How lignin sticks to cellulose-insights from atomic force microscopy enhanced by machine-learning analysis and molecular dynamics simulations.

Elucidating cellulose-lignin interactions at the molecular and nanometric scales is an important research topic with impacts on several pathways of biomass valorization. Here, the interaction forces between a cellulosic substrate and lignin are investigated. Atomic force microscopy with lignin-coated tips is employed to probe the site-specific adhesion to a cellulose film in liquid water. Over seven thousand force-curves are analyzed by a machine-learning approach to cluster the experimental data into types of cellulose-tip interactions. The molecular mechanisms for distinct types of cellulose-lignin interactions are revealed by molecular dynamics simulations of lignin globules interacting with different cellulose Iß crystal facets. This unique combination of experimental force-curves, data-driven analysis, and molecular simulations opens a new approach of investigation and updates the understanding of cellulose-lignin interactions at the nanoscale.

STAT1/IFIT2 signaling pathway is involved in PD-L1-mediated epithelial-to-mesenchymal transition in human esophageal cancer.

BACKGROUND: We have previously reported significant change of epithelial to mesenchymal transition (EMT) phenotype of Eca-109 cells upon PD-L1 operation, and the cytoplasmic domain of PD-L1 played an essential role in promoting EMT of esophageal cancer cells. However, the underlying mechanism of how PD-L1 regulated EMT in esophageal cancer remained unclear. METHODS: The overexpression and knockdown expression models of PD-L1 and IFIT2 were established by using lenti-virus transfection and RNAi method. Western blotting, qRT-PCR, CCK8 assay, transwell assay and wound healing assay were chosen to investigate their impact on the cells. The expression levels of IFIT2 and EMT markers in esophageal cancer tissues were examined by immunohistochemical staining. The rescue experiments were further applied to investigate the role of STAT1/IFIT2 signal pathway in the PD-L1-mediated EMT. Luciferase reporter assays were performed to examine the IFIT2 promoter activities upon knockdown expression of PD-L1 to identify the putative targeted region of IFIT2 promoter. RESULTS: The STAT1/IFIT2 signal pathway was activated when PD-L1 was knockdown in human esophageal cancer cells. Decreased IFIT2 expression significantly increased the cellular abilities of viability, invasion and migration by using RNAi method in human esophageal cancer cells. Decreased IFIT2 expression in esophageal cancer tissues significantly correlated with EMT status, and could be used as an independent prognostic predictor for the patients. Rescue experiments in PD-L1 knockdown cells further confirmed that STAT1/IFIT2 pathway was involved in the PD-L1 mediated EMT of esophageal cancer cells. Moreover, the luciferase reporter assay also confirmed that in esophageal cancer cells, the promoter region of IFIT2 (-3K~-1K) remains more active in PD-L1 knockdown expression cells compared with controls. CONCLUSION: Our present work reveals a novel mechanism of how PD-L1 regulates EMT of cancer cells, namely STAT1/IFIT2 signal pathway is required in PD-L1 mediated EMT in human esophageal cancer.

Silencing IKBKE inhibits the migration and invasion of glioblastoma by promoting Snail1 degradation.

PURPOSE: Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors in adults and has high mortality and relapse rates. Over the past few years, great advances have been made in the diagnosis and treatment of GBM, but unfortunately, the five-year overall survival rate of GBM patients is approximately 5.1%. Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE) is a major oncogenic protein in tumors and can promote evil development of GBM. Snail1, a key inducer of the epithelial-mesenchymal transition (EMT) transcription factor, is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumors remains unclear. Our study aimed to investigate the mechanism of IKBKE regulating Snail1 in GBM. METHODS: First, we analyzed the correlation between the expression of IKBKE and the tumor grade and prognosis through public databases and laboratory specimen libraries. Second, immunohistochemistry (IHC) and western blot were used to detect the correlation between IKBKE and Snail expression in glioma samples and cell lines. Western blot and immunofluorescence (IF) experiments were used to detect the quality and distribution of IKBKE and Snail1 proteins. Third, In situ animal model of intracranial glioma to detect the regulatory effect of IKBKE on intracranial tumors. RESULTS: In this study, Our study reveals a new connection between IKBKE and Snail1, where IKBKE can directly bind to Snail1, translocate Snail1 into the nucleus from the cytoplasm. Downregulation of IKBKE results in Snail1 destabilization and impairs the tumor cell migration and invasion capabilities. CONCLUSION: Our studies suggest that the IKBKE-Snail1 axis may serve as a potential therapeutic target for GBM treatment.

