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INTRODUCTION: The MonarchE trial explored the use of abemaciclib, a CDK4/6 inhibitor, as an adjuvant treatment in high-risk early-stage luminal-like breast cancer. The study's inclusion criteria, especially the N2 status, may require revisiting surgical interventions, including invasive axillary lymph node dissection (ALND)-a procedure that current guidelines generally do not recommend. METHODS: We conducted a single-centre, retrospective, observational cohort study on non-metastatic breast cancer patients managed from 2002 to 2011, at the Institut Curie. Data collection involved clinical and histological characteristics plus treatment follow-up. RESULTS: Out of 8715 treated patients, 721 met the inclusion criteria. Overall, 12% (87) were classified as N2 ( ≥ 4 positive lymph nodes), thus eligible for abemaciclib per "node criterion." Tumour size, positive sentinel lymph nodes, and lobular histology showed a significant correlation with N2 status. Approximately 1000 ALNDs would be required to identify 120 N2 cases and prevent four recurrences. CONCLUSION: The MonarchE trial may significantly affect surgical practices due to the need for invasive procedures to identify high-risk patients for adjuvant abemaciclib treatment. The prospect of unnecessary morbidity demands less invasive N2 status determination methods. Surgical decisions must consider patient health and potential treatment benefits.
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Aminopiridinas , Benzimidazóis , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Biópsia de Linfonodo Sentinela , Estudos Retrospectivos , Reoperação , Metástase Linfática/patologia , Excisão de Linfonodo/efeitos adversos , Axila/patologia , Linfonodos/patologiaRESUMO
BACKGROUND: The main objective of this study was to undertake an exhaustive investigation of sex-related differences in cancer surgery. METHODS: This observational study used data from the French national health insurance system database covering 98.8% of the population. Patients diagnosed with non-sex-specific solid invasive cancers between January 2018 and December 2019 were included. The main outcomes were likelihood of undergoing cancer surgery, type of oncological surgery performed, and associated 30-, 60-, and 90-day postoperative reoperation and mortality rates, by sex. RESULTS: For the 367 887 patients included, women were 44% more likely than men to undergo cancer surgery (OR 1.44, 95% c.i. 1.31 to 1.59; P < 0.001). However, the likelihood of surgery decreased with advancing age (OR 0.98, 0.98 to 0.98; P < 0.001), and with increasing number of co-morbid conditions (OR 0.95, 0.95 to 0.96; P < 0.001), especially in women. Men had higher 90-day reoperation (21.2 versus 18.8%; P < 0.001) and mortality (1.2 versus 0.9%; P < 0.001) rates than women, overall, and for most cancer types, with the exception of bladder cancer, for which the 90-day mortality rate was higher among women (1.8 versus 1.4%; P < 0.001). After adjustment for age, number of co-morbid conditions, and surgical procedure, 90-day mortality remained higher in men (OR 1.16, 1.07 to 1.26; P < 0.001), and men were 21% more likely than women to undergo reoperation within 90 days (OR 1.21, 1.18 to 1.23; P < 0.001). CONCLUSION: Women were much more likely than men to undergo cancer surgery than men, but the likelihood of surgery decreased with advancing age and with increasing number of co-morbid conditions, especially in women. These findings highlight a need for both increased awareness and strategies to ensure gender equality in access to oncological surgical treatment and improved outcomes.
