The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria ...that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.
Chronic low back pain due to intervertebral disc (IVD) degeneration is associated with increased levels of inflammatory mediators. Current medical treatment consists of oral anti-inflammatory drugs ...to alleviate pain. In this study, the efficacy and safety of a novel thermoreversible poly-N-isopropylacrylamide MgFe-layered double hydroxide (pNIPAAM MgFe-LDH) hydrogel was evaluated for intradiscal controlled delivery of the selective cyclooxygenase (COX) 2 inhibitor and anti-inflammatory drug celecoxib (CXB).
Degradation, release behavior, and the ability of a CXB-loaded pNIPAAM MgFe-LDH hydrogel to suppress prostaglandin E2 (PGE2) levels in a controlled manner in the presence of a proinflammatory stimulus (TNF-α) were evaluated in vitro. Biocompatibility was evaluated histologically after subcutaneous injection in mice. Safety of intradiscal application of the loaded and unloaded hydrogels was studied in a canine model of spontaneous mild IVD degeneration by histological, biomolecular, and biochemical evaluation. After the hydrogel was shown to be biocompatible and safe, an in vivo dose-response study was performed in order to determine safety and efficacy of the pNIPAAM MgFe-LDH hydrogel for intradiscal controlled delivery of CXB.
CXB release correlated to hydrogel degradation in vitro. Furthermore, controlled release from CXB-loaded hydrogels was demonstrated to suppress PGE2 levels in the presence of TNF-α. The hydrogel was shown to exhibit a good biocompatibility upon subcutaneous injection in mice. Upon intradiscal injection in a canine model, the hydrogel exhibited excellent biocompatibility based on histological evaluation of the treated IVDs. Gene expression and biochemical analyses supported the finding that no substantial negative effects of the hydrogel were observed. Safety of application was further confirmed by the absence of clinical symptoms, IVD herniation or progression of degeneration. Controlled release of CXB resulted in a nonsignificant maximal inhibition (approximately 35 %) of PGE2 levels in the mildly degenerated canine IVDs.
In conclusion, this study showed biocompatibility and safe intradiscal application of an MgFe LDH-pNIPAAM hydrogel. Controlled release of CXB resulted in only limited inhibition of PGE2 in this model with mild IVD degeneration, and further studies should concentrate on application of controlled release from this type of hydrogel in animal models with more severe IVD degeneration.
The mechanisms by which probiotic strains enhance the health of the host remain largely uncharacterized. Here we demonstrate that Lactobacillus salivarius UCC118, a recently sequenced and genetically ...tractable probiotic strain of human origin, produces a bacteriocin in vivo that can significantly protect mice against infection with the invasive foodborne pathogen Listeria monocytogenes. A stable mutant of Lb. salivarius UCC118 that is unable to produce the Abp118 bacteriocin also failed to protect mice against infection with two strains of L. monocytogenes, EGDe and LO28, confirming that bacteriocin production is the primary mediator of protection against this organism. Furthermore, Lb. salivarius UCC118 did not offer any protection when mice were infected with a strain of L. monocytogenes expressing the cognate Abp118 immunity protein AbpIM, confirming that the antimicrobial effect is a result of direct antagonism between Lb. salivarius and the pathogen, mediated by the bacteriocin Abp118.
Coherent plane-wave compound imaging (CPWCI) is used as alternative for conventional focused imaging (CFI) to increase frame rates linearly with the ratio number of imaging lines to steering angles. ...In this study, the image quality was compared between CPWCI and CFI, and the effect of steering angles (range and number) and beamforming strategies was evaluated in CPWCI. In automated breast volume scanners (ABVSs), which suffer from reduced volume rates, CPWCI might be an excellent candidate to replace CFI. Therefore, the image quality of CFI currently in ABVS and CPWCI was also compared in an in vivo breast lesion. Images were obtained by a Siemens Sequoia ultrasound system, and two transducers (14L5 and 10L4) in a CIRS multipurpose phantom (040GSE) and a breast lesion. Phantom results showed that contrast sensitivity and resolution, axial resolution, and generalized contrast-to-noise ratio (gCNR; imaging depths <45 mm) were similar for most imaging sequences. CNR (imaging depths ≥45 mm), penetration, and lateral resolution were significantly improved for CPWCI (15 angles) compared to CFI for both transducers. In CPWCI, certain combinations of steering angles and beamforming methods yielded improved gCNR (small angles and delay-and-sum) or lateral resolution (large angles and Lu's-fk). Image quality seemed similar between CPWCI and CFI (three angles incoherent compounded as in ABVS) by visual inspection of the in vivo breast lesion images.
In a randomized trial, 5400 patients scheduled to undergo CABG were assigned either to an anesthetic regimen that included a volatile anesthetic or to total intravenous anesthesia. At 1 year, there ...was no significant difference between the two groups in the number of deaths from any cause.
