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991.
Brian J. Werth Nathaniel K. Ashford Kelsi Penewit Adam Waalkes Elizabeth A. Holmes Dylan H. Ross Tianwei Shen Kelly M. Hines Stephen J. Salipante Libin Xu 《Clinical microbiology and infection》2021,27(6):910.e1-910.e8
ObjectivesDalbavancin is a lipoglycopeptide active against methicillin-resistant Staphylococcus aureus (MRSA). Its long half-life (8.5–16 days) allows for once-weekly or single-dose treatments but could prolong the mutant selection window, promoting resistance and cross-resistance to related antimicrobials such as vancomycin. The objective of this study was to evaluate the capacity of post-distributional pharmacokinetic exposures of dalbavancin to select for resistance and cross-resistance in MRSA.MethodsWe simulated average, post-distributional exposures of single-dose (1500 mg) dalbavancin (fCmax 9.9 μg/mL, β-elimination t1/2 204 h) in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for 28 days (672 h) against five MRSA strains and one methicillin-susceptible strain (MSSA). Samples were collected at least daily, and surviving colonies were enumerated and screened for resistance on drug-free and dalbavancin-supplemented medium respectively. Isolates from resistance screening plates were subjected to whole-genome sequencing (WGS) and susceptibly testing against dalbavancin, vancomycin, daptomycin, and six β-lactams with varying penicillin-binding protein (PBP) affinities.ResultsDalbavancin was bactericidal against most strains for days 1–4 before regrowth of less susceptible subpopulations occurred. Isolates with eight-fold increases in dalbavancin MIC were detected as early as day 4 but increased 64–128-fold in all models by day 28. Vancomycin and daptomycin MICs increased 4–16-fold, exceeding the susceptibly breakpoints for both antibiotics; β-lactam MICs generally decreased by two-to eight-fold, suggesting a dalbavancin–β-lactam seesaw effect, but increased by eight-fold or more in certain isolates. Resistant isolates carried mutations in a variety of genes, most commonly walKR, apt, stp1, and atl.ConclusionsIn our in vitro system, post-distributional dalbavancin exposures selected for stable mutants with reduced susceptibility to dalbavancin, vancomycin, and daptomycin, and generally increased susceptibility to β-lactams in all strains of MRSA tested. The clinical significance of these findings remains unclear, but created an opportunity to genotype a unique collection of dalbavancin-resistant strains for the first time. Mutations involved genes previously associated with vancomycin intermediate susceptibility and daptomycin non-susceptibility, most commonly walKR-associated genes. 相似文献
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Allison J. Armstrong Maria Sol Collado Brad R. Henke Matthew W. Olson Stephen A. Hoang Christin A. Hamilton Taylor D. Pourtaheri Kimberly A. Chapman Marshall M. Summar Brian A. Johns Brian R. Wamhoff John E. Reardon Robert A. Figler 《Molecular genetics and metabolism》2021,132(1):71-82
Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) are inborn errors of metabolism affecting the catabolism of valine, isoleucine, methionine, threonine and odd-chain fatty acids. These are multi-organ disorders caused by the enzymatic deficiency of propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT), resulting in the accumulation of propionyl-coenzyme A (P-CoA) and methylmalonyl-CoA (M-CoA in MMA only). Primary metabolites of these CoA esters include 2-methylcitric acid (MCA), propionyl-carnitine (C3), and 3-hydroxypropionic acid, which are detectable in both PA and MMA, and methylmalonic acid, which is detectable in MMA patients only (Chapman et al., 2012). We deployed liver cell-based models that utilized PA and MMA patient-derived primary hepatocytes to validate a small molecule therapy for PA and MMA patients. The small molecule, HST5040, resulted in a dose-dependent reduction in the levels of P-CoA, M-CoA (in MMA) and the disease-relevant biomarkers C3, MCA, and methylmalonic acid (in MMA). A putative working model of how HST5040 reduces the P-CoA and its derived metabolites involves the conversion of HST5040 to HST5040-CoA driving the redistribution of free and conjugated CoA pools, resulting in the differential reduction of the aberrantly high P-CoA and M-CoA. The reduction of P-CoA and M-CoA, either by slowing production (due to increased demands on the free CoA (CoASH) pool) or enhancing clearance (to replenish the CoASH pool), results in a net decrease in the CoA-derived metabolites (C3, MCA and MMA (MMA only)). A Phase 2 study in PA and MMA patients will be initiated in the United States. 相似文献
995.
