Between Bedside and Bench

Muscle diseases can take many forms, from the progressive muscle degeneration of dystrophies to the childhood cancer rhabdomyosarcoma. In 'Bench to Bedside', Joel R. Chamberlain and Jeffrey S. Chamberlain discuss studies using antisense oligonucleotides to treat Duchenne muscular dystrophy and myotonic dystrophy. In 'Bedside to Bench', Simone Hettmer and Amy J. Wagers examine the implications of clinical studies describing a type of rhabdomyosarcoma that resembles acute leukemia. The findings dovetail with other studies suggesting that some of these cancers might originate outside of muscle tissue and highlight the need for a better understanding of the cells that give rise to this condition.

The vasculature suffers damage as a result of diabetes, often leading to conditions such as kidney failure. In bench to bedside, Christian Rask-Madsen and George King examine endogenous factors that protect against damage of the vasculature, such as vascular-endothelial growth factor (VEGF). Recent studies report that VEGF is expressed by kidneys and fends off renal failure; such findings have implications for the development of treatments that harness endogenous factors and sound a note of caution for the therapeutic use of VEGF inhibitors. People with end-stage renal disease often die of cardiovascular complications and clinical studies have shown that one popular class of drugs, statins, does not work in this population. In bedside to bench, S. Ananth Karumanchi and Ravi Thadhani show how this clinical finding is spurring research into the biological mechanisms behind cardiovascular death in people with kidney disease.

There are many ways to modulate the immune response in a therapeutic setting. Drugs that target the proinflammatory mediator IL-1, for instance, can counteract disease in certain types of inflammatory conditions. But such drugs do not work well for other conditions, such as rheumatoid arthritis and other autoimmune diseases. New clinical studies, examined by Kingston Mills and Aisling Dunne, provide insight into this discrepancy. Another approach that has worked well in mice harnesses the ability of regulatory T cells to dampen the immune response. But one barrier in the way of successful application to people is the ability of such cells to change their character for the worse. Massimo Gadina and John O'Shea take a look at a basic research study that highlights this dilemma and examine what it means for the future of human trials.

Flu remains a major killer because of imperfect vaccines and widespread resistance to existing antivirals—problems particularly acute during a pandemic. New findings at the bedside and at the bench could lead to improvements on both fronts. Grace Chen and Kanta Subbarao discuss the implications of research identifying human antibodies than can neutralize a range of viral subtypes. The findings may help lead to a 'universal' vaccine against these diverse and rapidly evolving viruses. Estanislao Nistal-Villán and Adolfo García-Sastre examine two recent studies that reveal the crystal structure of a promising viral drug target, the unique endonuclease domain of the viral polymerase. The findings open the door to the rational design of new influenza virus inhibitors.

Hemorrhages in the brain are responsible for about 15% of strokes and are particularly difficult to treat. Costantino Iadecola assesses a new clinical study that may change the view of why a common form of hemorrhage, subarachnoid hemorrhage, often leads to death. Massive brain lesions often develop days after the initial event, a dangerous complication previously attributed to vasospasm, narrowing of the arteries. The study suggests that these lesions may instead by caused by neuronal depolarization, extending in waves across the brain. Gregory del Zoppo explores the connection between deposition of toxic amyloid-β peptides in the brain and hemorrhage. He discusses studies suggesting that the peptides inactivate proteins in the blood that can stop hemorrhage.

Before stem cell therapies become mainstream, several hurdles must be overcome. One challenge is developing air-tight approaches to assure that stem cell transplantation does not give rise to tumors. Another is finding safe ways to induce pluripotency in adult stem cells, which can then be used for transplantation. In Bedside to Bench, Evan Snyder and Rahul Jandial discuss the risks of tumorigenesis in stem cell therapies, and, in Bench to Bedside, Laura Clarke and Derek van der Kooy examine new ways to induce pluripotency.

Genetic approaches in animal models have recently led to new ways of thinking about inherited neuropsychiatric disorders. Many such disorders were thought to originate during early development, but newer findings have suggested that processes in the adult nervous system also contribute. Dan Ehninger and Alcino J. Silva outline how such events in the adult may be amenable to therapy, including some approaches in clinical trials. In Bedside to Bench, Petrus de Vries questions the utility of genome-wide association studies for autism spectrum disorders and other neuropsychiatric conditions.

People with damage to the central nervous system often undergo rehabilitation therapy. James Fawcett and Armin Curt examine how such therapy might work in conjunction with experimental approaches that increase the ability of neurons to form new connections. They discuss how animal studies raise questions about how to test such approaches in people in a field where firm data are already hard to come by. Phillip Popovich and Dana McTigue take a look at a specific type of nervous system damage—spinal cord injury—and argue that the role of the immune system is underappreciated. They also suggest that one common therapy, application of glucocorticoids, might actually exacerbate the condition.

Bariatric surgery is not only one of the most immediate and effective ways to slim down: recent clinical data show that certain procedures are also particularly good at quelling type 2 diabetes. In “Bedside to Bench,” Allison Goldfine, Steven Shoelson and Vincent Aguirre outline how researchers can better understand these new clinical findings at the mechanistic level. In the accompanying “Bench to Bedside,” Jorge Plutzky takes a look how proper regulation of the storage of fatty acids helps maintain their effectiveness as signaling molecules and reins in their potential pathological effects. Such research is leading to new ways of thinking about how to combat type 2 diabetes.

The immune response goes haywire during sepsis, a deadly condition triggered by infection. Richard S. Hotchkiss and his colleagues take the focus off of the prevailing view that the key aspect of this response is an exuberant inflammatory reaction. They assess recent human studies bolstering the notion that immunosuppression is also a major contributor to the disease. Many people with sepsis succumb to cardiac dysfunction, a process examined by Peter Ward. He showcases the factors that cause cardiomyocyte contractility to wane during the disease.