Avenues For Translational Research Research Articles

Metabolic complications of psychotropic medications in psychiatric disorders: Emerging role of de novo lipogenesis and therapeutic consideration.

Although significant advances have been made in understanding the patho-physiology of psychiatric disorders (PDs), therapeutic advances have not been very convincing. While psychotropic medications can reduce classical symptoms in patients with PDs, their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). The mechanism(s) underlying these metabolic abnormalities is not clear; however, lipid/fatty acid accumulation due to enhanced de novo lipogenesis (DNL) has been shown to reduce membrane fluidity, increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities. Intriguingly, emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity, diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs. In support of this, several adjunctive drugs comprising of anti-oxidants and anti-inflammatory agents, that are used in treating PDs in combination with psychotropic medications, have been shown to reduce insulin resistance and development of NAFLD. In conclusion, the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities, and a new avenue for translational research and therapeutic drug designing in PDs.

CLEC16A-An Emerging Master Regulator of Autoimmunity and Neurodegeneration.

CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic development. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypofunction predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms involved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with CLEC16A risk variants. Accordingly, interventions directed at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective therapy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the CLEC16A gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this information is being translated into practical and effective applications in the clinic.

Antisense Oligonucleotide Technologies to Combat Obesity and Fatty Liver Disease.

Synthetic oligonucleotide technologies are DNA or RNA based molecular compounds that are utilized to disrupt gene transcription or translation in target tissues or cells. Optimally, oligonucleotides are 10–30 base pairs in length, and mediate target gene suppression through directed sequence homology with messenger RNA (mRNA), leading to mRNA degradation. Examples of specific oligonucleotide technologies include antisense oligonucleotides (ASO), short hairpin RNAs (shRNA), and small interfering RNAs (siRNA). In vitro and in vivo studies that model obesity related disorders have demonstrated that oligonucleotide technologies can be implemented to improve the metabolism of cells and tissues, exemplified by improvements in fat utilization and hepatic insulin signaling, respectively. Oligonucleotide therapy has also been associated with reductions in lipid accumulation in both the liver and adipose tissue in models of diet-induced obesity. Recent advances in oligonucleotide technologies include the addition of chemical modifications such as N-acetylgalactosamine (GalNAc) conjugates that have been successful at achieving affinity for the liver, in turn improving specificity, and thus reducing off target effects. However, some challenges are still yet to be overcome relating to hepatic injury and off-target effects that have been reported with some compounds, including ASOs. In summary, oligonucleotide-based therapies are an effective tool to elucidate mechanistic insights into metabolic pathways and provide an attractive avenue for translational research into the clinic.

An inspirational reflection on Nobel Prize-winning researches in nerve signaling from over a century: some lessons for inquisitive minds

The fascinating field of Neuroscience is burgeoning with extensive research, and some have been remarkable in making breakthrough findings, worth a Nobel Prize. The discoveries in neuroscience unveiling the anatomical and physiological conundrums of nerve and the advancement of neurophysiological techniques for recording nerve signals are owed to some great minds who thought beyond the normal. Such studies are foundational and exemplar for the young generations, often inciting an unconventional perspective toward a problem. This article presents a motivational account of some Nobel Prize-winning researches in nerve signaling from Camillo Golgi and Santiago Ramón y Cajal describing the structure of nervous tissue in 1906 to Arvid Carlsson, Paul Greengard, and Eric R. Kandel unfolding the mechanisms of signaling pathways involved in brain function in the year 2000. This may sensitize the young researcher to take an interest in the historical work and understand that allegiance to investigate an idea may be driven by some striking past acquaintance or thoughtful insights. One may derive substantial inspiration to unravel further inscrutabilities and explore future avenues in translational research in nerve mechanisms.

Biofabrication in Congenital Cardiac Surgery: A Plea from the Operating Theatre, Promise from Science.

