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1.
J Pharmacokinet Pharmacodyn ; 49(5): 539-556, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35933452

RESUMO

Physiologically-based pharmacokinetic and cellular kinetic models are used extensively to predict concentration profiles of drugs or adoptively transferred cells in patients and laboratory animals. Models are fit to data by the numerical optimisation of appropriate parameter values. When quantities such as the area under the curve are all that is desired, only a close qualitative fit to data is required. When the biological interpretation of the model that produced the fit is important, an assessment of uncertainties is often also warranted. Often, a goal of fitting PBPK models to data is to estimate parameter values, which can then be used to assess characteristics of the fit system or applied to inform new modelling efforts and extrapolation, to inform a prediction under new conditions. However, the parameters that yield a particular model output may not necessarily be unique, in which case the parameters are said to be unidentifiable. We show that the parameters in three published physiologically-based pharmacokinetic models are practically (deterministically) unidentifiable and that it is challenging to assess the associated parameter uncertainty with simple curve fitting techniques. This result could affect many physiologically-based pharmacokinetic models, and we advocate more widespread use of thorough techniques and analyses to address these issues, such as established Markov Chain Monte Carlo and Bayesian methodologies. Greater handling and reporting of uncertainty and identifiability of fit parameters would directly and positively impact interpretation and translation for physiologically-based model applications, enhancing their capacity to inform new model development efforts and extrapolation in support of future clinical decision-making.


Assuntos
Modelos Biológicos , Animais , Teorema de Bayes , Cadeias de Markov , Método de Monte Carlo , Incerteza
3.
AAPS J ; 23(5): 103, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34453265

RESUMO

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.


Assuntos
Antineoplásicos/efeitos adversos , Modelos Biológicos , Neutropenia/prevenção & controle , Piperidonas/efeitos adversos , Quinazolinonas/efeitos adversos , Antineoplásicos/administração & dosagem , Variação Biológica da População , Simulação por Computador , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Farmacologia em Rede , Neutropenia/induzido quimicamente , Neutropenia/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Piperidonas/administração & dosagem , Quinazolinonas/administração & dosagem
4.
PLoS Med ; 17(11): e1003323, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33147277

RESUMO

BACKGROUND: The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases. METHODS AND FINDINGS: Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies. CONCLUSIONS: In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.


Assuntos
Medula Óssea/patologia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Microambiente Tumoral , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Prognóstico , Carga Tumoral
5.
Gigascience ; 9(7)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32696951

RESUMO

BACKGROUND: Mechanistic models, when combined with pertinent data, can improve our knowledge regarding important molecular and cellular mechanisms found in cancer. These models make the prediction of tissue-level response to drug treatment possible, which can lead to new therapies and improved patient outcomes. Here we present a data-driven multiscale modeling framework to study molecular interactions between cancer, stromal, and immune cells found in the tumor microenvironment. We also develop methods to use molecular data available in The Cancer Genome Atlas to generate sample-specific models of cancer. RESULTS: By combining published models of different cells relevant to pancreatic ductal adenocarcinoma (PDAC), we built an agent-based model of the multicellular pancreatic tumor microenvironment, formally describing cell type-specific molecular interactions and cytokine-mediated cell-cell communications. We used an ensemble-based modeling approach to systematically explore how variations in the tumor microenvironment affect the viability of cancer cells. The results suggest that the autocrine loop involving EGF signaling is a key interaction modulator between pancreatic cancer and stellate cells. EGF is also found to be associated with previously described subtypes of PDAC. Moreover, the model allows a systematic exploration of the effect of possible therapeutic perturbations; our simulations suggest that reducing bFGF secretion by stellate cells will have, on average, a positive impact on cancer apoptosis. CONCLUSIONS: The developed framework allows model-driven hypotheses to be generated regarding therapeutically relevant PDAC states with potential molecular and cellular drivers indicating specific intervention strategies.


