Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
J Biol Chem ; 300(10): 107745, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39236874

RESUMO

We have investigated the kinetic behavior of the electron-bifurcating crotonyl-CoA-dependent NADH: ferredoxin oxidoreductase EtfAB:bcd from Megasphaera elsdenii. The overall behavior of the complex in both the reductive and the oxidative half-reactions is consistent with that previously determined for the individual EtfAB and bcd components. This includes an uncrossing of the half-potentials of the bifurcating flavin of the EtfAB component in the course of ferredoxin-reducing catalysis, ionization of the bcd flavin semiquinone and the appearance of a charge transfer complex upon binding of the high potential acceptor crotonyl-CoA. The observed rapid-reaction rates of ferredoxin reduction are independent of [NADH], [crotonyl-CoA], and [ferredoxin], with an observed rate of ∼0.2 s-1, consistent with the observed steady-state kinetics. In enzyme-monitored turnover experiments, an approach to steady-state where the complex's flavins become reduced but no ferredoxin is generated is followed by a steady-state phase characterized by extensive ferredoxin reduction but little change in overall levels of flavin reduction. The approach to the steady-state phase can be eliminated by prior reduction of the complex, in which case there is no lag in the onset of ferredoxin reduction; this is consistent with the et FAD needing to be reduced to the level of the (anionic) semiquinone for bifurcation and concomitant ferredoxin reduction to occur. Single-turnover experiments support this conclusion, with the accumulation of the anionic semiquinone of the et FAD apparently required to prime the system for subsequent bifurcation and ferredoxin reduction.

2.
J Biol Chem ; 299(7): 104853, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37220854

RESUMO

We have investigated the equilibrium properties and rapid-reaction kinetics of the isolated butyryl-CoA dehydrogenase (bcd) component of the electron-bifurcating crotonyl-CoA-dependent NADH:ferredoxin oxidoreductase (EtfAB-bcd) from Megasphaera elsdenii. We find that a neutral FADH• semiquinone accumulates transiently during both reduction with sodium dithionite and with NADH in the presence of catalytic concentrations of EtfAB. In both cases full reduction of bcd to the hydroquinone is eventually observed, but the accumulation of FADH• indicates that a substantial portion of reduction occurs in sequential one-electron processes rather than a single two-electron event. In rapid-reaction experiments following the reaction of reduced bcd with crotonyl-CoA and oxidized bcd with butyryl-CoA, long-wavelength-absorbing intermediates are observed that are assigned to bcdred:crotonyl-CoA and bcdox:butyryl-CoA charge-transfer complexes, demonstrating their kinetic competence in the course of the reaction. In the presence of crotonyl-CoA there is an accumulation of semiquinone that is unequivocally the anionic FAD•- rather than the neutral FADH• seen in the absence of substrate, indicating that binding of substrate/product results in ionization of the bcd semiquinone. In addition to fully characterizing the rapid-reaction kinetics of both the oxidative and reductive half-reactions, our results demonstrate that one-electron processes play an important role in the reduction of bcd in EtfAB-bcd.


Assuntos
Butiril-CoA Desidrogenase , Megasphaera elsdenii , Oxirredutases , Butiril-CoA Desidrogenase/química , Butiril-CoA Desidrogenase/metabolismo , Elétrons , Ferredoxinas/metabolismo , Cinética , Megasphaera elsdenii/enzimologia , NAD/metabolismo , Oxirredução , Oxirredutases/química , Oxirredutases/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Estrutura Terciária de Proteína , Modelos Moleculares
3.
Radiology ; 311(2): e232286, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38771177

