Prognostic value of routine laboratory variables in prediction of breast cancer recurrence.

The prognostic value of routine laboratory variables in breast cancer has been largely overlooked. Based on laboratory tests commonly performed in clinical practice, we aimed to develop a new model to predict disease free survival (DFS) after surgical removal of primary breast cancer. In a cohort of 1,596 breast cancer patients, we analyzed the associations of 33 laboratory variables with patient DFS. Based on 3 significant laboratory variables (hemoglobin, alkaline phosphatase, and international normalized ratio), together with important demographic and clinical variables, we developed a prognostic model, achieving the area under the curve of 0.79. We categorized patients into 3 risk groups according to the prognostic index developed from the final model. Compared with the patients in the low-risk group, those in the medium- and high-risk group had a significantly increased risk of recurrence with a hazard ratio (HR) of 1.75 (95% confidence interval [CI] 1.30-2.38) and 4.66 (95% CI 3.54-6.14), respectively. The results from the training set were validated in the testing set. Overall, our prognostic model incorporating readily available routine laboratory tests is powerful in identifying breast cancer patients who are at high risk of recurrence. Further study is warranted to validate its clinical application

Association of lipid lowering drugs and the risk of systemic lupus erythematosus: a drug target Mendelian randomization

Background and objective: An interaction between low-density lipoprotein level, lipid-lowering drugs, and systemic lupus erythematosus (SLE) was reported by previous studies. However, whether lipid-lowering drugs provided protective effect for reducing the risk of SLE was unclear. We aimed to clarify this causal relationship through a drug-target Mendelian randomization (MR) study.Methods: Genetic instruments—single nucleotide polymorphism (SNPs)—were utilized to proxy inhibition of the three genes—3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-Like 1(NPC1L1), which was corresponded to three lipid-lowering drugs—statins, evolocumab, and ezetimibe. Low-density lipoprotein (LDL) cholesterol was selected as the biomarker for the measurement of the inhibitors of HMGCR, PCSK9, and NPC1L1, and the genetic data were acquired from the Global Lipids Genetics Consortium, which consisted of 1.3 million participants of European ancestry and 146.5 thousand participants of East Asian ancestry. The genetic dataset of SLE was acquired from two large-scale GWAS studies; one recruited 23,210 participants (7,219 SLE cases and 15,991 controls) of European ancestry and the other one recruited 12,653 participants (4,222 SLE cases and 8,431 controls) of Chinese ancestry. The primary analysis used the inverse variance weighted (IVW) method. Four additional sensitivity analyses, colocalization analysis, and stratification analysis were performed.Results: The primary analysis showed that inhibition of PCSK9 (evolocumab) was associated with a significantly lower risk of SLE [odds ratio (OR) 0.51, 95%CI 0.34 to 0.76, p = 0.001] in the European population. The secondary analyses had similar findings. Stratification analysis demonstrated that the preventive effect of PCSK9 inhibition for SLE was similar in both males and females. However, the results were not replicated in the East Asian population. The inhibition of HMGCR (statins) and NPC1L1 (ezetimibe) did not cause a lower risk of SLE.Conclusion: Evolocumab might provide a protective effect on the risk of SLE in the European population, but statins and ezetimibe might not have the protective effect. Further research is necessary to elucidate the specific mechanisms and potential therapeutic applications of PCSK9 inhibitors (evolocumab) in the context of SLE protection