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Neoplasias , Humanos , Feminino , França/epidemiologia , Masculino , Pessoa de Meia-Idade , Idoso , Neoplasias/cirurgia , Neoplasias/mortalidade , Neoplasias/epidemiologia , Fatores Sexuais , Adulto , Reoperação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Idoso de 80 Anos ou maisRESUMO
OBJECTIVE: To report the results of a multicenter cohort of preoperative brachytherapy (PBT) for treatment of early-stage cervical cancer (ESCC). METHODS: A retrospective analysis was conducted among five French comprehensive cancer centers on behalf of the SFRO Brachytherapy Group to examine the outcome of patients with ESCC who received PBT between 2001 and 2019 because of adverse prognostic factors (tumor size >2 cm, presence of lymphovascular invasion, adenocarcinoma).Brachytherapy was followed 4-8 weeks later by surgery. Local relapse free, distant metastasis-free survival, disease-free, and overall survival and adverse effects were examined. Uni- and multivariate analyses were conducted looking for oncological prognostic factors. RESULTS: A total of 451 patients were identified, with a mean tumor size of 24.7 mm. Adenocarcinoma accounted for 43.5% of cases, and lympho-vascular space invasion (LVSI) was present in 15.7%. A complete histological response was observed in 69.6%. With a mean follow-up of 75.4 months, DFS, LRFS, and OS rates at five years were 88% [95% CI (84-91), 98% [95% CI (96-99), and 92% [95% CI (87-95)], respectively. At the last follow-up, 8.2% of patients had died, including 31 (6.8%) from cervical cancer. Severe side effects range from 1.1% to 2%. At multivariate analysis, adenocarcinoma histological type, tumor size ≥2 cm, and the presence of residual tumors were prognosticators for DFS and DMFS. CONCLUSION: PBT shows excellent oncological outcomes in this cohort of patients with adverse histoprognostic factors. Favorable survival rates and low complications rates were observed, supporting this strategy in the management of ESCC.
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BACKGROUND: The effect of primary cytoreductive surgery vs interval cytoreductive surgery on International Federation of Gynecology and Obstetrics stage IV ovarian cancer outcomes remains uncertain and may vary depending on the stage and the location of extraperitoneal metastasis. Emulating target trials through causal assessment, combined with propensity score adjustment, has become a leading method for evaluating interventions using observational data. OBJECTIVE: This study aimed to assess the effect of primary vs interval cytoreductive surgery on progression-free and overall survival in patients with International Federation of Gynecology and Obstetrics stage IV ovarian cancer using target trial emulation. STUDY DESIGN: Using the comprehensive French national health insurance database, we emulated a target trial to explore the causal impacts of primary vs interval cytoreductive surgery on stage IV ovarian cancer prognosis (Surgery for Ovarian cancer FIGO 4: SOFI-4). The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and to balance baseline characteristics between the groups. Subgroup analyses were conducted based on the stages and extraperitoneal metastasis locations. The study included patients younger than 75 years of age, in good health condition, who were diagnosed with stage IV ovarian cancer between January 1, 2014, and December 31, 2022. The primary and secondary outcomes were respectively 5-year progression-free survival and 7-year overall survival. RESULTS: Among the 2772 patients included in the study, 948 (34.2%) were classified as having stage IVA ovarian cancer and 1824 (65.8%) were classified as having stage IVB ovarian cancer at inclusion. Primary cytoreductive surgery was performed for 1182 patients (42.6%), whereas interval cytoreductive surgery was conducted for 1590 patients (57.4%). The median progression-free survival for primary cytoreductive surgery was 19.7 months (interquartile range, 19.3-20.1) as opposed to 15.7 months (interquartile range, 15.7-16.1) for those who underwent interval cytoreductive surgery. The median overall survival was 63.1 months (interquartile range, 61.7-65.4) for primary cytoreductive surgery in comparison with 55.6 months (interquartile range, 53.8-56.3) for interval cytoreductive surgery. The findings of our study indicate that primary cytoreductive surgery is associated with a 5.0-month increase in the 5-year progression-free survival (95% confidence interval, 3.8-6.2) and a 3.9-month increase in 7-year overall survival (95% confidence interval, 1.9-6.2). These survival benefits of primary over interval cytoreductive surgery were observed in both the International Federation of Gynecology and Obstetrics stage IVA and IVB subgroups. Primary cytoreductive surgery demonstrated improved progression-free survival and overall survival in patients with pleural, supradiaphragmatic, or extra-abdominal lymph node metastasis. CONCLUSION: This study advocates for the benefits of primary cytoreductive surgery over interval cytoreductive surgery for patients with stage IV ovarian cancer and suggests that extraperitoneal metastases like supradiaphragmatic or extra-abdominal lymph nodes should not automatically preclude primary cytoreductive surgery consideration in suitable patients.
