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1.
Blood ; 141(13): 1584-1596, 2023 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-36375120

RESUMEN

Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a noncovalent BTK-binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR-mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at subnanomolar concentrations, and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Humanos , Agammaglobulinemia Tirosina Quinasa , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Xenoinjertos , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico
2.
Chem Res Toxicol ; 36(3): 402-419, 2023 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-36821828

RESUMEN

Per- and polyfluoroalkyl substances (PFAS) are a diverse set of commercial chemicals widely detected in humans and the environment. However, only a limited number of PFAS are associated with epidemiological or experimental data for hazard identification. To provide developmental neurotoxicity (DNT) hazard information, the work herein employed DNT new approach methods (NAMs) to generate in vitro screening data for a set of 160 PFAS. The DNT NAMs battery was comprised of the microelectrode array neuronal network formation assay (NFA) and high-content imaging (HCI) assays to evaluate proliferation, apoptosis, and neurite outgrowth. The majority of PFAS (118/160) were inactive or equivocal in the DNT NAMs, leaving 42 active PFAS that decreased measures of neural network connectivity and neurite length. Analytical quality control indicated 43/118 inactive PFAS samples and 10/42 active PFAS samples were degraded; as such, careful interpretation is required as some negatives may have been due to loss of the parent PFAS, and some actives may have resulted from a mixture of parent and/or degradants of PFAS. PFAS containing a perfluorinated carbon (C) chain length ≥8, a high C:fluorine ratio, or a carboxylic acid moiety were more likely to be bioactive in the DNT NAMs. Of the PFAS positives in DNT NAMs, 85% were also active in other EPA ToxCast assays, whereas 79% of PFAS inactives in the DNT NAMs were active in other assays. These data demonstrate that a subset of PFAS perturb neurodevelopmental processes in vitro and suggest focusing future studies of DNT on PFAS with certain structural feature descriptors.


Asunto(s)
Fluorocarburos , Síndromes de Neurotoxicidad , Humanos , Síndromes de Neurotoxicidad/metabolismo , Neuronas/metabolismo , Proyección Neuronal , Apoptosis , Fluorocarburos/toxicidad
3.
Perfusion ; 38(4): 747-754, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-35343293

RESUMEN

INTRODUCTION: The addition of cephalic drains (CDs) in extracorporeal membrane oxygenation (ECMO) to augment venous drainage may offer benefit, though their use is varied. Our objective was to describe our institution's experience with CDs including flow rates and patency. We also compared complication rates between patients with and without a CD. METHODS: This retrospective cohort study included infants <12 months of age cannulated for ECMO between January 1, 2010 and September 30, 2019 at a single institution. Flow data were obtained for those with a CD. Demographic and complication rates were obtained for all. RESULTS: Of 264 patients in the final cohort, 220 (83%) had a CD of which 93.2% remained patent to decannulation. CDs typically provided 30% or more of ECMO flow throughout the ECMO run. The median time to CD clot was 139 h (range 48-635 h). Patients with a clotted CD had longer ECMO runs than those whose CD remained patent (median 382 h [IQR 217-538] vs 139 h [IQR 91-246], p < 0.001). Survival to discharge was lower for those with clotted versus patent CD (14% vs 70%, p < 0.001). Mechanical complications were more common in patients with CD (p = 0.005). Seizures were more common in those without a CD (p = 0.021). CONCLUSIONS: In this cohort, the majority of CDs placed remained patent at decannulation and provided substantial additional venous drainage. Mechanical problems were common in patients with CDs, but without clinical sequelae. Further study is warranted to elucidate CD impact on short- and long-term outcomes.


Asunto(s)
Oxigenación por Membrana Extracorpórea , Humanos , Lactante , Oxigenación por Membrana Extracorpórea/efectos adversos , Estudios Retrospectivos , Factores de Tiempo , Drenaje , Alta del Paciente
4.
Bioorg Med Chem ; 62: 116722, 2022 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-35358864

RESUMEN

Early efforts to broaden the spectrum and potency of cyclic boronic acid ß-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important ß-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).


