miR-506-3p to upregulate NFIB expression, providing a new sight in chemoresistance of OC.

AZD3759 enhances radiation effects in non-small-cell lung cancer by a synergistic blockade of epidermal growth factor receptor and Janus kinase-1.

AZD3759 is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) on the basis of gefitinib and has been proven to enter the central nervous system. Although the promising antitumor effects of AZD3759 on non-small cell lung cancer (NSCLC) have been demonstrated in clinical trials, the regulatory effects of this inhibitor on the antitumor efficacy of radiation (RA) are unclear. The present study aimed to compare the effects of AZD3759 and osimertinib on RA efficacy in NSCLC and explore the potential mechanism of action of AZD3759. We found that the survival in RA-treated NSCLC cells was significantly decreased by treatment with 500 nM AZD3759 and osimertinib at the RA dosage of 8 Gy. The apoptotic rate, cell cycle arrest, and DNA damage in RA-treated NSCLC cells and brain metastasis in RA-treated xenograft nude mice were significantly enhanced by the co-administration of AZD3759 and osimertinib, respectively. In addition, AZD3759 showed a significantly stronger efficacy than osimertinib did. Mechanistically, the receptor tyrosine kinase signaling antibody array revealed that Janus kinase-1 (JAK1) was specifically inhibited by AZD3759, but not by osimertinib. The effects of AZD3759 on RA efficacy in PC-9 cells and in a brain metastasis animal model were significantly abolished by the overexpression of JAK1. Collectively, our results suggested that AZD3759 promoted RA antitumor effects in NSCLC by synergistic blockade of EGFR and JAK1.

AZD3759 inhibits glioma through the blockade of the epidermal growth factor receptor and Janus kinase pathways.

Glioma is an intracranial malignant tumor with high morbidity in China. Limited efficacy has been achieved in the treatment of glioma through the application of epidermal growth factor receptor (EGFR) inhibitors, which is reported to be related to the poor permeability of the brain-blood barrier (BBB) to EGFR inhibitors. AZD3759 and osimertinib are both BBB-penetrating EGFR inhibitors. The present study aimed to investigate the inhibitory effects of AZD3759 and osimertinib on glioma and compare their efficacy and the underlying mechanisms. C6 and U87 cells were incubated with different concentrations of AZD3759 (1, 2, and 4 µM) and 4 µM osimertinib, respectively. C6-LUC xenograft animals were administered different doses of AZD3759 (15, 30, and 60 mg/kg) and 60 mg/kg osimertinib. We found that proliferation was significantly suppressed and that apoptosis and cell cycle arrest were dramatically induced in both C6 and U87 cells by AZD3759 in a dose-dependent manner. Compared to AZD3759, osimertinib had inferior effects on proliferation, apoptosis, and cell cycle. In vivo experiments verified that the anti-tumor efficacy of AZD3759 against C6 xenograft tumors was dose dependent and superior to that of osimertinib. The inhibitory effects of AZD3759 on the Janus kinase (JAK)/STAT pathway were observed in both glioma cells and tumor tissues, which were more significant than those of osimertinib. In conclusion, AZD3759 may inhibit the progression of glioma via a synergistic blockade of the EGFR and JAK/STAT signaling pathways.

Distribution patterns of lymph node metastasis in early stage invasive cervical cancer.

The spatial distribution of lymph node (LN) metastasis was analyzed to provide data for an evidence-based approach to radiotherapy field design, particularly for guiding intensity-modulated radiation therapy. A total of 1886 postoperative patients were retrospectively reviewed. Pelvic LNs were classified as common iliac nodes, external iliac nodes, internal iliac nodes/obturator nodes, and deep inguinal nodes. The distribution of LN metastasis in these subgroups was calculated, and the distribution patterns of LN metastasis according to the pathologic types were investigated.We identified 392 eligible patients with LN metastasis. The frequency and number of external iliac node metastasis were higher in the left side in both single subgroup (P < .01) and cosubgroup (P = .04) analyses, whereas few differences were found in other subgroups. Among patients with squamous cell carcinoma, left external iliac node metastasis was observed in 102 (15.13%) patients, whereas right metastasis was observed in 65 (9.64%) patients, and the difference was significant (P < .01).The present results indicated uneven distribution of LN metastasis in the different subgroups, which could help surgeon focus on the dissection of the left subgroups, and help oncologists define margins, refine target volumes for radiation, and improve the accuracy of postoperative radiotherapy especially in patients with squamous cell carcinoma.

The use of apatinib in treating primary pleural synovial sarcoma: A case report.