Assuntos
Algoritmos , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/patologia , Suscetibilidade a Doenças , Modelos Biológicos , Comunicação Autócrina , Carcinoma Ductal Pancreático/metabolismo , Comunicação Celular/genética , Citocinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Especificidade de Órgãos , Comunicação Parácrina , Fenótipo
6.
PLoS One ; 14(11): e0224693, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31743345

RESUMO

Immune cell infiltration of tumors and the tumor microenvironment can be an important component for determining patient outcomes. For example, immune and stromal cell presence inferred by deconvolving patient gene expression data may help identify high risk patients or suggest a course of treatment. One particularly powerful family of deconvolution techniques uses signature matrices of genes that uniquely identify each cell type as determined from single cell type purified gene expression data. Many methods from this family have been recently published, often including new signature matrices appropriate for a single purpose, such as investigating a specific type of tumor. The package ADAPTS helps users make the most of this expanding knowledge base by introducing a framework for cell type deconvolution. ADAPTS implements modular tools for customizing signature matrices for new tissue types by adding custom cell types or building new matrices de novo, including from single cell RNAseq data. It includes a common interface to several popular deconvolution algorithms that use a signature matrix to estimate the proportion of cell types present in heterogenous samples. ADAPTS also implements a novel method for clustering cell types into groups that are difficult to distinguish by deconvolution and then re-splitting those clusters using hierarchical deconvolution. We demonstrate that the techniques implemented in ADAPTS improve the ability to reconstruct the cell types present in a single cell RNAseq data set in a blind predictive analysis. ADAPTS is currently available for use in R on CRAN and GitHub.


Assuntos
Biologia Computacional/métodos , Neoplasias/genética , RNA-Seq/métodos , Análise de Célula Única/métodos , Software , Análise por Conglomerados , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Máquina de Vetores de Suporte , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
7.
J Biol Chem ; 294(40): 14634-14647, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31387947

RESUMO

Mutations in the cardiac thin filament (TF) have highly variable effects on the regulatory function of the cardiac sarcomere. Understanding the molecular-level dysfunction elicited by TF mutations is crucial to elucidate cardiac disease mechanisms. The hypertrophic cardiomyopathy-causing cardiac troponin T (cTnT) mutation Δ160Glu (Δ160E) is located in a putative "hinge" adjacent to an unstructured linker connecting domains TNT1 and TNT2. Currently, no high-resolution structure exists for this region, limiting significantly our ability to understand its role in myofilament activation and the molecular mechanism of mutation-induced dysfunction. Previous regulated in vitro motility data have indicated mutation-induced impairment of weak actomyosin interactions. We hypothesized that cTnT-Δ160E repositions the flexible linker, altering weak actomyosin electrostatic binding and acting as a biophysical trigger for impaired contractility and the observed remodeling. Using time-resolved FRET and an all-atom TF model, here we first defined the WT structure of the cTnT-linker region and then identified Δ160E mutation-induced positional changes. Our results suggest that the WT linker runs alongside the C terminus of tropomyosin. The Δ160E-induced structural changes moved the linker closer to the tropomyosin C terminus, an effect that was more pronounced in the presence of myosin subfragment (S1) heads, supporting previous findings. Our in silico model fully supported this result, indicating a mutation-induced decrease in linker flexibility. Our findings provide a framework for understanding basic pathogenic mechanisms that drive severe clinical hypertrophic cardiomyopathy phenotypes and for identifying structural targets for intervention that can be tested in silico and in vitro.


Assuntos
Cardiomiopatia Hipertrófica/genética , Conformação Proteica , Tropomiosina/química , Troponina T/ultraestrutura , Citoesqueleto de Actina/química , Citoesqueleto de Actina/genética , Animais , Cálcio/metabolismo , Cardiomiopatia Hipertrófica/patologia , Transferência Ressonante de Energia de Fluorescência , Regulação da Expressão Gênica/genética , Humanos , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Miosinas/química , Miosinas/genética , Sarcômeros/genética , Sarcômeros/patologia , Tropomiosina/genética , Troponina T/química , Troponina T/genética
8.
Clin Diabetes ; 36(2): 120-127, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29686450

RESUMO

IN BRIEF Successful management of patients with diabetes requires individualizing A1C and treatment goals in conjunction with identifying and managing hypoglycemia risk. This article describes the Veterans Health Administration's Choosing Wisely Hypoglycemia Safety Initiative (CW-HSI), a voluntary program that aims to reduce the occurrence of hypoglycemia through shared decision-making about deintensifying diabetes treatment in a dynamic cohort of patients identified as being at high risk for hypoglycemia and potentially overtreated. The CW-HSI incorporates education for patients and clinicians, as well as clinical decision support tools, and has shown decreases in the proportions of high-risk patients potentially overtreated and impacts on the frequency of reported hypoglycemia.

