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1.
Artigo em Inglês | MEDLINE | ID: mdl-31600386

RESUMO

Importance: Despite various barriers identified to early pediatric access to cochlear implantation, barriers to timely access to pediatric hearing aids are not well characterized. Objective: To identify socioeconomic, demographic, and clinical factors that may be associated with pediatric access to hearing aids. Design, Setting, and Participants: This retrospective cohort study included 90 patients aged 1 to 15 years who were referred for auditory brainstem response (ABR) testing and evaluation for hearing aids at a single tertiary care academic medical center from March 2004 to July 2018. Children who did not receive both ABR testing and hearing aids at the same center were excluded from analysis. Main Outcomes and Measures: Associations of insurance type (private vs public), race/ethnicity (white vs other), primary language (English vs other), cause of hearing loss (complex vs not complex), zip code, hearing aid manufacturer, and severity of hearing loss (in decibels) with the duration of intervals from newborn hearing screening to ABR testing, from ABR testing to ordering of hearing aids, and from ABR testing to dispensing of hearing aids. Results: Of the 90 patients, mean (SD) age was 5.6 (3.7) years, 56% were female, and 77 (86%) were non-Hispanic. Results of χ2 tests indicated significant assocations existed between public insurance and race/ethnicity and between public insurance and primary language other than English. Variables associated with the interval from newborn hearing screening to ABR testing included insurance type (mean difference, 7.4 months; 95% CI, 2.6-12.2 months) and race/ethnicity (mean difference, 6.9 months; 95% CI, 2.7-11.1 months). Increased delays between birth and a child's first ABR test were associated with public insurance (mean difference, 6.0 months; 95% CI, 1.8-10.2 months) and race/ethnicity other than white (mean difference, 6.0 months; 95% CI, 2.3-9.7 months). The mean time from birth to initial ABR testing was a mean of 6 months longer for patients from non-English-speaking families than for those from English-speaking families (mean [SD] interval, 14.9 [16.3] months vs 9.0 [8.5] months), although the difference was not statistically significant. Severity of hearing loss was associated with a decrease in the interval from ABR testing to ordering of hearing aids after accounting for other potential barriers (odds ratio, 0.6; 95% CI, 0.4-0.9). Zip code and complexity of the child's medical condition did not appear to be associated with timely access to pediatric hearing aids. Conclusions and Relevance: This study's findings suggest that insurance type, race/ethnicity, and primary language may be barriers associated with pediatric access to hearing aids, with the greatest difference observed in time to initial ABR testing. Clinical severity of hearing loss appeared to be associated with a significant decrease in time from ABR testing to ordering of hearing aids. Greater efforts to assist parents with ABR testing and coordination of follow-up may help improve access for other at-risk children.

2.
Transpl Infect Dis ; : e13180, 2019 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-31544324

RESUMO

BACKGROUND: The gut microbiome is being associated increasingly with development of infections besides Clostridium difficile infection. A recent study found an association between butyrate-producing gut (BPG) bacteria and less frequent development of lower respiratory viral infections in allogeneic hematopoietic stem cell transplant recipients (Haak et al, Blood 131(26): 2978, 2018). In this investigation, we examine the relationship between the abundance of BPG bacteria and the development of viral infections in a cohort of kidney transplant recipients. METHODS: We recruited 168 kidney transplant recipients who provided 510 fecal specimens in the first 3 months after transplantation and profiled the gut microbiota using 16S rRNA gene sequencing of the V4-V5 hypervariable region. We classified the kidney transplant recipients into higher BPG Bacteria Group and lower BPG Bacteria Group using the same criteria of 1% relative gut abundance of BPG bacteria as the Haak et al study. RESULTS: Administration of antibiotics against anaerobes was associated with a significant decrease in the relative gut abundance of BPG bacteria. The higher BPG Bacteria Group was associated with less development of respiratory viral infections (Hazard Ratio [HR]: 0.28, P = .01) but not with less development of CMV viremia (HR: 0.38, P = .13) or BK viremia (HR: 1.02, P = .98) at 2 years post transplantation. CONCLUSION: Our pilot investigation supports future validation of the relationship between high relative gut abundance of BPG bacteria and decreased risk for development of respiratory viral infections.