RATIONALE: Apatinib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. It has been shown that apatinib is effective and safe for treatment of multiple solid tumors, including gastric cancer, liver cancer, non-small-cell lung cancer, and breast cancer. However, there is currently no consensus as to using Apatinib for the treatment of pleural synovial sarcoma, due to the rarity of primary pleural synovial sarcoma and lack of clinical studies as a consequence. PATIENT CONCERNS AND DIAGNOSES: We reported here in the case of a 26-year-old Chinese woman diagnosed with pleural synovial sarcoma. She has undergone 2 surgeries, multiple regimens of chemotherapy and traditional Chinese medicine in other hospitals. Then the patient was admitted to our hospital with the compliant of chest pain and dyspnea. The medical history and available data supported the diagnosis of recurrence of pleural synovial sarcoma. INTERVENTIONS AND OUTCOMES: Due to the lack of efficacy of previous standard treatment, the patient was given apatinib and radiotherapy to relieve the symptoms. This patient achieved stable disease with apatinib at a dose of 500 mg/day. Her progression-free survival time was more than 7 months, and her overall survival was 8.5 months. Except for hand-foot syndrome, no grade 3 or 4 side effects were observed. CONCLUSIONS: Apatinib may thus be an option for treatment of advanced synovial sarcoma after failure of other treatments. However, further study is needed to determine the efficacy of apatinib in pleural synovial sarcoma.

PTEN influences insulin and lipid metabolism in bovine hepatocytes in vitro.

Dairy cows with fatty liver or ketosis display decreased insulin sensitivity and defects in the insulin receptor substrate (IRS)/PI3K/AKT signaling pathway. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor and also a negative regulator of insulin signaling and peripheral insulin sensitivity. We investigated the hypothesis that PTEN may affect the insulin pathway-mediated hepatic glucose and lipid metabolism in dairy cows. Adenovirus vectors that over-express and silence PTEN were constructed, and then transfected into hepatocytes isolated from calves to investigate the effect of PTEN on PI3K/AKT signaling pathway. PTEN silencing increased the phosphorylation of AKT and the expression of PI3K but decreased the phosphorylation of IRS1, which increased the phosphorylation levels of glycogen synthase kinase-3ß (GSK-3ß) and expression of sterol regulatory element-binding protein-1c (SREBP-1c). Increased GSK-3ß phosphorylation further up-regulated expression of the key enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6-Pase) involved in gluconeogenesis. Furthermore, the expression of SREBP-1c target gene fatty acid synthase (FAS) also increased significantly. We further showed that PTEN over-expression could reverse the above results. PTEN negatively regulates the enzymes involved in hepatic gluconeogenesis and lipid synthesis, which suggests that PTEN may be a therapeutic target for ketosis and fatty liver in dairy cows.

Theoretical Studies on DNA-Cleavage Mechanism of Copper(II) Complexes: Probing Generation of Reactive Oxygen Species.

Theoretical studies on DNA-cleavage properties of [Cu(bba)(diimine)] 1-4 have been carried out using density functional theory (DFT) and docking methods. The optimized structures of Cu(II) complexes were docked into DNA, glutathiones (GSH), and ascorbic acids (VC) so that the corresponding docking models were obtained. To explore DNA-cleavage properties of Cu(II) complexes, the docking models of complexes with GSH and VC were further optimized using DFT method, while the docking models of complexes with DNA were optimized using QM/MM method because DNA is a supramolecular system. The rate constants ket between complexes and DNA, GSH, and VC, oxidation-reduction potentials of complexes, and binding energies of complexes with GSH and VC were computed. The DNA-cleavage abilities of Cu(II) complexes in the presence VC, GSH, and H2O2 were explored and the experimental results could be reasonably explained. Finally, the DNA-cleavage mechanism of Cu(II) complexes was described in detail, which would contribute to future design of novel anticancer Cu(II) complexes.

miRNA-200c enhances radiosensitivity of esophageal cancer by cell cycle arrest and targeting P21.