9.
Diabetes Spectr ; 30(3): 211-216, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28848316

RESUMO

Background.. Intensive glycemic control confers increased risk of hypoglycemia and little benefit among older individuals with diabetes. The aim of this quality improvement project was to reduce the number of patients treated to A1C levels that might confer greater risk than benefit (i.e., potential overtreatment) in the VA New England Healthcare System. Methods.. A provider report and clinical reminder were created to identify potentially overtreated patients and prompt clinicians to consider treatment de-intensification. Potentially overtreated patients were defined as those on insulin or a sulfonylurea whose most recent A1C was <7.0% and who were >74 years of age or diagnosed with dementia or cognitive impairment. The numbers of patients screened and whose treatment was de-intensified using the clinical reminder were counted from January to December 2014. The number of high-risk veterans at baseline was compared with that 6 and 18 months after implementation using t tests. Results.. A total of 2,830 patients were screened using the clinical reminder; 9.6% had their glycemic treatment de-intensified. Among the 261 patients reporting hypoglycemia, 37% had their treatment de-intensified. Higher percentages of patients had treatment de-intensified when reported symptoms were more severe. The monthly average in the high-risk cohort declined from baseline by 18% at 6 months and by 22% at 18 months (both P <0.005). Conclusions.. A clinical reminder helps clinicians identify and reduce the number of potentially overtreated patients. The large number of screened patients whose treatment was not de-intensified suggests that a clinical reminder should be combined with provider education, national guidelines, and performance measures aligned in the interest of reducing potential overtreatment.

10.
Biochemistry ; 56(26): 3403-3413, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28603979

RESUMO

The progression of genetically inherited cardiomyopathies from an altered protein structure to clinical presentation of disease is not well understood. One of the main roadblocks to mechanistic insight remains a lack of high-resolution structural information about multiprotein complexes within the cardiac sarcomere. One example is the tropomyosin (Tm) overlap region of the thin filament that is crucial for the function of the cardiac sarcomere. To address this central question, we devised coupled experimental and computational modalities to characterize the baseline function and structure of the Tm overlap, as well as the effects of mutations causing divergent patterns of ventricular remodeling on both structure and function. Because the Tm overlap contributes to the cooperativity of myofilament activation, we hypothesized that mutations that enhance the interactions between overlap proteins result in more cooperativity, and conversely, those that weaken interaction between these elements lower cooperativity. Our results suggest that the Tm overlap region is affected differentially by dilated cardiomyopathy-associated Tm D230N and hypertrophic cardiomyopathy-associated human cardiac troponin T (cTnT) R92L. The Tm D230N mutation compacts the Tm overlap region, increasing the cooperativity of the Tm filament, contributing to a dilated cardiomyopathy phenotype. The cTnT R92L mutation causes weakened interactions closer to the N-terminal end of the overlap, resulting in decreased cooperativity. These studies demonstrate that mutations with differential phenotypes exert opposite effects on the Tm-Tn overlap, and that these effects can be directly correlated to a molecular level understanding of the structure and dynamics of the component proteins.


Assuntos
Cardiomiopatia Dilatada/genética , Cardiomiopatia Hipertrófica Familiar/genética , Modelos Moleculares , Mutação Puntual , Sarcômeros/metabolismo , Tropomiosina/metabolismo , Troponina T/metabolismo , Trifosfato de Adenosina/metabolismo , Substituição de Aminoácidos , Animais , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Hipertrófica Familiar/metabolismo , Biologia Computacional , Humanos , Simulação de Dinâmica Molecular , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Estabilidade Proteica , Coelhos , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Sarcômeros/química , Tropomiosina/química , Tropomiosina/genética , Troponina/química , Troponina/genética , Troponina/metabolismo , Troponina C/química , Troponina C/genética , Troponina C/metabolismo , Troponina I/química , Troponina I/genética , Troponina I/metabolismo , Troponina T/química , Troponina T/genética
11.
Ecol Evol ; 7(4): 1259-1270, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28303194

RESUMO

Advances in understanding avian nesting ecology are hindered by a prevalent lack of agreement between nest-site characteristics and fitness metrics such as nest success. We posit this is a result of inconsistent and improper timing of nest-site vegetation measurements. Therefore, we evaluated how the timing of nest vegetation measurement influences the estimated effects of vegetation structure on nest survival. We simulated phenological changes in nest-site vegetation growth over a typical nesting season and modeled how the timing of measuring that vegetation, relative to nest fate, creates bias in conclusions regarding its influence on nest survival. We modeled the bias associated with four methods of measuring nest-site vegetation: Method 1-measuring at nest initiation, Method 2-measuring at nest termination regardless of fate, Method 3-measuring at nest termination for successful nests and at estimated completion for unsuccessful nests, and Method 4-measuring at nest termination regardless of fate while also accounting for initiation date. We quantified and compared bias for each method for varying simulated effects, ranked models for each method using AIC, and calculated the proportion of simulations in which each model (measurement method) was selected as the best model. Our results indicate that the risk of drawing an erroneous or spurious conclusion was present in all methods but greater with Method 2 which is the most common method reported in the literature. Methods 1 and 3 were similarly less biased. Method 4 provided no additional value as bias was similar to Method 2 for all scenarios. While Method 1 is seldom practical to collect in the field, Method 3 is logistically practical and minimizes inherent bias. Implementation of Method 3 will facilitate estimating the effect of nest-site vegetation on survival, in the least biased way, and allow reliable conclusions to be drawn.

