Pro-fibrotic pathway activation in trabecular meshwork and lamina cribrosa is the main driving force of glaucoma.

While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh-like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFß observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues.

Innovation in medicine: Ignaz the reviled and Egas the regaled.

In our current climate of rapid technological progress, it seems counterintuitive to think that modern science can learn anything of ethical value from the dark recesses of the nineteenth century or earlier. However, this happens to be quite true, with plenty of knowledge and wisdom to be gleaned by studying our scientific predecessors. Presently, our journals are flooded with original concepts and potential breakthroughs, a continuous stream of ideas pushing the frontiers of knowledge ever forward. Some ideas flourish while others flounder; but what sets the two apart? The distinguishing feature between success and failure within this context is the ability to discern the appropriate time to accept an innovation with open arms, versus when to take a more cautious approach. And the primary arbiters for whether an idea will catch on or not are the professional audience. I illustrate this concept by comparing the initial reception of two innovative ideas from Medicine's past: sterile technique, and prefrontal lobotomy. Sterile technique was first introduced by Dr. Ignaz Semmelweis and was initially ridiculed and rejected, with Semmelweis eventually dying in exile. Conversely, lobotomy was accepted and lauded and its inventor, Dr. Egas Moniz, won the Nobel Prize for his "discovery". This begs the question: why was a technique with the potential to save millions of lives initially rejected, whereas paradoxically, one that compromised and sometimes destroyed lives, accepted? Here I explore and analyze the potential reasons why, suggest how we can learn from these mistakes of the past and apply new insight to some current ethical dilemmas.

Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells.

For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated. In the present study we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using GeroScope pathway analysis and drug discovery platform we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also points to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.