Interaction of Cutibacterium (formerly Propionibacterium) acnes with bone cells: a step toward understanding bone and joint infection development

Cutibacterium acnes (formerly Propionibacterium acnes) is recognized as a pathogen in foreign-body infections (arthroplasty or spinal instrumentation). To date, the direct impact of C. acnes on bone cells has never been explored. The clade of 11 C. acnes clinical isolates was determined by MLST. Human osteoblasts and osteoclasts were infected by live C. acnes. The whole genome sequence of six isolates of this collection was analyzed. CC36 C. acnes strains were significantly less internalized by osteoblasts and osteoclasts than CC18 and CC28 C. acnes strains (p ≤ 0.05). The CC18 C. acnes ATCC6919 isolate could survive intracellularly for at least 96 hours. C. acnes significantly decreased the resorption ability of osteoclasts with a major impact by the CC36 strain (p ≤ 0.05). Genome analysis revealed 27 genes possibly linked to these phenotypic behaviors. We showed a direct impact of C. acnes on bone cells, providing new explanations about the development of C. acnes foreign-body infections

Development of broad-spectrum human monoclonal antibodies for rabies post-exposure prophylaxis

Currently available rabies post-exposure prophylaxis (PEP) for use in humans includes equine or human rabies immunoglobulins (RIG). The replacement of RIG with an equally or more potent and safer product is strongly encouraged due to the high costs and limited availability of existing RIG. In this study, we identified two broadly neutralizing human monoclonal antibodies that represent a valid and affordable alternative to RIG in rabies PEP. Memory B cells from four selected vaccinated donors were immortalized and monoclonal antibodies were tested for neutralizing activity and epitope specificity. Two antibodies, identified as RVC20 and RVC58 (binding to antigenic site I and III, respectively), were selected for their potency and broad-spectrum reactivity. In vitro, RVC20 and RVC58 were able to neutralize all 35 rabies virus (RABV) and 25 non-RABV lyssaviruses. They showed higher potency and breath compared to antibodies under clinical development (namely CR57, CR4098, and RAB1) and commercially available human RIG. In vivo, the RVC20-RVC58 cocktail protected Syrian hamsters from a lethal RABV challenge and did not affect the endogenous hamster post-vaccination antibody response

Semaphorins and their receptors: Novel features of neural guidance molecules

Semaphorins were originally identified as axon guidance cues involved in the development of the nervous system. In recent years, it is emerging that they also participate in various biological systems, including physiological and pathological processes. In this review, we primarily focus on our cumulative findings for the role of semaphorins and their receptors in the regulation of the immune system, while also summarizing recent progress in the context of cardiovascular system

A RasGAP SH3 Peptide Aptamer Inhibits RasGAP-Aurora Interaction and Induces Caspase-Independent Tumor Cell Death

The Ras GTPase-activating protein RasGAP catalyzes the conversion of active GTP-bound Ras into inactive GDP-bound Ras. However, RasGAP also acts as a positive effector of Ras and exerts an anti-apoptotic activity that is independent of its GAP function and that involves its SH3 (Src homology) domain. We used a combinatorial peptide aptamer approach to select a collection of RasGAP SH3 specific ligands. We mapped the peptide aptamer binding sites by performing yeast two-hybrid mating assays against a panel of RasGAP SH3 mutants. We examined the biological activity of a peptide aptamer targeting a pocket delineated by residues D295/7, L313 and W317. This aptamer shows a caspase-independent cytotoxic activity on tumor cell lines. It disrupts the interaction between RasGAP and Aurora B kinase. This work identifies the above-mentioned pocket as an interesting therapeutic target to pursue and points its cognate peptide aptamer as a promising guide to discover RasGAP small-molecule drug candidates

Genome wide screen identifies microsatellite markers associated with acute adverse effects following radiotherapy in cancer patients

<p>Abstract</p> <p>Background</p> <p>The response of normal tissues in cancer patients undergoing radiotherapy varies, possibly due to genetic differences underlying variation in radiosensitivity.</p> <p>Methods</p> <p>Cancer patients (n = 360) were selected retrospectively from the RadGenomics project. Adverse effects within 3 months of radiotherapy completion were graded using the National Cancer Institute Common Toxicity Criteria; high grade group were grade 3 or more (n = 180), low grade group were grade 1 or less (n = 180). Pooled genomic DNA (gDNA) (n = 90 from each group) was screened using 23,244 microsatellites. Markers with different inter-group frequencies (Fisher exact test <it>P </it>< 0.05) were analyzed using the remaining pooled gDNA. Silencing RNA treatment was performed in cultured normal human skin fibroblasts.</p> <p>Results</p> <p>Forty-seven markers had positive association values; including one in the <it>SEMA3A </it>promoter region (P = 1.24 × 10^-5). <it>SEMA3A </it>knockdown enhanced radiation resistance.</p> <p>Conclusions</p> <p>This study identified 47 putative radiosensitivity markers, and suggested a role for <it>SEMA3A </it>in radiosensitivity.</p

The Ecology of Antibiotic Use in the ICU: Homogeneous Prescribing of Cefepime but Not Tazocin Selects for Antibiotic Resistant Infection

Background: Antibiotic homogeneity is thought to drive resistance but in vivo data are lacking. In this study, we determined the impact of antibiotic homogeneity per se, and of cefepime versus antipseudomonal penicillin/beta-lactamase inhibitor combinations (APP-beta), on the likelihood of infection or colonisation with antibiotic resistant bacteria and/or two commonly resistant nosocomial pathogens (methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa). A secondary question was whether antibiotic cycling was associated with adverse outcomes including mortality, length of stay, and antibiotic resistance