RESUMO

Background Artificial intelligence (AI) is increasingly used to manage radiologists' workloads. The impact of patient characteristics on AI performance has not been well studied. Purpose To understand the impact of patient characteristics (race and ethnicity, age, and breast density) on the performance of an AI algorithm interpreting negative screening digital breast tomosynthesis (DBT) examinations. Materials and Methods This retrospective cohort study identified negative screening DBT examinations from an academic institution from January 1, 2016, to December 31, 2019. All examinations had 2 years of follow-up without a diagnosis of atypia or breast malignancy and were therefore considered true negatives. A subset of unique patients was randomly selected to provide a broad distribution of race and ethnicity. DBT studies in this final cohort were interpreted by a U.S. Food and Drug Administration-approved AI algorithm, which generated case scores (malignancy certainty) and risk scores (1-year subsequent malignancy risk) for each mammogram. Positive examinations were classified based on vendor-provided thresholds for both scores. Multivariable logistic regression was used to understand relationships between the scores and patient characteristics. Results A total of 4855 patients (median age, 54 years [IQR, 46-63 years]) were included: 27% (1316 of 4855) White, 26% (1261 of 4855) Black, 28% (1351 of 4855) Asian, and 19% (927 of 4855) Hispanic patients. False-positive case scores were significantly more likely in Black patients (odds ratio [OR] = 1.5 [95% CI: 1.2, 1.8]) and less likely in Asian patients (OR = 0.7 [95% CI: 0.5, 0.9]) compared with White patients, and more likely in older patients (71-80 years; OR = 1.9 [95% CI: 1.5, 2.5]) and less likely in younger patients (41-50 years; OR = 0.6 [95% CI: 0.5, 0.7]) compared with patients aged 51-60 years. False-positive risk scores were more likely in Black patients (OR = 1.5 [95% CI: 1.0, 2.0]), patients aged 61-70 years (OR = 3.5 [95% CI: 2.4, 5.1]), and patients with extremely dense breasts (OR = 2.8 [95% CI: 1.3, 5.8]) compared with White patients, patients aged 51-60 years, and patients with fatty density breasts, respectively. Conclusion Patient characteristics influenced the case and risk scores of a Food and Drug Administration-approved AI algorithm analyzing negative screening DBT examinations. © RSNA, 2024.


Assuntos
Algoritmos , Inteligência Artificial , Neoplasias da Mama , Mamografia , Humanos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Mamografia/métodos , Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Idoso , Adulto , Densidade da Mama
4.
AJR Am J Roentgenol ; 222(3): e2330503, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38090808

RESUMO

Ductal carcinoma in situ (DCIS) is a nonobligate precursor to invasive cancer that classically presents as asymptomatic calcifications on screening mammography. The increase in DCIS diagnoses with organized screening programs has raised concerns about overdiagnosis, while a patientcentric push for more personalized care has increased awareness about DCIS overtreatment. The standard of care for most new DCIS diagnoses is surgical excision, but nonsurgical management via active monitoring is gaining attention, and multiple clinical trials are ongoing. Imaging, along with demographic and pathologic information, is a critical component of active monitoring efforts. Commonly used imaging modalities including mammography, ultrasound, and MRI, as well as newer modalities such as contrast-enhanced mammography and dedicated breast PET, can provide prognostic information to risk stratify patients for DCIS active monitoring eligibility. Furthermore, radiologists will be responsible for closely surveilling patients on active monitoring and identifying if invasive progression occurs. Active monitoring is a paradigm shift for DCIS care, but the success or failure will rely heavily on the interpretations and guidance of radiologists.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Humanos , Feminino , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/terapia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Mamografia/métodos , Detecção Precoce de Câncer , Mama/patologia , Carcinoma Ductal de Mama/patologia
5.
AJR Am J Roentgenol ; 220(2): 212-223, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36102725

