The vectored Ebola vaccine rVSVΔG-ZEBOV-GP elicits protection against Ebola Virus Disease (EVD). In a study of forty-eight healthy adult volunteers who received either the rVSVΔG-ZEBOV-GP vaccine or ...placebo, we profiled intracellular microRNAs (miRNAs) from whole blood cells (WB) and circulating miRNAs from serum-derived extracellular vesicles (EV) at baseline and longitudinally following vaccination. Further, we identified early miRNA signatures associated with ZEBOV-specific IgG antibody responses at baseline and up to one year post-vaccination, and pinpointed target mRNA transcripts and pathways correlated to miRNAs whose expression was altered after vaccination by using systems biology approaches.
Several miRNAs were differentially expressed (DE) and miRNA signatures predicted high or low IgG ZEBOV-specific antibody levels with high classification performance. The top miRNA discriminators were WB-miR-6810, EV-miR-7151-3p, and EV-miR-4426. An eight-miRNA antibody predictive signature was associated with immune-related target mRNAs and pathways.
These findings provide valuable insights into early blood biomarkers associated with rVSVΔG-ZEBOV-GP vaccine-induced IgG antibody responses.
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•RVSV-ZEBOV-GP vaccination modulates human blood intracellular and circulating miRNome•Baseline and early post-vaccination miRNAs correlate with IgG antibody responses•Early post-vaccination miRNA signatures predict D28 and D360 IgG antibody levels•An eight-miRNA signature correlates with immune-related target mRNAs and pathways
Health sciences; Molecular biology; Immunology; Virology
Abstract Background and aims Obesity is a pro-atherogenic condition and postprandial lipoprotein profile and circulating cytokines changes may contribute to promote the process. The aim of this study ...is to investigate postprandial metabolic response, lipoprotein oxidation and circulating cytokine levels, after the ingestion of two different meals with different fat/carbohydrate ratio. Methods and results Ten prepubertal obese boys consumed two meals with the same energy and protein content but with a different carbohydrate to fat ratio: 1) moderate fat (MF): 61% carbohydrate, 27% fat; 2) high fat (HF): 37% carbohydrate, 52% fat. The AUC of glucose and insulin were significantly ( p < 0.05) lower after the HF meal. HF meal was followed by a significant decrease in the cholesterol carried in the HDL fractions, while cholesterol in the small, dense LDL and in the VLDL particles increased, as compared to baseline ( p < 0.05 for all). No differences were found in the cholesterol distribution after the MF meal. Moreover, HDL-C concentration was lower ( p < 0.05) at 300 min after HF vs. MF meal. Oxidized LDL (ox-LDL) concentration increased after the HF meal but not after the MF meal 9.3(2.2) vs 1.8(2.2)% from baseline, P < 0.02). A positive association ( r > 0.3, P < 0.05) was observed between the densest LDL particles and the ox-LDL plasma levels. A reduction of IL-6 was found at 120 min after the MF −23.3(5.5) vs −8.4(3.8)% from baseline, P < 0.05) compared with the HF meal. Conclusion A simple change of ≈25% of energy load from fat to carbohydrate in a meal significantly improves postprandial pro-atherogenic factors in obese boys.
We recently reported about the synthesis, expansion, and biological characterization of a new bicyclic scaffold toward potent Aurora-A kinase inhibitors. Here we report the expansion of the same ...class with the aim of achieving potent and selective CDK inhibitors.
We have recently reported about a new class of Aurora-A inhibitors based on a bicyclic tetrahydropyrrolo3,4-
cpyrazole scaffold. Here we describe the synthesis and early expansion of CDK2/cyclin A–E inhibitors belonging to the same chemical class. Synthesis of the compounds was accomplished using a solution-phase protocol amenable to rapid parallel expansion. Compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit CDK2-mediated tumor cell proliferation have been obtained.
Early portal vein thrombosis is a rare but severe complication of liver transplantation requiring retransplantation or at least surgical thrombectomy, both hampered by high morbidity and mortality.
...We describe of a case of successful long-term recanalization of early posttransplantation portal vein thrombosis by a minimally invasive percutaneous transhepatic angiographic approach using both mechanical fragmentation and pharmacological lysis of the thrombus followed by stent placement.
Mechanical fragmentation and contemporaneous local urokinase administration resulted in complete removal of the clot; the use of a vascular stent after balloon dilatation allowed restoration of normal blood flow to the liver after 9 months of follow-up.
This case report confirms the possibility of successful recanalization of the portal vein after early posttransplantation thrombosis by a minimally invasive angiographic approach. Balloon dilatation and placement of a vascular stent could help to decrease the risk of recurrent thrombosis.
