Miracle-dz/UniFAR-FTUs huggingface dataset:
Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews

Objective To synthesise evidence from exclusively primary prevention data on the effectiveness of statins for prevention of cardiovascular disease (CVD), including stroke, and outcomes stratified by baseline risk and gender. Design Overview of systematic reviews (SRs) using Revised-AMSTAR approach to assess quality. Data sources Cochrane Database of Systematic Reviews, MEDLINE, Embase, PubMed, Scopus and PROSPERO to June 2017. Eligibility criteria for selecting studies SRs of randomised control trials (RCTs) or individual patient data (IPD) from RCTs, examining the effectiveness of statins versus placebo or no treatment on all-cause mortality, coronary heart disease, CVD (including stroke) and composite endpoints, with stratification by baseline risk and gender. Data extraction and synthesis Two independent reviewers extracted data and assessed methodological quality. A narrative synthesis was conducted. Results Three SRs were included. Quality of included SRs was mixed, and none reported on the risk of bias of included trials. We found trends towards reduced all-cause mortality in all SRs (RR 0.91 [95% CI 0.85 to 0.97]), (RR 0.91 [95% CI 0.83 to 1.01]) and (RR 0.78 [95% CI 0.53 to 1.15]) though it was not statistically significant in two SRs. When stratified by baseline risk, the effect on all-cause mortality was no longer statistically significant except in one medium risk category. One review reported significant reductions (RR 0.85 [95% CI 0.77 to 0.95]) in vascular deaths and non-significant reductions in non-vascular deaths (RR 0.97 [95% CI 0.88 to 1.07]). There were significant reductions in composite outcomes overall, but mixed results were reported in these when stratified by baseline risk. These reviews included studies with participants considered risk equivalent to those with established CVD. Conclusions There is limited evidence on the effectiveness of statins for primary prevention with mixed findings from studies including participants with widely ranging baseline risks. Decision making for the use of statins should consider individual baseline risk, absolute risk reduction and whether risk reduction justifies potential harms and taking a daily medicine for life. Trial registration number CRD42017064761.
Disease burden of liver cancer in China from 1997 to 2016: an observational study based on the Global Burden of Diseases

Objective To evaluate the trends in disease burden and the epidemiological features of liver cancer in China while identifying potential strategies to lower the disease burden. Design Observational study based on the Global Burden of Diseases. Participants Data were publicly available and de-identified and individuals were not involved. Measurement and methods To measure the liver cancer burden, we extracted data from the Global Health Data Exchange using the metrics of prevalence, incidence, mortality and disability-adjusted life years (DALYs). Joinpoint and negative binomial regressions were applied to identify trends and risk factors. Results From 1997 to 2016, the prevalence, incidence, mortality and DALYs of liver cancer in China were from 28.22/100 000 to 60.04/100 000, from 27.33/100 000 to 41.40/100 000, from 27.40/100 000 to 31.49/100 000 and from 10 311 308 to 11 539 102, respectively. The prevalence, incidence and mortality were increasing, with the average annual percent changes (AAPCs) of 4.0% (95% CI 3.9% to 4.2%), 2.1% (95% CI 2.0% to 2.2%) and 0.5% (95% CI 0.2% to 0.9%), respectively. Meanwhile, the rate of DALYs was stable with the AAPCs of −0.1% (95% CI −0.4% to 0.3%). The mortality-to-incidence ratio of liver cancer decreased from 1.00 in 1997 to 0.76 in 2016 (β=−0.014, p<0.0001). Males (OR: 2.98, 95% CI 2.68 to 3.30 for prevalence, OR: 2.45, 95% CI 2.21 to 2.71 for incidence) and the elderly individuals (OR: 1.57, 95% CI 1.55 to 1.59 for prevalence, OR: 1.58, 95% CI 1.56 to 1.60 for incidence) had a higher risk. Hepatitis B accounted for the highest proportion of liver cancer cases (55.11%) and deaths (54.13%). Conclusions The disease burden of liver cancer continued to increase in China with viral factors as one of the leading causes. Strategies such as promoting hepatitis B vaccinations, blocking the transmission of hepatitis C and reducing alcohol consumption should be prioritised.
A Review of Durability and Strength Characteristics of Alkali-Activated Slag Concrete

