Translational Research Strategies Research Articles

Welcome to Journal of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) develops as a consequence of underlying chronic liver disease, most commonly cirrhosis. Therefore, HCC management draws on the expertise of a wide range of medical specialists. Currently, novel therapeutic modalities for HCC are investigated within the framework of a multidisciplinary approach. Therefore, there is a critical need for a dedicated journal for HCC with special emphasis on understanding pathogenesis, emerging diagnosis and treatment approaches, and translational research strategies.

Strategies for Facilitating Translational Research in Public Health

Strategies for Facilitating Translational Research in Public Health

Translational research strategy: an essential approach to fight the spread of antimicrobial resistance.

Translation research strategy in infectious diseases, combining the results from basic research with patient-orientated research, aims to bridge the gap between laboratory findings and clinical infectious disease practice to improve disease management. In an era of increasing antimicrobial resistance, there are four main areas of clinical and scientific uncertainty that need to be urgently addressed by translational research: (i) early diagnosis of antibiotic-resistant infections and the appropriateness of empirical antibiotic therapy; (ii) the identification of reservoirs of antibiotic-resistant pathogens; (iii) the development of new antibiotics with lower propensities to evoke resistance; and (iv) the development of new non-antibiotic drugs to be used in the prevention of the spread of resistant bacterial strains. Strict European collaboration among major stakeholders is therefore essential. Appropriate educational tools to train a new generation of scientists with regard to a multifaceted approach to antimicrobial resistance research should be developed. Key areas include the support and implementation of European networks focused on translational research and related education activities, making potential therapeutics more attractive to investors and helping academic investigators to determine whether new molecules can be developed with clinical applicability.

Incorporating translational research with clinical research to increase effectiveness in healthcare for better health.

BackgroundThe transfer of new scientific discoveries into healthcare interventions requires that basic and clinical researchers work together with health care providers to generate team science. These innovative models require translational teams, and need to extend beyond the academic environment. The future of translational science requires partnerships with the healthcare community as well as the broader, general community. This new integrated model of effective translational teams holds promise for addressing thorny and persistent health disparities, is consistent with the nation’s strategic priority of eliminating health disparities, and bodes well for increasing healthcare effectiveness aimed at better health for all.DiscussionAs part of the 13th Research Centers in Minority Institutions (RCMI) International Symposium on Health Disparities, several senior academic leaders joined efforts to hold a workshop to discuss a model that considers the incorporation of two translational research strategies in research career development programs: Comparative effectiveness research (CER) and community-based participatory research (CBPR) for increasing healthcare effectiveness and eliminating healthcare disparities. Discussion included what issues may be most germane to the concept of a unified model for research workforce development through formal training and career development leading to increased effectiveness in healthcare for better health.SummaryWe believe that there is a gap in knowledge and skills in formal research career development programs that will enable physicians, other clinicians, and basic scientists to actively participate in these two translational research strategies. The purpose of this paper is to share the outcomes of these discussions, and encourage further discussion and possible innovation in the formulation of a new model for translational research workforce development.

Developing N of 1 translational research strategies

Developing N of 1 translational research strategies

Angiotensin-Induced Abdominal Aortic Aneurysms in Hypercholesterolemic Mice: Role of Serum Cholesterol and Temporal Effects of Exposure

ObjectiveUnderstanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E−/− mice.ApproachA cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time.ResultsThe overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (−0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86).ConclusionsThese are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.

Abstract 282: Pattern of Development of Abdominal Aortic Aneurysms Induced by Angiotensin In Hypercholesterolemic Mice