RESUMO

BACKGROUND. Studies have shown improved targeting and sampling of noncalcified lesions (asymmetries, masses, and architectural distortion) with digital breast tomosynthesis (DBT)-guided biopsy in comparison with digital mammography (DM)-guided stereotactic biopsy. Literature that compares the two techniques specifically for sampling calcifications has been scarce. OBJECTIVE. The purpose of this study was to compare the performance and outcomes of DM- and DBT-guided biopsy of suspicious calcifications. METHODS. This retrospective study included 1310 patients (mean age, 58 ± 12 [SD] years) who underwent a total of 1354 9-gauge vacuum-assisted core biopsies of suspicious calcifications performed at a single institution from May 22, 2017, to December 31, 2021. The decision to use a DM-guided or DBT-guided technique was made at the discretion of the radiologist performing the biopsy. Procedure time, the number of exposures during the procedure, and the histopathologic outcomes were recorded. The two techniques were compared using a two-sample t test for continuous variables and a chi-square test for categoric variables. Additional tests were performed using generalized estimating equations to control for the effect of the individual radiologist performing the biopsy. RESULTS. A total of 348 (26%) biopsies used DM guidance, and 1006 (74%) used DBT guidance. The mean procedure time was significantly lower for DBT-guided biopsy (14.9 ± 8.0 [SD] minutes) than for DM-guided biopsy (24.7 ± 14.3 minutes) (p < .001). The mean number of exposures was significantly lower for DBT-guided biopsy (4.1 ± 1.0 [SD] exposures) than for DM-guided biopsy (9.1 ± 3.3 exposures) (p < .001). The differences in procedure time and number of exposures remained significant (both p < .001) when controlling for the effect of the radiologist performing the biopsy. There were no significant differences (all p > .05) between DM-guided and DBT-guided biopsy in terms of the malignancy rate on initial biopsy (20% vs 19%), the rate of high-risk lesion upgrading (14% vs 22%), or the final malignancy rate (23% vs 22%). CONCLUSION. DBT-guided biopsy of suspicious calcifications can be performed with shorter procedure time and fewer exposures compared with DM-guided biopsy, without a significant difference in rates of malignancy or high-risk lesion upgrading. CLINICAL IMPACT. The use of a DBT-guided, rather than a DM-guided, biopsy technique for suspicious calcifications can potentially reduce patient discomfort and radiation exposure without affecting clinical outcomes.


Assuntos
Doenças Mamárias , Neoplasias da Mama , Calcinose , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Estudos Retrospectivos , Mamografia/métodos , Biópsia , Doenças Mamárias/diagnóstico por imagem , Doenças Mamárias/patologia , Biópsia Guiada por Imagem/métodos , Biópsia por Agulha/métodos , Calcinose/diagnóstico por imagem , Calcinose/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Mama/diagnóstico por imagem , Mama/patologia
6.
Br J Anaesth ; 130(3): 272-286, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36404140

RESUMO

BACKGROUND: Network meta-analyses (NMAs) combine direct and indirect estimates to provide mixed (or network) estimates of effect sizes. The scientific rigour of the conduct and reporting of anaesthesia NMAs is unknown. This review assessed the epidemiological, methodological, and statistical characteristics of anaesthesia NMAs. METHODS: We searched four databases for anaesthesia NMAs and developed a 64-item checklist to evaluate NMAs. For 29 binary items, we defined compliance as 'the ratio of NMAs that was awarded a 'yes' for that item, divided by the total number of NMAs. The compliance of such binary items was reclassified as very low (≤25%), low (26-50%), fair (51-75%), and high (>75%). We amalgamated findings from 29 key items to provide specific recommendations (post hoc). We compared the compliance of NMAs in anaesthesia across 26 items, with that of cancer NMAs and Cochrane NMAs, and analysed improvement over time (post hoc). RESULTS: Among 62 included NMAs, compliance was low (26-50%) for protocol registration, use of PRISMA-NMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for NMA), publication bias assessment, evidence appraisal, reporting of Bayesian methodology and consistency evaluation. Compliance was very low (≤25%) for bias assessment, biostatistician involvement, search specialist, and use of predefined important differences. CONCLUSIONS: Anaesthesia NMAs need improvement in their conduct and reporting. Anaesthesia journals should mandate the registration of protocols and reporting of NMAs using PRISMA-NMA. Authors should carefully assess publication bias, and use updated bias assessment tools, and evidence appraisal methods designed for NMAs. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42021227608.


Assuntos
Anestesia , Anestesiologia , Humanos , Teorema de Bayes , Lista de Checagem , Metanálise em Rede
7.
Br J Anaesth ; 130(4): 412-420, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36503825