Propionate Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress

Propionate is a short chain fatty acid and abundant as butyrate in the gut and blood. However, propionate has been studied less extensively than butyrate in the treatment of colitis. The present study was to investigate the effects of sodium propionate on intestinal barrier function, inflammation and oxidative stress in dextran sulfate sodium (DSS)-induced mice. Animals in DSS group received drinking water from 1 to 6 days and DSS (3% (w/v) dissolved in double distilled water) instead of drinking water from 7 to 14 days. Animals in DSS+Prop group were given 1% sodium propionate for 14 consecutive days and supplemented with 3% DSS solution on day 7-14. Intestinal barrier function, proinflammatory factors, oxidative stress, and signal transducer and activator of transcription 3 (STAT3) signaling pathway in the colon were determined. It was found that sodium propionate ameliorated body weight loss, colon-length shortening and colonic damage in colitis mice. Sodium propionate significantly inhibited the increase of FITC-dextran in serum and the decrease of zonula occludens-1 (ZO-1), occludin and E-cadherin expression in the colonic tissue. It also inhibited the expression of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) mRNA and phosphorylation of STAT3 in colitis mice markedly, reduced the myeloperoxidase (MPO) level, and increased the superoxide dismutase (SOD) and catalase (CAT) level in colon and serum compared with DSS group. Sodium propionate inhibited macrophages with CD68 marker infiltration into the colonic mucosa of colitis mice. These results suggest that oral administration of sodium propionate could ameliorate DSS-induced colitis mainly by improving intestinal barrier function and reducing inflammation and oxidative stress via the STAT3 signaling pathway

Prevention of Ichthyophthirius multifiliis infestation in goldfish (Carassius auratus) by potassium ferrate(VI) treatment

Ichthyophthirius multifiliis is an important freshwater teleost pathogen that often leads to significant economic losses to the aquaculture industry. The purpose of this study was to assess the acute toxicity of potassium ferrate(VI) to I. multifiliis theront and the concentration needed to prevent I. multifiliis infestation in goldfish, Carassius auratus. Five hundred theronts were exposed to concentrations of potassium ferrate(VI) in each well of a 96-well microtiter plate and observed for 4 h to determine the acute toxicity. Results showed that the exposure of I. multifiliis theronts to potassium ferrate(VI) at concentrations of 4.80 mg/L or more resulted in 100% mortality by 4 h; the LC50 value was estimated to be 1.71 mg/L Aqueous static renewal 96-h bioassays were carried out to determine the acute toxicity of potassium ferrate(VI) to goldfish. The LC50 value for potassium ferrate(VI) in goldfish was 42.51 mg/L. Goldfish were exposed to 4000 theronts/fish in aerated tap water (a dose previously shown to result in consistent infestation) and treated with a single dose of potassium ferrate(VI) after 30 min contact with theronts. Infection level and prevalence were recorded everyday after exposure. The results revealed that potassium ferrate(VI) at the 4.80 mg/L or more concentrations can significantly reduce not only the number of trophonts on the fin of goldfish on day 3 (P < 0.05), but also the prevalence of ichthyophthiriasis (P<0.05). Potassium ferrate(VI) at a concentration of 4.80 mg/L was considered to be the lowest effective dose to prevent infestation of I. multifillis in goldfish. (C) 2009 Published by Elsevier B.V

Effects of salt stress on interspecific competition between an invasive alien plant Oenothera biennis and three native species

Biological invasions and soil salinization have become increasingly severe environmental problems under global change due to sea-level rise and poor soil management. Invasive species can often outcompete native species, but few studies focus on whether invasive alien species are always superior competitors under increasing stressors. We grew an invasive grass species, Oenothera biennis L., and three native grass species (Artemisia argyi Lévl. et Vant., Chenopodium album L., and Inula japonica Thunb.) as a monoculture (two seedlings of each species) or mixture (one seedling of O. biennis and one native species seedling) under three levels of salt treatments (0, 1, and 2 g/kg NaCl) in a greenhouse. We found that invasive O. biennis exhibited greater performance over native C. album and I. japonica, but lower performance compared to A. argyi, regardless of the soil salinity. However, salinity did not significantly affect the relative dominance of O. biennis. Interspecific competition enhanced the growth of O. biennis and inhibited the growth of I. japonica. Although O. biennis seedlings always had growth dominance over C. album seedlings, C. album was not affected by O. biennis at any salt level. At high salt levels, O. biennis inhibited the growth of A. argyi, while A. argyi did not affect the growth of O. biennis. Salt alleviated the competitive effect of O. biennis on I. japonica but did not mitigate the competition between O. biennis and the other two native species. Therefore, our study provides evidence for a better understanding of the invasive mechanisms of alien species under various salinity conditions