Currently, antimicrobial peptides (AMPs) are of growing interest as potential substitutes for antibiotic growth promoters in animal production. The present study was conducted to evaluate the effects ...of dietary supplementation of bioengineering artificial Parasin I protein (API) and artificial plectasin protein (APL) (named as compound bioengineering protein, CBP) on growth performance and intestinal health of broilers. A total of 450 one-day-old Arbor Acres male healthy broilers were randomly allotted to 5 dietary groups with 10 replicates of 9 individuals in each replicate and supplemented with 0, 250, 500, 750, and 1,000 mg/kg CBP for 6 wk. Dietary CBP supplementation increased (P < 0.01) body weight (6 wk), average daily gain (0–6 wk), and average daily feed intake (3–6 wk and 0–6 wk). CBP addition enhanced antioxidant capacity, which was accompanied by the higher (P < 0.05) activity of serum total antioxidant capacity (T-AOC) (750 mg/kg), jejunal glutathione peroxidase (750 mg/kg), and T-AOC (500 and 1,000 mg/kg). Dietary CBP addition improved intestinal health, reflecting by the increased (P < 0.05) villus height to crypt depth ratio in the duodenum, the upregulated (P < 0.01) mRNA levels of claudin-1 (500 and 750 mg/kg) in the ileum, the downregulated (P < 0.01) mRNA expression of occludin (500 mg/kg) in the duodenum and claudin-1 (500 mg/kg) and occludin (500 and 750 mg/kg) in the jejunum, and the upregulated mRNA expression of (P < 0.01) mucin2 (MUC2) (1,000 mg/kg) in the duodenum. In addition, CBP upregulated (P < 0.01) IL-10 (1,000 mg/kg) in duodenum and ileum, and downregulated (P < 0.05) the mRNA expression of IL-6 (750 and 1,000 mg/kg), interferon-γ (1,000 mg/kg) in the jejunum and TNF-α (250 mg/kg) in the ileum. Furthermore, dietary CBP increased (P < 0.01) the abundance of total bacteria and Lactobacillus (500 and 750 mg/kg), and reduced (P < 0.05) the abundance of Escherichia coli (750 mg/kg) in the cecum. In conclusion, CBP supplementation enhances the antioxidant capacity, intestinal health, immune function, and ameliorates the gut microflora population, thus improving the growth performance of broilers. Dietary supplementation of 750 mg/kg CBP exhibits a better beneficial effect.
Microglia are tissue macrophages of the central nervous system that monitor brain homeostasis and react upon neuronal damage and stress. Aging and neurodegeneration induce a hypersensitive, ...pro-inflammatory phenotype, referred to as primed microglia. To determine the gene expression signature of priming, the transcriptomes of microglia in aging, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) mouse models were compared using Weighted Gene Co-expression Network Analysis (WGCNA).
A highly consistent consensus transcriptional profile of up-regulated genes was identified, which prominently differed from the acute inflammatory gene network induced by lipopolysaccharide (LPS). Where the acute inflammatory network was significantly enriched for NF-κB signaling, the primed microglia profile contained key features related to phagosome, lysosome, antigen presentation, and AD signaling. In addition, specific signatures for aging, AD, and ALS were identified.
Microglia priming induces a highly conserved transcriptional signature with aging- and disease-specific aspects.
Selenium (Se), which can be both hazardous and beneficial to plants, animals and humans, plays a pivotal role in regulating soil-plant-human ecosystem functions. The biogeochemical behavior of Se and ...its environmental impact on the soil-plant-human system has received broad attention in the last decades. This review provides a comprehensive understanding of Se biogeochemistry in the soil-plant-human system. The speciation, transformation, bioavailability as well as the beneficial and hazardous effects of Se in the soil-plant-human system are summarized. Several important aspects in Se in the soil-plant-human system are detailed mentioned, including (1) strategies for biofortification in Se-deficient areas and phytoremediation of soil Se in seleniferous areas; (2) factors affecting Se uptake and transport by plants; (3) metabolic pathways of Se in the human body; (4) the interactions between Se and other trace elements in plant and animals, in particular, the detoxification of heavy metals by Se. Important research hotspots of Se biogeochemistry are outlined, including (1) the coupling of soil microbial activity and the Se biogeochemical cycle; (2) the molecular mechanism of Se metabolic in plants and animals; and (3) the application of Se isotopes as a biogeochemical tracer in research. This review provides up-to-date knowledge and guidelines on Se biogeochemistry research.
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•The double-edged sword effect of Se in soil, plants, and humans is reviewed.•Detoxification of Se on heavy metals in the soil-plant-human system is summarized.•Future research hotspots of Se biogeochemistry are outlined.
Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUC1 ...antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qβ carrier with MUC1 glycopeptides containing 20–22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qβ-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qβ-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.
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