translational approach
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2022 ◽  
Vol 23 (2) ◽  
pp. 807
Author(s):  
Charlotte Delrue ◽  
Reinhart Speeckaert ◽  
Joris R. Delanghe ◽  
Marijn M. Speeckaert

According to several animal and human studies, vitamin D appears to play a significant role in the development of diabetic nephropathy. However, the possible renoprotective effect of vitamin D and its influence on the reversal of already existing renal damage remains doubtful. At this moment, there are a few hypotheses concerning the underlying molecular and genetic mechanisms including the link between vitamin D and inflammation, oxidative stress, and extracellular matrix accumulation. The present review aims to investigate the potential role of vitamin D in the development of diabetic kidney disease from a translational approach.


2021 ◽  
Vol 12 (11) ◽  
pp. 1000-1008
Author(s):  
Guillermo Valenzuela ◽  
Joaquín Canepa ◽  
Carolina Simonetti ◽  
Loreto Solo de Zaldívar ◽  
Katherine Marcelain ◽  
...  

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
M Meyer ◽  
S Schneckener ◽  
R Loosen ◽  
K Coboeken ◽  
S Willmann ◽  
...  

Abstract Background/Introduction Vericiguat is a soluble guanylate cyclase (sGC) stimulator, like riociguat and nelociguat, and entered clinical development in 2012. Before entering Phase 2, pharmacokinetics (PK) and pharmacodynamics (PD) of vericiguat had been studied in healthy volunteers only, whereas riociguat and nelociguat had also been studied in patients with pulmonary hypertension (PH) and left ventricular dysfunction (LVD) or biventricular chronic heart failure (HF). We hypothesised that integrating all PK/PD data from these compounds into population PK/PD (popPK/PD) and physiology-based PK (PBPK) models could be used to predict optimal and safe dose ranges of vericiguat for Phase 2b studies in patients with worsening chronic HF. This novel bridging approach was applied in one of several translational stages to accelerate the development of vericiguat (Figure 1). Purpose We used prior knowledge from other sGC stimulators in a combined PK/PD and PBPK modelling approach to directly initiate Phase 2b studies of vericiguat in patients after Phase 1 studies in healthy volunteers. Methods PK, heart rate (HR) and systemic vascular resistance (SVR) data for vericiguat, nelociguat and riociguat were used to calculate PK/PD slopes of linear models, corrected with fraction unbound percentages (2.2%, 3.6% and 3.9%, respectively), to compare potency relative to riociguat based on unbound concentrations. PK estimates for nelociguat and riociguat were derived using population PK modelling (NONMEM) from patient studies with sparse PK sampling. PBPK models informed by preclinical physicochemical and PK data as well as clinical data for vericiguat were used to predict vericiguat PK in patients with HF (PK-Sim). Exposure–response data for riociguat in patients indicated the optimal range of PD responses for vericiguat (blood pressure for safety and cardiac index for efficacy). Results Vericiguat and nelociguat had lower potency than riociguat when comparing PK/PD slopes for HR and SVR (slope ratios of 0.23–0.32 for vericiguat and 0.33–0.47 for nelociguat). Plasma concentrations of vericiguat would need to be ∼3.6 times that of riociguat for equivalent responses. In patients with PH and LVD the optimal plasma concentration range for riociguat was ∼10–100 μg/l in exposure–response and safety studies, which translates to a target exposure range of ∼90–900 μg/l for vericiguat in patients with HF. PBPK modelling showed that vericiguat 2.5 mg and 10 mg would cover the target exposure range and that 1.25 mg would be a “non-effective” dose level with respect to haemodynamics. Conclusions Our novel translational approach combining popPK/PD analyses of other sGC stimulators with PBPK modelling enabled vericiguat to move directly from Phase 1 to Phase 2b, reducing development time by ∼2 years. PK and safety results from Phase 2b (SOCRATES-REDUCED) and Phase 3 (VICTORIA) trials confirmed that use of this translational approach to predict dose ranges of vericiguat was successful. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding for this research was provided by Bayer AG, Berlin, Germany Figure 1


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Susana Merino-Caviedes ◽  
Lilian K. Gutierrez ◽  
José Manuel Alfonso-Almazán ◽  
Santiago Sanz-Estébanez ◽  
Lucilio Cordero-Grande ◽  
...  

AbstractDelayed gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging requires novel and time-efficient approaches to characterize the myocardial substrate associated with ventricular arrhythmia in patients with ischemic cardiomyopathy. Using a translational approach in pigs and patients with established myocardial infarction, we tested and validated a novel 3D methodology to assess ventricular scar using custom transmural criteria and a semiautomatic approach to obtain transmural scar maps in ventricular models reconstructed from both 3D-acquired and 3D-upsampled-2D-acquired LGE-CMR images. The results showed that 3D-upsampled models from 2D LGE-CMR images provided a time-efficient alternative to 3D-acquired sequences to assess the myocardial substrate associated with ischemic cardiomyopathy. Scar assessment from 2D-LGE-CMR sequences using 3D-upsampled models was superior to conventional 2D assessment to identify scar sizes associated with the cycle length of spontaneous ventricular tachycardia episodes and long-term ventricular tachycardia recurrences after catheter ablation. This novel methodology may represent an efficient approach in clinical practice after manual or automatic segmentation of myocardial borders in a small number of conventional 2D LGE-CMR slices and automatic scar detection.


Author(s):  
Amanda A. Uliaszek ◽  
Marc A. Fournier ◽  
Matthew W. Southward ◽  
Nadia Al-Dajani ◽  
Matthew Quitasol

2021 ◽  
Vol 6 (3) ◽  
pp. 314-330
Author(s):  
Tara Coleman

Abstract Grounded in the heterogenous linguistic and cultural landscape of Hong Kong, this article proposes a translational approach to the practice of world cinema, focusing on director Wong Kar-wai, via World Literature and the poetry of Leung Ping-kwan. Wong is a lyrical cinematic stylist, while Leung had a strong scholarly interest in cinema and produced many collaborations with visual artists. Both are highly attuned to the distinctiveness of daily life in Hong Kong despite its infusion of international influences. Moving beyond a model which sees translation as a secondary process carrying a work beyond its local context, I use Sakai Naoki’s concept of the “heterolingual address” to trace how translation becomes foundational to these artists’ engagement with the multilayered space and uneven temporality of Hong Kong.


2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Annika Kengelbach-Weigand ◽  
Carolina Thielen ◽  
Tobias Bäuerle ◽  
Rebekka Götzl ◽  
Thomas Gerber ◽  
...  

AbstractTissue engineering principles allow the generation of functional tissues for biomedical applications. Reconstruction of large-scale bone defects with tissue-engineered bone has still not entered the clinical routine. In the present study, a bone substitute in combination with mesenchymal stem cells (MSC) and endothelial progenitor cells (EPC) with or without growth factors BMP-2 and VEGF-A was prevascularized by an arteriovenous (AV) loop and transplanted into a critical-size tibia defect in the sheep model. With 3D imaging and immunohistochemistry, we could show that this approach is a feasible and simple alternative to the current clinical therapeutic option. This study serves as proof of concept for using large-scale transplantable, vascularized, and customizable bone, generated in a living organism for the reconstruction of load-bearing bone defects, individually tailored to the patient’s needs. With this approach in personalized medicine for the reconstruction of critical-size bone defects, regeneration of parts of the human body will become possible in the near future.


Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3421
Author(s):  
Julien Ancel ◽  
Jeanne-Marie Perotin ◽  
Maxime Dewolf ◽  
Claire Launois ◽  
Pauline Mulette ◽  
...  

Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management.


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