Mfsd2a Promotes the Proliferation, Migration, Differentiation and Adipogenesis of Chicken Intramuscular Preadipocytes

Intramuscular fat (IMF) content is a crucial parameter for estimating meat quality. Growing evidence indicates that gene regulation plays an important role in IMF deposition. This study aimed to determine the function of Mfsd2a in chicken intramuscular preadipocytes. In the present study, high Mfsd2a mRNA levels were observed in the liver and adipose tissues of broilers. Subsequently, we synthesized small interfering RNAs to silence the expression of Mfsd2a in chicken intramuscular preadipocytes. The following results suggested that CDK2, PCNA, CCND1, CCND2 and MKI67 were inhibited, with CCK-8 and EdU assays revealing that cell proliferation was inhibited. Scratch test showed that cell migration ratios were declined. We also found that Mfsd2a silencing decreased the mRNA levels of PPARγ, RXRG and their target genes. The similar results were found in some key genes that contribute to lipid synthesis, including C/EBPα, C/EBPß, FABP4, FASN, ACACA and ACSL1. Finally, Oil red O staining showed that IMF accumulation was blocked after Mfsd2a silencing. In conclusion, our results implied that Mfsd2a promotes the proliferation and migration of chicken intramuscular preadipocytes, as well as the differentiation and adipogenesis through PPARγ signaling pathway, which may provide a potential target to improve chicken meat quality.(AU)

The Effect of Dietary Glucose Oxidase Supplementation on Production Performance, Egg Quality and Nutrient Digestibility in Laying Hens

The study was conducted to investigate the effect of GOX on performance, egg quality, and nutrient digestibility in laying hens. In total, 432, 50-week-old Hy-Line brown breeder hens were assigned into four treatments, and fed a basal diet with GOX at 0, 100, 200 and 300 units for 10 weeks, respectively. A Quadratic decrease in FI in week 3 (p<0.05) and linear increase in egg production in week 6 to 10 and overall experiment period (p<0.05) and Quadratic increase in egg production in week 7 (p<0.05), a linear decrease in broken egg rate in week 6 (p<0.05) a quadratic increase in egg weight on day 14 (p<0.05), alinear increase in egg weight on day 28 (p<0.05), and linear decrease in yolk color on day 7 (p<0.05), a linear increase in yolk color on day 42 and day 70 (p<0.05), and linear increase in haugh unit on day 28 and 70 (p<0.05), a linear increase albumen height on day 28 and day 56 (p<0.05), and linear decrease in shell color on day 14 (p<0.05) and day 28(p<0.05), a linear and quadratic increases in eggshell strength and eggshell thickness on day 56 (p<0.05), and linear increase in eggshell strength and eggshell thickness on day 70 (P0.05) were observed with the addition of GOX the the diet. Conclusion: This study suggested that the supplementation of GOX may have beneficial effects on feed intake and egg quality in laying hens.(AU)

Knockdown of CPT1A Induce Chicken Adipocyte Differentiation to Form Lipid Droplets

Lipid metabolism dysfunction is closely related to obesity, inflammation, diabetes, lipodystrophy, cardiovascular disease. Along with having a positive effect on energy homeostasis during fasting or prolonged exercise through mitochondrial fatty acid oxidation (FAO), more than two dozen enzymes and transport proteins are involved in the activation and transport of fatty acids into the mitochondrial, providing insights into their critical roles in metabolism. CPT1A has been reported to be expressed ubiquitously in the body and associated with dire consequences affecting fat deposition as the key rate-limiting enzyme of FAO. However, there is a dearth of data on the specific role of CPT1A on adipogenic differentiation and adipocyte lipolysis on chicken. This study assessed CPT1A's function in adipocyte differentiation andadipocyte lipolysis, and the mechanisms were investigated. We found that CPT1A knockdown (KD) promotes the differentiation of chicken preadipocytes into mature adipocytes. CPT1A KD increased PPARγ protein expression level. Expression levels of lipid synthesis-related genes were increased, and lipolysis genes were reduced. Also, CPT1A KD can encourage the formation of lipid droplets. So our results confirmed that knockdown of CPT1A induced the lipid differentiation and inhibited the ß-oxidation process to promote the formation of lipid droplets. These findings may deepen our understanding on CPT1A function, especially its regulatory role in adipocyte biology.(AU)

Experiments and Application of Reclamation of High-Mineralized Mine Wastewater for Confecting Grouting Slurry.