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The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly published comprehensive evidence-based guidelines on all relevant issues of diagnosis and treatment in endometrial carcinoma in a multidisciplinary setting. In order to improve their implementation, a free downloadable easy-to-use mobile app was developed.Two interactive decision tools were created for (1) helping users to identify the recommended surgical steps, especially in terms of nodal staging approach based on the pre-operatively assumed risk group (tool #1), and (2) to facilitate prognostic risk group allocation and adjuvant treatment decision-making after primary surgery integrating both clinicopathological and molecular markers (if known) (tool #2). Algorithms and readable guidelines were also incorporated into the mobile app on all relevant issues of diagnosis and treatment. The scientific content presented in the app will be updated and modified in the future based on new evidence and user feedback.This article presents the decision tools and two practical examples of using these calculators to illustrate that the ESGO mobile app (available without the necessity of an internet connection) can provide fast and accurate responses to complex clinical questions that require the evaluation of numerous parameters.
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Neoplasias do Endométrio , Aplicativos Móveis , Radioterapia (Especialidade) , Feminino , Humanos , Padrão de Cuidado , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/terapia , Neoplasias do Endométrio/patologiaRESUMO
OBJECTIVE: In order to define the clinical significance of low-volume metastasis, a comprehensive meta-analysis of published data and individual data obtained from articles mentioning micrometastases (MIC) and isolated tumor cells (ITC) in cervical cancer was performed, with a follow up of at least 3 years. METHODS: We performed a systematic literature review and meta-analysis, following Cochrane's review methods guide and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcome was the disease-free survival (DFS), and the secondary outcome was the overall survival (OS). The hazard ratio (HR) was taken as the measure of the association between the low-volume metastases (MIC+ITC and MIC alone) and DFS or OS; it quantified the hazard of an event in the MIC (+/- ITC) group compared to the hazard in node-negative (N0) patients. A random-effect meta-analysis model using the inverse variance method was selected for pooling. Forest plots were used to display the HRs and risk differences within individual trials and overall. RESULTS: Eleven articles were finally retained for the meta-analysis. In the analysis of DFS in patients with low-volume metastasis (MIC + ITC), the HR was increased to 2.60 (1.55-4.34) in the case of low-volume metastasis vs. N0. The presence of MICs had a negative prognostic impact, with an HR of 4.10 (2.71-6.20) compared to N0. Moreover, this impact was worse than that of MIC pooled with ITCs. Concerning OS, the meta-analysis shows an HR of 5.65 (2.81-11.39) in the case of low-volume metastases vs. N0. The presence of MICs alone had a negative effect, with an HR of 6.94 (2.56-18.81). CONCLUSIONS: In conclusion, the presence of MIC seems to be associated with a negative impact on both the DFS and OS and should be treated as MAC.
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Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Micrometástase de Neoplasia/patologia , Linfonodo Sentinela/patologia , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Estadiamento de Neoplasias , Biópsia de Linfonodo Sentinela , Taxa de Sobrevida , Carga Tumoral , Neoplasias do Colo do Útero/terapiaRESUMO
STUDY OBJECTIVE: To develop a nomogram for predicting the type of ureteral procedure in pelvic deep endometriosis (DE) surgery (1) and to describe the factors and complications associated with the ureteral procedure (2). DESIGN: Retrospective monocentric study of 920 patients who underwent surgery for pelvic DE between June 2009 and March 2020 in the gynecologic surgery department of the Versailles Hospital Center. The main criterion was evaluation of the ureteral procedure, classified as simple (isolation of the ureter) or complex (dissection of the ureter, segmental ureteral resection, or nephroureterectomy). Postoperative complications, including ureteral stenosis and fistula formation, were tabulated. SETTING: Tertiary referral hospital and expert center in endometriosis. PATIENTS: A total of 920 patients with DE. INTERVENTIONS: Ureteral procedure during surgery for DE. MEASUREMENTS AND MAIN RESULTS: In total, 724 patients (79%) underwent a ureteral procedure, of which 307 (33%) were complex, including 17 (1.8%) segmental ureteral resections. In multivariate analysis, the predictive variables for a complex ureteral procedure were age (p = .036), a previous surgery for endometriosis (p <.01), and ureteral dilatation on magnetic resonance imaging (p <.001). The area under the curve for the model predicting a complex ureteral procedure was 0.68 (95% confidence interval, 0.60-0.71). A complex ureteral procedure was associated with a 3.5% rate of ureteral fistula (n = 15). CONCLUSION: Age, a previous surgery for endometriosis, a rectovaginal nodule size ≥30 mm, endometriotic involvement of the rectum or sigmoid, and ureteral dilatation are significantly associated with a complex ureteral procedure. Our results allowed us to build a nomogram that can be used to better inform patients, anticipate the therapeutic strategy, and optimize the modalities of postoperative surveillance.
