RESUMO
Cao and colleagues present a follow-up analysis of a previous RCT among >1200 older adults (mean age 72 yr) undergoing cancer surgery, originally designed to evaluate the effect of propofol or sevoflurane general anaesthesia on delirium, here to evaluate the effect of anaesthetic technique on overall survival and recurrence-free survival. Neither anaesthetic technique conferred an advantage on oncological outcomes. We suggest that although it is entirely plausible that the observed results are truly robust neutral findings, the present study could be limited, like most published studies in the field, by its heterogeneity and understandable absence of underlying individual patient-specific tumour genomic data. We argue for a precision oncology approach to onco-anaesthesiology research that recognises that cancer is not one but rather many diseases and that tumour genomics (and multi-omics) is a fundamental determinant relating drugs to longer-term outcomes.
Assuntos
Analgesia , Anestesiologia , Anestésicos , Neoplasias , Oncologistas , Propofol , Humanos , Idoso , Sevoflurano , Neoplasias/cirurgia , Seguimentos , Medicina de Precisão , Anestesia Geral/métodosRESUMO
OBJECTIVE: To evaluate the association between intraoperative anaesthetic parameters, primarily intraoperative hypotension, and postoperative renal function in patients undergoing nephrectomy. PATIENTS AND METHODS: We reviewed data from 3240 consecutive patients who underwent nephrectomy between 2010 and 2018. Anaesthetic parameters evaluated included duration of hypotension, tachycardia, hypothermia, volatile anaesthetic use and mean arterial pressure in the post-anaesthesia care unit. Outcomes included acute kidney injury (AKI) and estimated glomerular filtration rate (eGFR) within the first year after nephrectomy. Associations between anaesthetic parameters and outcomes were evaluated with multivariable logistic regression and generalised estimating equation, respectively, adjusted for predictors of renal function after nephrectomy. RESULTS: Before nephrectomy, 677 (21%) patients had moderate-severe chronic kidney disease. A quarter of patients (n = 809) had postoperative AKI and 35% (n = 746) had Stage ≥3 chronic kidney disease 12-months after surgery. Only 12% of patients (n = 386) had >5 min of intraoperative hypotension. While not statistically significant, longer duration of intraoperative hypotension was associated with slightly higher rates of AKI (odds ratio [OR] per 10-min 1.14, 95% confidence interval [CI] 0.98, 1.32). Prolonged hypothermia was associated with increased rate of AKI (OR per 10-min 1.02, 95% CI 1.00, 1.04), and decreased eGFR (change in eGFR per 10-min -0.19, 95% CI -0.27, -0.12); however, these results have limited clinical significance. CONCLUSIONS: Under current practice, intraoperative anaesthetic parameters are tightly maintained, restricting the significance of their effect on postoperative renal function. Future studies should evaluate whether haemodynamic parameters during the early postoperative period, when they are monitored less frequently, are associated with renal functional outcome.