Owing to the high mineralization and high treatment cost, Ordovician limestone water is often regarded as a mine wastewater. In order to make rational use of mine water with high mineralization and turn waste into treasure. In this work, the natural water quality of Ordovician mine water in the Weibei coalfield had been tested, and the suspended matter and trace elements of Ordovician mine water in the selected deep detained area had been further tested. As a contrast, the water quality of Ordovician mine water after heating and concentration had been tested. The mechanical and hydraulic parameters of concentrated mine water-loess and concentrated mine water-cement slurry had been tested and compared with conventional slurry. The results showed characteristics of deep detained Ordovician limestone mine water is high salinity, certain suspended matters, limited special material and high permanent hardness. However, compressive strength of loess samples increased, while the permeability reduced. The initial setting-time of the modified material was short, while it showed an increased compressive strength. In practical terms, the quantity of grouting produced in engineering applications can be reduced by 16%, whereas the discharge of high-mineralized mine water can be decreased by about 40,000 m3/a.

Tumor microenvironment-associated gene C3 can predict the prognosis of colorectal adenocarcinoma: a study based on TCGA.

BACKGROUND: Colorectal cancer is one of the most common malignancies. With continuous exploration of the interaction between tumor cells and the immune system, tumor immunotherapy has become a revolution. However, CRC remains one of the less effective tumors for immunotherapy. The tumor microenvironment plays an important role in tumorigenesis and progression. The aim of this study is to explore tumor microenvironment-related genes that can predict the prognosis of colorectal adenocarcinoma, and also to provide new ideas for the mechanism of tumor development as well as immunotherapy. METHODS: After estimating Stromalscore and Immunescore of colorectal adenocarcinoma tumor samples according to RNA-Seq expression data downloaded from TCGA, we screened for TME-related differential genes. We filtered prognosis-related core genes by constructing protein-protein interaction networks and making one-factor cox analysis for prognosis. Finally, the relative content of 22 immune cells in tumor tissues was evaluated, and then immune cells associated with core genes were identified. RESULTS: We screened 773 differential genes related to the TME. Then we identified C3 as a core gene associated with prognosis. Single gene analysis showed that C3 expression was significantly higher in tumor tissues than in normal tissues (p < 0.001). High C3 expression was associated with lower overall survival (p = 0.046). Tumor immune cell analysis showed that mast cells resting, mast cells activated, T cells CD4 memory activated, eosinophils, and macrophages M0 were C3-associated immune cells. CONCLUSIONS: C3 has potential as a biomarker for colorectal adenocarcinoma and could provide new research ideas for the diagnosis and treatment of colorectal adenocarcinoma, especially for immunotherapy.

Hypoxia-mediated down-regulation of miRNAs' biogenesis promotes tumor immune escape in bladder cancer.

BACKGROUND: The study examines the function of hypoxia-mediated down-regulation of microRNAs (miRNAs) (mir-30c, mir-135a, and mir-27a) in the process of bladder cancer immune escape. METHODS: Quantitative Real-time PCR (qRT-PCR) was carried out to determine gene expression levels of Drosha and Dicer under hypoxia treatment, while western blotting and flow cytometry were used to determine protein expression. Seven reported miRNAs were identified via qRT-PCR assay. Flow cytometry detection of CD3/CD4/CD8-positive expression and statistics. Enzyme-linked immunosorbent assay (ELISA) detected cellular immune factors content. Cell apoptosis was checked via flow cytometry assay. Luciferase report assay and western blot assays were both used to verify the relationship between miRNAs and Casitas B-lineage lymphoma proto-oncogene b (Cbl-b). The animal model was established and Hematoxylin-eosin (HE) staining, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and immunohistochemistry (IHC) assays were separately used to verify the conclusions. RESULTS: The CD3 + /CD4 + expression was increased in the hypoxia group, while CD3 + /CD8 + expression, the cellular immune factors content Interleukin-2 (IL-2) and Tumor Necrosis Factor-α (TNFα) along with the cell apoptosis were suppressed. The protein expression of Cbl-b was found to be up-regulated in the hypoxia group. After constructing the overexpression/ knockdown of Cbl-b in peripheral blood mononuclear cell (PBMC), Cbl-b has been found to promote tumor immune escape in bladder cancer. Furthermore, Cbl-b had been identified as the co-targets of mir-30c, mir-135a, and mir-27a and down-regulation of miRNA biogenesis promotes Cbl-b expression and deactivating T cells in vitro/in vivo. CONCLUSION: Hypoxia-mediated down-regulation of miRNAs' biogenesis promotes tumor immune escape in bladder cancer, which could bring much more advance to the medical research on tumors.