RESUMO

BACKGROUND: Reproducibility of research is poor; this may be because many articles report statistically significant findings that are false positives. Two potential solutions are to lower the P-value for statistical significance testing from 0.05 to 0.005 and to report the minimum false-positive risk (minFPR). This study determined these metrics for randomised controlled trials (RCTs) in general anaesthesiology journals. METHODS: We identified superiority RCTs published between January 1, 2019 and March 15, 2021 from seven leading anaesthesia journals. P-values for primary outcomes were collected, and minFPRs for these outcomes were calculated using a formula assuming a 50% prior probability of an intervention being effective (minFPR50). The primary outcomes were the percentage of RCTs maintaining statistical significance at P<0.005 and minFPR50. RESULTS: We included 318 RCTs. P-values below 0.05 were reported in 205/318 (64%) of RCTs. Of these 205 RCTs, 119/205 (58%) maintained statistical significance at the P<0.005 threshold. The mean (standard deviation) minFPR50 was 22% (20). At P=0.005, the minFPR50 was approximately 5%. CONCLUSIONS: These proposed metrics aimed at mitigating reproducibility concerns would call a significant portion of the anaesthesiology literature into question. We found a minFPR of 22% and determined that 42% of primary outcomes would not maintain statistical significance if the P-value threshold changed from 0.05 to 0.005. These findings could partially explain the lack of reproducibility of research findings.


Assuntos
Anestesia , Anestesiologia , Humanos , Estudos Transversais , Ensaios Clínicos Controlados Aleatórios como Assunto
8.
Can J Anaesth ; 70(9): 1461-1473, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37420161

RESUMO

PURPOSE: The scientific rigour of the conduct and reporting of anesthesiology network meta-analyses (NMAs) is unknown. This systematic review and meta-epidemiological study assessed the methodological and reporting quality of NMAs in anesthesiology. METHODS: We searched four databases, including MEDLINE, PubMed, Embase, and the Cochrane Systematic Reviews Database, for anesthesiology NMAs published from inception to October 2020. We assessed the compliance of NMAs against A Measurement Tool to Assess Systematic Reviews (AMSTAR-2), Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement for Network Meta-Analyses (PRISMA-NMA), and PRISMA checklists. We measured the compliance across various items in AMSTAR-2 and PRISMA checklists and provided recommendations to improve quality. RESULTS: Using the AMSTAR-2 rating method, 84% (52/62) of NMAs were rated "critically low." Quantitatively, the median [interquartile range] AMSTAR-2 score was 55 [44-69]%, while the PRISMA score was 70 [61-81]%. Methodological and reporting scores showed a strong correlation (R = 0.78). Anesthesiology NMAs had a higher AMSTAR-2 score and PRISMA score if they were published in higher impact factor journals (P = 0.006 and P = 0.01, respectively) or followed PRISMA-NMA reporting guidelines (P = 0.001 and P = 0.002, respectively). Network meta-analyses from China had lower scores (P < 0.001 and P < 0.001, respectively). Neither score improved over time (P = 0.69 and P = 0.67, respectively). CONCLUSION: The current study highlights numerous methodological and reporting deficiencies in anesthesiology NMAs. Although the AMSTAR tool has been used to assess the methodological quality of NMAs, dedicated tools for conducting and assessing the methodological quality of NMAs are urgently required. STUDY REGISTRATION: PROSPERO (CRD42021227997); first submitted 23 January 2021.


RéSUMé: OBJECTIF: La rigueur scientifique de la conduite et de la communication des méta-analyses en réseau (MAR) en anesthésiologie est inconnue. Cette revue systématique et étude méta-épidémiologique a évalué la qualité méthodologique et de communication des MAR en anesthésiologie. MéTHODE: Nous avons mené des recherches dans quatre bases de données, soit MEDLINE, PubMed, Embase et la base de données des revues systématiques Cochrane, pour trouver des MAR en anesthésiologie publiées depuis la création de ces bases de données jusqu'en octobre 2020. Nous avons évalué la conformité des MAR par rapport à trois outils, soit : AMSTAR-2 (outil de mesure pour évaluer les revues systématiques), PRISMA-NMA et les listes de contrôle PRISMA. Nous avons mesuré la conformité de divers éléments des listes de contrôle AMSTAR-2 et PRISMA et formulé des recommandations pour améliorer la qualité. RéSULTATS: En utilisant la méthode de notation AMSTAR-2, 84 % (52/62) des MAR ont reçu la cote « extrêmement faible ¼. Quantitativement, le score médian [écart interquartile] sur l'AMSTAR-2 était de 55 [44-69] %, tandis que le score PRISMA était de 70 [61-81] %. Les scores méthodologiques et de communication ont montré une forte corrélation (R = 0,78). Les MAR en anesthésiologie avaient un score AMSTAR-2 et un score PRISMA plus élevés si elles étaient publiées dans des revues à facteur d'impact plus élevé (P = 0,006 et P = 0,01, respectivement) ou avaient suivi les lignes directrices de PRISMA-NMA en matière de communication des résultats (P = 0,001 et P = 0,002, respectivement). Les méta-analyses en réseau provenant de Chine avaient des scores plus faibles (P < 0,001 et P < 0,001, respectivement). Aucun des deux scores ne s'est amélioré au fil du temps (P = 0,69 et P = 0,67, respectivement). CONCLUSION: La présente étude met en évidence de nombreuses lacunes méthodologiques et de communication dans les MAR en anesthésiologie. Bien que l'outil AMSTAR ait été utilisé pour évaluer la qualité méthodologique des MAR, il est urgent de disposer d'outils spécialisés pour mener des MAR et en évaluer la qualité méthodologique. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021227997); soumis pour la première fois le 23 janvier 2021.