Assuntos
Injúria Renal Aguda , Carcinoma de Células Renais , Hipotensão , Hipotermia , Neoplasias Renais , Insuficiência Renal Crônica , Injúria Renal Aguda/etiologia , Carcinoma de Células Renais/cirurgia , Feminino , Taxa de Filtração Glomerular , Humanos , Hipotensão/etiologia , Hipotensão/cirurgia , Hipotermia/cirurgia , Rim/cirurgia , Neoplasias Renais/cirurgia , Masculino , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Complicações Pós-Operatórias , Estudos RetrospectivosRESUMO
BACKGROUND: Arousal and awareness are two important components of consciousness states. Functional neuroimaging has furthered our understanding of cortical and thalamocortical mechanisms of awareness. Investigating the relationship between subcortical functional connectivity and arousal has been challenging owing to the relatively small size of brainstem structures and thalamic nuclei, and their depth in the brain. METHODS: Resting state functional MRI scans of 72 healthy volunteers were acquired before, during, 1 h after, and 1 day after sevoflurane general anaesthesia. Functional connectivity of subcortical regions of interest vs whole brain and homotopic functional connectivity for assessment of left-right symmetry analyses of both cortical and subcortical regions of interest were performed. Both analyses used high resolution atlases generated from deep brain stimulation applications. RESULTS: Functional connectivity in subcortical loci within the thalamus and of the ascending reticular activating system was sharply restricted under anaesthesia, featuring a general lateralisation of connectivity. Similarly, left-right homology was sharply reduced under anaesthesia. Subcortical bilateral functional connectivity was not fully restored after emergence from anaesthesia, although greater restoration was seen between ascending reticular activating system loci and specific thalamic nuclei thought to be involved in promoting and maintaining arousal. Functional connectivity was fully restored to baseline by the following day. CONCLUSIONS: Functional connectivity in the subcortex is sharply restricted and lateralised under general anaesthesia. This restriction may play a part in loss and return of consciousness. CLINICAL TRIAL REGISTRATION: NCT02275026.
Assuntos
Anestésicos Inalatórios/farmacologia , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética , Sevoflurano/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia Geral/métodos , Anestésicos Inalatórios/administração & dosagem , Nível de Alerta , Conscientização , Feminino , Neuroimagem Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Sevoflurano/administração & dosagemRESUMO
BACKGROUND: Opioid-induced immunomodulation may be important in colon adenocarcinoma, where tumour DNA mismatch repair (MMR) can determine the level of immune activation with consequences for therapeutic response and prognosis. We evaluated the relationship between intraoperative opioid exposure, MMR subtype, and oncological outcomes after surgery for colon adenocarcinoma. METHODS: Intraoperative opioid use (standardised by calculating morphine milligram equivalents) during stage I-III colon adenocarcinoma resection was reviewed retrospectively. Tumours were classified as DNA mismatch repair deficient (dMMR) or proficient (pMMR) by immunohistochemistry. The primary outcome was local tumour recurrence, distant tumour recurrence, or both (multivariable analysis). The exposures of interest were intraoperative analgesia and tumour subtype. Opioid-related gene expression was analysed using The Cancer Genome Atlas Colon Adenocarcinoma transcriptomic data. RESULTS: Clinical and pathological data were analysed from 1157 subjects (median age, 60 [51-70] yr; 49% female) who underwent curative resection for stage I-III colon adenocarcinoma. Higher intraoperative opioid doses were associated with reduced risk of tumour recurrence (hazard ratio=0.92 per 10 morphine milligram equivalents; 95% confidence interval [95% CI], 0.87-0.98; P=0.007), but not with overall survival. In tumours deficient in DNA MMR, tumour recurrence was less likely (HR=0.38; 95% CI, 0.21-0.68; P=0.001), with higher opioid dose associated with eightfold lower recurrence rates. Gene expression related to opioid signalling was different between dMMR and pMMR tumours. CONCLUSIONS: Higher intraoperative opioid dose was associated with a lower risk of tumour recurrence after surgery for stage I-III colon adenocarcinoma, but particularly so in tumours in which DNA MMR was deficient.