Clinical significance of expression level of CX3CL1-CX3CR1 axis in bone metastasis of lung cancer.

PURPOSE: To investigate the clinical significance of CX3 chemokine ligand 1(CX3CL1) and CX3CR1 in patients with bone metastasis from lung cancer. The expression levels of CX3CL1 and CX3CR1 mRNA and protein in primary lung cancer and lung cancer bone metastasis were detected by qRT-PCR and Western blot. METHODS: One hundred patients with lung cancer were divided into a boneless metastasis group (50 patients with bone metastasis) and a bone metastasis group (50 patients without distant metastasis). The bone transfer component was graded by Soloway classification (0 to III). The expression levels of serum CX3CL1-CX3CR1 axis were detected by enzyme-linked immunosorbent assay (ELISA). RT-qPCR and Western Blot were used to verify the transfection efficiency. The scratching assay was used to detect the migration of CX3CL1 to 95-D cells after down-regulating the expression of CX3CR1. RESULTS: The expression levels of CX3CL1 and CX3CR1 mRNA and protein in the primary lung cancer and lung cancer bone metastasis were significantly higher than those in the adjacent tissues (P < 0.0001). The levels of serum CX3CL1 and CX3CR1 in bone metastasis group were significantly higher than those in boneless metastasis group and healthy control group (P < 0.05). In the bone metastasis group, the levels of serum CX3CL1 and CX3CR1 were significantly positively correlated with the degree of disease progression (P < 0.01). CONCLUSION: The expression level of serum CX3CL1-CX3CR1 axis is expected to be an auxiliary reference index for monitoring bone metastasis of lung cancer.

Sustained fetal hematopoiesis causes juvenile death from leukemia: evidence from a dual-age-specific mouse model.

It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age-specific mouse model, we demonstrate that (1) loss of Pten during the fetal-to-adult hematopoiesis switch (hematopoiesis switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; (2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); (3) the age specificity of juvenile myelomonocytic leukemia depends on the copy number of Pten and Nf1; (4) single-allelic Pten deletion during the hematopoiesis switch causes constitutive activation of MAPK in juvenile mice with Nf1 loss of heterozygosity (LOH); and (5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that 1 copy of Pten is sufficient to maintain an intact negative-feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile Pten+/ΔNf1LOH mice. However, 2 copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild-type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof of concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.

Evaluation of protection against bovine viral diarrhea virus type 2 after vaccination of the calves with bovine viral diarrhea virus type 1 combo inactivated vaccine / Avaliação da proteção contra o vírus da diarreia viral bovina tipo 2 após vacinação de bezerros com vacina combinada inativada do vírus da diarreia viral bovina tipo 1

This study was designed to evaluate the extent of the protection for bovine viral diarrhea virus type 2 (BVDV-2) infection, afforded by vaccination with a combo inactivated vaccine, which contains bovine viral diarrhea virus type 1 (BVDV-1) and infectious bovine rhinotracheitis virus (IBRV). Five 3-4-month-old calves were intramuscularly vaccinated with a single dose of the combo vaccine and boosted with same dose three weeks after the first vaccination, with five mock immunized calves serving as a control group. Twenty-one days after the second vaccination, all calves were challenged with BVDV-2 SX08 strain by spray into nostril. The unvaccinated animals developed typical clinical signs of high rectal temperature, diarrhoea with erosions and a dramatic drop in leukocyte counts. These signs occured markedly less in all vaccinated animals, the rectal temperature, leukopenia and virarmia of which, were significantly less than the mock immunized calves. It can be concluded that vaccination with the combo inactivated vaccine affords cross-protection against clinical effects of a challenge-infection with BVDV-2 SX08 strain, although it was part protection.(AU)

Este estudo foi desenvolvido para avaliar a extensão da proteção contra a infecção pelo vírus da diarréia viral bovina tipo 2 (BVDV-2) através da vacinação com uma vacina combinada inativada contendo o vírus da diarréia viral bovina tipo 1 (BVDV-1) e vírus da rinotraqueíte de bovinos infecciosos (IBRV). Cinco bezerros com 3 a 4 meses de idade foram vacinados via intramuscular com uma dose única da vacina combinada e reforçados com a mesma dose três semanas após a primeira vacinação, com cinco bezerros imunizados em simulação servindo como grupo controle. Vinte e um dias após a segunda vacinação, todos os bezerros foram desafiados com a cepa BVDV-2 SX08 por spray na narina. Os animais não vacinados desenvolveram sinais clínicos típicos, como alta temperatura retal, diarréia com erosões e queda drástica na contagem de leucócitos. Estes sinais tiveram ocorrência significativamente menor em todos os animais vacinados, cuja temperatura retal, leucopenia e virarmia eram significativamente menores do que os bezerros simulados. É possível concluir que a vacinação com a vacina combinada inativada proporciona proteção cruzada contra os efeitos clínicos de uma infecção provocada pela cepa BVDV-2 SX08, embora tenha sido parcialmente protegida.(AU)