Assuntos
Anestesiologia , Humanos , Metanálise em Rede , Estudos Epidemiológicos , Projetos de Pesquisa , Lista de Checagem , Relatório de Pesquisa
9.
PLoS Comput Biol ; 17(9): e1008100, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34555020

RESUMO

Neuronal activity within the premotor region HVC is tightly synchronized to, and crucial for, the articulate production of learned song in birds. Characterizations of this neural activity detail patterns of sequential bursting in small, carefully identified subsets of neurons in the HVC population. The dynamics of HVC are well described by these characterizations, but have not been verified beyond this scale of measurement. There is a rich history of using local field potentials (LFP) to extract information about behavior that extends beyond the contribution of individual cells. These signals have the advantage of being stable over longer periods of time, and they have been used to study and decode human speech and other complex motor behaviors. Here we characterize LFP signals presumptively from the HVC of freely behaving male zebra finches during song production to determine if population activity may yield similar insights into the mechanisms underlying complex motor-vocal behavior. Following an initial observation that structured changes in the LFP were distinct to all vocalizations during song, we show that it is possible to extract time-varying features from multiple frequency bands to decode the identity of specific vocalization elements (syllables) and to predict their temporal onsets within the motif. This demonstrates the utility of LFP for studying vocal behavior in songbirds. Surprisingly, the time frequency structure of HVC LFP is qualitatively similar to well-established oscillations found in both human and non-human mammalian motor areas. This physiological similarity, despite distinct anatomical structures, may give insight into common computational principles for learning and/or generating complex motor-vocal behaviors.


Assuntos
Potenciais de Ação/fisiologia , Tentilhões/fisiologia , Córtex Motor/fisiologia , Vocalização Animal/fisiologia , Animais , Masculino
10.
AJR Am J Roentgenol ; 218(6): 997-998, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34935404

RESUMO

This study describes 94 patients who presented with suspected COVID-19 vaccine-related axillary adenopathy on breast imaging. All biopsies recommended within 12 weeks of the second vaccine dose were benign. Among women not recommended for biopsy, the median interval between the second vaccine dose and ultrasound follow-up was 15.9 weeks. Three biopsies yielding malignant diagnoses were recommended 12.0-13.1 weeks after the second vaccine dose. Lengthening imaging follow-up to 12-16 weeks after the second dose may reduce unnecessary biopsy recommendations.


Assuntos
Neoplasias da Mama , COVID-19 , Linfadenopatia , Vacinas , Neoplasias da Mama/diagnóstico por imagem , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Feminino , Seguimentos , Humanos , Linfadenopatia/induzido quimicamente , Linfadenopatia/diagnóstico por imagem , SARS-CoV-2
11.
AJR Am J Roentgenol ; 219(5): 724-733, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35703412