Alkali-activated slag (AAS) is a promising alternative to ordinary Portland cement (OPC) as sole binder for reinforced concrete structures. OPC is reportedly responsible for over 5% of the global CO2 emission. In addition, slag is an industrial by-product that must be land-filled if not re-used. Therefore, it has been studied by many investigators as environmentally friendly replacement of OPC. In addition to recycling, AAS offers favorable properties to concrete such as rapid development of compressive strength and high resistance to sulfate attack. Some of the potential shortcomings of AAS include high shrinkage, short setting time, and high rate of carbonation. Using ground granulated blast furnace slag (GGBS) as an alternative to OPC requires its activation with high alkalinity compounds such as sodium hydroxide (NaOH), sodium sulfate (Na2SO3), sodium carbonate (Na2CO3), or combination of these compounds such as NaOH and Na2SO3. The mechanism of alkali-activation is still not fully understood and further research is required. This paper overviews the properties, advantages, and potential shortcomings of AAS concrete.
Progesterone Application to the Rat Forehead Produces Corneal Antinociception

Purpose Ocular pain and discomfort are the most defining symptoms of dry eye disease. We determined the ability of topical progesterone to affect corneal sensitivity and brainstem processing of nociceptive inputs. Methods Progesterone or vehicle gel was applied to the shaved forehead in male Sprague Dawley rats. As a site control, gel also was applied to the cheek on the side contralateral to corneal stimulation. Corneal mechanical thresholds were determined using the Cochet-Bonnet esthesiometer in intact and lacrimal gland excision–induced dry eye animals. Eye wipe behaviors in response to hypertonic saline and capsaicin were examined, and corneal mustard oil-induced c-Fos immunohistochemistry was quantified in the brainstem spinal trigeminal nucleus. Results Progesterone gel application to the forehead, but not the contralateral cheek, increased corneal mechanical thresholds in intact and lacrimal gland excision animals beginning <30 minutes after treatment. Subcutaneous injection of the local anesthetic bupivacaine into the forehead region before application of progesterone prevented the increase in corneal mechanical thresholds. Furthermore, progesterone decreased capsaicin-evoked eye wipe behavior in intact animals and hypertonic saline evoked eye wipe behavior in dry eye animals. The number of Fos-positive neurons located in the caudal region of the spinal trigeminal nucleus after corneal mustard oil application was reduced in progesterone-treated animals. Conclusions Results from this study indicate that progesterone, when applied to the forehead, produces analgesia as indicated by increased corneal mechanical thresholds and decreased nociceptive responses to hypertonic saline and capsaicin.
The Effects of Epigallocatechin Gallate (EGCG) on Pulmonary Fibroblasts of Idiopathic Pulmonary Fibrosis (IPF)—A Next-Generation Sequencing and Bioinformatic Approach

Idiopathic pulmonary fibrosis (IPF) is a disabling and lethal chronic progressive pulmonary disease. Epigallocatechin gallate (EGCG) is a polyphenol, which is the major biological component of green tea. The anti-oxidative, anti-inflammatory, and anti-fibrotic effects of EGCG have been shown in some studies, whereas its effects in altering gene expression in pulmonary fibroblasts have not been systematically investigated. This study aimed to explore the effect of EGCG on gene expression profiles in fibroblasts of IPF. The pulmonary fibroblasts from an IPF patient were treated with either EGCG or water, and the expression profiles of mRNAs and microRNAs were determined by next-generation sequencing (NGS) and analyzed with the bioinformatics approach. A total of 61 differentially expressed genes and 56 differentially expressed microRNAs were found in EGCG-treated IPF fibroblasts. Gene ontology analyses revealed that the differentially expressed genes were mainly involved in the biosynthetic and metabolic processes of cholesterol. In addition, five potential altered microRNA–mRNA interactions were found, including hsa-miR-939-5p–PLXNA4, hsa-miR-3918–CTIF, hsa-miR-4768-5p–PDE5A, hsa-miR-1273g-3p–VPS53, and hsa-miR-1972–PCSK9. In summary, differentially expressed genes and microRNAs in response to EGCG treatment in IPF fibroblasts were identified in the current study. Our findings provide a scientific basis to evaluate the potential benefits of EGCG in IPF treatment, and warrant future studies to understand the role of molecular pathways underlying cholesterol homeostasis in the pathogenesis of IPF.
Targeting Filamin A Reduces Macrophage Activity and Atherosclerosis.

BACKGROUND The actin-binding protein filamin A (FLNA) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored. METHODS We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice ( Flnao/ fl) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis in vivo was studied by transplanting bone-marrow (BMT) from male Flnao/ fl/ LC mice to atherogenic low-density lipoprotein receptor-deficient ( Ldlr-/-) mice; and by infecting Flnao/ fl and Flnao/ fl/ LC mice with an adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9 (AdPCSK9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage. RESULTS We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques. Flnao/ fl/ LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; and exhibited reduced foam cell formation and lipid uptake, and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr -/-BMT: Flnao/fl/LC and AdPCSK9-infected Flnao/fl/LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient than control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, IL-6 secretion, foam cell formation and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9. CONCLUSIONS Genetic inactivation of Flna and/or chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis.
LINC00473/miR‐374a‐5p regulates esophageal squamous cell carcinoma via targeting SPIN1 to weaken the effect of radiotherapy

