It's Time to Reverse our Thinking: The Reverse Translation Research Paradigm

Shakhnovich, Valentina

doi:10.1111/cts.12538

Cited by 51 publications

(39 citation statements)

References 7 publications

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“…Instead, associations inferred directly from patients undergoing well-defined perturbations could accelerate the discovery of new mechanisms of microbiota-host interaction to benefit human health 3 . This idea fits the concept of reverse translational research 4 : Microbiota data acquired from well-monitored patients could be reused in other studies beyond the study for which it was originally collected; the longitudinal data could empower causal inference and lead to hypotheses that are more likely to produce microbiota-targeted therapies for patients.…”

Section: Background and Summarymentioning

confidence: 97%

Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients

et al. 2021

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The impact of the gut microbiota in human health is affected by several factors including its composition, drug administrations, therapeutic interventions and underlying diseases. Unfortunately, many human microbiota datasets available publicly were collected to study the impact of single variables, and typically consist of outpatients in cross-sectional studies, have small sample numbers and/or lack metadata to account for confounders. These limitations can complicate reusing the data for questions outside their original focus. Here, we provide comprehensive longitudinal patient dataset that overcomes those limitations: a collection of fecal microbiota compositions (>10,000 microbiota samples from >1,000 patients) and a rich description of the “hospitalome” experienced by the hosts, i.e., their drug exposures and other metadata from patients with cancer, hospitalized to receive allogeneic hematopoietic cell transplantation (allo-HCT) at a large cancer center in the United States. We present five examples of how to apply these data to address clinical and scientific questions on host-associated microbial communities.

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Section: Background and Summarymentioning

confidence: 97%

Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients

et al. 2021

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“…In order to tackle the issue of whether TRLs or RLPs are causatively involved in exacerbating atherosclerosis, animal models have been used to investigate potential atherogenic effects of TRLs and RLPs and to provide mechanistic insight through an approach that has sometimes been termed “reverse translation,” “human-first,” or “bedside-to-bench” research, which begins with observations in the clinic and works “backwards” to uncover the mechanisms behind the clinical observations ( 32 ). In fact, the first genetic mouse model of atherosclerosis with advanced lesions—the APOE-deficient mouse—was generated in the Breslow and Maeda laboratories in the early 1990's in part to mimic the impaired clearance of RLPs and severe premature coronary and peripheral vessel risk observed in patients with remnant removal disease ( 33 , 34 ).…”

Section: What Are Remnant Lipoprotein Particles and Do They Promote Amentioning

confidence: 99%

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Basu

Bornfeldt

2020

Front. Endocrinol.

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Human studies support a strong association between hypertriglyceridemia and atherosclerotic cardiovascular disease (CVD). However, whether a causal relationship exists between hypertriglyceridemia and increased CVD risk is still unclear. One plausible explanation for the difficulty establishing a clear causal role for hypertriglyceridemia in CVD risk is that lipolysis products of triglyceride-rich lipoproteins (TRLs), rather than the TRLs themselves, are the likely mediators of increased CVD risk. This hypothesis is supported by studies of rare mutations in humans resulting in impaired clearance of such lipolysis products (remnant lipoprotein particles; RLPs). Several animal models of hypertriglyceridemia support this hypothesis and have provided additional mechanistic understanding. Mice deficient in lipoprotein lipase (LPL), the major vascular enzyme responsible for TRL lipolysis and generation of RLPs, or its endothelial anchor GPIHBP1, are severely hypertriglyceridemic but develop only minimal atherosclerosis as compared with animal models deficient in apolipoprotein (APO) E, which is required to clear TRLs and RLPs. Likewise, animal models convincingly show that increased clearance of TRLs and RLPs by LPL activation (achieved by inhibition of APOC3, ANGPTL3, or ANGPTL4 action, or increased APOA5) results in protection from atherosclerosis. Mechanistic studies suggest that RLPs are more atherogenic than large TRLs because they more readily enter the artery wall, and because they are enriched in cholesterol relative to triglycerides, which promotes pro-atherogenic effects in lesional cells. Other mechanistic studies show that hepatic receptors (LDLR and LRP1) and APOE are critical for RLP clearance. Thus, studies in animal models have provided additional mechanistic insight and generally agree with the hypothesis that RLPs derived from TRLs are highly atherogenic whereas hypertriglyceridemia due to accumulation of very large TRLs in plasma is not markedly atherogenic in the absence of TRL lipolysis products.

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“…We need to better understand what is going on here, i.e. how much of the preclinical research effort is spent on animal studies designed to inform or predict the human situation, and how much is focused on other activities such as drug repurposing or reverse translation [69]. It is important to gain a more accurate picture of how new knowledge is produced, as well as the relative contributions of clinical and preclinical research activities in contributing to this new knowledge.…”

Section: How Is Clinical Knowledge Actually Produced?mentioning

confidence: 99%

Can prospective systematic reviews of animal studies improve clinical translation?

Pound

Ritskes‐Hoitinga

2020

J Transl Med

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Systematic reviews are powerful tools with the potential to generate high quality evidence. Their application to animal studies has been instrumental in exposing the poor quality of these studies, as well as a catalyst for improvements in study design, conduct and reporting. It has been suggested that prospective systematic reviews of animal studies (i.e. systematic reviews conducted prior to clinical trials) would allow scrutiny of the preclinical evidence, providing valuable information on safety and efficacy, and helping to determine whether clinical trials should proceed. However, while prospective systematic reviews allow valuable scrutiny of the preclinical animal data, they are not necessarily able to reliably predict the safety and efficacy of an intervention when trialled in humans. Consequently, they may not reliably safeguard humans participating in clinical trials and might potentially result in lost opportunities for beneficial clinical treatments. Furthermore, animal and human studies are often conducted concurrently, which not only makes prospective systematic reviews of animal studies impossible, but suggests that animal studies do not inform human studies in the manner presumed. We suggest that this points to a confused attitude regarding animal studies, whereby tradition demands that they precede human studies but practice indicates that their findings are often ignored. We argue that it is time to assess the relative contributions of animal and human research in order to better understand how clinical knowledge is actually produced.

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It's Time to Reverse our Thinking: The Reverse Translation Research Paradigm

Cited by 51 publications

References 7 publications

Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients

Compilation of longitudinal microbiota data and hospitalome from hematopoietic cell transplantation patients

Hypertriglyceridemia and Atherosclerosis: Using Human Research to Guide Mechanistic Studies in Animal Models

Can prospective systematic reviews of animal studies improve clinical translation?

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