Profibrotic agents for venous malformations?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108378/1/bjd13164.pd

Pachyonychia congenita cornered: report on the 11th A nnual I nternational P achyonychia C ongenita C onsortium Meeting

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109650/1/bjd13341.pd

Multi-Armed Bandits for Correlated Markovian Environments with Smoothed Reward Feedback

We study a multi-armed bandit problem in a dynamic environment where arm rewards evolve in a correlated fashion according to a Markov chain. Different than much of the work on related problems, in our formulation a learning algorithm does not have access to either a priori information or observations of the state of the Markov chain and only observes smoothed reward feedback following time intervals we refer to as epochs. We demonstrate that existing methods such as UCB and $\varepsilon$-greedy can suffer linear regret in such an environment. Employing mixing-time bounds on Markov chains, we develop algorithms called EpochUCB and EpochGreedy that draw inspiration from the aforementioned methods, yet which admit sublinear regret guarantees for the problem formulation. Our proposed algorithms proceed in epochs in which an arm is played repeatedly for a number of iterations that grows linearly as a function of the number of times an arm has been played in the past. We analyze these algorithms under two types of smoothed reward feedback at the end of each epoch: a reward that is the discount-average of the discounted rewards within an epoch, and a reward that is the time-average of the rewards within an epoch.Comment: Significant revision of prior version including deeper discussion of related work, gap-independent regret bounds, and regret bounds for discounted reward

Hypo‐collagenesis in photoaged skin predicts response to anti‐aging cosmeceuticals

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98115/1/jocd12037.pd

Metalloproteinase-Mediated, Context-Dependent Function of Amphiregulin and HB-EGF in Human Keratinocytes and Skin

Human keratinocytes (KCs) express multiple EGF receptor (EGFR) ligands; however, their functions in specific cellular contexts remain largely undefined. To address this issue, first we measured mRNA and protein levels for multiple EGFR ligands in KCs and skin. Amphiregulin (AREG) was by far the most abundant EGFR ligand in cultured KCs, with >19 times more mRNA and >7.5 times more shed protein than any other family member. EGFR ligand expression in normal skin was low (<8‰ of RPLP0/36B4); however, HB-EGF and AREG mRNAs were strongly induced in human skin organ culture. KC migration in scratch wound assays was highly metalloproteinase (MP)- and EGFR dependent, and was markedly inhibited by EGFR ligand antibodies. However, lentivirus-mediated expression of soluble HB-EGF, but not soluble AREG, strongly enhanced KC migration, even in the presence of MP inhibitors. Lysophosphatidic acid (LPA)-induced ERK phosphorylation was also strongly EGFR and MP dependent and markedly inhibited by neutralization of HB-EGF. In contrast, autocrine KC proliferation and ERK phosphorylation were selectively blocked by neutralization of AREG. These data show that distinct EGFR ligands stimulate KC behavior in different cellular contexts, and in an MP-dependent fashion

Matricellular protein CCN3 mitigates abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality; however, the mechanisms that are involved in disease initiation and progression are incompletely understood. Extracellular matrix proteins play an integral role in modulating vascular homeostasis in health and disease. Here, we determined that the expression of the matricellular protein CCN3 is strongly reduced in rodent AAA models, including angiotensin II-induced AAA and elastase perfusion-stimulated AAA. CCN3 levels were also reduced in human AAA biopsies compared with those in controls. In murine models of induced AAA, germline deletion of Ccn3 resulted in severe phenotypes characterized by elastin fragmentation, vessel dilation, vascular inflammation, dissection, heightened ROS generation, and smooth muscle cell loss. Conversely, overexpression of CCN3 mitigated both elastase- and angiotensin II-induced AAA formation in mice. BM transplantation experiments suggested that the AAA phenotype of CCN3-deficient mice is intrinsic to the vasculature, as AAA was not exacerbated in WT animals that received CCN3-deficient BM and WT BM did not reduce AAA severity in CCN3-deficient mice. Genetic and pharmacological approaches implicated the ERK1/2 pathway as a critical regulator of CCN3-dependent AAA development. Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease

Aging Alters Functionally Human Dermal Papillary Fibroblasts but Not Reticular Fibroblasts: A New View of Skin Morphogenesis and Aging

Understanding the contribution of the dermis in skin aging is a key question, since this tissue is particularly important for skin integrity, and because its properties can affect the epidermis. Characteristics of matched pairs of dermal papillary and reticular fibroblasts (Fp and Fr) were investigated throughout aging, comparing morphology, secretion of cytokines, MMPs/TIMPs, growth potential, and interaction with epidermal keratinocytes. We observed that Fp populations were characterized by a higher proportion of small cells with low granularity and a higher growth potential than Fr populations. However, these differences became less marked with increasing age of donors. Aging was also associated with changes in the secretion activity of both Fp and Fr. Using a reconstructed skin model, we evidenced that Fp and Fr cells do not possess equivalent capacities to sustain keratinopoiesis. Comparing Fp and Fr from young donors, we noticed that dermal equivalents containing Fp were more potent to promote epidermal morphogenesis than those containing Fr. These data emphasize the complexity of dermal fibroblast biology and document the specific functional properties of Fp and Fr. Our results suggest a new model of skin aging in which marked alterations of Fp may affect the histological characteristics of skin

Report of the 13th Annual International Pachyonychia Congenita Consortium Symposium

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137611/1/bjd15417.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137611/2/bjd15417_am.pd