Assuntos
Adenocarcinoma , Neoplasias do Colo , Adenocarcinoma/genética , Adenocarcinoma/cirurgia , Analgésicos Opioides/uso terapêutico , Neoplasias do Colo/genética , Neoplasias do Colo/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derivados da Morfina/uso terapêutico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction are the most common complications for older surgical patients. General anesthesia may contribute to the development of these conditions, but there are little data on the association of age with cognitive recovery from anesthesia in the absence of surgery or underlying medical condition. METHODS: We performed a single-center cohort study of healthy adult volunteers 40 to 80 years old (N = 71, mean age 58.5 years, and 44% women) with no underlying cognitive dysfunction. Volunteers underwent cognitive testing before and at multiple time points after 2 hours of general anesthesia consisting of propofol induction and sevoflurane maintenance, akin to a general anesthetic for a surgical procedure, although no procedure was performed. The primary outcome was time to recovery to cognitive baseline on the Postoperative Quality of Recovery Scale (PQRS) within 30 days of anesthesia. Secondary cognitive outcomes were time to recovery on in-depth neuropsychological batteries, including the National Institutes of Health Toolbox and well-validated paper-and-pencil tests. The primary hypothesis is that time to recovery of cognitive function after general anesthesia increases across decades from 40 to 80 years of age. We examined this with discrete-time logit regression (for the primary outcome) and linear mixed models for interactions of age decade with time postanesthesia (for secondary outcomes). RESULTS: There was no association between age group and recovery to baseline on the PQRS; 36 of 69 (52%) recovered within 60-minute postanesthesia and 63 of 69 (91%) by day 1. Hazard ratios (95% confidence interval) for each decade compared to 40- to 49-year olds were: 50 to 59 years, 1.41 (0.50-4.03); 60 to 69 years, 1.03 (0.35-3.00); and 70 to 80 years, 0.69 (0.25-1.88). There were no significant differences between older decades relative to the 40- to 49-year reference decade in recovery to baseline on secondary cognitive measures. CONCLUSIONS: Recovery of cognitive function to baseline was rapid and did not differ between age decades of participants, although the number in each decade was small. These results suggest that anesthesia alone may not be associated with cognitive recovery in healthy adults of any age decade.
Assuntos
Período de Recuperação da Anestesia , Anestesia Geral/métodos , Cognição/efeitos dos fármacos , Testes Neuropsicológicos , Recuperação de Função Fisiológica/efeitos dos fármacos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anestesia Geral/tendências , Anestésicos Inalatórios/administração & dosagem , Cognição/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Recuperação de Função Fisiológica/fisiologia , Sevoflurano/administração & dosagem , VoluntáriosRESUMO
BACKGROUND: Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC. METHODS: Consecutive patients with stage I-III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data. RESULTS: A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88-0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89-1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells. CONCLUSIONS: We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.
Assuntos
Analgésicos Opioides/administração & dosagem , Cuidados Intraoperatórios , Mastectomia , Recidiva Local de Neoplasia/prevenção & controle , Receptores Opioides/agonistas , Neoplasias de Mama Triplo Negativas/cirurgia , Analgésicos Opioides/efeitos adversos , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Cuidados Intraoperatórios/efeitos adversos , Cuidados Intraoperatórios/mortalidade , Mastectomia/efeitos adversos , Mastectomia/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Receptores Opioides/genética , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Microambiente TumoralRESUMO
BACKGROUND: Opioids have been linked to worse oncologic outcomes in surgical patients. Studies in certain cancer types have identified associations between survival and intra-tumoural opioid receptor gene alterations, but no study has investigated whether the tumour genome interacts with opioid exposure to affect survival. We sought to determine whether intraoperative opioid exposure is associated with recurrence-specific survival and overall survival in early-stage lung adenocarcinoma, and whether selected tumour genomics are associated with this relationship. Associations between ketamine and dexmedetomidine and outcomes were also studied. METHODS: Surgical patients (N=740) with pathological stage I-III lung adenocarcinoma and next-generation sequencing data were retrospectively reviewed from a prospectively maintained database. RESULTS: On multivariable analysis, ketamine administration was protective for recurrence-specific survival (hazard ratio = 0.44, 95% confidence interval 0.24-0.80; P=0.007), compared with no adjunct. Higher intraoperative oral morphine milligram equivalents were significantly associated with worse overall survival (hazard ratio=1.09/10 morphine milligram equivalents, 95% confidence interval 1.02-1.17; P=0.010). Significant interaction effects were found between morphine milligram equivalents and fraction genome altered and morphine milligram equivalents and CDKN2A, such that higher fraction genome altered or CDKN2A alterations were associated with worse overall survival at higher morphine milligram equivalents (P=0.044 and P=0.052, respectively). In contrast, alterations in the Wnt (P=0.029) and Hippo (P=0.040) oncogenic pathways were associated with improved recurrence-specific survival at higher morphine milligram equivalents, compared with unaltered pathways. CONCLUSIONS: Intraoperative opioid exposure is associated with worse overall survival, whereas ketamine exposure is associated with improved recurrence-specific survival in patients with early-stage lung adenocarcinoma. This is the first study to investigate tumour-specific genomic interactions with intraoperative opioid administration to modify survival associations.
Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Analgésicos Opioides/efeitos adversos , Genômica/tendências , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia/genética , Adenocarcinoma de Pulmão/mortalidade , Idoso , Analgésicos Opioides/administração & dosagem , Feminino , Humanos , Cuidados Intraoperatórios/efeitos adversos , Cuidados Intraoperatórios/tendências , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida/tendênciasRESUMO
BACKGROUND: Postoperative neurocognitive disorders may arise in part from adverse effects of general anaesthetics on the CNS, especially in older patients or individuals otherwise vulnerable to neurotoxicity because of systemic disease or the presence of pre-existing neuropathology. Previous studies have documented cytokine and injury biomarker responses to surgical procedures that included general anaesthesia, but it is not clear to what degree anaesthetics contribute to these responses. METHODS: We performed a prospective cohort study of 59 healthy volunteers aged 40-80 yr who did not undergo surgery. Plasma markers of neurological injury and inflammation were measured immediately before and 5 h after induction of general anaesthesia with 1 minimum alveolar concentration of sevoflurane. Biomarkers included interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), C-reactive protein (CRP), and neural injury (tau, neurofilament light [NF-L], and glial fibrillary acidic protein [GFAP]). RESULTS: Baseline biomarkers were in the normal range, although NF-L and GFAP were elevated as a function of age. At 5 h after induction of anaesthesia, plasma tau, NF-L, and GFAP were significantly decreased relative to baseline. Plasma IL-6 was significantly increased after anaesthesia, but by a biologically insignificant degree (<1 pg ml-1); plasma TNF-α and CRP were unchanged. CONCLUSIONS: Sevoflurane general anaesthesia without surgery, even in older adults, did not provoke an inflammatory state or neuronal injury at a concentration that is detectable by an acute elevation of measured plasma biomarkers in the early hours after exposure. CLINICAL TRIAL REGISTRATION: NCT02275026.
Assuntos
Anestesia Geral/métodos , Anestésicos Inalatórios/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Proteína C-Reativa/efeitos dos fármacos , Estudos de Coortes , Feminino , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/efeitos dos fármacos , Estudos Prospectivos , Valores de Referência , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
BACKGROUND: A growing body of literature addresses the possible long-term cognitive effects of anaesthetics, but no study has delineated the normal trajectory of neural recovery attributable to anaesthesia alone in adults. We obtained resting-state functional MRI scans on 72 healthy human volunteers between ages 40 and 80 (median: 59) yr before, during, and after general anaesthesia with sevoflurane, in the absence of surgery, as part of a larger study on cognitive function postanaesthesia. METHODS: Region-of-interest analysis, independent component analysis, and seed-to-voxel analysis were used to characterise resting-state functional connectivity and to differentiate between correlated and anticorrelated connectivity before, during, and after general anaesthesia. RESULTS: Whilst positively correlated functional connectivity remained essentially unchanged across these perianaesthetic states, anticorrelated functional connectivity decreased globally by 35% 1 h after emergence from general anaesthesia compared with baseline, as seen by the region-of-interest analysis. This decrease corresponded to a consistent reduction in expression of canonical resting-state networks, as seen by independent component analysis. All measures returned to baseline 1 day later. CONCLUSIONS: The normal perianaesthesia trajectory of resting-state connectivity in healthy adults is characterised by a transient global reduction in anticorrelated activity shortly after emergence from anaesthesia that returns to baseline by the following day. CLINICAL TRIAL REGISTRATION: NCT02275026.