Age-Related Loss of Innate Immune Antimicrobial Function of Dermal Fat Is Mediated by Transforming Growth Factor Beta

Dermal immature adipocytes fightagainstStaphylococcusaureusinfectionby secreting antimicrobial peptidesduring adipogenesis. Zhang et al.demonstrate that activation of the TGF-bpathway suppresses the adipogenicpotential of dermal fibroblasts andtherefore leads to an age-dependent lossof antimicrobial protection fromdermal fat. 皮下脂肪细胞作为皮肤的最后一道防线，有很重要的免疫抗菌功能，分化中脂肪细胞释放大量抗菌肽，这是一种人自源抗生素，能有效地抑制细菌生长。但这一重要的宿主天然免疫功能在发育和老化过程中如何被调控还不为人知。研究人员发现，老化过程中皮肤脂肪丢失是和真皮成纤维细胞（dermal fibroblasts）失去脂肪分化能力密切相关的。真皮成纤维细胞是皮肤深处的特化细胞，可以产生结缔组织并帮助皮肤从损伤中恢复。【Abstract】Dermal fibroblasts (dFBs) resist infection by locallydifferentiating into adipocytes and producing cathe-licidin antimicrobial peptide in response toStaphylo-coccusaureus(S.aureus). Here, we show thatneonatal skin was enriched with adipogenic dFBsand immature dermal fat that highly expressed cath-elicidin. The pool of adipogenic and antimicrobialdFBs declined after birth, leading to an age-depen-dent loss of dermal fat and a decrease in adipogene-sis and cathelidicin production in response to infec-tion. Transforming growth factor beta (TGF-b),which acted on uncommitted embryonic and adultdFBs and inhibited their adipogenic and antimicro-bial function, was identified as a key upstream regu-lator of this process. Furthermore, inhibition of theTGF-breceptor restored the adipogenic and antimi-crobial function of dFBs in culture and increasedresistance of adult mice toS.aureusinfection. Theseresults provide insight into changes that occur in theskin innate immune system between the perinataland adult periods of life.This work was supported by NIH grant R01-AR069653 to L.Z. and R.L.G. and NIH grants R01-AI083358, R01-AR052728, and U19-AI117673 to R.L.G. M.V.P. is supported by a Pew Charitable Trust grant, NIH grants U01-AR073159 and R01-AR067273, National Science Foundation (NSF) grant DMS1763272, and Simons Foundation grant 594598 (to Qing Nie). C.F.G.J. is supported by NSF-GRFP grant DGE-1321846 and MBRS-IMSD training grant GM055246. Y.Z. is supported by NIH grant R01-AI107027. 该项目研究得到了厦门大学双一流启动基金的支持

Monoester-Diterpene Aconitum

Aconitum, widely used to treat rheumatoid arthritis for thousands of years, is a toxic herb that can frequently cause fatal cardiac poisoning. Aconitum toxicity could be decreased by properly hydrolyzing diester-diterpene alkaloids into monoester-diterpene alkaloids. Monoester-diterpene alkaloids, including benzoylaconine (BAC), benzoylmesaconine (BMA), and benzoylhypaconine (BHA), are the primary active and toxic constituents of processed Aconitum. Cytochrome P450 (CYP) enzymes protect the human body by functioning as the defense line that limits the invasion of toxicants. Our purposes were to identify the CYP metabolites of BAC, BMA, and BHA in human liver microsomes and to distinguish which isozymes are responsible for their metabolism through the use of chemical inhibitors, monoclonal antibodies, and cDNA-expressed CYP enzyme. High-resolution mass spectrometry was used to characterize the metabolites. A total of 7, 8, and 9 metabolites were detected for BAC, BMA, and BHA, respectively. The main metabolic pathways were demethylation, dehydrogenation, demethylation-dehydrogenation, hydroxylation and didemethylation, which produced less toxic metabolites by decomposing the group responsible for the toxicity of the parent compound. Taken together, the results of the chemical inhibitors, monoclonal antibodies, and cDNA-expressed CYP enzymes experiments demonstrated that CYP3A4 and CYP3A5 have essential functions in the metabolism of BAC, BMA, and BHA