Evaluation of protection against bovine viral diarrhea virus type 2 after vaccination of the calves with bovine viral diarrhea virus type 1 combo inactivated vaccine / Avaliação da proteção contra o vírus da diarreia viral bovina tipo 2 após vacinação de bezerros com vacina combinada inativada do vírus da diarreia viral bovina tipo 1

This study was designed to evaluate the extent of the protection for bovine viral diarrhea virus type 2 (BVDV-2) infection, afforded by vaccination with a combo inactivated vaccine, which contains bovine viral diarrhea virus type 1 (BVDV-1) and infectious bovine rhinotracheitis virus (IBRV). Five 3-4-month-old calves were intramuscularly vaccinated with a single dose of the combo vaccine and boosted with same dose three weeks after the first vaccination, with five mock immunized calves serving as a control group. Twenty-one days after the second vaccination, all calves were challenged with BVDV-2 SX08 strain by spray into nostril. The unvaccinated animals developed typical clinical signs of high rectal temperature, diarrhoea with erosions and a dramatic drop in leukocyte counts. These signs occured markedly less in all vaccinated animals, the rectal temperature, leukopenia and virarmia of which, were significantly less than the mock immunized calves. It can be concluded that vaccination with the combo inactivated vaccine affords cross-protection against clinical effects of a challenge-infection with BVDV-2 SX08 strain, although it was part protection.(AU)

Este estudo foi desenvolvido para avaliar a extensão da proteção contra a infecção pelo vírus da diarréia viral bovina tipo 2 (BVDV-2) através da vacinação com uma vacina combinada inativada contendo o vírus da diarréia viral bovina tipo 1 (BVDV-1) e vírus da rinotraqueíte de bovinos infecciosos (IBRV). Cinco bezerros com 3 a 4 meses de idade foram vacinados via intramuscular com uma dose única da vacina combinada e reforçados com a mesma dose três semanas após a primeira vacinação, com cinco bezerros imunizados em simulação servindo como grupo controle. Vinte e um dias após a segunda vacinação, todos os bezerros foram desafiados com a cepa BVDV-2 SX08 por spray na narina. Os animais não vacinados desenvolveram sinais clínicos típicos, como alta temperatura retal, diarréia com erosões e queda drástica na contagem de leucócitos. Estes sinais tiveram ocorrência significativamente menor em todos os animais vacinados, cuja temperatura retal, leucopenia e virarmia eram significativamente menores do que os bezerros simulados. É possível concluir que a vacinação com a vacina combinada inativada proporciona proteção cruzada contra os efeitos clínicos de uma infecção provocada pela cepa BVDV-2 SX08, embora tenha sido parcialmente protegida.(AU)

Association between maternal exposure to particulate matter (PM2.5) and adverse pregnancy outcomes in Lima, Peru.

The literature shows associations between maternal exposures to PM2.5 and adverse pregnancy outcomes. There are few data from Latin America. We have examined PM2.5 and pregnancy outcomes in Lima. The study included 123,034 births from 2012 to 2016, at three public hospitals. We used estimated daily PM2.5 from a newly created model developed using ground measurements, satellite data, and a chemical transport model. Exposure was assigned based on district of residence (n = 39). Linear and logistic regression analyzes were used to estimate the associations between air pollution exposure and pregnancy outcomes. Increased exposure to PM2.5 during the entire pregnancy and in the first trimester was inversely associated with birth weight. We found a decrease of 8.13 g (-14.0; -1.84) overall and 18.6 g (-24.4, -12.8) in the first trimester, for an interquartile range (IQR) increase (9.2 µg/m3) in PM2.5. PM2.5 exposure was positively associated with low birth weight at term (TLBW) during entire pregnancy (OR: 1.11; 95% CI: 1.03-1.20), and at the first (OR: 1.11; 95% CI: 1.03-1.20), second (OR: 1.09; 95% CI: 1.01-1.17), and third trimester (OR: 1.10; 95% CI: 1.02-1.18) per IQR (9.2 µg/m3) increase. Higher exposure to PM2.5 was also associated with increased risk of small for gestational age (SGA). There were no statistically significant associations between PM2.5 exposure and preterm births (PTB). Exposure to higher concentrations of PM2.5 in Lima may decrease birth weight and increase the frequency of TLBW and SGA. Our study was inconsistent with the literature in finding no associations with preterm birth.

