BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable ...responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021, NCT01957709, and NCT03063632.
Introducción El fútbol ha evolucionado debido a que han aumentado las demandas a nivel técnico, físico, fisiológico, táctico y mental que obligan al jugador a tener un mejor rendimiento. Para ...ejemplificar, los jugadores de alto rendimiento pueden recorrer hasta 10 kilómetros en acciones de juego como correr, saltar, patear, girar, acelerar, desacelerar, contextualizadas dentro de acciones tácticas que implican movimientos a nivel ofensivo y defensivo en un sistema de juego especifico implementado por los jefes técnicos lo cual implica que deben estar preparados para afrontar entrenamientos y partidos al máximo nivel de exigencia física. La fuerza es el pilar de desarrollo de las demás cualidades físicas debido a que combina diferentes factores morfológicos y neurales como la sección trasversal muscular, arquitectura muscular, reclutamiento de unidades motoras con su sincronización e inhibición neuromuscular. El entrenamiento de la fuerza excéntrica es el punto de partida para desarrollar habilidades de rendimiento especificas debido a que tiene efectos significativos en la reducción de lesiones y aumento de habilidades físicas.Metodología Se realizó un estudio cuasi experimental no aleatorizado que tenía como fin evaluar el efecto de un entrenamiento preventivo basado en ejercicios de sobrecarga excéntrica y determinar valores de referencia para jugadores de fútbol de la liga profesional colombiana en la cadena muscular anterior. Se definió como variables de medición la potencia media excéntrica medida mediante el sistema SmartCoach a través del dispositivo kBox Exxentric. Resultados Se realizó la prueba en t para medias emparejadas en el software excel donde la media para la 1 evaluación fue de 271,4 Watts y la 2 evaluación de 534,2 watts, se obtuvo un valor de P=0,000000014 lo cual indica que hubo una diferencia significativa. Para los arqueros el valor promedio fue de 352watts, defensas laterales 374 watts, defensas centrales 475 watts, volantes 385 watts, extremos 401 watts y delanteros 418 watts. Conclusión el entrenamiento preventivo de fuerza y sobrecarga excéntrica enfocado en la cadena muscular anterior tiene efectos significativos en la fuerza muscular en jugadores de futbol profesional.
The liver is a well-known immunotolerogenic environment, which provides the adequate setting for liver infectious pathogens persistence such as the hepatitis B virus (HBV). Consequently, HBV ...infection can derive in the development of chronic disease in a proportion of the patients. If this situation persists in time, chronic hepatitis B (CHB) would end in cirrhosis, hepatocellular carcinoma and eventually, the death of the patient. It is thought that this immunotolerogenic environment is the result of complex interactions between different elements of the immune system and the viral biology. Therefore, the purpose of this work is to unravel the mechanisms implied in the development of CHB and to design a tool able to help in the study of adequate therapies. Firstly, a conceptual framework with the main components of the immune system and viral dynamics was constructed providing an overall insight on the pathways and interactions implied in this disease. Secondly, a review of the literature was performed in a modular fashion: (i) viral dynamics, (ii) innate immune response, (iii) humoral and (iv) cellular adaptive immune responses and (v) tolerogenic aspects. Finally, the information collected was integrated into a single topological representation that could serve as the plan for the systems pharmacology model architecture. This representation can be considered as the previous unavoidable step to the construction of a quantitative model that could assist in biomarker and target identification, drug design and development, dosing optimization and disease progression analysis.
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Myokines are a group of protein mediators produced by skeletal muscle under stress or physical exertion. Even though their discovery and effects in cell culture and animal models of disease have ...elicited great enthusiasm, very little is known about their role in human metabolism. We assessed whether plasma concentrations of three known myokines myonectin, myostatin, and fibroblast-derived growth factor 21 (FGF-21) would be associated with direct and indirect indicators of insulin resistance (IR) in individuals who did not have a diagnosis of diabetes.
We studied 81 adults of both sexes comprising a wide range of body adiposity and insulin sensitivity. All participants underwent a thorough clinical assessment and a 5-point oral glucose tolerance test with calculation of multiple IR and insulin sensitivity indices. Twenty-one of them additionally underwent a hyperinsulinemic-euglycemic clamp with determination of steady-state whole-body insulin-stimulated glucose disposal ("M"). We compared plasma myokine concentrations across quartiles of IR indices and clinical IR surrogates, and explored the correlation of each myokine with the
-value.