Assuntos
Período de Recuperação da Anestesia , Anestesia Geral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Sevoflurano/farmacologiaRESUMO
BACKGROUND: Mechanistic aspects of cognitive recovery after anesthesia and surgery are not yet well characterized, but may be vital to distinguishing the contributions of anesthesia and surgery in cognitive complications common in the elderly such as delirium and postoperative cognitive dysfunction. This article describes the aims and methodological approach to the ongoing study, Trajectory of Recovery in the Elderly (TORIE), which focuses on the trajectory of cognitive recovery from general anesthesia. METHODS: The study design employs cognitive testing coupled with neuroimaging techniques such as functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labeling to characterize cognitive recovery from anesthesia and its biological correlates. Applying these techniques to a cohort of age-specified healthy volunteers 40-80 years of age, who are exposed to general anesthesia alone, in the absence of surgery, will assess cognitive and functional neural network recovery after anesthesia. Imaging data are acquired before, during, and immediately after anesthesia, as well as 1 and 7 days after. Detailed cognitive data are captured at the same time points as well as 30 days after anesthesia, and brief cognitive assessments are repeated at 6 and 12 months after anesthesia. RESULTS: The study is underway. Our primary hypothesis is that older adults may require significantly longer to achieve cognitive recovery, measured by Postoperative Quality of Recovery Scale cognitive domain, than younger adults in the immediate postanesthesia period, but all will fully recover to baseline levels within 30 days of anesthesia exposure. Imaging data will address systems neuroscience correlates of cognitive recovery from general anesthesia. CONCLUSIONS: The data acquired in this project will have both clinical and theoretical relevance regardless of the outcome by delineating the mechanism behind short-term recovery across the adult age lifespan, which will have major implications for our understanding of the effects of anesthetic drugs.
Assuntos
Período de Recuperação da Anestesia , Anestesia Geral/efeitos adversos , Anestésicos/efeitos adversos , Recuperação Demorada da Anestesia/epidemiologia , Delírio do Despertar/epidemiologia , Testes de Estado Mental e Demência , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia Geral/tendências , Anestésicos/administração & dosagem , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Recuperação Demorada da Anestesia/induzido quimicamente , Recuperação Demorada da Anestesia/diagnóstico , Delírio do Despertar/induzido quimicamente , Delírio do Despertar/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Adenocarcinoma de Pulmão/cirurgia , Anti-Inflamatórios não Esteroides/efeitos adversos , Biomarcadores Tumorais/genética , Cetorolaco/efeitos adversos , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia , Pneumonectomia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adenocarcinoma de Pulmão/patologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Redes Reguladoras de Genes , Genômica , Humanos , Cuidados Intraoperatórios , Cetorolaco/administração & dosagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Fator 2 Relacionado a NF-E2/genética , Pneumonectomia/efeitos adversos , Pneumonectomia/mortalidade , Proteínas Proto-Oncogênicas c-mdm2/genética , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoAssuntos
Analgésicos Opioides/efeitos adversos , Analgésicos/efeitos adversos , Anestesia , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Cuidados Intraoperatórios , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Idoso , Idoso de 80 Anos ou mais , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
To study transport through the nuclear pore complex, we developed a computational simulation that is based on known structural elements rather than a particular transport model. Results agree with a variety of experimental data including size cutoff for cargo transport with (30-nm diameter) and without (< 10 nm) nuclear localization signals (NLS), macroscopic transport rates (hundreds per second), and single cargo transit times (milliseconds). The recently observed bimodal cargo distribution is predicted, as is the relative invariance of single cargo transit times out to large size (even as macroscopic transport rate decreases). Additional predictions concern the effects of the number of NLS tags, the RanGTP gradient, and phenylalanine-glycine nucleopore protein (FG-Nup) structure, flexibility, and cross-linking. Results are consistent with and elucidate the molecular mechanisms of some existing hypotheses (selective phase, virtual gate, and selective gate models). A model emerges that is a hybrid of a number of preexisting models as well as a Brownian ratchet model, in which a cargo-karyopherin complex remains bound to the same FG-Nups for its entire trajectory through the nuclear pore complex until RanGTP severs the cargo-Nup bonds to effect release into the nucleus.