Esophageal squamous cell carcinoma (ESCC) is the most prevalent type in esophageal cancers. Despite accumulating achievements in treatments of ESCC, patients still suffer from recurrence because of the treatment failures, one of the reasons for which is radioresistance. Therefore, it is a necessity to explore the molecular mechanism underlying ESCC radioresistance. Long intergenic noncoding RNA 473 (LINC00473) has been reported to be aberrantly expressed in several human malignancies. However, its biological function in radiosensitivity of ESCC remains to be fully understood. This study explored the role of LINC00473 in radiosensitivity of ESCC cells and whether LINC00473 acted as a competing endogenous RNA to realize its modulation on radioresistance. We found that LINC00473 was markedly upregulated in ESCC tissues and cell lines, and its expression was remarkably related to cellular response to irradiation. In addition, knockdown of LINC00473 could sensitize ESCC cells to radiation in vitro. As for the underlying mechanism, we uncovered that there was a mutual inhibition between LINC00473 and miR‐374a‐5p. Spindlin1 (SPIN1) was verified as a downstream target of miR‐374a‐5p, and LINC00473 upregulated SPIN1 expression through negatively modulating miR‐374a‐5p expression. Furthermore, we revealed that SPIN1 could aggravate the radioresistance of ESCC cells. Finally, overexpression of SPIN1 reversed the LINC00473 silencing‐enhanced radiosensitivity in ESCC cells. To sum up, we demonstrated that LINC00473 facilitated radioresistance by regulating the miR‐374a‐5p/SPIN1 axis in ESCC.
The Shifting Architecture of Cognition and Brain Function in Older Adulthood

Cognitive aging is often described in the context of loss or decline. Emerging research suggests that the story is more complex, with older adults showing both losses and gains in cognitive ability. With increasing age, declines in controlled, or fluid, cognition occur in the context of gains in crystallized knowledge of oneself and the world. This inversion in cognitive capacities, from greater reliance on fluid abilities in young adulthood to increasingly crystallized or semanticized cognition in older adulthood, has profound implications for cognitive and real-world functioning in later life. The shift in cognitive architecture parallels changes in the functional network architecture of the brain. Observations of greater functional connectivity between lateral prefrontal brain regions, implicated in cognitive control, and the default network, implicated in memory and semantic processing, led us to propose the default-executive coupling hypothesis of aging. In this review we provide evidence that these changes in the functional architecture of the brain serve as a neural mechanism underlying the shifting cognitive architecture from younger to older adulthood. We incorporate findings spanning cognitive aging and cognitive neuroscience to present an integrative model of cognitive and brain aging, describing its antecedents, determinants, and implications for real-world functioning.
Biodistribution and Physiologically-Based Pharmacokinetic Modeling of Gold Nanoparticles in Mice with Interspecies Extrapolation

Gold nanoparticles (AuNPs) are a focus of growing medical research applications due to their unique chemical, electrical and optical properties. Because of uncertain toxicity, “green” synthesis methods are emerging, using plant extracts to improve biological and environmental compatibility. Here we explore the biodistribution of green AuNPs in mice and prepare a physiologically-based pharmacokinetic (PBPK) model to guide interspecies extrapolation. Monodisperse AuNPs were synthesized and capped with epigallocatechin gallate (EGCG) and curcumin. 64 CD-1 mice received the AuNPs by intraperitoneal injection. To assess biodistribution, groups of six mice were sacrificed at 1, 7, 14, 28 and 56 days, and their organs were analyzed for gold content using inductively coupled plasma mass spectrometry (ICP-MS). A physiologically-based pharmacokinetic (PBPK) model was developed to describe the biodistribution data in mice. To assess the potential for interspecies extrapolation, organism-specific parameters in the model were adapted to represent rats, and the rat PBPK model was subsequently evaluated with PK data for citrate-capped AuNPs from literature. The liver and spleen displayed strong uptake, and the PBPK model suggested that extravasation and phagocytosis were key drivers. Organ predictions following interspecies extrapolation were successful for rats receiving citrate-capped AuNPs. This work lays the foundation for the pre-clinical extrapolation of the pharmacokinetics of AuNPs from mice to larger species.
Influence of Sodium Citrate Supplementation after Dehydrating Exercise on Responses of Stress Hormones to Subsequent Endurance Cycling Time-Trial in the Heat