Asunto(s)
Profármacos , Inhibidores de beta-Lactamasas , Antibacterianos/química , Antibacterianos/farmacología , Disponibilidad Biológica , Profármacos/farmacología , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/metabolismo
5.
Pediatr Surg Int ; 38(11): 1517-1523, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36069916

RESUMEN

PURPOSE: Enhanced recovery protocols [ERPs] standardize care and have been demonstrated to improve surgical quality in adults. We retrospectively compared outcomes before and after implementation of ERPs in children undergoing elective laparoscopic cholecystectomy [ELC] surgery. METHODS: A pediatric-specific ERP was implemented for children undergoing ELC at one [C1] of the two Pediatric Surgical Centers in July 2016. We retrospectively reviewed 606 patients undergoing ELC between July 2014 and December 2019. Of these, 206 patients underwent ELC prior to ERP implementation [Pre-ERP] were compared to 400 patients undergoing ELC managed in the post-ERP implementation period (between January 2017 and December 2019), 21 of which were managed by enhanced recovery protocol. Primary Outcomes included immediate peri-operative and post-operative narcotic use in mean morphine equivalents [MME], narcotics at discharge, complications, nurse calls and returns to system [RTS]. RESULTS: There was a significant decrease in opioid use both post-operatively and at time of discharge in the ERP managed cohort. The MME use during the post-operative period was 0.85 in the in ERP-compliant patients compared to 6.40 in the non-compliant group (p < 0.027). Eighty-six percent of ERP-compliant patients in the study required no narcotics at discharge, which was statistically significant when compared to ERP non-compliant cohort (p < 0.0001). There was also no change in RTS, nurse calls or complications. In addition, in the post-ERP period (2017-2019), a dominant proportion of patients at C1 partially complied with the ERP, resulting in a statistically significantly decrease of opioid use between sites in the post-op period (6.54 vs 10.57 MME) post-ERP (p < 0.001). Similar effects were noted in discharge narcotics. CONCLUSION: The use of pediatric-specific ERP in children undergoing ELC is safe, effective, and provides compassionate pain control while leading to a reduction in opioid use peri-operatively and at discharge. This improvement occurred without changes in RTS, nursing calls or complications. LEVEL OF EVIDENCE: Level III; Retrospective study.


Asunto(s)
Colecistectomía Laparoscópica , Adulto , Analgésicos Opioides/uso terapéutico , Niño , Endrín/análogos & derivados , Humanos , Tiempo de Internación , Morfina , Dolor Postoperatorio/tratamiento farmacológico , Estudios Retrospectivos
6.
J Pediatr Gastroenterol Nutr ; 73(2): 169-177, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34016879

RESUMEN

OBJECTIVES: To advance our understanding of monogenic forms of intrahepatic cholestasis. METHODS: Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. RESULTS: Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. CONCLUSIONS: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.


Asunto(s)
Colestasis Intrahepática , Colestasis , Transportadoras de Casetes de Unión a ATP/genética , Niño , Preescolar , Colestasis/genética , Colestasis Intrahepática/genética , Humanos , Estudios Longitudinales , Mutación
7.
Hepatology ; 65(5): 1645-1654, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28027587

RESUMEN

To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis-1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ-glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder-to-colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. CONCLUSION: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645-1654).


Asunto(s)
Colestasis Intrahepática/cirugía , Procedimientos Quirúrgicos del Sistema Digestivo/estadística & datos numéricos , Circulación Enterohepática , Adolescente , Niño , Preescolar , Colestasis Intrahepática/sangre , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
8.
J Surg Res ; 210: 32-46, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28457339

RESUMEN

BACKGROUND: Numerous thoracoscopic techniques have been used in the management of primary spontaneous pneumothorax (PSP), including wedge resection, pleurectomy, pleural abrasion, chemical pleurodesis, and staple line covering. The purpose of this systematic review was to compare outcomes for the most commonly reported techniques. MATERIALS AND METHODS: A systematic literature search looking at pneumothorax recurrence rate, length of stay, and chest tube duration after surgery was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed database. RESULTS: Fifty-one unique studies comprised of 6907 patients published between January 1988 and June 2015 were identified. Heterogeneity among effect sizes was significant for all outcomes. The lowest recurrence rates were observed in the wedge resection + chemical pleurodesis (1.7%; 95% confidence interval [CI], 1.0%-2.7%) and the wedge resection + pleural abrasion + chemical pleurodesis (2.8%; 95% CI, 1.7%-4.7%) groups. The shortest chest tube duration and length of stay were observed in the wedge resection + staple line covering ± other group (2.1 d; 95% CI, 1.4-2.9 and 3.3 d; 95% CI, 2.6-4.0, respectively). CONCLUSIONS: The variability in reported outcomes and the lack of published multicenter randomized controlled trials highlights a need for more robust investigations into the optimal surgical technique in the management of PSP. Based on the limited quality studies available, this systematic review favors wedge resection + chemical pleurodesis and wedge resection + pleural abrasion + chemical pleurodesis in terms of recurrence rate after surgery for PSP.