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Endometriose , Laparoscopia , Ureter , Doenças Ureterais , Endometriose/complicações , Endometriose/cirurgia , Feminino , Humanos , Laparoscopia/métodos , Masculino , Nomogramas , Estudos Retrospectivos , Resultado do Tratamento , Ureter/cirurgia , Doenças Ureterais/cirurgiaRESUMO
Designed enzymes are of fundamental and technological interest. Experimental directed evolution still has significant limitations, and computational approaches are a complementary route. A designed enzyme should satisfy multiple criteria: stability, substrate binding, transition state binding. Such multi-objective design is computationally challenging. Two recent studies used adaptive importance sampling Monte Carlo to redesign proteins for ligand binding. By first flattening the energy landscape of the apo protein, they obtained positive design for the bound state and negative design for the unbound. We have now extended the method to design an enzyme for specific transition state binding, i.e., for its catalytic power. We considered methionyl-tRNA synthetase (MetRS), which attaches methionine (Met) to its cognate tRNA, establishing codon identity. Previously, MetRS and other synthetases have been redesigned by experimental directed evolution to accept noncanonical amino acids as substrates, leading to genetic code expansion. Here, we have redesigned MetRS computationally to bind several ligands: the Met analog azidonorleucine, methionyl-adenylate (MetAMP), and the activated ligands that form the transition state for MetAMP production. Enzyme mutants known to have azidonorleucine activity were recovered by the design calculations, and 17 mutants predicted to bind MetAMP were characterized experimentally and all found to be active. Mutants predicted to have low activation free energies for MetAMP production were found to be active and the predicted reaction rates agreed well with the experimental values. We suggest the present method should become the paradigm for computational enzyme design.
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Enzimas , Método de Monte Carlo , Ligação Proteica/genética , Engenharia de Proteínas/métodos , Especificidade por Substrato/genética , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Azidas/química , Azidas/metabolismo , Sítios de Ligação/genética , Catálise , Enzimas/química , Enzimas/genética , Enzimas/metabolismo , Metionina/análogos & derivados , Metionina/química , Metionina/metabolismo , Metionina tRNA Ligase/química , Metionina tRNA Ligase/genética , Metionina tRNA Ligase/metabolismo , Mutação/genética , Norleucina/análogos & derivados , Norleucina/química , Norleucina/metabolismoRESUMO
Importance: Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear. Objective: To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury. Design, Setting, and Participants: Multicenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020. Interventions: Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension. Main Outcomes and Measures: The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality. Results: Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, -2.6% [95% CI, -12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, -4.9% [95% CI, -12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]). Conclusions and Relevance: Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03143751.
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Lesões Encefálicas Traumáticas/terapia , Hidratação , Solução Salina Hipertônica/uso terapêutico , Adulto , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Terapia Combinada , Feminino , Escala de Resultado de Glasgow , Humanos , Hipernatremia/etiologia , Hipnóticos e Sedativos/uso terapêutico , Infusões Intravenosas , Hipertensão Intracraniana/etiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Solução Salina Hipertônica/administração & dosagem , Solução Salina Hipertônica/efeitos adversosRESUMO
We describe methods for physics-based protein design and some recent applications from our work. We present the physical interpretation of a MC simulation in sequence space and show that sequences and conformations form a well-defined statistical ensemble, explored with Monte Carlo and Boltzmann sampling. The folded state energy combines molecular mechanics for solutes with continuum electrostatics for solvent. We usually assume one or a few fixed protein backbone structures and discrete side chain rotamers. Methods based on molecular dynamics, which introduce additional backbone and side chain flexibility, are under development. The redesign of a PDZ domain and an aminoacyl-tRNA synthetase enzyme were successful. We describe a versatile, adaptive, Wang-Landau MC method that can be used to design for substrate affinity, catalytic rate, catalytic efficiency, or the specificity of these properties. The methods are transferable to all biomolecules, can be systematically improved, and give physical insights.