Assuntos
Núcleo Celular/metabolismo , Simulação de Dinâmica Molecular , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Poro Nuclear/metabolismo , Transporte Ativo do Núcleo Celular , Glicina/metabolismo , Carioferinas/metabolismo , Modelos Biológicos , Sinais de Localização Nuclear/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Fenilalanina/metabolismo , Ligação Proteica , Proteína ran de Ligação ao GTP/metabolismoRESUMO
Background: Opioids are the primary analgesics for cancer pain. Recent clinical evidence suggests opioids may counteract the effect of immune checkpoint inhibition (ICI) immunotherapy, but the mechanism for this interaction is unknown. The following experiments study how opioids and immunotherapy modulate a common RNA expression pathway in triple negative breast cancer (TNBC), a cancer subtype in which immunotherapy is increasingly used. This study identifies a mechanism by which opioids may decrease ICI efficacy, and compares ketamine, a non-opioid analgesic with emerging use in cancer pain, for potential ICI interaction. Methods: Tumor RNA expression and clinicopathologic data from a large cohort with TNBC (N=286) was used to identify RNA expression signatures of disease. Various drug-induced RNA expression profiles were extracted from multimodal RNA expression datasets and analyzed to estimate the RNA expression effects of ICI, opioids, and ketamine on TNBC. Results: We identified a RNA expression network in CD8+ T-cells that was relevant to TNBC pathogenesis and prognosis. Both opioids and anti-PD-L1 ICI regulated RNA expression in this network, suggesting a nexus for opioid-ICI interaction. Morphine and anti-PD-L1 therapy regulated RNA expression in opposing directions. By contrast, there was little overlap between the effect of ketamine and anti-PD-L1 therapy on RNA expression. Conclusions: Opioids and ICI may target a common immune network in TNBC and regulate gene expression in opposing fashion. No available evidence supports a similar interaction between ketamine and ICI.
RESUMO
While opioids constitute the major component of perioperative analgesic regimens for surgery in general, a variety of evidence points to an association between perioperative opioid exposure and longer term oncologic outcomes. The mechanistic details underlying these effects are not well understood. In this study, we focused on clear cell renal cell carcinoma (ccRCC) and utilized RNA sequencing and outcome data from both The Cancer Genome Atlas, as well as a local patient cohort to identify survival-associated gene coexpression networks. We then projected drug-induced transcriptional profiles from in vitro cancer cells to predict drug effects on these networks and recurrence-free, cancer-specific, and overall survival. The opioid receptor agonist, leu-enkephalin, was predicted to have antisurvival effects in ccRCC, primarily through Th2 immune- and NRF2-dependent macrophage networks. Conversely, the antagonist, naloxone, was predicted to have prosurvival effects, primarily through angiogenesis, fatty acid metabolism, and hemopoesis pathways. Eight coexpression networks associated with survival endpoints in ccRCC were identified, and master regulators of the transition from the normal to disease state were inferred, a number of which are linked to opioid pathways. These results are the first to suggest a mechanism for opioid effects on cancer outcomes through modulation of survival-associated coexpression networks. While we focus on ccRCC, this methodology may be employed to predict opioid effects on other cancer types and to personalize analgesic regimens in patients with cancer for optimal outcomes. SIGNIFICANCE: This study suggests a possible molecular mechanism for opioid effects on cancer outcomes generally, with implications for personalization of analgesic regimens.