Asunto(s)
Pleurodesia/métodos , Neumonectomía/métodos , Neumotórax/cirugía , Grapado Quirúrgico , Toracoscopía/métodos , Humanos , Recurrencia , Resultado del Tratamiento
9.
Pediatr Surg Int ; 33(5): 559-567, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28039511

RESUMEN

BACKGROUND: Infants with congenital cardiac disease (CCD) often require gastrostomy tube placement (GT) and need antireflux procedures, such as fundoplications. Our purpose was to compare morbidity/mortality rates among infants with CCD undergoing GT, fundoplication, or both. METHODS: Using the NSQIP-Pediatric, we identified 4070 patients <1-year-old who underwent GT and/or fundoplication from 2012 to 2014. 2346 infants (58%) had CCD categorized as minor, major or severe. Regression models were used to estimate the association of CCD with morbidity/mortality. RESULTS: Among all patients undergoing fundoplication, there were increased odds of morbidity/mortality among CCD patients compared to non-CCD patients (OR 2.15; p < 0.001). Odds of complications decreased when procedures were performed laparoscopically or later in the first year of life. Using GT alone as a reference, fundoplication alone (OR 1.67; p < 0.001) and GT with fundoplication (OR 1.82; p < 0.001) had increased odds of morbidity/mortality among cardiac patients. Increased risk persisted after stratification by severity of CCD and after accounting for surgical approach. CONCLUSION: Fundoplication is associated with increased odds of morbidity/mortality in infants with CCD compared to GT alone. Risks are lower with laparoscopic approach and if surgery is delayed until later in the first year of life. Timing and surgical approach for patients with CCD requires further investigation.


Asunto(s)
Fundoplicación/estadística & datos numéricos , Reflujo Gastroesofágico/epidemiología , Reflujo Gastroesofágico/cirugía , Cardiopatías Congénitas/epidemiología , Cardiopatías Congénitas/cirugía , Complicaciones Posoperatorias/epidemiología , Comorbilidad , Femenino , Humanos , Lactante , Masculino , Resultado del Tratamiento , Estados Unidos/epidemiología
10.
Pediatr Emerg Care ; 33(3): 147-151, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27050738

RESUMEN

BACKGROUND: Little is known regarding the effect of different emergency department (ED) practice models on computed tomography (CT) and ultrasound (US) utilization for suspected appendicitis in the ED and through the potential inpatient hospital stay. OBJECTIVES: Examination rates of CT and US for suspected appendicitis at 2 different pediatric EDs (PEDs) through hospital admission: an academic affiliated tertiary PED (site A) compared with a private practice tertiary care PED (site B). METHODS: All visits with the ICD-9 (International Classification of Diseases, Ninth Revision) chief complaint of abdominal pain were retrospectively examined from May 1, 2009, to February 21, 2012. Suspected appendicitis visits were defined as any visit with the chief complaint of abdominal pain where a complete blood cell count was obtained. Abdominal CT and US in the PED and during hospital admission were compared across the 2 sites. Return visits within 72 hours were evaluated for any missed appendicitis. RESULTS: Overall appendicitis rates were similar at both sites: site A, 4.7%; site B, 4.0%. The odds of having a CT scan performed during visits to the PED for abdominal pain were significantly higher at site B (odds ratio [OR], 3.19; 95% confidence interval [95% CI], 2.74-3.71), whereas the odds of having an US at site B were the opposite (OR, 0.34; 95% CI, 0.28-0.40). When evaluating only the admitted visits, the odds of having a CT were also greater at site B (OR, 2.32; 95% CI, 1.86-2.94) and having an US were less (OR, 0.57; 95% CI, 0.44-0.73). CONCLUSIONS: In this study of 2 PEDs with differing practice models, we identified a dramatic difference in imaging utilization among patients with suspected appendicitis.


