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181.
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Carlos Rodriguez‐Galindo MD Mark Krailo PhD Lindsay Frazier MD Murali Chintagumpala MD James Amatruda MD Howard Katzenstein MD Marcio Malogolowkin MD Logan Spector PhD Farzana Pashankar MD Rebecka Meyers MD Gail Tomlinson MD PhD 《Pediatric blood & cancer》2013,60(6):1016-1021
In the US, approximately 2,000 children are diagnosed with rare cancers each year, with 5‐year survival ranging from <20% for children with advanced carcinomas to >95% for children with intraocular retinoblastoma or localized germ cell tumors. During the last years, 12 clinical studies have been successfully completed in children with retinoblastoma, liver tumors, germ cell tumors, and infrequent malignancies, including therapeutic, epidemiologic, and biologic studies. Current efforts are centered in the development of large international collaborations to consolidate evidence‐based definitions and risk stratifications that will support international Phase 3 clinical trials in germ cell tumors, hepatoblastoma, and other rare cancers. Pediatr Blood Cancer 2013; 60: 1016–1021. © 2012 Wiley Periodicals, Inc. 相似文献
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Chorell E Bengtsson C Sainte-Luce Banchelin T Das P Uvell H Sinha AK Pinkner JS Hultgren SJ Almqvist F 《European journal of medicinal chemistry》2011,46(4):1103-1116
Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Aβ aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp3-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously. 相似文献
187.
Pinkner JS Remaut H Buelens F Miller E Aberg V Pemberton N Hedenström M Larsson A Seed P Waksman G Hultgren SJ Almqvist F 《Proceedings of the National Academy of Sciences of the United States of America》2006,103(47):17897-17902
A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by approximately 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors. 相似文献
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Pascale S. Guiton Chia S. Hung Lynn E. Hancock Michael G. Caparon Scott J. Hultgren 《Infection and immunity》2010,78(10):4166-4175
Catheter-associated urinary tract infections (CAUTIs) constitute the majority of nosocomial UTIs and pose significant clinical challenges. Enterococcal species are among the predominant causative agents of CAUTIs. However, very little is known about the pathophysiology of Enterococcus-mediated UTIs. We optimized a murine model of foreign body-associated UTI in order to mimic conditions of indwelling catheters in patients. In this model, the presence of a foreign body elicits major histological changes and induces the expression of several proinflammatory cytokines in the bladder. In addition, in contrast to naïve mice, infection of catheter-implanted mice with Enterococcus faecalis induced the specific expression of interleukin 1β (IL-1β) and macrophage inflammatory protein 1α (MIP-1α) in the bladder. These responses resulted in a favorable niche for the development of persistent E. faecalis infections in the murine bladders and kidneys. Furthermore, biofilm formation on the catheter implant in vivo correlated with persistent infections. However, the enterococcal autolytic factors GelE and Atn (also known as AtlA), which are important in biofilm formation in vitro, are dispensable in vivo. In contrast, the housekeeping sortase A (SrtA) is critical for biofilm formation and virulence in CAUTIs. Overall, this murine model represents a significant advance in the understanding of CAUTIs and underscores the importance of urinary catheterization during E. faecalis uropathogenesis. This model is also a valuable tool for the identification of virulence determinants that can serve as potential antimicrobial targets for the treatment of enterococcal infections.Catheter-associated urinary tract infections (CAUTIs) are the most common complications resulting from the use of indwelling urinary catheters (25, 70). CAUTIs account for 40% of all nosocomial infections (48) with more than one million cases diagnosed annually in hospitals and nursing homes in the United States, generating approximately $600 million in medical expenditures every year (26, 69, 70). The pathophysiology of CAUTIs results from the disruption of the normal mechanical and antimicrobial defenses of the bladder and the injuries ensuing from urinary catheterization, which render the bladder environment vulnerable to microbial