Abstract Aim Recombinant human thyroid-stimulating hormone (rhTSH) has been approved in Europe as a preparation tool for radioiodine ablation of post-surgical thyroid remnants in patients with ...low-risk differentiated thyroid cancer (DTC). Published studies report that, both thyroid hormone withdrawal and rhTSH preparation result in similar rates of successful remnant ablation, but few studies have determined the effectiveness of rhTSH preparation on disease recurrence. We sought to determine the clinical outcome, considering both ablation success and disease recurrence, of low-risk DTC patients who underwent131 I ablation. Materials and methods This retrospective study describes the clinical outcome of 100 patients treated with131 I remnant ablation after preparation with rhTSH. After ablation, patients were classified as in complete remission, as having no evidence of persistent disease, or as having clinical recurrence on the basis of a subsequent diagnostic whole body scan with131 I, stimulated thyroglobulin and cross-sectional imaging studies. Results Overall assessment of ablation success was verified and obtained in 75% of patients (75/100). Considering only patients who underwent a diagnostic whole body scan and stimulated thyroglobulin without interfering anti-thyroglobulin antibody, complete ablation was obtained in 96% of patients (75/78). After a follow-up of about 4 years, 78 patients are in complete remission: 75 with initial ablation success and three who achieved a complete remission during subsequent follow-up. Among the remaining 22 patients, 21 have no clinical evidence of disease (NCED), indicating the inability to verify the complete remission or to detect residual disease, as in patients with positive thyroglobulin antibody, whereas one has persistent disease demonstrated only by stimulated thyroglobulin. No recurrences were observed. Of four patients initially classified as having persistent disease, one obtained a complete remission and two are now considered NCED. Conclusion Our data confirm the favourable outcome, with low rates of recurrence and persistent disease, of patients with low-risk DTC who underwent131 I ablation after rhTSH. Moreover, our results compare favourably with those reported in the literature in patients prepared with rhTSH, but also in patients prepared with hormone withdrawal.
Alloantigen specific T cells have been shown to be required for allograft rejection. The chemokine, stromal cell derived factor-1 (SDF-1) at high concentration, has been shown to act as a T-cell ...chemorepellent and abrogate T-cell infiltration into a site of antigen challenge in vivo via a mechanism termed fugetaxis or chemorepulsion. We postulated that this mechanism could be exploited therapeutically and that allogeneic cells engineered to express a chemorepellent protein would not be rejected.
Allogeneic murine insulinoma beta-TC3 cells and primary islets from BALB/C mice were engineered to constitutively secrete differential levels of SDF-1 and transplanted into allogeneic diabetic C57BL/6 mice. Rejection was defined as the permanent return of hyperglycemia and was correlated with the level of T-cell infiltration. The migratory response of T-cells to SDF-1 was also analyzed by transwell migration assay and time-lapse videomicroscopy. The cytotoxicity of cytotoxic T cell (CTLs) against beta-TC3 cells expressing high levels of SDF-1 was measured in standard and modified chromium-release assays in order to determine the effect of CTL migration on killing efficacy.
Control animals rejected allogeneic cells and remained diabetic. In contrast, high level SDF-1 production by transplanted cells resulted in increased survival of the allograft and a significant reduction in blood glucose levels and T-cell infiltration into the transplanted tissue.
This is the first demonstration of a novel approach that exploits T-cell chemorepulsion to induce site specific immune isolation and thereby overcomes allograft rejection without the use of systemic immunosuppression.
Three new series of tricyclic pyridazinones have been synthesized and tested in vitro in order to assess (i) their ability to inhibit aldose reductase enzyme (ALR2) and (ii) their specificity toward ...the target enzyme with respect to other related oxidoreductases, such as aldehyde reductase, sorbitol dehydrogenase, and glutathione reductase. The inhibitory capability of the most effective compounds (IC50 values ranging from 6.44 to 12.6 μM) appears to be associated with a rather significant specificity for ALR2. Molecular mechanics and molecular dynamic calculations performed on the ALR2−inhibitor complex give indications of specific interaction sites responsible for the binding, thus providing information for the design of new inhibitors with improved affinity for the enzyme.
Calcium and phosphate are essential for cell functions, and their serum concentrations result from the balance between intestinal absorption, bony storage, and urinary excretion. Fibroblast growth ...factor 23 (
FGF23
), expressed by osteocytes and osteoblasts, acts in the kidney, leading to hypophosphatemia and low 1,25‐dihydroxycholecalciferol synthesis, but suppresses parathyroid function. The aim of this study was to explore the effects of a high‐energy demanding cycling race on this bone–kidney–parathyroid axis. We studied nine cyclists during the 2011
G
iro d'
I
talia
stage race. Pre‐analytical and analytical phases followed academic and anti‐doping recommendations. Serum parathyroid hormone (
PTH
), 25(
OH
)
D
, total calcium, inorganic phosphorus, and plasma
FGF23
were measured on days −1, 12, and 22 and corrected for changes in plasma volume. Dietary calcium and phosphorus, anthropometric parameters (height, weight, and body mass index) and indexes of metabolic effort (net energy expenditure, power output) were recorded. Dietary calcium and phosphorus intakes were kept at the same levels throughout the race. Twenty‐five (
OH
)
D
,
PTH
, and calcium concentrations remained stable.
FGF23
increased 50% with a positive correlation with the indexes of metabolic effort and, consequently, phosphorous decreased, although only in the first half. The strong metabolic effort acts on the bone–kidney–parathyroid system, and the rise in
FGF23
plasma concentration might be aimed at maintaining calcium and phosphorus homeostasis.
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