Autocrine Epiregulin Activates EGFR Pathway for Lung Metastasis Via EMT in Salivary Adenoid Cystic Carcinoma

Salivary adenoid cystic carcinoma (SACC) is characterized by invasive local growth and a high incidence of lung metastasis. Patients with lung metastasis have a poor prognosis. Treatment of metastatic SACC has been unsuccessful, largely due to a lack of specific targets for the metastatic cells. In this study, we showed that epidermal growth factor receptors (EGFR) were constitutively activated in metastatic lung subtypes of SACC cells, and that this activation was induced by autocrine expression of epiregulin (EREG), a ligand of EGFR. Autocrine EREG expression was increased in metastatic SACC-LM cells compared to that in non-metastatic parental SACC cells. Importantly, EREG-neutralizing antibody, but not normal IgG, blocked the autocrine EREG-induced EGFR phosphorylation and the migration of SACC cells, suggesting that EREG-induced EGFR activation is essential for induction of cell migration and invasion by SACC cells. Moreover, EREG-activated EGFR stabilized Snail and Slug, which promoted EMT and metastatic features in SACC cells. Of note, targeting EGFR with inhibitors significantly suppressed both the motility of SACC cells in vitro and lung metastasis in vivo. Finally, elevated EREG expression showed a strong correlation with poor prognosis in head and neck cancer. Thus, targeting the EREG-EGFR-Snail/Slug axis represents a novel strategy for the treatment of metastatic SACC even no genetic EGFR mutation

Network of Interactions Between Gut Microbiome, Host Biomarkers, and Urine Metabolome in Carotid Atherosclerosis

Comprehensive analyses of multi-omics data may provide insights into interactions between different biological layers concerning distinct clinical features. We integrated data on the gut microbiota, blood parameters and urine metabolites of treatment-naive individuals presenting a wide range of metabolic disease phenotypes to delineate clinically meaningful associations. Trans-omics correlation networks revealed that candidate gut microbial biomarkers and urine metabolite feature were covaried with distinct clinical phenotypes. Integration of the gut microbiome, the urine metabolome and the phenome revealed that variations in one of these three systems correlated with changes in the other two. In a specific note about clinical parameters of liver function, we identified Eubacteriumeligens, Faecalibacteriumprausnitzii and Ruminococcuslactaris to be associated with a healthy liver function, whereas Clostridium bolteae, Tyzzerellanexills, Ruminococcusgnavus, Blautiahansenii, and Atopobiumparvulum were associated with blood biomarkers for liver diseases. Variations in these microbiota features paralleled changes in specific urine metabolites. Network modeling yielded two core clusters including one large gut microbe-urine metabolite close-knit cluster and one triangular cluster composed of a gut microbe-blood-urine network, demonstrating close inter-system crosstalk especially between the gut microbiome and the urine metabolome. Distinct clinical phenotypes are manifested in both the gut microbiome and the urine metabolome, and inter-domain connectivity takes the form of high-dimensional networks. Such networks may further our understanding of complex biological systems, and may provide a basis for identifying biomarkers for diseases. Deciphering the complexity of human physiology and disease requires a holistic and trans-omics approach integrating multi-layer data sets, including the gut microbiome and profiles of biological fluids. By studying the gut microbiome on carotid atherosclerosis, we identified microbial features associated with clinical parameters, and we observed that groups of urine metabolites correlated with groups of clinical parameters. Combining the three data sets, we revealed correlations of entities across the three systems, suggesting that physiological changes are reflected in each of the omics. Our findings provided insights into the interactive network between the gut microbiome, blood clinical parameters and the urine metabolome concerning physiological variations, and showed the promise of trans-omics study for biomarker discovery.publishedVersio