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Proteínas/química , Algoritmos , Química Computacional , Interpretação Estatística de Dados , Simulação de Dinâmica Molecular , Método de Monte Carlo , Conformação Proteica , Dobramento de Proteína , Software , TermodinâmicaRESUMO
Objectives: The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Methods: Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets. Results: Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Conclusions: Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.
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Antibacterianos/farmacocinética , Estado Terminal , Daptomicina/farmacocinética , Insuficiência Renal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Bioestatística , Daptomicina/administração & dosagem , Daptomicina/efeitos adversos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Plasma/química , Urina/química , Adulto JovemRESUMO
INTRODUCTION: Whereas spontaneous onset of labor and vaginal delivery for breech presentation is considered to be a safe and effective option in selected cases, the safety of induction of labor is not established yet. The objectives of this study were to describe the outcomes of pregnancy in women induced with a fetus in breech presentation and compare the outcomes with those undergoing planned cesarean delivery. MATERIAL AND METHODS: We performed a secondary analysis of the observational prospective multicenter PREMODA study, including all singleton breech deliveries after 37 weeks in 174 centers in France and Belgium. We excluded women with spontaneous onset of labor, scarred uterus or intrauterine fetal death. Our study population consisted of women with either induction of labor or planned cesarean delivery. The primary outcome was the composite criteria of neonatal mortality and serious morbidity used in the Term Breech Trial and in the PREMODA prospective cohort. RESULTS: Our study population consisted of 4138 women, 218 with induction of labor and 3920 with planned cesarean. Two-thirds (67.4%) of the women in the induction of labor group delivered vaginally. There was no significant difference between the groups for the primary outcome (48 [1.2%] in the planned cesarean group vs 3 [1.4%] in the induction of labor group, P = 0.75). Moreover, none of the criteria of the composite primary outcome was significantly more frequent in the induction of labor group. CONCLUSIONS: Induction of labor for breech presentation does not seem to increase neonatal mortality or severe neonatal morbidity compared with planned cesarean delivery.
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Apresentação Pélvica , Trabalho de Parto Induzido , Resultado da Gravidez , Adulto , Bélgica , Cesárea , Feminino , França , Humanos , Lactente , Mortalidade Infantil , Gravidez , Estudos Prospectivos , Fatores de RiscoRESUMO
Computer-aided protein-ligand binding predictions are a valuable help in drug discovery. Protein-ligand docking programs generally consist of two main components: a scoring function and a search algorithm. It is of interest to evaluate the intrinsic performance of scoring functions, independently of conformational exploration, to understand their strengths and weaknesses and suggest improvements. The comparative assessment of scoring functions (CASF) provides such an evaluation. Here we add the AutoDock and Vina scoring functions to the CASF-2013 benchmark. We find that these popular, free software docking programs are generally in the first half (AutoDock) and first quarter (Vina) among all methods tested in CASF-2013. Vina is the best of all methods in terms of docking power. We also find that ligand minimization has an important impact, reducing the performance difference between AutoDock and Vina.
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Desenho Assistido por Computador , Descoberta de Drogas , Simulação de Acoplamento Molecular , Software , Bases de Dados de Proteínas , Desenho de Fármacos , Humanos , Ligantes , Ligação Proteica , Proteínas/química , Proteínas/metabolismoRESUMO
With the increasing number of protein structures available, there is a need for tools capable of automating the comparison of ensembles of structures, a common requirement in structural biology and bioinformatics. PSSweb is a web server for protein structural statistics. It takes as input an ensemble of PDB files of protein structures, performs a multiple sequence alignment and computes structural statistics for each position of the alignment. Different optional functionalities are proposed: structure superposition, Cartesian coordinate statistics, dihedral angle calculation and statistics, and a cluster analysis based on dihedral angles. An interactive report is generated, containing a summary of the results, tables, figures and 3D visualization of superposed structures. The server is available at http://pssweb.org.