adhesion, multiplication, and dissemination within the urinary tract (15, 47, 49, 51, 78). Furthermore, indwelling urinary catheters provide an additional surface for microbial attachment and biofilm formation, which is a major component of the pathophysiology of CAUTIs and other chronic device-associated persistent infections (4, 6, 12, 14, 37, 46, 68). Once formed, biofilms provide a favorable milieu for microbial survival within the host as the organisms are shielded from the host immune response, as well as antibiotics and antimicrobial agents (36, 67, 81), leading to chronic or recurrent infections that are difficult to treat. If untreated, CAUTIs can lead to more severe diseases such as acute pyelonephritis, bacteremia, urosepsis, and in some cases, death (38, 77). The high incidence of CAUTIs and their medical and economic challenges underscore the need for a better understanding of CAUTI pathogenesis.While community-acquired UTIs are most commonly due to uropathogenic Escherichia coli (UPEC), UPEC represent only 50% of bacterial isolates derived from patients with CAUTIs (34). The Enterococcus species, especially Enterococcus faecalis and Enterococcus faecium, account for 15% to 30% of CAUTIs (38) and are now considered the third leading cause of hospital-acquired UTIs (20, 68). The ability of many enterococcal isolates to produce biofilms (41, 60, 73) and the increasing microbial resistance to antibiotics, including vancomycin, pose significant challenges for the treatment of enterococcal infections (11, 80).Several rodent models have been developed to study E. faecalis pathogenesis in the urinary tract in single and mixed infections with other Gram-negative pathogens (21, 29, 43, 61, 75). These models involve the transurethral inoculation of bacterial suspensions into the bladders of healthy animals or streptozocin-induced diabetic animals (56) and have been shown to be primarily useful for the study of E. faecalis-mediated pyelonephritis. The experimental conditions defined by these models are inadequate for the investigation of persistent enterococcal CAUTI, since the bacteria are readily cleared from the bladder and fail to establish chronic cystitis (29, 56, 61). Nonetheless, data obtained from these models have implicated some enterococcal factors in UTI pathogenesis, including the enterococcal surface protein Esp (61), the pilus-associated sortase C (SrtC) (30), and the endocarditis and biofilm-associated pilus (Ebp) (65). However, well-characterized adhesins and biofilm determinants often associated with enterococcal UTI isolates, like aggregation substance (AS) and the housekeeping sortase A (SrtA) (17, 27, 33), were reported to be dispensable for virulence in the urinary tract (27, 30). Since these conclusions are drawn from models where persistent infections cannot be established, it is imperative to reexamine the existing paradigm in an animal model that better mimics the transition of E. faecalis from a commensal organism to a virulent pathogen in the urinary tract.In this study, we optimized a rodent model of foreign body-associated UTI, developed in rats by Kurosaka et al. (35) and adapted for mice by Kadurugamuwa et al. (28), to investigate the pathophysiology of E. faecalis-mediated CAUTIs. We report that the presence of silicone catheter implants causes major physiological changes in the bladder, which becomes predisposing to E. faecalis biofilm formation, and is associated with persistent enterococcal cystitis and pyelonephritis. We further demonstrate that biofilm formation on the silicone implants and the development of successful enterococcal UTI are independent of autolytic factors GelE and Atn, also known as AtlA (13), but requires the presence of the housekeeping sortase A (SrtA). Overall, this optimized murine model is well suited to identify host and enterococcal factors critical for pathogenesis in the urinary tract which will provide a better understanding of the mechanisms underlying the pathophysiology of CAUTIs. 相似文献
190.
Clinical and Serologic Features in Patients With Incomplete Lupus Classification Versus Systemic Lupus Erythematosus Patients and Controls 下载免费PDF全文
Teresa Aberle Rebecka L. Bourn Melissa E. Munroe Hua Chen Virginia C. Roberts Joel M. Guthridge Krista Bean Julie M. Robertson Kathy L. Sivils Astrid Rasmussen Meghan Liles Joan T. Merrill John B. Harley Nancy J. Olsen David R. Karp Judith A. James 《Arthritis care & research》2017,69(12):1780-1788