Background Understanding the pattern of development of abdominal aortic aneurysms (AAA) may help optimize translational research strategies. Thus we sought mechanistic insight on the pattern of AAA evolution in apolipoprotein E -/- mice. Methods Fifty-nine mice underwent a 4-week pump-mediated infusion of saline (controls; n=13) or 1500 ng/kg/min of AngII (n=46), and AAA development was tracked via in vivo serial ultrasound imaging. We adjusted for hemodynamic covariates in the mixed logistic regression model for AAA occurrence in relation to time. Results The incidence of intact AAA in AngII infused mice was 59% (27/46) of which 55.6% (15/27) were small AAA and 44.4% were large AAA (1.2-1.5 vs. &gt;1.5x baseline diameter, respectively). The incidence of rupture was 22% (10/46). All large aneurysms and most ruptures occurred within the first week of AngII exposure. Subsequent aneurysms were small and evolved in the second week of AngII infusion. The overall effect of time was statistically significant (p&lt;0.001) (Figure). When compared to day 7 of the study period, there was no decrease in the log odds of AAA occurrence by day 14 (-0.234, p = 0.65). However, compared to 21 and 28 days into AngII infusion, the log odds of an AAA occurrence decreased by -9.07 (p&lt; 0.001) and -2.35 (p= 0.04), respectively (Figure). Conclusions These are the first formal estimates of the odds of AAA occurrence vis-à-vis time in the context of a consistent pattern of AAA development in this mouse model of AngII-induced AAA. They occur in the first (large AAA) and second (small AAA) weeks of AngII infusion, and the odds of occurrence diminish thereafter. These findings provide guidance for experimental strategies.

Biomarkers Predicting Antidepressant Treatment Response: How Can We Advance the Field?

Major depression, affecting an estimated 350 million people worldwide, poses a serious social and economic threat to modern societies. There are currently two major problems calling for innovative research approaches, namely, the absence of biomarkers predicting antidepressant response and the lack of conceptually novel antidepressant compounds. Both, biomarker predicting a priori whether an individual patient will respond to the treatment of choice as well as an early distinction of responders and nonresponders during antidepressant therapy can have a significant impact on improving this situation. Biosignatures predicting antidepressant response a priori or early in treatment would enable an evidence-based decision making on available treatment options. However, research to date does not identify any biologic or genetic predictors of sufficient clinical utility to inform the selection of specific antidepressant compound for an individual patient. In this review, we propose an optimized translational research strategy to overcome some of the major limitations in biomarker discovery. We are confident that early transfer and integration of data between both species, ideally leading to mutual supportive evidence from both preclinical and clinical studies, are most suitable to address some of the obstacles of current depression research.

&lt;b&gt;Multi-user equipment, core-facilities and technological platforms: the evolution of organizational strategies for translational health research&lt;/b&gt; - DOI: 10.3395/reciis.v6i3.600en

This paper examines how institutions organize and manage the research and development (R&D) infrastructure and facilities required to stimulate innovation and convert research into practical applications (‘translational research’). We have focused our analysis on universities and biomedical institutions that have created dedicated facilities to optimize this type of activity either working in isolation or in partnership with the industrial sector. We have detected three main types of infrastructure arrangements: multi-user equipment, corefacilities and technological platforms. Although most of the institutions share a common vision and definition for the first two categories, we have identified different perceptions on the nature, role and mission of existing, self denominated ‘technological platforms’. A review of these structures has led us to propose a unifying categorization and nomenclature system of these critical components of health innovation systems. Based on this conceptual framework we have analyzed the evolution of organizational R&D structures and initiatives of Fiocruz and developed a web-based system for the strategic planning, implementation and management of its network of translational research facilities located in several cities in Brazil. This approach may prove useful for organizations facing similar transitions and challenges.

Unique and potent effects of acute ibogaine on zebrafish: The developing utility of novel aquatic models for hallucinogenic drug research

An indole alkaloid, ibogaine is the principal psychoactive component of the iboga plant, used by indigenous peoples in West Africa for centuries. Modulating multiple neurotransmitter systems, the drug is a potent hallucinogen in humans, although its psychotropic effects remain poorly understood. Expanding the range of model species is an important strategy for translational neuroscience research. Here we exposed adult zebrafish (Danio rerio) to 10 and 20mg/L of ibogaine, testing them in the novel tank, light–dark box, open field, mirror stimulation, social preference and shoaling tests. In the novel tank test, the zebrafish natural diving response (geotaxis) was reversed by ibogaine, inducing initial top swimming followed by bottom dwelling. Ibogaine also attenuated the innate preference for dark environments (scototaxis) in the light–dark box test. While it did not exert overt locomotor or thigmotaxic responses in the open field test, the drug altered spatiotemporal exploration of novel environment, inducing clear preference of some areas over others. Ibogaine also promoted ‘mirror’ exploration in the mirror stimulation test, disrupted group cohesion in the shoaling test, and evoked strong coloration responses due to melanophore aggregation, but did not alter brain c-fos expression or whole-body cortisol levels. Overall, our results support the complex pharmacological profile of ibogaine and its high sensitivity in zebrafish models, dose-dependently affecting multiple behavioral domains. While future investigations in zebrafish may help elucidate the mechanisms underlying these unique behavioral effects, our study strongly supports the developing utility of aquatic models in hallucinogenic drug research. High sensitivity of three-dimensional phenotyping approaches applied here to behavioral effects of ibogaine in zebrafish provides further evidence of how 3D reconstructions of zebrafish swimming paths may be useful for high-throughput pharmacological screening.