Asunto(s)
Dolor Abdominal/etiología , Apendicitis/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Ultrasonografía/métodos , Niño , Servicio de Urgencia en Hospital , Femenino , Hospitalización/estadística & datos numéricos , Hospitales de Enseñanza , Humanos , Clasificación Internacional de Enfermedades , Masculino , Práctica Privada , Estudios Retrospectivos
11.
J Biol Chem ; 290(9): 5555-65, 2015 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-25533465

RESUMEN

Bacterial ATP-binding cassette (ABC) importers are primary active transporters that are critical for nutrient uptake. Based on structural and functional studies, ABC importers can be divided into two distinct classes, type I and type II. Type I importers follow a strict alternating access mechanism that is driven by the presence of the substrate. Type II importers accept substrates in a nucleotide-free state, with hydrolysis driving an inward facing conformation. The ribose transporter in Escherichia coli is a tripartite complex consisting of a cytoplasmic ATP-binding cassette protein, RbsA, with fused nucleotide binding domains; a transmembrane domain homodimer, RbsC2; and a periplasmic substrate binding protein, RbsB. To investigate the transport mechanism of the complex RbsABC2, we probed intersubunit interactions by varying the presence of the substrate ribose and the hydrolysis cofactors, ATP/ADP and Mg(2+). We were able to purify a full complex, RbsABC2, in the presence of stable, transition state mimics (ATP, Mg(2+), and VO4); a RbsAC complex in the presence of ADP and Mg(2+); and a heretofore unobserved RbsBC complex in the absence of cofactors. The presence of excess ribose also destabilized complex formation between RbsB and RbsC. These observations suggest that RbsABC2 shares functional traits with both type I and type II importers, as well as possessing unique features, and employs a distinct mechanism relative to other ABC transporters.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Unión Periplasmáticas/metabolismo , Ribosa/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Transporte Biológico/genética , Western Blotting , Dicroismo Circular , Espectroscopía de Resonancia por Spin del Electrón , Proteínas de Escherichia coli/genética , Magnesio/metabolismo , Proteínas de Transporte de Membrana/genética , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Mutación , Proteínas de Unión Periplasmáticas/genética , Unión Proteica , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo
12.
Environ Res ; 144(Pt A): 81-91, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26584066

RESUMEN

Pyrethroid insecticides are widely used to control insects in both agricultural and residential settings worldwide. Few data are available on the temporal variability of pyrethroid metabolites in the urine of non-occupationally exposed adults. In this work, we describe the study design and sampling methodology for the Pilot Study to Estimate Human Exposures to Pyrethroids using an Exposure Reconstruction Approach (Ex-R study). Two major objectives were to quantify the concentrations of several pyrethroid metabolites in bedtime, first morning void (FMV), and 24-h urine samples as concentration (wet weight), specific-gravity (SG) corrected, creatinine (CR) corrected, and excretion rate values for 50 Ex-R adults over a six-week monitoring period and to determine if these correction approaches for urine dilution reduced the variability of the biomarker levels. The Ex-R study was conducted at the United States Environmental Protection Agency's Human Studies Facility in Chapel Hill, North Carolina USA and at participants' homes within a 40-mile radius of this facility. Recruitment of participants and field activities occurred between October 2009 and May 2011. Participants, ages 19-50 years old, provided daily food, activity, and pesticide-use diaries and collected their own urine samples (bedtime, FMV, and 24-h) during weeks 1, 2, and 6 of a six-week monitoring period. A total of 2503 urine samples were collected from the study participants. These samples were analyzed for the pyrethroid metabolites 3-phenoxybenzoic acid (3-PBA), cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane carboxylic acid (cis/trans-DCCA), and 2-methyl-3-phenylbenzoic acid (MPA) using high performance liquid chromatography/tandem mass spectrometry. Only 3-PBA was frequently detected (>50%) in the adult urine samples. Median urinary 3-PBA levels were 0.88 ng/mL, 0.96 ng/mL-SG, 1.04 ng/mg, and 1.04 ng/min for concentration, SG-corrected, CR-corrected, and excretion rate values, respectively, across all urine samples. The results showed that median urinary 3-PBA concentrations were consistently the lowest in FMV samples (0.77 ng/mL, 0.68 ng/mL-SG, 0.68 ng/mg, and 0.58 ng/min) and the highest in 24-h samples (0.92 ng/mL, 1.06 ng/mL-SG, 1.18 ng/mg, and 1.19 ng/min) across all four methods. Intraclass correlation coefficient (ICC) estimates for 3-PBA indicated poor reproducibility (<0.22) for all urine sample types and methods over a day, week, and six weeks. Correcting for urine sample dilution, based on either SG, CR or urine output, introduced additional measurement variability both between- and within-individuals. These results indicate that a single measure of urinary 3-PBA was not sufficient to characterize average exposure regardless of sample type, correction method, and time frame of collection. In addition, the study results can be used to inform the design of exposure characterization strategies in relevant environmental epidemiology studies in the future.


