Vaccination provides the most potent measure against infectious disease, and recombinant (r) viable vaccines expressing defined pathogen-derived antigens represent powerful candidates for future ...vaccination strategies. In a new approach we constructed r-aroA-Salmonella typhimurium displaying p60 or listeriolysin (Hly) antigen of Listeria monocytogenes in secreted or somatic form in the host cell. Vaccination of mice with r-aroA-S. typhimurium induced protection against the intracellular pathogen L. monocytogenes only with secreted and not with somatic antigen. Secreted Hly was slightly more potent in inducing protective immunity than secreted p60. Both r-aroA-S. typhimurium secreting p60 in the endosome and r-aroA-S. typhimurium secreting Hly in the cytosol induced protective CD4+and CD8+T-cells suggesting CD8+T-cell stimulation independent from intracellular residence of r-aroA-S. typhimurium carriers. Hence, not only the type of antigen but also its display by the r-carrier within the host cell critically influences vaccine efficacy.
To evaluate the safety of intra-articular sprifermin (primary), and to evaluate systemic exposure, biomarkers, histology, and other cartilage parameters in patients with advanced osteoarthritis (OA).
...This was a first-in-human, double-blind, randomised, placebo-controlled trial of single and multiple ascending doses of sprifermin from 3-300 μg in knee OA patients scheduled for total knee replacement. Patients were randomised 3:1 to sprifermin or placebo, injected into the target knee once or once weekly for 3 weeks, and followed-up for 24 weeks.
Fifty-five patients were treated with sprifermin, 25 with single and 30 with multiple doses, 18 received placebo. There was no clear difference between the active and placebo groups in incidence, severity, and nature of reported treatment emergent adverse events. Acute inflammatory reactions were slightly more common with sprifermin 300 μg, but none led to discontinuation. No clear difference was seen between placebo and sprifermin in physician-assessed local tolerability, pain, or swelling in the knee. No meaningful changes over time, or differences between treatment groups, were observed for safety laboratory parameters or ECG. Although individual abnormalities were observed, no patterns were evident suggesting a relation to treatment or potential safety concern. No systemic sprifermin exposure, anti-FGF18 antibodies, or clear-cut effects on systemic biomarkers were detected.
This first clinical trial of sprifermin revealed no serious safety concerns, although larger studies are needed. The possibility of positive effects of intra-articular sprifermin on histological and other cartilage parameters in knee OA also warrant further investigation.
Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The ...acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.
Objective
To determine the relationship between biochemical markers involved in bone turnover and bone features on imaging in knees with osteoarthritis (OA).
Methods
We analyzed data from the ...Foundation for the National Institutes of Health OA Biomarkers Consortium within the Osteoarthritis Initiative (n = 600). Bone marrow lesions (BMLs), osteophytes, and subchondral bone area (mm2) and shape (position on 3‐D vector) were assessed on magnetic resonance images, and bone trabecular integrity (BTI) was assessed on radiographs. Serum and urinary markers (serum C‐terminal crosslinked telopeptide of type I collagen CTX‐I, serum crosslinked N‐telopeptide of type I collagen NTX‐I, urinary NTX‐I, urinary C‐terminal crosslinked telopeptide of type II collagen CTX‐II, and urinary CTX‐Iα and CTX‐Iβ) were measured. The associations between biochemical and imaging markers at baseline and over 24 months were assessed using regression models adjusted for covariates.
Results
At baseline, most biochemical markers were associated with BMLs, with C statistics for the presence/absence of any BML ranging from 0.675 to 0.688. At baseline, urinary CTX‐II was the marker most consistently associated with BMLs (with odds of having ≥5 subregions affected compared to no BML increasing by 1.92‐fold 95% confidence interval (95% CI) 1.25, 2.96 per 1 SD of urinary CTX‐II), large osteophytes (odds ratio 1.39 95% CI 1.10, 1.77), bone area and shape (highest partial R2 = 0.032), and changes in bone shape over 24 months (partial R2 range 0.008 to 0.024). Overall, biochemical markers were not predictive of changes in BMLs or osteophytes. Serum NTX‐I was inversely associated with BTI of the vertical trabeculae (quadratic slope) in all analyses (highest partial R2 = 0.028).
Conclusion
We found multiple significant associations, albeit mostly weak ones. The role of systemic biochemical markers as predictors of individual bone anatomic features of single knees is limited based on our findings.
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