3.
Transpl Infect Dis ; : e13167, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31502737

RESUMO

BACKGROUND: In kidney transplant recipients, gastrointestinal (GI) pathogens in feces are only evaluated during diarrheal episodes. Little is known about the prevalence of GI pathogens in asymptomatic individuals in this population. METHODS: We recruited 142 kidney transplant recipients who provided a non-diarrheal fecal sample within the first 10 days after transplantation. The specimens were evaluated for GI pathogens using the BioFire® FilmArray® GI Panel (BioFire Diagnostics, LLC), which tests for 22 pathogens. The fecal microbiome was also characterized using 16S rRNA gene sequencing of the V4-V5 hypervariable region. We evaluated whether detection of Clostridioides difficile and other GI pathogens was associated with post-transplant diarrhea within the first 3 months after transplantation. RESULTS: Among the 142 subjects, a potential pathogen was detected in 43 (30%) using the GI Panel. The most common organisms detected were C difficile (n = 24, 17%), enteropathogenic Escherichia coli (n = 8, 6%), and norovirus (n = 5, 4%). Detection of a pathogen on the GI panel or detection of C difficile alone was not associated with future post-transplant diarrhea (P > .05). The estimated number of gut bacterial species was significantly lower in subjects colonized with C difficile than those not colonized with a GI pathogen (P = .01). CONCLUSION: Colonization with GI pathogens, particularly C difficile, is common at the time of kidney transplantation but does not predict subsequent diarrhea. Detection of C difficile carriage was associated with decreased microbial diversity and may be a biomarker of gut dysbiosis.

4.
Health Qual Life Outcomes ; 17(1): 106, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221151

RESUMO

BACKGROUND: Clinical registries, which capture information about the health and healthcare use of patients with a health condition or treatment, often contain patient-reported outcomes (PROs) that provide insights about the patient's perspectives on their health. Missing data can affect the value of PRO data for healthcare decision-making. We compared the precision and bias of several missing data methods when estimating longitudinal change in PRO scores. METHODS: This research conducted analyses of clinical registry data and simulated data. Registry data were from a population-based regional joint replacement registry for Manitoba, Canada; the study cohort consisted of 5631 patients having total knee arthroplasty between 2009 and 2015. PROs were measured using the 12-item Short Form Survey, version 2 (SF-12v2) at pre- and post-operative occasions. The simulation cohort was a subset of 3000 patients from the study cohort with complete PRO information at both pre- and post-operative occasions. Linear mixed-effects models based on complete case analysis (CCA), maximum likelihood (ML) and multiple imputation (MI) without and with an auxiliary variable (MI-Aux) were used to estimate longitudinal change in PRO scores. In the simulated data, bias, root mean squared error (RMSE), and 95% confidence interval (CI) coverage and width were estimated under varying amounts and types of missing data. RESULTS: Three thousand two hundred thirty (57.4%) patients in the study cohort had complete data on the SF-12v2 at both occasions. In this cohort, mixed-effects models based on CCA resulted in substantially wider 95% CIs than models based on ML and MI methods. The latter two methods produced similar estimates and 95% CI widths. In the simulation cohort, when 50% of the data were missing, the MI-Aux method, in which a single hypothetical auxiliary variable was strongly correlated (i.e., 0.8) with the outcome, reduced the 95% CI width by up to 14% and bias and RMSE by up to 50 and 45%, respectively, when compared with the MI method. CONCLUSIONS: Missing data can substantially affect the precision of estimated change in PRO scores from clinical registry data. Inclusion of auxiliary information in MI models can increase precision and reduce bias, but identifying the optimal auxiliary variable(s) may be challenging.


Assuntos
Artroplastia do Joelho/psicologia , Viés , Confiabilidade dos Dados , Medidas de Resultados Relatados pelo Paciente , Sistema de Registros/normas , Idoso , Simulação por Computador , Feminino , Humanos , Modelos Lineares , Masculino , Manitoba , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
J Pharm Biomed Anal ; 171: 30-34, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959317