Despite significant advances in numerous fields of biofabrication, clinical application of biomaterials combined with bioactive molecules and/or cells largely remains a promise in an individualized patient settings. Three-dimensional (3D) printing and bioprinting evolved as promising techniques used for tissue-engineering, so that several kinds of tissue can now be printed in layers or as defined structures for replacement and/or reconstruction in regenerative medicine and surgery. Besides technological, practical, ethical and legal challenges to solve, there is also a gap between the research labs and the patients’ bedside. Congenital and pediatric cardiac surgery mostly deal with reconstructive patient-scenarios when defects are closed, various segments of the heart are connected, valves are implanted. Currently available biomaterials lack the potential of growth and conduits, valves derange over time surrendering patients to reoperations. Availability of viable, growing biomaterials could cancel reoperations that could entail significant public health benefit and improved quality-of-life. Congenital cardiac surgery is uniquely suited for closing the gap in translational research, rapid application of new techniques, and collaboration between interdisciplinary teams. This article provides a succinct review of the state-of-the art clinical practice and biofabrication strategies used in congenital and pediatric cardiac surgery, and highlights the need and avenues for translational research and collaboration.

Searching the Dark Genome for Alzheimer's Disease Risk Variants.

Sporadic Alzheimer’s disease (AD) is a complex genetic disease, and the leading cause of dementia worldwide. Over the past 3 decades, extensive pioneering research has discovered more than 70 common and rare genetic risk variants. These discoveries have contributed massively to our understanding of the pathogenesis of AD but approximately half of the heritability for AD remains unaccounted for. There are regions of the genome that are not assayed by mainstream genotype and sequencing technology. These regions, known as the Dark Genome, often harbour large structural DNA variants that are likely relevant to disease risk. Here, we describe the dark genome and review current technological and bioinformatics advances that will enable researchers to shed light on these hidden regions of the genome. We highlight the potential importance of the hidden genome in complex disease and how these strategies will assist in identifying the missing heritability of AD. Identification of novel protein-coding structural variation that increases risk of AD will open new avenues for translational research and new drug targets that have the potential for clinical benefit to delay or even prevent clinical symptoms of disease.

Metabolic Consequences of Solid Organ Transplantation.

Metabolic complications affect over 50% of solid organ transplant recipients. These include posttransplant diabetes, nonalcoholic fatty liver disease, dyslipidemia, and obesity. Preexisting metabolic disease is further exacerbated with immunosuppression and posttransplant weight gain. Patients transition from a state of cachexia induced by end-organ disease to a pro-anabolic state after transplant due to weight gain, sedentary lifestyle, and suboptimal dietary habits in the setting of immunosuppression. Specific immunosuppressants have different metabolic effects, although all the foundation/maintenance immunosuppressants (calcineurin inhibitors, mTOR inhibitors) increase the risk of metabolic disease. In this comprehensive review, we summarize the emerging knowledge of the molecular pathogenesis of these different metabolic complications, and the potential genetic contribution (recipient +/- donor) to these conditions. These metabolic complications impact both graft and patient survival, particularly increasing the risk of cardiovascular and cancer-associated mortality. The current evidence for prevention and therapeutic management of posttransplant metabolic conditions is provided while highlighting gaps for future avenues in translational research.

KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus scrofa Pigs

Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRASG12D-TP53R167H cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreatic duct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.

Sepsis Needs Follow-Up Studies in Intensive Care Units- Another Avenue for Translational Research

Sepsis Needs Follow-Up Studies in Intensive Care Units- Another Avenue for Translational Research

The impact of maternal neglect on genetic hyperactivity

Early environmental conditions are increasingly appreciated as critical in shaping behavior and cognition. Evidence suggests that stressful rearing environments can have an enduring impact on behaviors in adulthood, but few studies have explored the possibility that rearing environment could exacerbate genetic hyperactivity disorders. Uncovering a strong environmental influence on the transmission of hyperactivity could provide novel avenues for translational research. Recently we developed a selectively bred High-Active line of mice to model ADHD, providing a unique resource to address the question of environmental transmission. The High-Active line demonstrates transgenerational hyperactivity, but the influence of the postnatal environment (i.e. maternal care provided by dams) on hyperactivity had not been systemically quantified. This study employed a cross-fostering method to simultaneously address 1) whether High-Active and Control pups are provided with similar levels of care in the early environment, and 2) whether any differences in rearing environment influence hyperactive behavior. High-Active dams demonstrated impairment in all measures of maternal competence relative to Controls, which reduced survival rates and significantly reduced the body mass of offspring in early life and at weaning. While the deteriorated postnatal environment provided by High-Active dams was ultimately sufficient to depress Control activity, the hyperactivity of High-Active offspring remained unaffected by fostering condition. These data not only confirm the power of genetics to influence hyperactivity across generations, but also provide evidence that early rearing environments may not have a significant impact on the extreme end of hyperactive phenotypes.

Large animal models of atherosclerosis--new tools for persistent problems in cardiovascular medicine.

Coronary heart disease and ischaemic stroke caused by atherosclerosis are leading causes of illness and death worldwide. Small animal models have provided insight into the fundamental mechanisms driving early atherosclerosis, but it is increasingly clear that new strategies and research tools are needed to translate these discoveries into improved prevention and treatment of symptomatic atherosclerosis in humans. Key challenges include better understanding of processes in late atherosclerosis, factors affecting atherosclerosis in the coronary bed, and the development of reliable imaging biomarker tools for risk stratification and monitoring of drug effects in humans. Efficient large animal models of atherosclerosis may help tackle these problems. Recent years have seen tremendous advances in gene-editing tools for large animals. This has made it possible to create gene-modified minipigs that develop atherosclerosis with many similarities to humans in terms of predilection for lesion sites and histopathology. Together with existing porcine models of atherosclerosis that are based on spontaneous mutations or severe diabetes, such models open new avenues for translational research in atherosclerosis. In this review, we discuss the merits of different animal models of atherosclerosis and give examples of important research problems where porcine models could prove pivotal for progress.

Effects on DNA Damage and/or Repair Processes as Biological Mechanisms Linking Psychological Stress to Cancer Risk.

Considerable research effort in the past several decades has focused on the impact of psychological stress, and stress hormones, on cancer progression. Numerous studies have reported that stress hormone treatment or in vivo stress exposure can enhance the growth of tumor cell lines in vitro, as well as tumors in animal models, and have begun to explore molecular mechanisms. Comparatively little research has focused on the impact of psychological stress and stress hormones on cancer initiation, in part due to inherent methodological challenges, but also because potential underlying biological mechanisms have remained obscure. In this review, we present a testable theoretical model of pathways by which stress may result in cellular transformation and tumorigenesis. This model supports our overarching hypothesis that psychological stress, acting through increased levels of catecholamines and/or cortisol, can increase DNA damage and/or reduce repair mechanisms, resulting in increased risk of DNA mutations leading to carcinogenesis. A better understanding of molecular pathways by which psychological stress can increase the risk of cancer initiation would open new avenues of translational research, bringing together psychologists, neuroscientists, and molecular biologists, potentially resulting in the development of novel approaches for cancer risk reduction at the population level.

The Clinical Relevance of Cancer Cell Lines

Although advances in genomics during the last decade have opened new avenues for translational research and allowed the direct evaluation of clinical samples, there is still a need for reliable preclinical models to test therapeutic strategies. Human cancer-derived cell lines are the most widely used models to study the biology of cancer and to test hypotheses to improve the efficacy of cancer treatment. Since the development of the first cancer cell line, the clinical relevance of these models has been continuously questioned. Based upon recent studies that have fueled the debate, we review the major events in the development of the in vitro models and the emergence of new technologies that have revealed important issues and limitations concerning human cancer cell lines as models. All cancer cell lines do not have equal value as tumor models. Some have been successful, whereas others have failed. However, the success stories should not obscure the growing body of data that motivates us to develop new in vitro preclinical models that would substantially increase the success rate of new in vitro-assessed cancer treatments.

Costimulatory blockade with monoclonal antibodies to induce alloanergy in donor lymphocytes

Alloreactive donor T cells are central to the pathogenesis of Graft-versus-Host Disease (GvHD). Non-specific T cell depletion of donor grafts reduces GvHD, but increases infection and disease relapse. Several strategies are, therefore, in development to selectively remove alloreactive donor T cells prior to transplant while retaining beneficial donor T cells. An alternative approach is ex vivo alloanergization of donor T cells via allostimulation and blockade of costimulatory signals with fusion proteins or monoclonal antibodies. This strategy, which selectively inactivates alloreactive donor T cells, has been tested with some success in previous clinical trials of HLA-mismatched bone marrow transplantation. To build on the findings of these early trials, the strategy is now being tested in a multi-center clinical study of alloanergized donor lymphocyte infusion after HLA-mismatched stem cell transplantation. Recent advances in the understanding of alloanergization include the recognition of the central role played by CD4(+) regulatory T cells and new applications include the combination of alloanergization with T cell redirection to maximize anti-tumor activity. This mini-review will give an overview of the immunological basis for alloanergization, the previous and current clinical applications, and how new pre-clinical data have helped to create exciting new avenues of translational research in this area.

The renin–angiotensin system in 2011: new avenues for translational research

As pointed out by Nishimura [1], angiotensin II (Ang II) is an ancient peptide, even found in some primitive vertebrates and most probably evolved as a regulator of salt and water balance. Since the discovery of a pressor agent emanating from the mammalian kidney [2,3] focus on the rennin–angiotensin system (RAS) has been pivotal in fostering our understanding of the pathogenesis of a variety of cardiovascular and renal diseases. In this issue of Current Opinion in Pharmacology the emphasis is on novel mechanisms that involve the RAS and the mechanisms of its diverse functions. In a recent Pub Med search (1/28/2011) the term ‘angiotensin’ found 94,836 papers published since 1945. The impact of the physiology and pharmacology surrounding this peptide and its receptors is enormous. The treatment of hypertension and chronic heart failure has been revolutionized by drugs that target the production of Ang II and the blockade of its primary membrane target, the AT1 receptor. Angiotensin Converting Enzyme (ACE) Inhibitors and Ang II receptor blockers result in significant reductions in mortality and cardiovascular events for patients with hypertension and heart failure [4,5].

Cancer epigenomics: DNA methylomes and histone-modification maps

An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide - an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.

New Avenues of Translational Research in Leukemia and Lymphoma: Outgrowth of a Leukemia Society of America-National Cancer Institute Workshop

The workshop was organized on the premise that truly innovative approaches are needed if we are to significantly change the clinical outcomes for leukemias and lymphomas. Several new concepts and pioneering approaches surfaced during the workshop discussions, as summarized above. The design and implementation of translational clinical trials that emphasize these innovative strategies were encouraged as a way to test the concepts put forward at the workshop. Representatives of the Leukemia Society of America and the National Cancer Institute plan to continue their dialogue to develop recommendations regarding the priorities for linked clinical-laboratory investigations on the hematopoietic malignancies and the optimal ways in which to foster such translational research. To this end, the explosion in basic science discoveries during the last two decades and especially during the last 5 years is producing a critical mass of knowledge. This knowledge, in turn, allows us to view leukemia from new perspectives that span molecular pathogenesis, epidemiology, early detection of minimal disease, and the selective targeting of critical leukemogenic mechanisms for therapeutic and ultimately preventive purposes. As in previous decades, during which leukemia has served as the testing ground for precedent-setting concepts of curative therapy (dose-intensity, non-cross-resistance-inducing combinations and aggressive therapy in the minimal residual disease state), leukemia should again serve as a clinical beacon for the identification and exploitation of new molecular targets for therapy. Any impact on curability and duration and quality of survival will be achieved only by building on the cumulative knowledge accrued at multiple levels--molecular and cellular levels as well as in the intact patient--and augmenting the momentum of the bidirectional exchange of information between the laboratory and the clinic that has characterized leukemia research from its incipience. The challenge is formidable and worthy of our most creative and concerted efforts.