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Internet , Proteínas/química , Software , Algoritmos , Análise por Conglomerados , Biologia Computacional , Computadores , Bases de Dados de Proteínas , Humanos , Alinhamento de SequênciaRESUMO
The prediction of protein side chain conformations from backbone coordinates is an important task in structural biology, with applications in structure prediction and protein design. It is a difficult problem due to its combinatorial nature. We study the performance of an "MMGBSA" energy function, implemented in our protein design program Proteus, which combines molecular mechanics terms, a Generalized Born and Surface Area (GBSA) solvent model, with approximations that make the model pairwise additive. Proteus is not a competitor to specialized side chain prediction programs due to its cost, but it allows protein design applications, where side chain prediction is an important step and MMGBSA an effective energy model. We predict the side chain conformations for 18 proteins. The side chains are first predicted individually, with the rest of the protein in its crystallographic conformation. Next, all side chains are predicted together. The contributions of individual energy terms are evaluated and various parameterizations are compared. We find that the GB and SA terms, with an appropriate choice of the dielectric constant and surface energy coefficients, are beneficial for single side chain predictions. For the prediction of all side chains, however, errors due to the pairwise additive approximation overcome the improvement brought by these terms. We also show the crucial contribution of side chain minimization to alleviate the rigid rotamer approximation. Even without GB and SA terms, we obtain accuracies comparable to SCWRL4, a specialized side chain prediction program. In particular, we obtain a better RMSD than SCWRL4 for core residues (at a higher cost), despite our simpler rotamer library. Proteins 2016; 84:803-819. © 2016 Wiley Periodicals, Inc.
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Proteínas/química , Aminoácidos/química , Animais , Bases de Dados de Proteínas , Humanos , Modelos Moleculares , Conformação Proteica , Eletricidade Estática , TermodinâmicaRESUMO
Computational protein design (CPD) aims at predicting new proteins or modifying existing ones. The computational challenge is huge as it requires exploring an enormous sequence and conformation space. The difficulty can be reduced by considering a fixed backbone and a discrete set of sidechain conformations. Another common strategy consists in precalculating a pairwise energy matrix, from which the energy of any sequence/conformation can be quickly obtained. In this work, we examine the pairwise decomposition of protein MMGBSA energy functions from a general theoretical perspective, and an implementation proposed earlier for CPD. It includes a Generalized Born term, whose many-body character is overcome using an effective dielectric environment, and a Surface Area term, for which we present an improved pairwise decomposition. A detailed evaluation of the error introduced by the decomposition on the different energy components is performed. We show that the error remains reasonable, compared to other uncertainties.
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Conformação Proteica , Proteínas/química , Termodinâmica , Biologia ComputacionalRESUMO
Iron as an element is a double-edged sword, essential for living but also potentially toxic through the generation of oxidative stress. The recent study by Chen and colleagues in Critical Care reminds us of this elegantly. In a mouse model of acute lung injury, they showed that silencing hepcidin (the master regulator of iron metabolism) locally in airway epithelial cells aggravates lung injury by increasing the release of iron from alveolar macrophages, which in turn enhances pulmonary bacterial growth and reduces the macrophages' killing properties. This work underscores that hepcidin acts not only systematically (as a hormone) but also locally for iron metabolism regulation. This opens areas of research for sepsis treatment but also for iron deficiency or anaemia treatment, since the local and systemic iron regulation appear to be independent.