RESUMO

BACKGROUND. Recall rates are lower for digital breast tomosynthesis (DBT) than for full-field digital mammography (FFDM). This difference could have important implications with respect to one-view asymmetries given that missed cancers are often visible on one view. OBJECTIVE. The purpose of this study is to compare the outcomes of one-view asymmetries recalled from DBT versus FFDM screening examinations and to determine predictors of malignancy among recalled asymmetries. METHODS. This retrospective study first determined recall rates associated with one-view asymmetries for screening mammography performed using DBT and FFDM from July 14, 2016, through July 14, 2020. Further analyses included patients recalled for a one-view asymmetry who completed subsequent diagnostic workup and all recommended follow-up. Patient and cancer characteristics were extracted from the electronic health record. RESULTS. The recall rate associated with asymmetries was lower for DBT screening (2.5% [3169/128,755]) than for FFDM screening (3.4% [815/23,898]) (p < .001). Further analyses of patients who completed diagnostic workup and subsequent follow-up included 3119 patients (mean age, 57 years) for DBT screening and 811 patients (mean age, 56 years) for FFDM screening. Distribution of final BI-RADS categories from subsequent diagnostic workup was not different between the two modalities (p > .99). The frequency of malignancy was not different between asymmetries recalled from DBT (1.7% [54/3119]) and FFDM (1.7% [14/811]) (p > .99). Malignant asymmetries identified on FFDM versus DBT were more frequently associated with architectural distortion on diagnostic workup (35.7% [5/14] vs 9.3% [5/54]) (p < .001) and were more commonly invasive ductal carcinoma (92.9% vs 57.4%) and less commonly invasive lobular carcinoma (0.0% vs 24.1%) (p = .05). In multivariable analysis, independent predictors of malignancy among recalled asymmetries from DBT were age (for 55-69 years, odds ratio [OR] = 2.40 [p = .04]; for ≥ 70 years, OR = 7.93 [p < .001]; reference, < 55 years) and breast density (not dense, OR = 2.47 [p = .001]; reference, dense breasts). CONCLUSION. Recalled asymmetries were less frequent for DBT than for FFDM. The malignancy rate was low for both modalities (1.7%). Age 55 years old and older and lower breast density predicted malignancy for DBT-recalled asymmetries. CLINICAL IMPACT. Our results support the use of DBT to reduce unnecessary recalls without altering PPV for asymmetry-associated malignancies. Patient factors should be considered when assessing whether a potential asymmetry on DBT screening represents overlapping fibroglandular tissue or a suspicious finding that requires diagnostic workup.


Assuntos
Neoplasias da Mama , Mamografia , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Mamografia/métodos , Detecção Precoce de Câncer/métodos , Neoplasias da Mama/diagnóstico por imagem , Estudos Retrospectivos , Densidade da Mama
12.
Nature ; 535(7611): 252-7, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27338790

RESUMO

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.


Assuntos
Antineoplásicos/farmacologia , Peptídeo Hidrolases/metabolismo , Fatores de Terminação de Peptídeos/metabolismo , Compostos de Fenilureia/farmacologia , Talidomida/análogos & derivados , Proteínas Adaptadoras de Transdução de Sinal , Motivos de Aminoácidos , Antineoplásicos/química , Sítios de Ligação , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Humanos , Fator de Transcrição Ikaros/química , Fator de Transcrição Ikaros/metabolismo , Modelos Moleculares , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Peptídeo Hidrolases/química , Fatores de Terminação de Peptídeos/química , Fatores de Terminação de Peptídeos/deficiência , Compostos de Fenilureia/química , Ligação Proteica , Proteólise/efeitos dos fármacos , Especificidade por Substrato , Talidomida/química , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo
13.
Emerg Radiol ; 29(6): 987-993, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35971026

RESUMO

PURPOSE: Pediatric patients with breast-related symptoms often initially present to the emergency department for evaluation. While pediatric radiologists are accustomed to evaluating acute infectious and traumatic etiologies, they may be less familiar with breast-specific findings. This study compares management recommendations of pediatric breast ultrasounds performed in the emergency setting between pediatric and breast imaging radiologists. METHODS: This retrospective cohort study reviewed data from all pediatric breast ultrasounds performed in the emergency setting from a single academic institution from 1/1/14 to 12/31/19. During the study period, 12 pediatric radiologists with experience ranging from 1 to 33 years interpreted pediatric breast ultrasounds. Three breast imaging radiologists (with 3, 8, and 25 years of experience) retrospectively reviewed each case and recorded whether further management was recommended. Differences in recommendations were compared using Fisher's exact test. Cohen's kappa was used to assess agreement between subspecialty radiologists. RESULTS: This study included 75 pediatric patients, with mean age 13 ± 5.6 years and malignancy rate of 1.3% (1/75). Pediatric radiologists and the most experienced breast imaging radiologist had moderate agreement in management recommendations (k = 0.54). There was no significant difference in recommendations for further management between pediatric radiologists (22/75 [29.3%]) and the most experienced breast imaging radiologist (15/75 [20.0%]), p = 0.26. CONCLUSION: Recommendations for pediatric breast complaints in the emergency setting are comparable between subspecialties.