Clinicopathological and prognostic value of hypoxia-inducible factor-1α in breast cancer: a meta-analysis including 5177 patients.

PURPOSE: Mounting studies have investigated the clinicopathological and prognostic value of hypoxia-inducible factor-1α (HIF-1α) in breast cancer (BC), yet conclusions remain controversial. Therefore, we conducted this meta-analysis to clarify this issue. METHODS: All relevant studies were searched using Cochrane Library, Web of Science, PubMed, and EMBASE online databases. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate the clinicopathological and prognostic value of HIF-1α, respectively. Subgroup analysis and sensitivity analysis were performed to investigate heterogeneity and stability of the results. Begg's funnel plot and Egger's test were used to examine publication bias. RESULTS: A total of 31 eligible studies including 5177 subjects were enrolled. Of these, 25 studies assessed the prognostic role of HIF-1α and included 4546 individuals. Twenty-three studies involving 3277 individuals evaluated the clinicopathological significance of HIF-1α. High expression level of HIF-1α was correlated with poor overall survival (OS) (HR = 1.59, 95% CI = 1.40-1.80, P < 0.001), disease-free survival (DFS) (HR = 1.87, 95% CI = 1.53-2.28, P < 0.001), relapse-free survival (HR = 1.36, 95% CI = 1.07-1.73, P = 0.001), and cancer-specific survival (HR = 1.55, 95% CI = 1.10-2.19, P = 0.012). Pooled data from studies using multivariate survival analysis also showed that HIF-1α expression was associated with worse OS (HR = 1.59, 95% CI = 1.32-1.92, P < 0.001) and DFS (HR = 1.60, 95% CI = 1.39-1.84, P < 0.001). Additionally, high HIF-1α expression was associated with advanced tumor-node-metastasis stage, positive lymph-node status, negative ER status, ductal type, advanced histologic grade, high Ki67 expression, and strong VEGF expression. CONCLUSION: HIF-1α might serve as an independent prognostic biomarker and a promising therapeutic target for BC. Future large-scale prospective randomized trials are needed to confirm our findings.

Effects of different doses of propofol on the growth and expression of PCNA, CD34 and pAKT proteins in xenografted tumor of BALB/C mice with liver cancer.

OBJECTIVE: To observe the effects of different doses of propofol on the growth of transplanted liver tumor in BALB/C mice and check the expression of PCNA, CD34 and pAKT proteins to clarify the mechanism on molecule level. METHOD: Human primary liver cancer cells SMMC-7721 were subcutaneously cultured in BALB/C mice, and the transplanted tumor model of BALB/C mice was constructed. Forty mice successfully modeled were randomly divided into 5 groups (n = 8): the blank control group (group C), low-fat milk group (group I), low-dose (50 mg/kg) propofol group (P1), middle-dose (100 mg/kg) propofol group (P2) and high dose (150 mg/kg) propofol group (P3). Tumor volume changes were observed at 3, 6, 9, 12, 15 and 18 days (T1, T2, T3, T4, T5, T6 and T7) before and after administration of the drug, and tumor growth curves were plotted. After 19 days of administration, all mice were killed for tumor collection, tumor weight was measured, and the tumor inhibition rate of propofol was calculated. The protein expression of cluster of differentiation 34 (CD34) in transplanted tumor was detected by immunohistochemistry, and the protein expression of proliferating cell nuclear antigen (PCNA) and phospho-Akt (pAKT) was detected by immunofluorescence. RESULTS: Compared with group C, there was no significant difference in tumor volume in group I. At T2 ~ 7, the tumor volume of group P1, P2 and P3 decreased successively (P < 0.05). There was no significant difference in the inhibitory rate of tumor in group I, and the inhibitory rate of tumor in group P1, P2 and P3 increased successively (P < 0.05). There was no significant difference in PCNA, CD34, and pAKT protein expression in group I, while PCNA, CD34, and pAKT protein content in P1, P2, P3 groups were successively decreased (P < 0.05). CONCLUSION: Propofol had a dose-dependent effect on the growth of liver cancer xenografts in mice, inhibiting the expression of PCNA, CD34 and pAKT proteins, and the effect was most obvious in the 150 mg/kg propofol group.