Brian M. Wendel Suzanne Hollingsworth Charmain T. Courcelle Justin Courcelle 《Genes to cells : devoted to molecular & cellular mechanisms》2021,26(2):94-108
Replication initiation, elongation and completion are tightly coordinated to ensure that all sequences replicate precisely once each generation. UV-induced DNA damage disrupts replication and delays elongation, which may compromise this coordination leading to genome instability and cell death. Here, we profiled the Escherichia coli genome as it recovers from UV irradiation to determine how these replicational processes respond. We show that oriC initiations continue to occur, leading to copy number enrichments in this region. At late times, the combination of new oriC initiations and delayed elongating forks converging in the terminus appear to stress or impair the completion reaction, leading to a transient over-replication in this region of the chromosome. In mutants impaired for restoring elongation, including recA, recF and uvrA, the genome degrades or remains static, suggesting that cell death occurs early after replication is disrupted, leaving partially duplicated genomes. In mutants impaired for completing replication, including recBC, sbcCD xonA and recG, the recovery of elongation and initiation leads to a bottleneck, where the nonterminus region of the genome is amplified and accumulates, indicating that a delayed cell death occurs in these mutants, likely resulting from mis-segregation of unbalanced or unresolved chromosomes when cells divide. 相似文献
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Brian A. Walker Christopher P. Wardell Fiona M. Ross Gareth J. Morgan 《Genes, chromosomes & cancer》2013,52(9):817-822
IGH translocations in myeloma are a primary event and determine the prognostic outcome of a patient. These events are characterized by FISH and classical cytogenetics, but in a small proportion of samples a translocation involving the IGH locus can be detected but the partner chromosome cannot be identified. These cases are usually genetically complex and are the result of cryptic events that cannot be discerned at the resolution of FISH. Here we analyzed a sample with an unidentified translocation partner using a targeted capture and massively parallel sequencing. We identified the partner chromosome as a t(7;14) with the breakpoint upstream of EGFR. This sample over‐expresses the target oncogene, EGFR. This case represents a rare and novel translocation in myeloma, from which a targeted personalized treatment, in the form of EGFR inhibitors, which are commonly used in other cancer types, could be used. © 2013 Wiley Periodicals, Inc. 相似文献
1000.
Masafumi Terada Brian G. Pietrosimone Phillip A. Gribble 《Journal of Athletic Training》2013,48(5):696-709
Context:
Clinicians perform therapeutic interventions, such as stretching, manual therapy, electrotherapy, ultrasound, and exercises, to increase ankle dorsiflexion. However, authors of previous studies have not determined which intervention or combination of interventions is most effective.Objective:
To determine the magnitude of therapeutic intervention effects on and the most effective therapeutic interventions for restoring normal ankle dorsiflexion after ankle sprain.Data Sources:
We performed a comprehensive literature search in Web of Science and EBSCO HOST from 1965 to May 29, 2011, with 19 search terms related to ankle sprain, dorsiflexion, and intervention and by cross-referencing pertinent articles.Study Selection:
Eligible studies had to be written in English and include the means and standard deviations of both pretreatment and posttreatment in patients with acute, subacute, or chronic ankle sprains. Outcomes of interest included various joint mobilizations, stretching, local vibration, hyperbaric oxygen therapy, electrical stimulation, and mental-relaxation interventions.Data Extraction:
We extracted data on dorsiflexion improvements among various therapeutic applications by calculating Cohen d effect sizes with associated 95% confidence intervals (CIs) and evaluated the methodologic quality using the Physiotherapy Evidence Database (PEDro) scale.Data Synthesis:
In total, 9 studies (PEDro score = 5.22 ± 1.92) met the inclusion criteria. Static-stretching interventions with a home exercise program had the strongest effects on increasing dorsiflexion in patients 2 weeks after acute ankle sprains (Cohen d = 1.06; 95% CI = 0.12, 2.42). The range of effect sizes for movement with mobilization on ankle dorsiflexion among individuals with recurrent ankle sprains was small (Cohen d range = 0.14 to 0.39).Conclusions:
Static-stretching intervention as a part of standardized care yielded the strongest effects on dorsiflexion after acute ankle sprains. The existing evidence suggests that clinicians need to consider what may be the limiting factor of ankle dorsiflexion to select the most appropriate treatments and interventions. Investigators should examine the relationship between improvements in dorsiflexion and patient progress using measures of patient self-reported functional outcome after therapeutic interventions to determine the most appropriate forms of therapeutic interventions to address ankle-dorsiflexion limitation.Key Words: chronic ankle instability, range of motion, stretching, joint mobilizationKey Points
- A static-stretching intervention as part of a standardized home exercise program had the strongest effects on ankle-dorsiflexion improvement after acute ankle sprains.
- Clinicians need to consider what may be the limiting factor of ankle dorsiflexion to select the most appropriate treatments and interventions.
- Investigators should examine the long-term effects of treatments on ankle dorsiflexion and a relationship between an improvement in ankle dorsiflexion and measures of patient self-reported and physical function to determine the most appropriate forms of therapeutic interventions to address limited dorsiflexion.