Asunto(s)
Contaminantes Ambientales/orina , Plaguicidas/orina , Piretrinas/orina , Adulto , Monitoreo del Ambiente , Femenino , Humanos , Masculino , Persona de Mediana Edad , North Carolina , Factores de Tiempo , Adulto Joven
13.
Proc Natl Acad Sci U S A ; 110(2): 731-6, 2013 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-23267070

RESUMEN

Enteritis caused by Clostridium difficile toxin (Tx) is a nosocomial disease of increasing clinical concern, but the local mediators of C. difficile TxA inflammation are unknown. The potent vasodilator calcitonin gene-related peptide mediates neurogenic inflammation via the calcitonin receptor-like receptor (CLR). Here we examined the ileum-specific effects of reducing CLR on TxA ileitis by local preinjection of double-stranded RNAs. Treatment with CLR dsRNA for 7 d decreased CLR immunoreactivity, whereas treatment with non-CLR dsRNA did not. Subsequent injection of TxA in the same location increased CLR in rats treated with non-CLR dsRNA but not in rats treated with CLR dsRNA, documenting that local injection of dsRNA is effective in preventing the increase in CLR immunoreactivity in response to local TxA. After non-CLR dsRNA pretreatment, TxA induced robust intestinal secretion, myeloperoxidase activity, and histopathologic indications of inflammation including epithelial damage, congestion, neutrophil infiltration, loss of mucin from goblet cells, and increase in mast cell numbers. After CLR dsRNA pretreatment, TxA-induced changes in intestinal secretion and histopathologic inflammation were improved, including normal mucin staining and fewer resident mast cells. Loss of CLR prevented TxA-mediated activation of NF-κB and concomitant increases in pERK1/2 and TNF-α mRNA. Locally produced CLR plays a proinflammatory role in TxA ileitis via MAPK signaling and TNF-α. The results reported here strongly suggest that a local injection of dsRNA targeting CLR could be an effective local therapeutic approach at the inflammation site in the treatment of a growing, clinically relevant hospital-acquired disease, C. difficile infection.


Asunto(s)
Toxinas Bacterianas/toxicidad , Proteína Similar al Receptor de Calcitonina/metabolismo , Enterotoxinas/toxicidad , Ileítis/inducido químicamente , Ileítis/tratamiento farmacológico , ARN Bicatenario/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Western Blotting , Proteína Similar al Receptor de Calcitonina/administración & dosificación , Proteína Similar al Receptor de Calcitonina/inmunología , Células Caliciformes/efectos de los fármacos , Masculino , Mastocitos/efectos de los fármacos , Microscopía Fluorescente , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mucinas/metabolismo , FN-kappa B/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Peroxidasa/metabolismo , Interferencia de ARN , ARN Bicatenario/administración & dosificación , ARN Bicatenario/metabolismo , Ratas , Ratas Sprague-Dawley , Estadísticas no Paramétricas , Factor de Necrosis Tumoral alfa/metabolismo
14.
J Infect Dis ; 212 Suppl 2: S167-71, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25957961

RESUMEN

Ebolaviruses cause severe hemorrhagic fever. Central to the Ebola life cycle is the matrix protein VP40, which oligomerizes and drives viral budding. Here we present the crystal structure of the Sudan virus (SUDV) matrix protein. This structure is higher resolution (1.6 Å) than previously achievable. Despite differences in the protein purification, we find that it still forms a stable dimer in solution, as was noted for other Ebola VP40s. Although the N-terminal domain interface by which VP40 dimerizes is conserved between Ebola virus and SUDV, the C-terminal domain interface by which VP40 dimers may further assemble is significantly smaller in this SUDV assembly.