Clinical proteomics and OMICS clues useful in translational medicine research

Since the advent of the new proteomics era more than a decade ago, large-scale studies of protein profiling have been used to identify distinctive molecular signatures in a wide array of biological systems, spanning areas of basic biological research, clinical diagnostics, and biomarker discovery directed toward therapeutic applications. Recent advances in protein separation and identification techniques have significantly improved proteomic approaches, leading to enhancement of the depth and breadth of proteome coverage.Proteomic signatures, specific for multiple diseases, including cancer and pre-invasive lesions, are emerging. This article combines, in a simple manner, relevant proteomic and OMICS clues used in the discovery and development of diagnostic and prognostic biomarkers that are applicable to all clinical fields, thus helping to improve applications of clinical proteomic strategies for translational medicine research.

Perspectives of zebrafish models of epilepsy: What, how and where next?

Epilepsy is a complex brain disorder with multiple underlying causes and poorly understood pathogenetic mechanisms. Animal models have been indispensable tools in experimental epilepsy research. Zebrafish (Danio rerio) are rapidly emerging as a promising model organism to study various brain disorders. Seizure-like behavioral and neurophysiological responses can be evoked in larval and adult zebrafish by various pharmacological and genetic manipulations, collectively emphasizing the growing utility of this model for studying epilepsy. Here, we discuss recent developments in using zebrafish models to study the seizure-like behavior involved in epilepsy, outlining current challenges and strategies for further translational research in this field.

From maps to mechanisms through neuroimaging of schizophrenia

Functional and structural brain imaging has identified neural and neurotransmitter systems involved in schizophrenia and their link to cognitive and behavioural disturbances such as psychosis. Mapping such abnormalities in patients, however, cannot fully capture the strong neurodevelopmental component of schizophrenia that pre-dates manifest illness. A recent strategy to address this issue has been to focus on mechanisms of disease risk. Imaging genetics techniques have made it possible to define neural systems that mediate heritable risk linked to candidate and genome-wide-supported common variants, and mechanisms for environmental risk and gene-environment interactions are emerging. Characterizing the neural risk architecture of schizophrenia provides a translational research strategy for future treatments.

Science Translational Medicine Podcast: 7 July 2010

A conversation with Samuel Broder about early discoveries in HIV-1/AIDS research and strategies for successful translational research in the future.

Food Security: Translational Agriculture

In the Perspective “Radically rethinking agriculture for the 21st century” (12 February, special section on Food Security, p. [833][1]) N. V. Fedoroff et al. rightfully propose a rethinking of the regulatory system to support public-sector development of genetically modified (GM) crops in the United States and as an international precedent. This strategy will only be effective if it is coupled with a comprehensive translational research paradigm for public agricultural research—analogous to the approach that the National Institutes of Health has been adopting since 2003 to better link basic research to patient needs. In the past 20 years, private companies have only invested in the development of a few traits in a few major crops. As a result, specialty crops and traits with high environmental or social value but low economic value have been completely bypassed. Despite more than two decades of public research investment, only two GM crops developed in the public research sector have been approved for commercial release. How can the public agricultural research sector implement a paradigm of translational research? First, researchers in agricultural biotechnology should anticipate the downstream development, deployment, and commercialization requirements from the start, rather than as an afterthought. They should address regulatory requirements and intellectual property access, and they should determine how to bring the project results to scale. Second, to achieve both basic research goals and successful translation, research teams should include members from multiple disciplines and maintain a high degree of connectivity and communication. Finally, translational research should be characterized by clear accountability focused on progress toward deliverables. Philanthropic sponsors of agricultural development are now beginning to demand clearly articulated translational research strategies that encompass these components. If the public sector is going to contribute in tangible ways to Fedoroff et al. 's vision of the future of agriculture, the public research system needs to be tuned up for translation. [1]: pending:yes

