AsrR Is an Oxidative Stress Sensing Regulator Modulating Enterococcus faecium Opportunistic Traits, Antimicrobial Resistance, and Pathogenicity

Oxidative stress serves as an important host/environmental signal that triggers a wide range of responses in microorganisms. Here, we identified an oxidative stress sensor and response regulator in the important multidrug-resistant nosocomial pathogen Enterococcus faecium belonging to the MarR family and called AsrR (antibiotic and stress response regulator). The AsrR regulator used cysteine oxidation to sense the hydrogen peroxide which results in its dissociation to promoter DNA. Transcriptome analysis showed that the AsrR regulon was composed of 181 genes, including representing functionally diverse groups involved in pathogenesis, antibiotic and antimicrobial peptide resistance, oxidative stress, and adaptive responses. Consistent with the upregulated expression of the pbp5 gene, encoding a low-affinity penicillin-binding protein, the asrR null mutant was found to be more resistant to \u3b2-lactam antibiotics. Deletion of asrR markedly decreased the bactericidal activity of ampicillin and vancomycin, which are both commonly used to treat infections due to enterococci, and also led to over-expression of two major adhesins, acm and ecbA, which resulted in enhanced in vitro adhesion to human intestinal cells. Additional pathogenic traits were also reinforced in the asrR null mutant including greater capacity than the parental strain to form biofilm in vitro and greater persistance in Galleria mellonella colonization and mouse systemic infection models. Despite overexpression of oxidative stress-response genes, deletion of asrR was associated with a decreased oxidative stress resistance in vitro, which correlated with a reduced resistance to phagocytic killing by murine macrophages. Interestingly, both strains showed similar amounts of intracellular reactive oxygen species. Finally, we observed a mutator phenotype and enhanced DNA transfer frequencies in the asrR deleted strain. These data indicate that AsrR plays a major role in antimicrobial resistance and adaptation for survival within the host, thereby contributes importantly to the opportunistic traits of E. faecium

Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b, open-label trial

Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30–0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors

Landscape of Resistance-Nodulation-Cell Division (RND)-Type Efflux Pumps in Enterobacter cloacae Complex

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Cluster-dependent colistin hetero-resistance in Enterobacter cloacae complex

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Prescreening in Oncology Using Data Sciences: The PreScIOUS Study

International audienceThe development of precision medicine in oncology to define profiles of patients who could benefit from specific and relevant anti-cancer therapies is essential. An increasing number of specific eligibility criteria are necessary to be eligible to targeted therapies. This study aimed to develop an automated algorithm based on natural language processing to detect patients and tumor characteristics to reduce the time-consuming prescreening for trial inclusions. Hence, 640 anonymized multidisciplinary team meeting (MTM) reports concerning lung cancer were extracted from one teaching hospital data warehouse in France and annotated. To automate the extraction of 52 bioclinical information corresponding to 8 major eligibility criteria, regular expressions were implemented and evaluated. The performance parameters were satisfying: macroaverage F1-score 93%; rates reached 98% for precision and 92% for recall. In MTM, fill rates variabilities among patients and tumors information remained important (from 31.4% to 100%). The least reported characteristics and the most difficult to automatically collect were genetic mutations and rearrangement test results

In vitro activity of novel anti-MRSA cephalosporins and comparator antimicrobial agents against staphylococci involved in prosthetic joint infections

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Solution Structure of ERK2 Binding Domain of MAPK Phosphatase MKP-3: Structural Insights into MKP-3 Activation by ERK2

MAP kinases (MAPKs), which control mitogenic signal transduction in all eukaryotic organisms, are inactivated by dual specificity MAPK phosphatases (MKPs). MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. The solution structure and biochemical analysis of the ERK2 binding (EB) domain of MKP-3 show that regions that are essential for ERK2 binding partly overlap with its sites that interact with the C-terminal catalytic domain, and that these interactions are functionally coupled to the active site residues of MKP-3. Our findings suggest a novel mechanism by which the EB domain binding to ERK2 is transduced to cause a conformational change of the C-terminal catalytic domain, resulting in the enzymatic activation of MKP-3