RESUMO

Conjugation of macromolecular drugs to polyethylene glycol (PEG) improves their therapeutic potential by reducing their rate of degradation, thereby extending the drugs half life. As a substantial component of the drug, it is necessary to measure the pharmacokinetic (PK) characteristics of PEG in vivo. A quantitative NMR-based method was developed and successfully applied to measuring double-branched polyethylene glycol 40 kDa (PEG40) in serum samples, enabling determination of PK parameters of PEG40 in preclinical species. NMR is ideal for measuring such polymers because a single, sharp peak is obtained for all the equivalent methylene protons; this amplifies the signal and makes the method insensitive to polymeric heterogeneity. High field NMR (600 MHz) with proton-observe cryoprobe technology allowed for analysis of samples in 300 nM range. Mice received 50 mg/kg of PEG40 intravenously (IV) and serum samples were collected at regular intervals for up to 72 h after dosing. The serum samples were analyzed for PEG40 using the NMR method and PK parameters were calculated using non-compartmental analysis. The volume of distribution was determined to be 0.17 L/kg for IV dosing, indicating limited distribution to interstitial space. A low clearance and observed half life of 18 h is consistent with previous reports on the PK properties of a variety of different PEG molecules ranging from 3 kDa to 190 kDa using 125I-labeled PEG in mice. The current NMR technique is easy to implement and does not require labeling of the PEG. Additionally, this is the first report, to our knowledge, of NMR spectroscopy application to PK profiling in serum.

6.
J Inherit Metab Dis ; 42(3): 470-479, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30714174

RESUMO

Glycogen storage disease type-Ia (GSD-Ia), caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), is characterized by impaired glucose homeostasis with a hallmark hypoglycemia, following a short fast. We have shown that G6pc-deficient (G6pc-/-) mice treated with recombinant adeno-associated virus (rAAV) vectors expressing either wild-type (WT) (rAAV-hG6PC-WT) or codon-optimized (co) (rAAV-co-hG6PC) human (h) G6Pase-α maintain glucose homeostasis if they restore ≥3% of normal hepatic G6Pase-α activity. The co vector, which has a higher potency, is currently being used in a phase I/II clinical trial for human GSD-Ia (NCT03517085). While routinely used in clinical therapies, co vectors may not always be optimal. Codon-optimization can impact RNA secondary structure, change RNA/DNA protein-binding sites, affect protein conformation and function, and alter posttranscriptional modifications that may reduce potency or efficacy. We therefore sought to develop alternative approaches to increase the potency of the G6PC gene transfer vectors. Using an evolutionary sequence analysis, we identified a Ser-298 to Cys-298 substitution naturally found in canine, mouse, rat, and several primate G6Pase-α isozymes, that when incorporated into the WT hG6Pase-α sequence, markedly enhanced enzymatic activity. Using G6pc-/- mice, we show that the efficacy of the rAAV-hG6PC-S298C vector was 3-fold higher than that of the rAAV-hG6PC-WT vector. The rAAV-hG6PC-S298C vector with increased efficacy, that minimizes the potential problems associated with codon-optimization, offers a valuable vector for clinical translation in human GSD-Ia.

7.
Thyroid ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30398411

RESUMO

BACKGROUND: BRAF mutation is the most common somatic mutation in thyroid cancer. The mechanism associated with BRAF mutant tumor aggressiveness remains unclear. Lysyl oxidase (LOX) is highly expressed in aggressive thyroid cancers, and involved in cancer metastasis. The objective is to determine whether LOX mediates the effect of the activated MAPK pathway in thyroid cancer. METHODS: The prognostic value of LOX and its association with BRAF mutation was analyzed in the TCGA and an independent cohort. Inhibition of mutant BRAF and the MAPK pathway, and overexpression of BRAF mutant and mouse models of BRAFV600E were used to test the effect on LOX expression. RESULTS: In the TCGA cohort, LOX expression was higher in BRAF mutant tumors compared to wild-type tumors (P<0.0001).Patients with BRAF mutant tumors with high LOX expression had a shorter disease-free survival (DFS) (P=0.03) compared to patients with BRAF mutation and low LOX group. In the independent cohort, a significant positive correlation between LOX and percentage of BRAF mutated cells was found. The independent cohort confirmed high LOX expression to be associated with a shorter DFS (P=0.01). Inhibition of BRAFV600E and MEK decreased LOX expression. Conversely overexpression of mutant BRAF increased LOX expression. The mice with thyroid-specific expression of BRAFV600E, showed a strong LOX and p-ERK expressions in tumor tissue. Inhibition of BRAFV600E in transgenic and orthotopic mouse models significantly reduced the tumor burden as well as LOX and p-ERK expressions. CONCLUSIONS: Our data suggests that BRAFV600E tumors with high LOX expression are associated with more aggressive disease. The biological underpinnings of the clinical findings were confirmed by showing that BRAF and the MAPK pathway regulate LOX expression.

8.
Otol Neurotol ; 39(10): e1160-e1167, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30444849

RESUMO

OBJECTIVE: To compare postoperative hearing outcomes between transmastoid and middle fossa craniotomy (MFC) approaches for surgical repair of superior semicircular canal dehiscence syndrome (SCDS) in a tertiary referral center. STUDY DESIGN: Historical cohort study. SETTING: Tertiary referral center. PATIENTS: Twelve consecutive SCDS cases who underwent transmastoid plugging of the superior canal; "controls" were 18 audiogram-matched patients who underwent MFC plugging and resurfacing. MAIN OUTCOME MEASURES: Differences between preoperative, 7-day postoperative, and long-term (>6 wk) postoperative air and bone conduction, speech discrimination scores (SDS), and pure-tone averages (PTA) in TM cases versus MFC controls. METHODS: MFC controls were selected by matching preoperative bone conduction (BC) pure-tone thresholds from the TM cases within 10-dBs NHL in ≥80% of recorded frequencies. Wilcoxon signed-rank tests were performed to compare primary outcomes between matches, with a Bonferroni corrected p value of 0.004 (n = 13 variables measured at each time period). RESULTS: No statistically significant differences were found in long-term postoperative air conduction and BC thresholds at any frequency both during the immediate postoperative period as well as at long-term follow-up (p > 0.004). Similarly, there were no differences in long-term SDS or PTA (p > 0.004). CONCLUSIONS: In this pilot study, there were no long-term significant differences in hearing outcomes between the two repair techniques for SCDS. We recommend continuing with the established practice for recommending surgical repair based on individual patient characteristics and preferences in managing both vestibular and auditory function.

9.
Nat Commun ; 9(1): 4172, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301885

RESUMO

Adrenocortical cancer (ACC) is a rare cancer with poor prognosis and high mortality due to metastatic disease. All reported genetic alterations have been in primary ACC, and it is unknown if there is molecular heterogeneity in ACC. Here, we report the genetic changes associated with metastatic ACC compared to primary ACCs and tumor heterogeneity. We performed whole-exome sequencing of 33 metastatic tumors. The overall mutation rate (per megabase) in metastatic tumors was 2.8-fold higher than primary ACC tumor samples. We found tumor heterogeneity among different metastatic sites in ACC and discovered recurrent mutations in several novel genes. We observed 37-57% overlap in genes that are mutated among different metastatic sites within the same patient. We also identified new therapeutic targets in recurrent and metastatic ACC not previously described in primary ACCs.

10.
Oncotarget ; 9(68): 33030-33042, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30250647

RESUMO

Drug repurposing is an effective approach to identify active drugs with known toxicity profiles for rare cancers such as ACC. The objective of this study was to determine the anticancer activity of combination treatment for ACC from previously identified candidate agents using quantitative high-throughput screening (qHTS). In this study, we evaluated the anticancer activity of flavopiridol and carfilzomib in three ACC cell lines in vitro and in vivo. Human ACC samples were analyzed for drug-target analysis, and cancer-related pathway arrays were used to identify biomarkers of treatment response. Because flavopiridol is a potent cyclin-dependent kinase (CDK) inhibitor, we found significantly higher CDK1 and CDK2 mRNA expression in three independent cohorts human ACC (p<0.01) and CDK1 protein by immunohistochemistry (p<0.01) in human ACC samples. In vitro treatment with flavopiridol and carfilzomib in all three ACC cell lines resulted in a dose-dependent, anti-proliferative effect, and the combination had synergistic activity as well as in three-dimensional tumor spheroids. We observed increased G2M cell-cycle arrest and apoptosis with combination treatment compared to other groups in vitro. The combination treatment decreased XIAP protein expression in ACC cell lines. Mice with human ACC xenografts treated with flavopiridol and carfilzomib had significantly lower tumor burden, compared to other groups (p<0.05). We observed increased cleaved-caspase expression and decreased XIAP in tumor xenografts of mice treated with combined agents. Our preclinical data supports the evaluation of combination therapy with flavopiridol and carfilzomib in patients with advanced ACC.

11.
Am J Transplant ; 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29920927

RESUMO

Posttransplant diarrhea is associated with kidney allograft failure and death, but its etiology remains unknown in the majority of cases. Because altered gut microbial ecology is a potential basis for diarrhea, we investigated whether posttransplant diarrhea is associated with gut dysbiosis. We enrolled 71 kidney allograft recipients for serial fecal specimen collections in the first 3 months of transplantation and profiled the gut microbiota using 16S ribosomal RNA (rRNA) gene V4-V5 deep sequencing. The Shannon diversity index was significantly lower in 28 diarrheal fecal specimens from 25 recipients with posttransplant diarrhea than in 112 fecal specimens from 46 recipients without posttransplant diarrhea. We found a lower relative abundance of 13 commensal genera (Benjamini-Hochberg adjusted P ≤ .15) in the diarrheal fecal specimens including the same 4 genera identified in our prior study. The 28 diarrheal fecal specimens were also evaluated by a multiplexed polymerase chain reaction (PCR) assay for 22 bacterial, viral, and protozoan gastrointestinal pathogens, and 26 specimens were negative for infectious etiologies. Using PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to predict metagenomic functions, we found that diarrheal fecal specimens had a lower abundance of metabolic genes. Our findings suggest that posttransplant diarrhea is not associated with common infectious diarrheal pathogens but with a gut dysbiosis.

12.
Schizophr Bull ; 44(suppl_2): S468-S479, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29684178

RESUMO

Elucidating schizotypal traits is important if we are to understand the various manifestations of psychosis spectrum liability and to reliably identify individuals at high risk for psychosis. The present study examined the network structures of (1) 9 schizotypal personality domains and (2) 74 individual schizotypal items, and (3) explored whether networks differed across gender and culture (North America vs China). The study was conducted in a sample of 27001 participants from 12 countries and 21 sites (M age = 22.12; SD = 6.28; 37.5% males). The Schizotypal Personality Questionnaire (SPQ) was used to assess 74 self-report items aggregated in 9 domains. We used network models to estimate conditional dependence relations among variables. In the domain-level network, schizotypal traits were strongly interconnected. Predictability (explained variance of each node) ranged from 31% (odd/magical beliefs) to 55% (constricted affect), with a mean of 43.7%. In the item-level network, variables showed relations both within and across domains, although within-domain associations were generally stronger. The average predictability of SPQ items was 27.8%. The network structures of men and women were similar (r = .74), node centrality was similar across networks (r = .90), as was connectivity (195.59 and 199.70, respectively). North American and Chinese participants networks showed lower similarity in terms of structure (r = 0.44), node centrality (r = 0.56), and connectivity (180.35 and 153.97, respectively). In sum, the present article points to the value of conceptualizing schizotypal personality as a complex system of interacting cognitive, emotional, and affective characteristics.

13.
Schizophr Res ; 199: 128-134, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29567403

RESUMO

BACKGROUND: Schizotypal traits are expressions of underlying vulnerability to psychotic disorders which have a potential impact on mental health status, neurocognition, quality of life, and daily functioning. To date, little research has examined epidemiologic landscape of schizotypal traits at the cross-national level. Our aim was to study the expression of schizotypal traits by sex, age, and country in a combined sample gathered from 12 countries. METHODS: A total of 27,001 participants completed the Schizotypal Personality Questionnaire (SPQ). The mean age of participants was 22.12 (SD=6.28); 37.5% (n=10,126) were males. RESULTS: Schizotypal traits varied according to sex, age, and country. Females scored higher than males in the positive dimension, whereas males scored higher in the disorganization dimension. By age, a significant decrease in the positive schizotypal traits was observed. Epidemiological expression of schizotypal traits varied by country. Moreover, several interactions by sex, age, and country were found. CONCLUSIONS: This pattern is similar to those found in patients with psychosis and psychotic-like experiences. These findings provide new insights and the opportunity to explore the phenotypic expression of schizotypal traits at cross-national level.

14.
Surg Endosc ; 32(3): 1111-1122, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29282577

RESUMO

BACKGROUND: Surgical site infection (SSI) is a common complication in gastrointestinal surgery. Wound protection devices are being increasingly used in the attempt to reduce infection rates. We performed a meta-analysis to determine if wound protectors reduce the incidence of SSIs in lower gastrointestinal surgery. METHODS: MEDLINE and EMBASE databases were searched between 1946 and 2016. Randomized controlled trials comparing wound protector versus no wound protector in lower gastrointestinal surgery were included. Our primary outcome was surgical site infection. Subgroup analysis was conducted comparing single-ring versus dual-ring wound protectors. RESULTS: Twelve RCTs with 3029 participants were included. There was a significant decrease in the odds of developing SSI in the wound protector group (OR 0.64, 95% CI 0.45-0.90, P < 0.01, I 2 = 55%). There was evidence of a subgroup effect (P = 0.01) with dual-ring wound protectors associated with significantly lower incidence of SSIs (OR 0.31, 95% CI 0.18-0.52, P < 0.0001, I 2 = 12%), which was not appreciated in the single-ring group (OR 0.84, 95% CI 0.67-1.04, P = 0.11, I 2 = 0%). CONCLUSIONS: Wound protector use is associated with decreased odds of developing SSI in patients undergoing lower gastrointestinal surgery. There was a subgroup effect when comparing dual-ring to single-ring devices.

15.
Schizophr Res ; 2017 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-29113776

RESUMO

The Schizotypal Personality Questionnaire-Brief (SPQ-B) was developed with the aim of examining variations in healthy trait schizotypy, as well as latent vulnerability to psychotic-spectrum disorders. No previous study has studied the cross-cultural validity of the SPQ-B in a large cross-national sample. The main goal of the present study was to analyze the reliability and the internal structure of SPQ-B scores in a multinational sample of 28,426 participants recruited from 14 countries. The mean age was 22.63years (SD=7.08; range 16-68years), 37.7% (n=10,711) were men. The omega coefficients were high, ranging from 0.86 to 0.92 for the total sample. Confirmatory factor analysis revealed that SPQ-B items were grouped either in a theoretical structure of three first-order factors (Cognitive-Perceptual, Interpersonal, and Disorganized) or in a bifactor model (three first-order factors plus a general factor of schizotypal personality). In addition, the results supported configural but not strong measurement invariance of SPQ-B scores across samples. These findings provide new information about the factor structure of schizotypal personality, and support the validity and utility of the SPQ-B, a brief and easy tool for assessing self-reported schizotypal traits, in cross-national research. Theoretical and clinical implications for diagnostic systems, psychosis models, and cross-national mental health strategies are derived from these results.

16.
Clin Cancer Res ; 23(17): 5044-5054, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28600475

RESUMO

Purpose: There is currently no standard therapy for anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancer (PDTC), which account for two-thirds of thyroid cancer-related deaths. Driver mutations in the PI3K/AKT and RAF/RAS/MEK/ERK pathways are common in ATC and PDTC. Histone deacetylases (HDAC) regulate cancer initiation and progression. Our aim was to determine the therapeutic efficacy of simultaneously targeting these pathways in thyroid cancer with a single agent and to evaluate biomarkers of treatment response.Experimental Design: CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and the PI3K/AKT pathway. We investigated its antiproliferative effect in vitro and in vivoResults: CUDC-907 significantly inhibited cellular proliferation in thyroid cancer cell lines, induced G2-M arrest with decreased levels of the checkpoint regulators cyclin B1, AURKA, AURKB, PLK1, and increased p21 and p27. Treatment induced apoptosis with increased caspase-3/7 activity and decreased survivin levels and decreased cellular migration and invasion. CUDC-907 treatment caused H3 hyperacetylation and decreased HDAC2 expression. HDAC2 was upregulated in ATC and other thyroid cancer histologic subtypes. CUDC-907 treatment reduced both p-AKT and p-ERK1/2 levels. Finally, CUDC-907 treatment, in a metastatic mouse model of thyroid cancer, showed significant inhibition of growth and metastases, and tumors from treated mice had decreased HDAC2 expression, suggesting that this may be a useful biomarker of response.Conclusions: Dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for advanced, metastatic thyroid cancer. Clin Cancer Res; 23(17); 5044-54. ©2017 AACR.


Assuntos
Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Histona Desacetilases/genética , Humanos , Camundongos , Morfolinas/administração & dosagem , Metástase Neoplásica , Estadiamento de Neoplasias , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Pirimidinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Clin Cancer Res ; 23(17): 5302-5310, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28450405

RESUMO

Purpose: Adrenal incidentalomas must be differentiated from adrenocortical cancer (ACC). Currently, size, growth, and imaging characteristics determine the potential for malignancy but are imperfect. The aim was to evaluate whether urinary small molecules (<800 Da) are associated with ACC.Experimental Design: Preoperative fasting urine specimens from patients with ACC (n = 19) and benign adrenal tumors (n = 46) were analyzed by unbiased ultraperformance liquid chromatography/mass spectrometry. Creatinine-normalized features were analyzed by Progenesis, SIMCA, and unpaired t test adjusted by FDR. Features with an AUC >0.8 were identified through fragmentation patterns and database searches. All lead features were assessed in an independent set from patients with ACC (n = 11) and benign adrenal tumors (n = 46) and in a subset of tissue samples from patients with ACC (n = 15) and benign adrenal tumors (n = 15) in the training set.Results: Sixty-nine features were discovered and four known metabolites identified. Urinary creatine riboside was elevated 2.1-fold (P = 0.0001) in patients with ACC. L-tryptophan, Nε,Nε,Nε-trimethyl-L-lysine, and 3-methylhistidine were lower 0.33-fold (P < 0.0001), 0.56-fold (P < 0.0001), and 0.33-fold (P = 0.0003) in patients with ACC, respectively. Combined multivariate analysis of the four biomarkers showed an AUC of 0.89 [sensitivity 94.7% (confidence interval {CI}, 73.9%-99.1%), specificity 82.6% (CI, 68.6%-92.2%), PPV 69.2% (CI, 48.2%-85.6%), and NPV 97.4% (CI, 86.5%-99.6%)] for distinguishing ACC from benign tumors. Of the four, creatine riboside and four unknown features were validated. Creatine riboside, Nε,Nε,Nε-trimethyl-L-lysine, and two unknown features were elevated in ACC tumors.Conclusions: There are unique urinary metabolic features in patients with ACC with some metabolites present in patient tumor samples. Urinary creatine riboside can differentiate benign adrenal neoplasms from ACC. Clin Cancer Res; 23(17); 5302-10. ©2017 AACR.


Assuntos
Neoplasias das Glândulas Suprarrenais/urina , Biomarcadores Tumorais/urina , Creatina/análogos & derivados , Neoplasias/urina , Ribonucleosídeos/urina , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Creatina/urina , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia
18.
Hum Mol Genet ; 26(10): 1890-1899, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28334808

RESUMO

Glycogen storage disease type Ia (GSD-Ia) is characterized by impaired glucose homeostasis and long-term risks of hepatocellular adenoma (HCA) and carcinoma (HCC). We have shown that the non-tumor-bearing (NT), recombinant adeno-associated virus (rAAV) vector-treated GSD-Ia mice (AAV-NT mice) expressing a wide range (0.9-63%) of normal hepatic glucose-6-phosphatase-α activity maintain glucose homeostasis and display physiologic features mimicking animals living under calorie restriction (CR). We now show that in AAV-NT mice, the signaling pathways of the CR mediators, AMP-activated protein kinase (AMPK) and sirtuin-1 are activated. AMPK/sirtuin-1 inhibit the activity of STAT3 (signal transducer and activator of transcription 3) and NFκB (nuclear factor κB), the pro-inflammatory and cancer-promoting transcription factors. Sirtuin-1 also inhibits cancer metastasis via increasing the expression of E-cadherin, a tumor suppressor, and decreasing the expression of mesenchymal markers. Consistently, in AAV-NT mice, hepatic levels of active STAT3 and NFκB-p65 were reduced as were expression of mesenchymal markers, STAT3 targets, NFκB targets and ß-catenin targets, all of which were consistent with the promotion of tumorigenesis. AAV-NT mice also expressed increased levels of E-cadherin and fibroblast growth factor 21 (FGF21), targets of sirtuin-1, and ß-klotho, which can acts as a tumor suppressor. Importantly, treating AAV-NT mice with a sirtuin-1 inhibitor markedly reversed many of the observed anti-inflammatory/anti-tumorigenic signaling pathways. In summary, activation of hepatic AMPK/sirtuin-1 and FGF21/ß-klotho signaling pathways combined with down-regulation of STAT3/NFκB-mediated inflammatory and tumorigenic signaling pathways can explain the absence of hepatic tumors in AAV-NT mice.


Assuntos
Glucose-6-Fosfatase/metabolismo , Fígado/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Caderinas/genética , Carcinogênese/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Expressão Gênica , Terapia Genética , Vetores Genéticos , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo I/terapia , Inflamação/metabolismo , Neoplasias Hepáticas/metabolismo , Camundongos , NF-kappa B , Fator de Transcrição STAT3 , Transdução de Sinais , Sirtuína 1/metabolismo , beta Catenina/genética
19.
J Gastrointest Surg ; 21(5): 896-903, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28101722

RESUMO

OBJECTIVE: This meta-analysis aims to determine if antibiotic-impregnated sutures for abdominal fascial closure prevent postoperative surgical site infections (SSIs), hernias, and/or dehiscence. METHODS: MEDLINE and EMBASE databases (1946-2016) were searched. Randomized controlled trials comparing antibiotic-impregnated sutures to standard sutures for abdominal closure were eligible. Risk of bias was evaluated using the Cochrane Handbooks definitions. RESULTS: Four-hundred fifty articles were reviewed; five eligible studies (N = 3117) were identified. All studies routinely used prophylactic antibiotics. Overall risk of SSI in the antibiotic-impregnated suture group was 10.4 vs. 13.0% in the control group. Pooled data showed no difference in SSI between suture types (odds ratio 0.79, 95% CI 0.57-1.09, P = 0.15, I 2 = 44%). There was no evidence of subgroup effect by suture material (polydioxanone vs. polyglactin 910; P = 0.19) or by comparing colorectal surgery studies to others (P = 0.67). There was a high risk of bias in two studies, one for high loss to follow-up and one for not using an intent-to-treat analysis. CONCLUSION: Our meta-analysis is the most comprehensive review on the utility of antibiotic-impregnated sutures in abdominal surgery to prevent SSI. We found no evidence to support routine use of these sutures.


Assuntos
Técnicas de Fechamento de Ferimentos Abdominais/instrumentação , Antibacterianos/administração & dosagem , Infecção da Ferida Cirúrgica/epidemiologia , Suturas , Parede Abdominal/cirurgia , Técnicas de Fechamento de Ferimentos Abdominais/efeitos adversos , Administração Tópica , Procedimentos Cirúrgicos do Sistema Digestório , Hérnia Abdominal/epidemiologia , Hérnia Abdominal/etiologia , Hérnia Abdominal/prevenção & controle , Humanos , Incidência , Ensaios Clínicos Controlados Aleatórios como Assunto , Deiscência da Ferida Operatória/epidemiologia , Deiscência da Ferida Operatória/etiologia , Deiscência da Ferida Operatória/prevenção & controle , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controle
20.
J Pers Disord ; 31(1): 1-15, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-26845533

RESUMO

The prevailing theoretical model of the Schizotypal Personality Questionnaire (SPQ) is a three-factor model based on subscale-level analyses. However, recent item-level factor analyses of the SPQ suggest a four- or five-factor model. To examine the factor structure of the SPQ and how this structure may differ between undergraduate and community samples, the authors conducted exploratory and confirmatory item-level factor analyses of this measure on undergraduate (N = 1,850) and community participants (N = 1,464). A clear three-factor solution was found in the community sample, whereas a somewhat equivocal four-factor solution was found in the undergraduate sample. Both structures displayed gender invariance. This is the first study to address the issues of undergraduate sample generalizability and gender invariance in an item-level exploratory factor analysis of the SPQ. Given the disparate findings in the samples, this study indicates the importance of using both community and undergraduate samples when examining the factor structure of the SPQ.


Assuntos
Inventário de Personalidade/normas , Personalidade/fisiologia , Psicometria/instrumentação , Transtorno da Personalidade Esquizotípica/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudantes/estatística & dados numéricos , Universidades , Adulto Jovem
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