Assuntos
Analgésicos Opioides/farmacologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Redes Reguladoras de Genes , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Estudos de Coortes , Epistasia Genética/efeitos dos fármacos , Epistasia Genética/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de SobrevidaRESUMO
Cognitive dysfunction after surgery under general anesthesia is a well-recognized clinical phenomenon in the elderly. Physiological effects of various anesthetic agents have been studied at length. Very little is known about potential effects of anesthesia on brain structure. In this study we used Diffusion Tensor Imaging to compare the white matter microstructure of healthy control subjects under sevoflurane anesthesia with their awake state. Fractional Anisotropy, a white mater integrity index, transiently decreases throughout the brain during sevoflurane anesthesia and then returns back to baseline. Other DTI metrics such as mean diffusivity, axial diffusivity and radial diffusivity were increased under sevoflurane anesthesia. Although DTI metrics are age dependent, the transient changes due to sevoflurane were independent of age and sex. Volumetric analysis shows various white matter volumes decreased whereas some gray matter volumes increased during sevoflurane anesthesia. These results suggest that sevoflurane anesthesia has a significant, but transient, effect on white matter microstructure. In spite of the transient effects of sevoflurane anesthesia there were no measurable effects on brain white matter as determined by the DTI metrics at 2 days and 7 days following anesthesia. The role of white matter in the loss of consciousness under anesthesia will need to be studied and MRI studies with subjects under anesthesia will need to take these results into account.
Assuntos
Anestesia Geral/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Encéfalo/patologia , Complicações Cognitivas Pós-Operatórias/patologia , Sevoflurano/efeitos adversos , Substância Branca/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Estudos de Casos e Controles , Imagem de Tensor de Difusão , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Complicações Cognitivas Pós-Operatórias/induzido quimicamente , Complicações Cognitivas Pós-Operatórias/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacosRESUMO
We report a computational model for the assembly of HIV-1 Gag into immature viral particles at the plasma membrane. To reproduce experimental structural and kinetic properties of assembly, a process occurring on the order of minutes, a coarse-grained representation consisting of a single particle per Gag molecule is developed. The model uses information relating the functional interfaces implicated in Gag assembly, results from cryo electron-tomography, and biophysical measurements from fluorescence microscopy, such as the dynamics of Gag assembly at single virions. These experimental constraints eliminated many classes of potential interactions, and narrowed the model to a single interaction scheme with two non-equivalent interfaces acting to form Gags into a hexamer, and a third interface acting to link hexamers together. This model was able to form into a hexameric structure with correct lattice spacing and reproduced biologically relevant growth rates. We explored the effect of genomic RNA seeding punctum growth, finding that RNA may be a factor in locally concentrating Gags to initiate assembly. The simulation results infer that completion of assembly cannot be governed simply by Gag binding kinetics. However the addition of membrane curvature suggests that budding of the virion from the plasma membrane could factor into slowing incorporation of Gag at an assembly site resulting in virions of the same size and number of Gag molecules independent of Gag concentration or the time taken to complete assembly. To corroborate the results of our simulation model, we developed an analytic model for Gag assembly finding good agreement with the simulation results.