Asunto(s)
Ebolavirus/química , Proteínas de la Matriz Viral/química , Ebolavirus/metabolismo , Escherichia coli/metabolismo , Multimerización de Proteína/fisiología , Estructura Terciaria de Proteína/fisiología , Soluciones/química , Sudán , Proteínas de la Matriz Viral/metabolismo
15.
J Struct Funct Genomics ; 16(2): 91-9, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25832174

RESUMEN

The methylmalonyl Co-A mutase-associated GTPase MeaB from Methylobacterium extorquens is involved in glyoxylate regulation and required for growth. In humans, mutations in the homolog methylmalonic aciduria associated protein (MMAA) cause methylmalonic aciduria, which is often fatal. The central role of MeaB from bacteria to humans suggests that MeaB is also important in other, pathogenic bacteria such as Mycobacterium tuberculosis. However, the identity of the mycobacterial MeaB homolog is presently unclear. Here, we identify the M. tuberculosis protein Rv1496 and its homologs in M. smegmatis and M. thermoresistibile as MeaB. The crystal structures of all three homologs are highly similar to MeaB and MMAA structures and reveal a characteristic three-domain homodimer with GDP bound in the G domain active site. A structure of Rv1496 obtained from a crystal grown in the presence of GTP exhibited electron density for GDP, suggesting GTPase activity. These structures identify the mycobacterial MeaB and provide a structural framework for therapeutic targeting of M. tuberculosis MeaB.


Asunto(s)
Proteínas Bacterianas/química , GTP Fosfohidrolasas/química , Mycobacterium tuberculosis/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/aislamiento & purificación , Humanos , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Chaperonas Moleculares/aislamiento & purificación , Mycobacterium tuberculosis/genética
17.
Environ Health ; 14: 23, 2015 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-25884939

RESUMEN

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in many household items. Given concerns over their potential adverse health effects, we identified predictors and evaluated temporal changes of PBDE serum concentrations. METHODS: PBDE serum concentrations were measured in young children (2-8 years old; N = 67), parents of young children (<55 years old; N = 90), and older adults (≥55 years old; N = 59) in California, with concurrent floor wipe samples collected in participants' homes in 2008-2009. We also measured serum concentrations one year later in a subset of children (N = 19) and parents (N = 42). RESULTS: PBDE serum concentrations in children were significantly higher than in adults. Floor wipe concentration is a significant predictor of serum BDE-47, 99, 100 and 154. Positive associations were observed between the intake frequency of canned meat and serum concentrations of BDE-47, 99 and 154, between canned meat entrees and BDE-154 and 209, as well as between tuna and white fish and BDE-153. The model with the floor wipe concentration and food intake frequencies explained up to 40% of the mean square prediction error of some congeners. Lower home values and renting (vs. owning) a home were associated with higher serum concentrations of BDE-47, 99 and 100. Serum concentrations measured one year apart were strongly correlated as expected (r = 0.70-0.97) with a slight decreasing trend. CONCLUSIONS: Floor wipe concentration, food intake frequency, and housing characteristics can explain 12-40% of the prediction error of PBDE serum concentrations. Decreasing temporal trends should be considered when characterizing long-term exposure.