Esophageal squamous cancer is one of the most fatal malignancies and often suffer recurrence after radiotherapy. Downregulation of miRNA-200c is associated with radiotolerance. We aim to investigate the role of miRNA-200c in radiosensitivity and develop a systemic treatment strategy for esophageal squamous cancer. Overexpression of miRNA-200c by transfection was determined by RT-PCR. Radiosensitizing effect of miRNA-200c on esophageal squamous cancer cells was determined by clonogenic assay and xenograft model. Cell cycle was analyzed by flow cytometry. The levels of Cyclin B1, cyclin D1, cyclin E1, CDK2, CDK4, Cdc2 and P21 protein expressions were detected by western blotting. The results of our study revealed that miRNA-200c enhanced the radiosensitivity significantly in esophageal squamous cancer cell line in vitro and in vivo. miRNA-200c induced G2/M and sub-G1 phase arrest and reduced S phase rate of the irradiated Eca-109 cells and downregulated expression levels of Cyclin B1, cdc2 and upregulated P21 expression level. Present results demonstrate that downregulation of miRNA-200c is associated with radiotolerance. miRNA-200c increases radiosensitivity by G2/M and sub-G1 phase arrest through modulating Cyclin B1, cdc2 and P21 expression levels.

Curcumin Inhibits Gastric Carcinoma Cell Growth and Induces Apoptosis by Suppressing the Wnt/ß-Catenin Signaling Pathway.

BACKGROUND Curcumin has well-known, explicit biological anti-tumor properties. The Wnt/ß-catenin signaling pathway plays a central role in tumor cell proliferation and curcumin can regulate the Wnt/b-catenin signaling pathway of several carcinomas. The aim of this study was to investigate the impact of curcumin on the Wnt/ß-catenin signaling pathway in human gastric cancer cells. MATERIAL AND METHODS We used 3 gastric cancer cell lines: SNU-1, SNU-5, and AGS. Research methods used were MTT assay, flow cytometry, clonogenic assay, annexin V/PI method, Western blotting analysis, tumor formation assay, and in vivo in the TUNEL assay. RESULTS Curcumin markedly impaired tumor cell viability and induced apoptosis in vitro. Curcumin significantly suppressed the levels of Wnt3a, LRP6, phospho-LRP6, ß-catenin, phospho-ß-catenin, C-myc, and survivin. Xenograft growth in vivo was inhibited and the target genes of Wnt/ß-catenin signaling were also reduced by curcumin treatment. CONCLUSIONS Curcumin exerts anti-proliferative and pro-apoptotic effect in gastric cancer cells and in a xenograft model. Inhibition of the Wnt/ß-catenin signaling pathway and the subsequently reduced expression of Wnt target genes show potential as a newly-identified molecular mechanism of curcumin treatment.

Dietary fibre intake and risk of breast cancer: A systematic review and meta-analysis of epidemiological studies.

Current evidence from randomised controlled trials on the effects of dietary fibre intake on breast cancer risk is inconsistent. We conducted a meta-analysis to determine the effectiveness of dietary fibre intake in reducing breast cancer risk. We searched for prospective and case-control studies on dietary fibre intake and breast cancer risk in the English language through March 2016. Twenty-four epidemiologic studies obtained through the PubMed, Embase, Web of Science, and Cochrane Library databases were systematically reviewed. A random-effects model was used to compute the pooled risk estimates by extracting the risk estimate of the highest and lowest reported categories of intake from each study. The meta-analyses showed a 12% decrease in breast cancer risk with dietary fibre intake. The association between dietary fibre intake and breast cancer risk was significant when stratified according to Jadad scores, study types, and menopause status. Dose-response analysis showed that every 10 g/d increment in dietary fibre intake was associated with a 4% reduction in breast cancer risk, and little evidence of publication bias was found. Thus, dietary fibre consumption is significantly associated with a reduced risk of breast cancer, particularly in postmenopausal women.

Epigenetic therapy potential of suberoylanilide hydroxamic acid on invasive human non-small cell lung cancer cells.

Metastasis is the reason for most cancer death, and a crucial primary step for cancer metastasis is invasion of the surrounding tissue, which may be initiated by some rare tumor cells that escape the heterogeneous primary tumor. In this study, we isolated invasive subpopulations of cancer cells from human non-small cell lung cancer (NSCLC) H460 and H1299 cell lines, and determined the gene expression profiles and the responses of these invasive cancer cells to treatments of ionizing radiation and chemotherapeutic agents. The subpopulation of highly invasive NSCLC cells showed epigenetic signatures of epithelial-mesenchymal transition, cancer cell stemness, increased DNA damage repair and cell survival signaling. We also investigated the epigenetic therapy potential of suberoylanilide hydroxamic acid (SAHA) on invasive cancer cells, and found that SAHA suppresses cancer cell invasiveness and sensitizes cancer cells to treatments of IR and chemotherapeutic agents. Our results provide guidelines for identification of metastatic predictors and for clinical management of NSCLC. This study also suggests a beneficial clinical potential of SAHA as a chemotherapeutic agent for NSCLC patients.