Background and objectives: In temperate environments, acute orally induced metabolic alkalosis alleviates exercise stress, as reflected in attenuated stress hormone responses to relatively short-duration exercise bouts. However, it is unknown whether the same phenomenon occurs during prolonged exercise in the heat. This study was undertaken with aim to test the hypothesis that ingestion of an alkalizing substance (sodium citrate; CIT) after dehydrating exercise would decrease blood levels of stress hormones during subsequent 40 km cycling time-trial (TT) in the heat. Materials and Methods: Male non-heat-acclimated athletes (n = 20) lost 4% of body mass by exercising in the heat. Then, during a 16 h recovery period prior to TT in a warm environment (32 °C), participants ate the prescribed food and ingested CIT (600 mg·kg−1) or placebo (PLC) in a double-blind, randomized, crossover manner with 7 days between the two trials. Blood aldosterone, cortisol, prolactin and growth hormone concentrations were measured before and after TT. Results: Total work performed during TT was similar in the two trials (p = 0.716). In CIT compared to PLC trial, lower levels of aldosterone occurred before (72%) and after (39%) TT (p ˂ 0.001), and acute response of aldosterone to TT was blunted (29%, p ˂ 0.001). Lower cortisol levels in CIT than in PLC trial occurred before (13%, p = 0.039) and after TT (14%, p = 0.001), but there were no between-trial differences in the acute responses of cortisol, prolactin or growth hormone to TT, or in concentrations of prolactin and growth hormone before or after TT (in all cases p > 0.05). Conclusions: Reduced aldosterone and cortisol levels after TT and blunted acute response of aldosterone to TT indicate that CIT ingestion during recovery after dehydrating exercise may alleviate stress during the next hard endurance cycling bout in the heat.
B Cells and Antibodies in Kawasaki Disease

The etiology of Kawasaki disease (KD), the leading cause of acquired heart disease in children, is currently unknown. Epidemiology supports a relationship of KD to an infectious disease. Several pathological mechanisms are being considered, including a superantigen response, direct invasion by an infectious etiology or an autoimmune phenomenon. Treating affected patients with intravenous immunoglobulin is effective at reducing the rates of coronary aneurysms. However, the role of B cells and antibodies in KD pathogenesis remains unclear. Murine models are not clear on the role for B cells and antibodies in pathogenesis. Studies on rare aneurysm specimens reveal plasma cell infiltrates. Antibodies generated from these aneurysmal plasma cell infiltrates showed cross-reaction to intracellular inclusions in the bronchial epithelium of a number of pathologic specimens from children with KD. These antibodies have not defined an etiology. Notably, a number of autoantibody responses have been reported in children with KD. Recent studies show acute B cell responses are similar in children with KD compared to children with infections, lending further support of an infectious disease cause of KD. Here, we will review and discuss the inconsistencies in the literature in relation to B cell responses, specific antibodies, and a potential role for humoral immunity in KD pathogenesis or diagnosis.
Usefulness of the heparin-binding protein level to diagnose sepsis and septic shock according to Sepsis-3 compared with procalcitonin and C reactive protein: a prospective cohort study in China

Objectives Our aim was to assess the release level of heparin-binding protein (HBP) in sepsis and septic shock under the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Design Prospective cohort study. Setting A general teaching hospital in China. Participants Adult infected patients with suspected sepsis and people who underwent physical examination were included. According to the health status and severity of illness, the research subjects were divided into healthy, local infection, sepsis non-shock and septic shock under Sepsis-3 definitions. Main outcome measures Plasma levels of HBP, procalcitonin (PCT), C reactive protein (CRP) and complete blood count were detected in all subjects. Single-factor analysis of variance was used to compare the biomarker levels of multiple groups. A receiver operating characteristic (ROC) curve was used to assess the diagnostic capacity of each marker. Results HBP levels were significantly higher in patients with sepsis non-shock than in those with local infections (median 49.7ng/mL vs 11.8 ng/mL, p<0.01) at enrolment. Moreover, HBP levels in patients with septic shock were significantly higher than in patients with sepsis without shock (median 153.8ng/mL vs 49.7 ng/mL, p<0.01). The area under the ROC curve (AUC) of HBP (cut-off ≥28.1 ng/mL) was 0.893 for sepsis which was higher than those of PCT (0.856) for a cut-off ≥2.05 ng/mL and of CRP (0.699) for a cut-off ≥151.9 mg/L. Moreover, AUC of HBP (cut-off ≥103.5 ng/mL) was 0.760 for septic shock which was higher than the ROC curve of sequential [sepsis-related] organ failure assessment (SOFA) Score (0.656) for a cut-off ≥5.5. However, there was no significant difference between 28-d survivors (n=56) and 28-d non-survivors (n=37) with sepsis in terms of HBP value (p=0.182). Conclusions A high level of HBP in plasma is associated with sepsis, which might be a useful diagnostic marker in patients with suspected sepsis.
Inflammasomes in neuroinflammatory and neurodegenerative diseases

Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid‐β, α‐synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host‐derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)‐1β and IL‐18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS‐resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome‐targeted strategies that may potentially treat these diseases.