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Lesão Pulmonar Aguda/microbiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Hepcidinas/fisiologia , Ferro/metabolismo , Sepse/microbiologia , Animais , MasculinoRESUMO
BACKGROUND: Patients with acute brain injury are at high risk of ventilator-associated pneumonia (VAP). The benefit of short-term antibiotic prophylaxis remains debated. We aimed to establish the effect of an early, single dose of the antibiotic ceftriaxone on the incidence of early VAP in patients with severe brain injury who required mechanical ventilation. METHODS: PROPHY-VAP was a multicentre, randomised, double-blind, placebo-controlled, assessor-masked, superiority trial conducted in nine intensive care units in eight French university hospitals. We randomly assigned comatose (Glasgow Coma Scale score [GCS] ≤12) adult patients (age ≥18 years) who required mechanical ventilation for at least 48 h after acute brain injury to receive intravenous ceftriaxone 2 g or placebo once within the 12 h following tracheal intubation. Participants did not receive selective oropharyngeal and digestive tract decontamination. The primary outcome was the proportion of patients developing early VAP from the 2nd to the 7th day of mechanical ventilation, confirmed by masked assessors. The analysis was reported in the modified intention-to-treat population, which comprised all randomly assigned patients except those who withdrew or did not give consent to continue and those who did not receive the allocated treatment because they met a criterion for non-eligibility. The trial is registered with ClinicalTrials.gov, NCT02265406. FINDINGS: From Oct 14, 2015, to May 27, 2020, 345 patients were randomly assigned (1:1) to receive ceftriaxone (n=171) or placebo (n=174); 330 received the allocated intervention and 319 were included in the analysis (162 in the ceftriaxone group and 157 in the placebo group). 166 (52%) participants in the analysis were men and 153 (48%) were women. 15 patients did not receive the allocated intervention after randomisation and 11 withdrew their consent. Adjudication confirmed 93 cases of VAP, including 74 early infections. The incidence of early VAP was lower in the ceftriaxone group than in the placebo group (23 [14%] vs 51 [32%]; hazard ratio 0·60 [95% CI 0·38-0·95], p=0·030), with no microbiological impact and no adverse effects attributable to ceftriaxone. INTERPRETATION: In patients with acute brain injury, a single ceftriaxone dose decreased the risk of early VAP. On the basis of our findings, we recommend that an early, single dose of ceftriaxone be included in all bundles for the prevention of VAP in patients with brain injury who require mechanical ventilation. FUNDING: French Ministry of Social Affairs and Health.
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Antibacterianos , Ceftriaxona , Pneumonia Associada à Ventilação Mecânica , Respiração Artificial , Humanos , Ceftriaxona/administração & dosagem , Ceftriaxona/uso terapêutico , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Feminino , Masculino , Método Duplo-Cego , Pessoa de Meia-Idade , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Respiração Artificial/efeitos adversos , Adulto , Idoso , Antibioticoprofilaxia/métodos , Lesões Encefálicas/complicações , Lesões Encefálicas/prevenção & controle , França , Unidades de Terapia Intensiva , Intubação Intratraqueal/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: We found a need for balancing the application of clinical guidelines and tailored approaches to follow-up of cervical cancer (CC) patients in the lymph node micrometastatic (MICs) setting. This review aimed to determine the current knowledge of management of MIC-positive CC cases. METHODOLOGY: We addressed prognostic and risk of recurrence monitoring impacts associated with MIC+ cases. The electronic databases for literature and relevant articles were analysed. RESULTS: Fifteen studies, (4882 patients), were included in our systematic review. While the results show that MICs significantly worsen prognosis in early CC. A tertiary prevention algorithm for low volume lymph node disease may stratify follow-up according to the burden of nodal disease and provide data that helps improve follow-up performance. CONCLUSION: MICs worsen prognosis and should be managed as suggested by the algorithm. However, this algorithm must be externally validated. The clinical impact of isolated tumor cells (ITC) remains unclear.
Assuntos
Metástase Linfática , Micrometástase de Neoplasia , Neoplasias do Colo do Útero , Feminino , Humanos , Linfonodos/patologia , Micrometástase de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/patologia , Prognóstico , Prevenção Terciária/métodos , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controleRESUMO
We describe an automated procedure for protein design, implemented in a flexible software package, called Proteus. System setup and calculation of an energy matrix are done with the XPLOR modeling program and its sophisticated command language, supporting several force fields and solvent models. A second program provides algorithms to search sequence space. It allows a decomposition of the system into groups, which can be combined in different ways in the energy function, for both positive and negative design. The whole procedure can be controlled by editing 2-4 scripts. Two applications consider the tyrosyl-tRNA synthetase enzyme and its successful redesign to bind both O-methyl-tyrosine and D-tyrosine. For the latter, we present Monte Carlo simulations where the D-tyrosine concentration is gradually increased, displacing L-tyrosine from the binding pocket and yielding the binding free energy difference, in good agreement with experiment. Complete redesign of the Crk SH3 domain is presented. The top 10000 sequences are all assigned to the correct fold by the SUPERFAMILY library of Hidden Markov Models. Finally, we report the acid/base behavior of the SNase protein. Sidechain protonation is treated as a form of mutation; it is then straightforward to perform constant-pH Monte Carlo simulations, which yield good agreement with experiment. Overall, the software can be used for a wide range of application, producing not only native-like sequences but also thermodynamic properties with errors that appear comparable to other current software packages.