The efficacy and safety of docetaxel, cisplatin and fluorouracil (TPF)-based induction chemotherapy followed by concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma: a meta-analysis.

OBJECTIVES: In recent years, docetaxel, cisplatin and fluorouracil (TPF)-based induction chemotherapy (IC) has been widely applied in the treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, it remains unclear whether TPF is the ideal IC regimen. Thus, we carried out a meta-analysis to compare the efficacy and safety of TPF-based IC plus concurrent chemoradiotherapy (CCRT) versus CCRT alone or double-drug-based IC plus CCRT for LA-NPC. METHODS: We systematically searched PubMed, Embase and the Cochrane Library from inception until December 2018. After rigorous screening of all relevant studies that reported the use of TPF-based IC followed by CCRT for patients with LA-NPC, eight studies met the inclusion criteria and were assessed for design and quality. Among them, three articles were classified as having a high risk of bias and were excluded from the meta-analysis. The outcomes, including overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), locoregional failure-free survival (LRFFS) and incidence of adverse events, were pooled with the use of hazard ratio (HR) or odds ratio (OR). Heterogeneity and sensitivity analyses were also carried out. RESULTS: Five trials involving 4223 patients were included in the meta-analysis. Compared to CCRT alone, TPF-based IC plus CCRT significantly improved OS (HR 0.54, 95% confidence interval [CI] 0.35-0.84, P = 0.006), PFS (HR 0.64, 95% CI 0.46-0.88, P = 0.006), LRFFS (HR 0.57, 95% CI 0.34-0.94, P = 0.03), and DMFS (HR 0.58, 95% CI 0.38-0.88, P = 0.01). Moreover, compared to double-drug-based IC plus CCRT, OS (HR 0.74, 95% CI 0.62-0.87, P = 0.0004), PFS (HR 0.76, 95% CI 0.66-0.88, P = 0.0001) and LRFFS (HR 0.75, 95% CI 0.61-0.92, P = 0.006) were also significantly improved by TPF-based IC plus CCRT. Notably, TPF-based IC plus CCRT mainly led to an increased risk of hematologic toxicities, such as leucopenia (OR = 3.20, 95% CI 2.13-4.81, P < 0.0001) and neutropenia (OR = 3.84, 95% CI 0.66-22.36, P = 0.13). However, these were uncomplicated and manageable with growth factor support. CONCLUSIONS: Compared to CCRT alone or double-drug-based IC plus CCRT, TPF-based IC plus CCRT results in better survival outcomes with manageable toxicities. Thus, it is reasonable to recommend the addition of TPF-based IC to CCRT as an excellent choice for patients with LA-NPC.

Time-series analysis of ambient PM2.5 and cardiorespiratory emergency room visits in Lima, Peru during 2010-2016.

INTRODUCTION: There have been no time-series studies of air pollution in Peru. Here we evaluate the effect of ambient PM2.5 on emergency room (ER) visits in Lima. METHODS: We estimated daily PM2.5 levels at a 1 km2 resolution during 2010-2016 using ground measurements, satellite data, and chemical transport model simulations. Population-weighted average daily PM2.5 levels were calculated for each district in Lima (n = 40), and assigned to patients based on residence. ER visits for respiratory and circulatory diseases were gathered from nine large public hospitals. Poisson regression was used to estimate the rate ratio for daily ER visits with change in daily PM2.5, controlling for meteorology, time trends, and district. RESULTS: For each interquartile range (IQR) increase in PM2.5, respiratory disease ER visits increased 4% (95% CI: 0-5%), stroke visits 10% (3-18%), and ischemic heart disease visits (adults, 18-64 years) 11% (-1, 24%). Districts with higher poverty showed significantly stronger associations of PM2.5 and respiratory disease ER visits than districts with lower poverty. Effects were diminished 24-42% using Lima-wide instead of district-specific PM2.5 levels. CONCLUSIONS: Short-term exposure to ambient PM2.5 is associated with increases in ER visits in Lima for respiratory diseases and stroke, and among middle-aged adults, ischemic heart disease.

IKBKE enhances TMZ-chemoresistance through upregulation of MGMT expression in glioblastoma.

PURPOSE: Glioblastoma multiforme (GBM) is the most common and aggressive malignant type of brain tumor. Despite advances in diagnosis and therapy, the prognosis of patients with GBM has remained dismal. Multidrug resistance and high recurrence are two of the major challenges in successfully treating brain tumors. IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) is a major oncogenic protein in tumors and can inhibit glioblastoma cell proliferation, migration, and tumorigenesis. Our study aimed to investigate the mechanism of IKBKE enhancing the resistance of glioma cells to temozolomide. METHODS: For the in vitro experiments, LN18 and U118 glioblastoma cells were treated with a combination of sh/oe-IKBKE lentivirus and TMZ. Cell proliferation was determined by the EdU assay and colony formation assays. Apoptosis was analyzed by the TUNEL assay. In vivo, LN18 NC and LN18 sh-IKBKE cells were implanted into the cerebrums of nude mice to detect the effect of combination therapy. The protein and mRNA levels were assayed by western blot, immunohistochemistry, and qRT-PCR. RESULTS: In this study, we demonstrated that IKBKE enhances the resistance of glioblastoma cells to temozolomide (TMZ) by activating the AKT/NF-κB signaling pathway to upregulate the expression of the DNA repair enzyme o6-methylguanine-dna methyltransferase (MGMT). In glioblastoma cells, IKBKE knockdown enhances apoptosis and suppresses cell proliferation, clone formation, and tumor development in vivo induced by TMZ. However, overexpression of IKBKE reduces the effects of TMZ. CONCLUSION: Our studies suggest that inhibition of IKBKE can enhance the therapeutic effect of TMZ on GBM in vitro and in vivo, providing new research directions and therapeutic targets for the treatment of GBM.

Effect of feeding grape seed Proanthocyanidin extract on production performance, metabolic and anti-oxidative status of dairy cattle / Efeito da alimentação do extrato de semente de uva Proanthocyanidin sobre o desempenho da produção e o status metabólico e antioxidante de gado leiteiro

Aims to investigate the effects of grape seed proanthocyanidin extract (GSPE) on production performance, metabolism, and anti-oxidative status of Holstein dairy cattle in early lactation. Forty-eight multiparous Holstein dairy cattle were assigned to four groups (CON, G20, G40 and G80) and supplied with 0, 20, 40, and 80mg GSPE/kg of body weight/day. G20 significantly increased milk yield compared with other groups. Milk protein and non-fat-solids were increased in G20, G40 and G80 groups compared with the control group only at the 7th day during the experiment. No significant difference was observed in milk fat and somatic cell count, nor on parameters of energy metabolism in blood, liver function and kidney function between the four groups. There was no significant difference in glutathione peroxidase, superoxide dismutase, total antioxidant capacity, and hydrogen peroxide between the groups; but the malondialdehyde content of G20 significantly increased at day 14 in comparison with CON, and tended to increase at the 28th day. In conclusion, feeding 20mg GSPE/kg of body weight/day was associated with a significant increase in milk yield without detrimental effects on liver or kidney function and with substantial energy metabolism and antioxidant parameters improvement in early lactation dairy cattle.(AU)

O presente trabalho visa investigar os efeitos do extrato de semente de uva Proanthocyanidin (GSPE) sobre o desempenho da produção, o metabolismo e o status antioxidante de gado leiteiro Holstein em lactação precoce. Quarenta e oito vacas leiteiras multíparas Holstein foram divididas em quatro grupos (CON, G20, G40 e G80) e receberam 0, 20, 40 e 80mg de GSPE/kg de peso corporal/dia, respectivamente. O G20 aumentou significativamente o rendimento do leite em comparação com os outros grupos. A proteína e os sólidos não gordurosos do leite foram aumentados nos grupos G20, G40 e G80 somente no sétimo dia durante a experiência. Não foi observada diferença significativa na gordura do leite e na contagem de células somáticas, bem como nos parâmetros de metabolismo energético no sangue, na função hepática e na função renal entre os grupos em relação ao grupo controle. Não houve diferença significativa na glutationa peroxidase, na dimutase de superóxido, na capacidade antioxidante total e no peróxido de hidrogênio entre os grupos, mas o conteúdo malondialdeído do G20 aumentou significativamente no dia 14 em comparação com o CON, e tendia a aumentar no dia 28. Em conclusão, a alimentação de 20mg de GSPE/kg de peso corporal/dia foi associada a um aumento significativo no rendimento do leite, sem efeitos nocivos sobre a função hepática ou a renal, com o metabolismo de energia substancial e a melhoria dos parâmetros antioxidantes de gado leiteiro no início da lactação.(AU)