13.
J Physiol ; 593(17): 3899-916, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26096258

RESUMO

Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent. From experiments at the cellular and whole organ level, in humans and rats, we show that actomyosin-related force development contributes significantly to high diastolic stiffness in environments where high ADP and increased diastolic [Ca(2+) ] are present, such as the failing myocardium. Our basal study provides a mechanical mechanism which may partly underlie diastolic dysfunction. Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca(2+) ] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca(2+) handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca(2+) ] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca(2+) in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca(2+) both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathological levels of ADP and diastolic [Ca(2+) ] revealed a 76 ± 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca(2+) overload. In isolated Langendorff-perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca(2+) ]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, even at low Ca(2+) , and thereby increase myocardial stiffness.


Assuntos
Difosfato de Adenosina/fisiologia , Cálcio/fisiologia , Coração/fisiologia , Actomiosina/fisiologia , Animais , Cardiomiopatia Dilatada/fisiopatologia , Creatina Quinase/antagonistas & inibidores , Creatina Quinase/fisiologia , Diástole , Humanos , Iodoacetamida/farmacologia , Contração Isométrica , Masculino , Miócitos Cardíacos/fisiologia , Ratos Wistar
16.
J Interv Card Electrophysiol ; 31(3): 185-9, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21491124

RESUMO

PURPOSE: The purpose of this study is to describe the results of manual and automatic electronic medical record-based screening of patients at risk of sudden cardiac arrest (SCA) based on measurements of left ventricular ejection fraction (LVEF). METHODS: Counseling regarding SCA risk and implantable cardioverter defibrillator (ICD) therapy is underutilized in patients with reduced LVEF. We developed and implemented an electronic medical record (EMR)-based system for screening of such patients to improve care. In phase one, manual screening of electronic records and LVEF databases was initially performed by trained cardiac device nurses. In phase two, records were screened automatically by a customized program, and candidate patient records were sent to cardiac device nurses for final review and disposition. RESULTS: In phase one, 2,531 patients with LVEF ≤35% were identified over 398 days. Manual EMR review showed that 1,918 patients (76%) received appropriate counseling regarding SCA risk, received ICDs, or had disqualifying comorbidities. In phase two, 1,081 patients with LVEF ≤35% were identified after automatic screening of 44,672 echocardiograms and EMR over 251 days. Of these, 513 patients (58%) received appropriate counseling regarding SCA risk, received ICDs, or had disqualifying comorbidities. CONCLUSIONS: These data detail the utilization of consultation regarding SCA risk and ICDs in patients with reduced LVEF at a tertiary care center with ready access to arrhythmia specialists. Notification of primary providers of reduced LVEF with recommendation for consultation was not effective in improving patient care.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Programas de Rastreamento , Sistemas Computadorizados de Registros Médicos , Disfunção Ventricular Esquerda/diagnóstico , Adulto , Idoso , Comorbidade , Aconselhamento , Técnicas de Apoio para a Decisão , Desfibriladores Implantáveis , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Volume Sistólico , Disfunção Ventricular Esquerda/fisiopatologia
17.
J Am Chem Soc ; 129(43): 13193-200, 2007 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-17918939

RESUMO

The synthesis and characterization of 1,4,5,8,9,12-hexamethyltriphenylene (5) is described. In the solid state, X-ray crystallographic studies reveal that compound 5 presents a highly distorted C2 geometry with a 53 degrees end-to-end twist. In solution, variable-temperature 1H NMR studies and molecular modeling present a story of rapid dynamic conformational interconversions between two C2 enantiomers (with a low activation barrier) and a slower C2-D3 interconversion (with a relatively high barrier)--the first time clear evidence of conformational interchange for these hindered triphenylenes has been provided. Further studies have established that 5 is a fluorescent stable blue emitter, and that the compound undergoes an irreversible one-electron electrochemical oxidation. Calculations have predicted this to be a radical cation of C2 geometry with 60 degrees end-to-end twist.

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