Enpatoran in COVID-19 pneumonia: Safety and efficacy results from a phase II randomized trial.

Enpatoran is a selective inhibitor of toll-like receptors 7 and 8 (TLR7/8) that potentially targets pro-inflammatory pathways induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A phase II study conducted in Brazil, the Philippines, and the USA during the early pandemic phase assessed the safety and efficacy of enpatoran in patients hospitalized with COVID-19 pneumonia (NCT04448756). A total of 149 patients, who scored 4 on the World Health Organization's (WHO) 9-point ordinal severity scale, were randomized 1:1:1 and received enpatoran 50 mg (n = 54) or 100 mg (n = 46), or placebo (n = 49) twice daily (b.i.d.) for 14 days plus standard of care. The primary objectives were safety and time to recovery (WHO 9-point scale ≤3). Clinical deterioration (WHO 9-point scale ≥ 5) was a key secondary objective. Treatment-emergent adverse events (TEAEs) were comparable across groups (56.5%-63.0%). Treatment-related TEAEs were numerically higher with enpatoran 50 mg (14.8%) than 100 mg (10.9%) or placebo (8.2%). Serious TEAEs were numerically lower with enpatoran (50 mg 9.3%, 100 mg 2.2%) than placebo (18.4%). The primary efficacy objective was not met; median time to recovery was 3.4-3.9 days across groups, with placebo-treated patients recovering on average faster than anticipated. Clinical deterioration event-free rates up to Day 7 were 90.6%, 95.6%, and 81.6% with enpatoran 50 mg, 100 mg, and placebo, respectively. Enpatoran was well tolerated by patients acutely ill and hospitalized with COVID-19 pneumonia. Positive signals in some secondary end points suggested potential beneficial effects, supporting further evaluation of enpatoran in patients with hyperinflammation due to infection or autoimmunity.

Effect of Nonwoven Carbon Tissue-Reinforced Epoxy Resin Adhesive Layer on the Single Lap Bonding Strength of Aluminum Alloy Joints.

The present paper provides a solution to enhance the reliability of bonding. The effect of the nonwoven carbon tissue (NWCT) composite adhesive layer on the bonding strength and reliability of aluminum alloy of single lap joints (SLJ) was investigated by embedding NWCT into the epoxy adhesive layer. The bonding strength, Weibull distribution, metallography of cross section, and fracture surface morphology of NWCT specimens were investigated. The results showed that the average bonding strength and Weibull characteristic strength (WCS) of NWCT-reinforced specimen were 16.78 and 17.17 MPa, which increased by 70.2 and 66.7%, respectively, compared with the neat specimen, and the Weibull modulus increased from 11.46 to 22.83, which indicated that NWCT specimens had higher bonding reliability. The mechanism of microcrack formation was obtained by analyzing the cross section of specimen loaded 95% WCS without macroscopic damage. The metallographic section showed that the microcrack of the neat specimen originated from the adhesive-aluminum interface, while the microcracks of the NWCT specimen originated from the interface between short carbon fibers (SCF) and adhesive. Typical failure modes were gained from visual observation and SEM. The failure mode of the neat specimen included more Al-adhesive interface failure, while the NWCT specimen included more internal failure of adhesive-SCFs with the fracture, pullout, peeling, and slippage of SCFs improving the toughness and bonding strength of the adhesive layer. The bridging effect of SCFs in the adhesive layer reinforced by NWCT can even the load and release the stress to improve the bonding reliability.

Erythromycin inhibits wear debris-induced inflammatory osteolysis in a murine model.

