Signaling modality within gp130 receptor enhances tissue regeneration

Adult mammals are incapable of multi-tissue regeneration and augmentation of this potential may drastically shift current therapeutic paradigms. Here, we found that a common co-receptor of IL-6 cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) exhibit regenerative, not reparative, responses after wounding in skin and anti-degenerative responses in the synovial joint. In addition, pharmacological inhibition of gp130 Y814 results in regeneration of multiple tissues in several species as well as disease modification in animal models of osteoarthritis. Our study characterizes a novel molecular mechanism that, if selectively manipulated, enhances the intrinsic regenerative capacity while preventing pathological outcomes in injury and disease.

Disease Modification in Gout: A Qualitative Study of Gout Expert Rheumatologists

Objective To examine healthcare provider views of disease modification in gout to potentially derive a provisional set of domains for disease modification in gout. Methods We performed a qualitative nominal group (NG) study with 20 gout experts (15 were authors/expert panel members of the 2012 and/or 2020 ACR gout guidelines, and/or 2015 ACR/EULAR gout classification criteria) about what constitutes “disease modification” in gout – “What sorts of things do you think constitute a change in the course of disease in gout? (positive); What are all the ways in which gout as a disease can be modified?” Results Decrease in gout flares was rated #1 rank in all six NGs as indicative of disease modification in gout, followed by serum urate (SU) lowering, which was rated #1 rank in 1 of the 6 NGs (tied score with flares in one NG). Other components of gout disease modification were to improve quality of life/productivity; restore function; reduce/eliminate pain; reduce tophi burden; and joint preservation or resolution of joint damage. Potential additional components that were not ranked in the top 3 votes within each NG were: Decrease healthcare cost/utilization; cardiovascular/renal morbidity/mortality reduction; and stop urate crystals formation. Conclusion This qualitative study provides a provisional set of domains for disease modification in gout. Future studies for the development of thresholds for disease modification domains, and wider consensus on this definition are needed.

Impact of potential modifications to Alzheimer’s disease clinical trials in response to disruption by COVID-19: a simulation study

Background The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made. Methods We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined. Results Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned. Discussion These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials’ validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

RECENT ADVANCES INPHARMACOTHERAPY OF ALZHEIMER’S DISEASE

The management of Alzheimer's disease (AD) has been a long-standing challenge and area of interest. Advances in knowledge of the pathogenesis of disease and an increase in disease burden have prompted investigation into innovative therapeutics over the last two decades. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the 'Aβ hypothesis', there are a number of newer approaches to treat AD. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.