Assuntos
HIV-1/fisiologia , RNA Viral/metabolismo , Produtos do Gene gag do Vírus da Imunodeficiência Humana/química , Produtos do Gene gag do Vírus da Imunodeficiência Humana/metabolismo , Algoritmos , Microscopia Crioeletrônica , Cinética , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Multimerização Proteica , Estrutura Terciária de Proteína , Montagem de VírusRESUMO
The phenylalanine-glycine-repeat nucleoporins (FG-Nups), which occupy the lumen of the nuclear pore complex (NPC), are critical for transport between the nucleus and cytosol. Although NPCs differ in composition across species, they are largely conserved in organization and function. Transport through the pore is on the millisecond timescale. Here, to explore the dynamics of nucleoporins on this timescale, we use coarse-grained computational simulations. These simulations generate predictions that can be experimentally tested to distinguish between proposed mechanisms of transport. Our model reflects the conserved structure of the NPC, in which FG-Nup filaments extend into the lumen and anchor along the interior of the channel. The lengths of the filaments in our model are based on the known characteristics of yeast FG-Nups. The FG-repeat sites also bind to each other, and we vary this association over several orders of magnitude and run 100-ms simulations for each value. The autocorrelation functions of the orientation of the simulated FG-Nups are compared with in vivo anisotropy data. We observe that FG-Nups reptate back and forth through the NPC at timescales commensurate with experimental measurements of the speed of cargo transport through the NPC. Our results are consistent with models of transport where FG-Nup filaments are free to move across the central channel of the NPC, possibly informing how cargo might transverse the NPC.
Assuntos
Simulação de Dinâmica Molecular , Complexo de Proteínas Formadoras de Poros Nucleares/química , Poro Nuclear/metabolismo , Animais , Glicina/química , Glicina/metabolismo , Humanos , Poro Nuclear/química , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Fenilalanina/química , Fenilalanina/metabolismoRESUMO
General anesthetics bind reversibly to ion channels, modifying their global conformational distributions, but the underlying atomic mechanisms are not completely known. We examine this issue by way of the model protein Gloeobacter violaceous ligand-gated ion channel (GLIC) using computational molecular dynamics, with a coarse-grained model to enhance sampling. We find that in flooding simulations, both propofol and a generic particle localize to the crystallographic transmembrane anesthetic binding region, and that propofol also localizes to an extracellular region shared with the crystallographic ketamine binding site. Subsequent simulations to probe these binding modes in greater detail demonstrate that ligand binding induces structural asymmetry in GLIC. Consequently, we employ residue interaction correlation analysis to describe the internal allosteric network underlying the coupling of ligand and distant effector sites necessary for conformational change. Overall, the results suggest that the same allosteric network may underlie the actions of various anesthetics, regardless of binding site.
Assuntos
Anestésicos Gerais/metabolismo , Anestésicos Gerais/farmacologia , Canais Iônicos de Abertura Ativada por Ligante/química , Canais Iônicos de Abertura Ativada por Ligante/metabolismo , Simulação de Dinâmica Molecular , Multimerização Proteica , Regulação Alostérica/efeitos dos fármacos , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cianobactérias , Propofol/metabolismo , Propofol/farmacologia , Estrutura Quaternária de ProteínaRESUMO
OBJECTIVE: To develop and apply a novel modeling approach to support medical and public health disaster planning and response using a sarin release scenario in a metropolitan environment. METHODS: An agent-based disaster simulation model was developed incorporating the principles of dose response, surge response, and psychosocial characteristics superimposed on topographically accurate geographic information system architecture. The modeling scenarios involved passive and active releases of sarin in multiple transportation hubs in a metropolitan city. Parameters evaluated included emergency medical services, hospital surge capacity (including implementation of disaster plan), and behavioral and psychosocial characteristics of the victims. RESULTS: In passive sarin release scenarios of 5 to 15 L, mortality increased nonlinearly from 0.13% to 8.69%, reaching 55.4% with active dispersion, reflecting higher initial doses. Cumulative mortality rates from releases in 1 to 3 major transportation hubs similarly increased nonlinearly as a function of dose and systemic stress. The increase in mortality rate was most pronounced in the 80% to 100% emergency department occupancy range, analogous to the previously observed queuing phenomenon. Effective implementation of hospital disaster plans decreased mortality and injury severity. Decreasing ambulance response time and increasing available responding units reduced mortality among potentially salvageable patients. Adverse psychosocial characteristics (excess worry and low compliance) increased demands on health care resources. Transfer to alternative urban sites was possible. CONCLUSIONS: An agent-based modeling approach provides a mechanism to assess complex individual and systemwide effects in rare events.