Asunto(s)
Dieta , Exposición a Riesgos Ambientales , Contaminantes Ambientales/sangre , Éteres Difenilos Halogenados/sangre , Vivienda , Adulto , Anciano , Carga Corporal (Radioterapia) , California , Niño , Preescolar , Monitoreo del Ambiente , Contaminantes Ambientales/análisis , Femenino , Retardadores de Llama/análisis , Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/análisis , Humanos , Masculino , Persona de Mediana Edad , Estaciones del Año
18.
Environ Sci Technol ; 48(3): 1931-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24422434

RESUMEN

Since the 2001 U.S. federally mandated phase-out of residential uses of organophosphates (OPs), use of and potential for human exposure to pyrethroids in the indoor residential environment has increased. We report concentrations of common pyrethroids, pyrethroid metabolites, and chlorpyrifos in floor wipes, and urinary concentrations of pyrethroid metabolites and 3,5,6-trichloro-2-pyridinol (TCPy) in samples collected in 2007-2009 from 90 northern California families as part of the Study of Use of Products and Exposure Related Behavior (SUPERB). Correlation and regression analyses examined associations between floor wipe and urine sample concentrations. The most frequently detected urinary metabolites were TCPy (64.7%, median concentration of 1.47 ng/mL) and 3-phenoxybenzoic acid (3PBA) (62.4%, 0.79 ng/mL). Compared to the National Health and Nutrition Examination Survey (NHANES) 2001-2002 general U.S. population, this population had substantially higher pyrethroid metabolite and lower TCPy urinary concentrations. This may be related to the increased residential use of pyrethroids after the phase-out of OPs. Chlorpyrifos (98.7%), cis- and trans-permethrin (97.5%), bifenthrin (59.3%), and 3PBA (98.7%) were frequently detected in the floor wipes. Floor wipe concentrations for pyrethroid insecticides were found to be significant predictors of child creatinine-adjusted urinary metabolite concentrations (log-log regression coefficients ranging from 0.26 to 0.29; p < 0.05) suggesting that indoor residential exposure to pyrethroid insecticides is an important exposure route for children.


Asunto(s)
Cloropirifos/orina , Pisos y Cubiertas de Piso/estadística & datos numéricos , Vivienda/estadística & datos numéricos , Insecticidas/análisis , Piretrinas/orina , Adulto , Benzoatos/orina , California , Niño , Preescolar , Creatinina , Monitoreo del Ambiente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , Permetrina/análisis , Piretrinas/análisis , Piridonas/orina , Estados Unidos , Adulto Joven
19.
Acta Crystallogr F Struct Biol Commun ; 80(Pt 4): 82-91, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38656226

RESUMEN

The rise in antimicrobial resistance is a global health crisis and necessitates the development of novel strategies to treat infections. For example, in 2022 tuberculosis (TB) was the second leading infectious killer after COVID-19, with multi-drug-resistant strains of TB having an ∼40% fatality rate. Targeting essential biosynthetic pathways in pathogens has proven to be successful for the development of novel antimicrobial treatments. Fatty-acid synthesis (FAS) in bacteria proceeds via the type II pathway, which is substantially different from the type I pathway utilized in animals. This makes bacterial fatty-acid biosynthesis (Fab) enzymes appealing as drug targets. FabG is an essential FASII enzyme, and some bacteria, such as Mycobacterium tuberculosis, the causative agent of TB, harbor multiple homologs. FabG4 is a conserved, high-molecular-weight FabG (HMwFabG) that was first identified in M. tuberculosis and is distinct from the canonical low-molecular-weight FabG. Here, structural and functional analyses of Mycolicibacterium smegmatis FabG4, the third HMwFabG studied to date, are reported. Crystal structures of NAD+ and apo MsFabG4, along with kinetic analyses, show that MsFabG4 preferentially binds and uses NADH when reducing CoA substrates. As M. smegmatis is often used as a model organism for M. tuberculosis, these studies may aid the development of drugs to treat TB and add to the growing body of research that distinguish HMwFabGs from the archetypal low-molecular-weight FabG.


Asunto(s)
Proteínas Bacterianas , Mycobacterium smegmatis , Mycobacterium smegmatis/metabolismo , Mycobacterium smegmatis/enzimología , Mycobacterium smegmatis/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Cristalografía por Rayos X , Modelos Moleculares , Secuencia de Aminoácidos , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
20.
J Med Chem ; 67(4): 2321-2336, 2024 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-38300987

RESUMEN

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.


Asunto(s)
Inhibidores de Proteínas Quinasas , Proteínas Tirosina Quinasas , Humanos , Agammaglobulinemia Tirosina Quinasa , Inhibidores de Proteínas Quinasas/efectos adversos , Transducción de Señal
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