Assuntos
Radiologistas , Ultrassonografia Mamária , Feminino , Humanos , Criança , Adolescente , Estudos Retrospectivos
14.
AJR Am J Roentgenol ; 217(5): 1081-1082, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33624508

RESUMO

Among 707 women who were recommended to undergo annual diagnostic mammography (DM) surveillance after lumpectomy for breast cancer, 94.9%, 90.4%, and 84.3% of women presented for DM at years 1, 2, and 3 after lumpectomy. A total of 18.8%, 11.0%, and 9.9% of women received additional views at years 1, 2, and 3, compared with the 10.1% institutional screening recall rate. The postlumpectomy year 3 cancer detection rate of 11.7 cancers per 1000 DM examinations was below DM benchmarks. These preliminary findings suggest that returning to screening mammography may be acceptable after 1 year of postlumpectomy DM follow-up.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Detecção Precoce de Câncer/métodos , Mamografia , Mastectomia Segmentar , Idoso , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Retrospectivos
15.
Breast J ; 27(12): 872-876, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34668275

RESUMO

We present a retrospective cohort study evaluating the utilization and effectiveness of digital breast tomosynthesis (DBT) for breast cancer screening with a focus on racial differences. 46,236 females underwent screening mammography between 4/1/2013 and 3/30/2020, during which there was an increase in DBT utilization from 18.8% in year 1 to 89.6% in year 7. Black and Asian women were significantly less likely to have a screening study with DBT compared to White women. Overall, the DBT group had a lower recall rate (9.1% versus 11.2%, p < 0.001) and higher cancer detection rate (6.0 vs 4.1, p < 0.001) compared to the FFDM group.


Assuntos
Neoplasias da Mama , Mamografia , Neoplasias da Mama/diagnóstico por imagem , Detecção Precoce de Câncer , Feminino , Humanos , Programas de Rastreamento , Estudos Retrospectivos
16.
Emerg Radiol ; 28(3): 589-599, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33452965

RESUMO

PURPOSE: The aim of this study was to assess the perceived value and impact of a hands-on mock call simulation program on resident confidence with interpretation of emergency department overnight call cases. METHODS: A five-session course was implemented in June of 2018 for rising PGY-3/R2 residents to mimic the experience of overnight call with indirect supervision. Sessions were led by senior residents in the program and consisted of timed, independent interpretation of 15-20 high-yield cases per day which highlighted "do-not miss" critical findings and simulated workflow interruptions including phone calls, consultations, and questions from technologists. IRB-approved, and anonymous pre- and post-course surveys were administered to participants which assessed residents' degree of confidence in interpretation of on-call cases and comparison of the mock call experience with existing preparatory strategies. Survey responses were analyzed using McNemar's test and Mann-Whitney U test. RESULTS: Our survey response rate was 91% (29/32). After completing the mock call simulation, there was a significant increase in the mean Likert score of resident confidence levels and feelings of preparedness from 4.59 to 7.38 (p < 0.01). The majority of respondents (72.4% [21/29]) felt that the mock call simulation was "extremely useful." One hundred percent of respondents indicated that the mock call simulation should be implemented for the following year. CONCLUSION: Implementation of a hands-on mock call simulation significantly improves the confidence levels of radiology residents before assuming on-call responsibilities and may serve as an adjunct to existing preparatory strategies.


Assuntos
Internato e Residência , Radiologia , Humanos , Radiologia/educação
17.
Breast J ; 26(10): 2021-2025, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32924192

RESUMO

It is a clinical dilemma when a finding reported as suspicious on a breast MRI is not visualized at the time of a scheduled MRI-guided breast biopsy. We retrospectively reviewed all canceled MRI-guided biopsies at our institution between 6/1/2009 and 9/20/2019 and found a cancellation rate of 6.9% (72/1051). In one case, a mastectomy was performed after the canceled biopsy revealing a focus of DCIS in the same quadrant as the original finding (malignancy rate 2.1%). Our results support the current practice of 6-month follow-up MRI recommendation after a canceled MRI-guided biopsy for lesion nonvisualization.