Up to 20% of patients with total joint arthroplasty will develop radiographic evidence of aseptic loosening (AL), which most likely results from an inflammatory response to billions of wear debris shed from the implant. Our previous work has demonstrated that erythromycin (EM), a macrolide antibiotic, inhibits wear debris-induced inflammatory osteoclastogenesis through the reduction of cytokine production and osteoclast differentiation, both of which involve the NF-kappaB pathway. The aim of the current study was to determine whether EM inhibits wear debris-induced inflammatory osteolysis in a murine osteolysis model. Ultrahigh molecular-weight polyethylene (UHMWPE) debris was introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. EM (2 mg/kg/day) was given to mice intraperitoneally 2 days before UHMWPE introduction and maintained until the sacrifice of the mice. Mice with and without EM treatment, as well as control mice injected with saline alone were included in this study. Pouch tissues were collected 14 days after UHMWPE inoculation for molecular and histology analysis. Our findings indicate that: (1) EM reduced UHMWPE-induced tissue inflammation, including the diminished pouch membrane thickness, reduced inflammatory cellular infiltration, and lowered IL-1beta and TNF-alpha expression (mRNA and protein); (2) EM inhibited UHMWPE-induced osteoclastogenesis, with reduced gene activation of RANK, RANKL, and CPK, and diminished RANKL expression in UHMWPE stimulated pouches, and (3) EM markedly reduced the number of TRAP(+) cells in pouch tissues, and protected against bone collagen depletion. In conclusion, this study provides the evidence that EM inhibits the UHMWPE particles-induced inflammatory osteolysis in a murine model, and represents a promising therapeutic candidate for the prevention and treatment of AL.

Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy.

Neurofibrillary tangles (NFT), mainly consisting of fibrillar aggregates of hyperphosphorylated tau, are a defining pathological feature of Alzheimer's Disease and other tauopathies. Progressive accumulation of tau into NFT is considered to be a toxic cellular event causing neurodegeneration. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification and O-GlcNAcylation of tau has been suggested to regulate tau phosphorylation. We tested if an increase in tau O-GlcNAcylation affected tau phosphorylation and aggregation in the rTg4510 tau transgenic mouse model. Acute treatment of rTg4510 mice with an O-GlcNAcase inhibitor transiently reduced tau phosphorylation at epitopes implicated in tau pathology. More importantly, long-term inhibitor treatment strongly increased tau O-GlcNAcylation, reduced the number of dystrophic neurons, and protected against the formation of pathological tau species without altering the phosphorylation of non-pathological tau. This indicates that O-GlcNAcylation prevents the aggregation of tau in a manner that does not affect its normal phosphorylation state. Collectively, our results support O-GlcNAcase inhibition as a potential therapeutic strategy for the treatment of Alzheimer's Disease and other tauopathies.

Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer's disease.

Amyloid plaques associated with Alzheimer's disease (AD) induce inflammatory responses associated with activated microglia and reactive astrocytes, which exacerbate neurodegeneration through release of inflammatory cytokines, reactive oxygen species, and other factors. Inflammation contributes to neurodegeneration at later stages of AD, but it may also play a role in early disease pathogenesis. We found that before plaque deposition, amyloid precursor protein (APP)/presenilin 1 (PSEN1) transgenic mice (PSAPP mice), a well-characterized model of AD, exhibit evidence of cerebrovascular inflammation. Expression of the endothelial cell-specific antigen MECA-32 (mouse endothelial cell antigen-32) was upregulated in the cerebrovasculature of young PSAPP mice (3 months old) and was similar to that observed in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis characterized by neuroinflammation. MECA-32 is normally expressed in central and peripheral vasculature throughout development, but expression in the cerebrovasculature is downregulated on establishment of the blood-brain barrier (BBB). However, CNS inflammation triggers re-expression of MECA-32 in compromised cerebrovasculature. Our study indicates that MECA-32 may be a robust marker of cerebrovascular inflammation and compromised BBB integrity, triggered by soluble amyloid-ß early in disease pathogenesis.

Engineered lentivector targeting of dendritic cells for in vivo immunization.

We report a method of inducing antigen production in dendritic cells by in vivo targeting with lentiviral vectors that specifically bind to the dendritic cell-surface protein DC-SIGN. To target dendritic cells, we enveloped the lentivector with a viral glycoprotein from Sindbis virus engineered to be DC-SIGN-specific. In vitro, this lentivector specifically transduced dendritic cells and induced dendritic cell maturation. A high frequency (up to 12%) of ovalbumin (OVA)-specific CD8(+) T cells and a significant antibody response were observed 2 weeks after injection of a targeted lentiviral vector encoding an OVA transgene into naive mice. This approach also protected against the growth of OVA-expressing E.G7 tumors and induced regression of established tumors. Thus, lentiviral vectors targeting dendritic cells provide a simple method of producing effective immunity and may provide an alternative route for immunization with protein antigens.