Genetics as a tool for the dissociation of mental operations over the course of development

In recent years it has become possible to differentiate separable aspects of attention and to characterize the anatomical structure and dynamic states of their underlying networks. When individual differences in the structure and dynamics of these networks are used as dependent measures in associations with individual genetic variation, it becomes possible to assign cellular and molecular changes that occur over the course of normal development to specific aspects of network structure and function. In this way, a more granular understanding of the physiology of neural networks can be obtained. Here we review a translational research strategy focused on how genetic variation contributes to the normal development of attentional function. We seek to use genetic information to help construct a multinode, multinetwork model that can explain, in part, individual differences in the development of attention over the course of development.

Novel Translational Research Concepts and Strategies in Radiation Oncology

The discovery of X-rays by Roentgen in 1895 and the discovery of radiations emitted from Uranium compounds by Becquerel led to the establishment of the field of Radiation Sciences. When Radiation Sciences utilized the knowledge in the field of Physics, Chemistry, Biology and Medicine, newer fields were established such as Radiation Oncology, -Chemistry, -Biology, -Protection, Physics, Radiology and Nuclear Medicine. Fields of Radiation Oncology and Radiation Biology have gained significant strides by embracing the modern concepts in molecular biology and physics of imaging. To discuss the recent trends and advances in these fields, Indian Society for Radiation Biology organized an “International Conference on Radiation Biology and Translational Research in Radiation Oncology (ICRB-TRRO)” in Jaipur, India during November 10-12, 2008. The primary theme of this international meeting was to focus on the translational research perspectives in radiation oncology using radiation biology findings as a reservoir of ideas. The second major theme was to focus on research initiatives and recent perspectives in radiation protection. A common dynamic theme constantly interacted with the primary and secondary themes was an influx of extensive discussion on the scientific utility and validity of novel agents obtained from different traditional systems of Indian medicine and herbal plant extracts that can be potent radio-sensitizers as well as potent radio-protectors (as countermeasure agents). Overall, four major thrust areas of the conference such as Radiation-induced signaling networks, novel therapeutics for cancer,

Strategy for Translational Research and Breakthroughs for Common Human Diseases Using Excellent Animal Models and Rare Human Diseases

Strategy for Translational Research and Breakthroughs for Common Human Diseases Using Excellent Animal Models and Rare Human Diseases

Integrative biology — a strategy for systems biomedicine

The precision of genome sequences, together with advanced computational approaches, allows complex, clinically relevant biological systems to be examined. Here, I describe the experiences of the Genome Institute of Singapore (GIS) in using genome-to-systems strategies to accelerate biomedical research. To maximize clinically relevant output, we have explored an organizational strategy that encourages coordinated experimentation among investigators with diverse skills and interests through building a culture of integrative science. Our experience suggests that systems biomedicine is a real and potentially fruitful strategy for translational research.

Curiosity and cure: Translational research strategies for neural repair‐mediated rehabilitation

Clinicians who seek interventions for neural repair in patients with paralysis and other impairments may extrapolate the results of cell culture and rodent experiments into the framework of a preclinical study. These experiments, however, must be interpreted within the context of the model and the highly constrained hypothesis and manipulation being tested. Rodent models of repair for stroke and spinal cord injury offer examples of potential pitfalls in the interpretation of results from developmental gene activation, transgenic mice, endogeneous neurogenesis, cellular transplantation, axon regeneration and remyelination, dendritic proliferation, activity-dependent adaptations, skills learning, and behavioral testing. Preclinical experiments that inform the design of human trials ideally include a lesion of etiology, volume and location that reflects the human disease; examine changes induced by injury and by repair procedures both near and remote from the lesion; distinguish between reactive molecular and histologic changes versus changes critical to repair cascades; employ explicit training paradigms for the reacquisition of testable skills; correlate morphologic and physiologic measures of repair with behavioral measures of task reacquisition; reproduce key results in more than one laboratory, in different strains or species of rodent, and in a larger mammal; and generalize the results across several disease models, such as axonal regeneration in a stroke and spinal cord injury platform. Collaborations between basic and clinical scientists in the development of translational animal models of injury and repair can propel experiments for ethical bench-to-bedside therapies to augment the rehabilitation of disabled patients.