Assuntos
Neoplasias da Mama , Biópsia , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Biópsia Guiada por Imagem , Imageamento por Ressonância Magnética , Mastectomia , Estudos Retrospectivos
19.
Acad Radiol ; 31(7): 2654-2662, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38184419

RESUMO

RATIONALE AND OBJECTIVES: To determine the imaging changes and their associated positive predictive value (PPV) for invasive breast cancer in women undergoing active monitoring for ductal carcinoma in situ (DCIS). MATERIALS AND METHODS: In this seven-year follow-up retrospective IRB-exempted cohort study, we reviewed patients diagnosed with DCIS who elected active monitoring between 2003 and 2022 at a single academic institution. Imaging characteristics, histopathology at initial diagnosis, and subsequent follow-up were recorded. Low-risk DCIS was defined as low or intermediate grade and hormone receptor (HR) positive (estrogen and/or progesterone receptor positive) disease diagnosed in women at least 40 years of age. Progression was defined as subsequent ipsilateral invasive breast cancer diagnosis. RESULTS: There were 39 patients with a median age of 58.4 years (IQR: 51.1-69.6 years) and a median follow-up of 4.3 years (range: 0.6-16.4 years). Nearly two thirds of patients (64%, 25/39) had stable imaging (range: 0.6-16.4 years) and remained progression-free during active monitoring. Among the remaining 14 patients (36%), there were 24 imaging findings which prompted 22 subsequent core needle biopsies (range: 1-3 biopsies per patient) and two surgical biopsies. The PPV of invasive cancer was 29% (7/24) overall and 38% (3/8) for masses, 33% (3/9) for calcifications, 17% (1/6) for non-mass enhancement, and 0% (0/1) for architectural distortion. CONCLUSION: Of the radiographic changes prompting an additional biopsy, development of a new mass (38%) and new calcifications (33%) had the highest PPV for invasive progression. Close imaging follow-up should be a critical component for patients undergoing monitoring for DCIS.


Assuntos
Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Mamografia , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/diagnóstico por imagem , Idoso , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/patologia , Seguimentos , Estudos Retrospectivos , Progressão da Doença , Conduta Expectante , Valor Preditivo dos Testes
20.
Acad Radiol ; 31(4): 1239-1247, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37914625

RESUMO

RATIONALE AND OBJECTIVES: To assess patient preferences for breast radiologists' attire and appearance. MATERIALS AND METHODS: A multi-institutional anonymous, voluntary 19-question survey was administered to patients undergoing screening and diagnostic mammography examinations over a 5-week period. Using a 5-point Likert scale, respondents were asked about their preferences for gender-neutral attire (white coat), male-presenting attire (scrubs, dress shirt with tie, or dress shirt without tie), and female-presenting attire (scrubs, dress, blouse with pants, and blouse with skirt). Patient responses were compared to demographic data using bivariable analysis and multivariable regression. RESULTS: Response rate was 84.7% (957/1130). Mean respondent age was 57.2 years±11.9. Most respondents agreed/strongly agreed that the breast radiologist's appearance mattered (52.5%, 502/956) followed by being indifferent (28.1%, 269/956). Respondents with greater education levels felt less strongly (p=0.001) about the radiologist's appearance: 63.3% (70/110) less than college cared about appearance compared to 53.5% (266/497) college/vocational and 47.4% (165/348) graduate. Most respondents felt indifferent about a breast radiologist wearing a white coat (68.9%, 657/954) or about male-presenting breast radiologists wearing a tie (77.1%, 734/952) without significant demographic differences. Almost all respondents either prefer/strongly prefer (60.1%, 572/951) or were indifferent (39.6%, 377/951) to all breast radiologists wearing scrubs when performing procedures. While respondents approved of all attire choices overall, most respondents preferred scrubs for both male- and female-presenting breast radiologists (64.0%, 612/957 and 64.9%, 621/957, respectively). CONCLUSION: A variety of breast radiologists' attire can be worn while maintaining provider professionalism and without compromising patient expectations.


Assuntos
Preferência do Paciente , Relações Médico-Paciente , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Vestuário , Estudos Transversais , Radiologistas , Inquéritos e Questionários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA