Between Bedside and Bench

Given the multisystemic nature of the metabolic syndrome, the field is now aiming at perusing both intrinsic and environmental factors from a biological and therapeutic standpoint. Physicians often advise obese individuals suffering from type 2 diabetes to lose weight through exercise and healthy diets. Although it may be an obvious recommendation, a large study has recently shown that weight loss achieved through these lifestyle changes does not significantly reduce cardiovascular disease events in these patients compared to conventional diabetes care. In 'Bedside to Bench', Julie A. Lovshin and Daniel J. Drucker discuss the limitations of this study, the conclusions that can be drawn regarding the true benefit of weight loss in this context and the molecular factors that deserve further attention at the bench in light of this trial. In 'Bench to Bedside', Eleftheria Maratos-Flier examines the role of antidiabetic drugs in both host and gut microbiota metabolism. These effects in the intestinal flora support advocating an increase in our understanding of how the gut microbiome affects obesity for finding the means to harness its therapeutic potential.

The field of tumor immunology has been flooded with exciting therapeutic advances on many fronts. Immunotherapies targeting T cell inhibitory molecules have proven highly effective in some cancers, but additional strategies to induce tumor immunity, such as cancer vaccination, could further increase tumor killing. The combination of both will probably be the way forward in future immunotherapy. In 'Bedside to Bench', Robert Vonderheide and Katherine Nathanson discuss the potential of cancer genomics to identify specific tumor mutations in patients that may be used as targets in cancer vaccines to overcome problems linked to self-antigen epitopes used nowadays. Despite the existing biological and technical hurdles, a framework to implement personalized cancer vaccines in the clinic may be worth considering. In 'Bench to Bedside', Glenn Dranoff peruses the clinical efficacy and detrimental effects of two T cell immune-checkpoint inhibitors, alone and in combination, in patients with melanoma. The studies underscore the need to continue investigating specific tumor events directly involving tumor evasion to develop combinatorial strategies that will reduce drug-related pathology while achieving anti-tumor efficacy.

How eosinophils function in different tissues during health and disease is not completely understood. On the one hand, they seem to be crucial in inflammatory disorders, which suggests that pathways related to their activation and regulation may be potential therapeutic targets. In asthma, the role of these cells is well known; however, airway inflammation owing to increased eosinophils in lung tissue in nonallergic asthma has only recently started to be in the limelight. In 'Bedside to Bench', Guy G. Brusselle, Tania Maes and Ken R. Bracke peruse the disease pathway triggering eosinophilic inflammation in nonallergic eosinophilic asthma and the potential targets that may lead to effective therapies. The authors also discuss a clinical study that highlights the need to phenotype patients using cellular and molecular markers to improve treatment responses. However, on the other hand, a recent study has also shown a homeostatic role of eosinophils in metabolism in fat tissue. In 'Bench to Bedside', Clare M. Lloyd and Sejal Saglani examine evidence that hints at the crucial role of the location of eosinophils in different tissues such as lung, where they cause inflammation, and visceral fat, where they improve glucose homeostasis. Clinical data that correlate lung tissue eosinophilia with obesity may spur new research to shed light on the role of these inflammatory cells in obese individuals with asthma and on how to improve treatments in these patients.

Discerning which mediators drive pathogenesis in chronic inflammatory diseases can be complex: immune cells can release various pathogenic cytokines, and numerous cytokines may either cause one specific disease or many. Human validation and mechanistic studies will be necessary to identify the key immune cells and cytokines for a given inflammatory disorder and to pinpoint which cytokine might be the appropriate target for tackling each disease. In 'Bedside to Bench', Georg Schett et al. discuss how human trials targeting different cytokines suggest the existence of a hierarchical framework of cytokines that defines groups of chronic inflamatory diseases rather differently from the homogenous molecular disease pattern previously assumed. In 'Bench to Bedside', Vijay Kuchroo and Dominique Baeten peruse the role of interleukin-17A as drug target in several autoimmune diseases to highlight how success in the clinic will need understanding of pathogenic pathways and the immunological and tissue context of each inflammatory disease.

Using brain surgery, specific areas in the brain can be stimulated with electrical impulses to reversibly change their activity and alleviate symptoms related to mental illnesses. This so-called deep brain stimulation and other methodological advances that even more selectively activate specific groups of neurons can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective. In 'Bedside to Bench', Eric Nestler discusses two trials of individuals with anorexia nervosa in which deep brain stimulation of different brain areas resulted in improvement of behavioral domains associated with the syndrome. The results and potential of this technique in animals and humans may bring us closer to understanding the neurobiology of anorexia nervosa, which still remains a mystery and poses a challenge for treatment. In 'Bench to Bedside', Jennifer Warner-Schmidt peruses recent findings that uncover the functional connectivity of brain regions involved in depression and how activation of cortical regions can result in antidepressant effects that can compensate for the malfunction of other brain circuits that results in depression.

Myocardial infarction can cause irreversible heart muscle cell damage and lingering cardiac problems that can eventually lead to heart failure. For over a decade, researchers have been trying to coax stem cells to differentiate into cardiomyocytes to repair damaged heart tissue, with limited success. In 'Bedside to Bench', Christine L. Mummery and Richard T. Lee lay out a framework for re-evaluating cardiac cell therapies in the context of two recent clinical trials, in which autologous cardiac stem cells derived from heart biopsies were transferred into patients, with promising, albeit difficult to interpret, results. Results from previous clinical trials using autologous bone marrow–derived adult stem cells to induce cardiac regeneration add to the debate about how to cautiously move forward in the cardiac regeneration field and to the questions that need to be urgently answered at the bench. In 'Bench to Bedside', Young-Jae Nam, Kunhua Song and Eric N. Olson discuss a number of recent studies in rodents showing that cardiac fibroblasts can be reprogrammed, via miRNAs and a transcription factor 'cocktail', to express cardiac genes, which resulted in improved cardiac function in the animals, suggesting a new way forward for fixing damaged heart tissue.

Cancer resistance to targeted therapies seems to be a field of active research. But there are still open questions as to what drives drug resistance not only in metastatic tumor cells but also in disseminated tumor cells (DTCs) during adjuvant treatment, before metastases are established in other organs. Targeting this residual cancer disease or keeping these DTCs in a dormant state may be a way to stop progression to metastatic disease. For this, a further understanding of the biology of these cells is necessary. In 'Bedside to Bench', Bernhard Polzer and Christopher Klein put forward several scenarios to explain the different resistant mechanisms that might account for DTCs unresponsiveness to cancer drugs and emphasize the relevance of synchronizing targeted therapies with the changing responsive or dormant state of disseminated cancer cells in the clinic. In 'Bench to Bedside', Julio A Aguirre-Ghiso, Paloma Bragado and Maria Soledad Sosa discuss possible cell-intrinsic and microenvironment-derived signaling pathways that may be exploited to maintain dormancy in DTCs and explore the possibility of using dormancy gene signatures to identify individuals with dormant disease.

Modern medicine keeps unraveling new ways to investigate autoimmunity, leading to the production of boundless amounts of genetic, cellular and imaging data. Although the precision with which this information can define the etiology and mechanisms of a particular autoimmune disease is encouraging, much work lies ahead until all the knowledge acquired can be translated into the clinic. In 'Bedside to Bench', Calliope A. Dendrou, John I. Bell and Lars Fugger discuss the promises and limitations of genome-wide and next-generation genetic studies to provide further understanding of mechanisms driving autoimmune disorders and the role of experimental medicine in the new era of integrative clinical practice and personalized medicine. In 'Bench to Bedside', Lawrence Steinman argues the concept of a 'hub and spoke' pattern of T cell activation and organ targeting in multiple sclerosis, inflammatory bowel disease and type 1 diabetes. This paradigm suggests new ways to develop drugs to keep autoreactive T cells in the organ where activation occurs and preclude them from reaching the target organ and cause disease.

Despite the irrefutable role of inflammation in psoriasis, a complete knowledge of what immune cells and cytokines are involved during initiation and progression of this skin disease is lacking. Moreover, the complexities of the immune cell network and potential differences between mice and humans have led to translational failures. It is therefore important that we acquire in-depth understanding of what inflammatory players, of the many involved, are crucial, if we wish to develop effective therapies. In 'Bedside to Bench', James Krueger discusses how a subset of T cells, T_H17 cells, which release interleukin-17 in humans, seem to be essential for pathogenesis of psoriasis. The interplay between interleukin-17 and other cytokines that may potentially be involved in psoriasis also needs further investigation. Additionally, there are open questions as to what subset of T cells, other than T_H17, also produce interleukin-17 and when. In 'Bench to Bedside', Burkhard Becher and Stanislav Pantelyushin examine this issue by looking at a mouse model of skin inflammation that resembles psoriasis in humans. A class of skin-invading innate immune cells called γδ T cells was shown to drive skin inflammation in this model, particularly during the early stages of the disease, suggesting that innate immunity plays an important part in the initiation of psoriasis.

There is increasing interest in understanding how epilepsy initiates and how to thwart the establishment of the disease. Many questions remain open as to what targets may the best for preventing epilepsy and whether any common triggering pathway exists to treat this complex malady. In 'Bedside to Bench', Rod C. Scott and Gregory Holmes discuss alternative therapies to treat neonatal seizures to prevent chronic cognitive impairment and brain developmental problems, which can lead to epilepsy later in life. Increasing inhibitory signals in the developing brain may be useful in dampening brain hyperexcitability—and enhanced susceptibility for seizures—and blocking epilepsy development in children. In 'Bench to Bedside', Annamaria Vezzani argues how the mTOR pathway may be a potential target for blocking epileptogenesis. The role of mTOR in seizures in early life and progression of established disease raises the possibility that mTOR could be a common mediator involved in epilepsy at different stages of disease initiation and progression. Given the lack of current antiepileptic drugs to prevent seizures in children and to block epileptogenesis, developing new disease-modifying therapies remains a priority.