Plasma myonectin levels increased monotonically across quartiles of the incremental area under the insulin curve (higher values indicate more IR) (
-trend = 0.021) and decreased monotonically across quartiles of the insulin sensitivity index (ISI - higher values indicate less IR) (
-trend = 0.012). After multivariate adjustment for other relevant determinants of IR (body mass index, age, and sex), the negative association of myonectin with ISI persisted (standardized beta = -0.235,
= 0.023). Myostatin was not associated with any clinical IR indicator or direct IR index measure. In multivariate analyses, FGF-21 showed a trend toward a positive correlation with glucose disposal that did not reach statistical significance (standardized beta = 0.476,
= 0.091).
The secretion of myonectin may constitute an attempt at a compensatory mechanism against IR in humans.
To improve resident oral case communication and preparatory skills by providing residents an opportunity to prepare for and conduct a new interdisciplinary Radiology-Pathology (Rad-Path) conference ...series.
To assess whether conference goals were being achieved, we surveyed trainees and attendings in the radiology and pathology departments. Percentages were examined for each variable. Mann-Whitney U test for ordinal variable significance was applied to determine statistical significance between radiology trainee and attending survey responses.
Most surveyed radiology trainees (57.1%) strongly agreed or agreed with: "I wish I felt more comfortable with oral presentations." Sixty-five percent of radiology attendings (34 of 52) either agreed or strongly agreed that the residents should be more comfortable with oral case presentations. Of resident Rad-Path conference presenters, 69% (9 of 13) either agreed or strongly agreed that the conference improved their confidence and/or ability to present case information orally. Of responders who attended at least one Rad-Path conference in person, 83% of residents (19/23) and 61% (17/28) of attendings agreed or strongly agreed that the conference improved their ability to formulate a differential diagnosis. Using the Mann-Whitney U test, no significant difference was found between radiology trainees and attendings' responses.
Our Rad-Path correlation conference was specifically designed and structured to provide residents with focused experience in formal oral case preparation and presentation. We consider our conference a success, with 69% of resident presenters reporting that the Rad-Path conference improved their confidence and/or ability to present case information orally.
Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these ...cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing Vmax and Km. Pharmacological activation of AMP‐activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF‐1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF‐1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia.
Creatine, phosphocreatine, and creatine kinases comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes depend on uptake by a specialized transporter to maintain intracellular creatine levels. Here we demonstrate that hypoxia rapidly decreases creatine transport in cardiomyocytes in culture. Creatine supplementation of cardiomyocytes prior to exposure to hypoxia increases the cellular content of ATP and phosphocreatine and enhances the HIF‐1‐mediated adaptive physiological responses to hypoxia.
Drug development in Systemic Lupus Erythematosus (SLE) has been hindered by poor translation from successful preclinical experiments to clinical efficacy. This lack of success has been attributed to ...the high heterogeneity of SLE patients and to the lack of understanding of disease physiopathology. Modelling approaches could be useful for supporting the identification of targets, biomarkers and patient subpopulations with differential response to drugs. However, the use of traditional quantitative models based on differential equations is not justifiable in a sparse data situation. Boolean networks models are less demanding on the required data to be implemented and can provide insights into the dynamics of biological networks. This methodology allows the integration of all the available knowledge into a single framework to evaluate the behavior of the system under different conditions and test hypotheses about unknown aspects of the disease. In this proof-of-concept study, we explored the potential of a systems pharmacology model based on Boolean networks to support drug development in SLE. We focused the analysis on the antigen presentation by the antigen presenting cells (APC) to the T-cells to evaluate the scope of this methodology in a medium size network before full implementation of the whole SLE pathway. The heterogeneity of SLE patients was replicated using this methodology simulating subjects with distinct pathway alterations. A perturbation analysis of the network coupled with clustering analysis showed potential to identify drug targets, optimal combinatorial regimens and subpopulations of responders and non-responders to drug treatment. We propose this approach as a first step towards the development of more quantitative platforms to address the current challenges in drug development for complex diseases.
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Chondrosarcoma is one of the most common malignant bone tumors in adults. Conventional chondrosarcoma represents around 85% of all chondrosarcomas and is notoriously difficult to treat with ...chemotherapy.
We describe a 67-year-old man with metastatic conventional chondrosarcoma who was treated with nivolumab. Treatment was discontinued after restaging showed increased tumor burden, which later proved to be pseudoprogression. The patient restarted nivolumab and continues to have a near complete response.
Conventional chondrosarcoma may be sensitive to checkpoint inhibitors. Further, this case demonstrates clearly the phenomenon of pseudo-progression in this disease, a factor that must be considered in the design of clinical trials and clinical care. This case supports additional study of immunomodulatory agents in this deadly disease.
Purpose
To build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated ...drug-drug interactions (DDIs).
Methods
The Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002–80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model.
Results
The carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUC
last
ratios (AUC
last
during DDI/AUC
last
without co-administration) and DDI C
max
ratios (C
max
during DDI/C
max
without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values.
Conclusions
A whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).
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