Translational strategies in drug development for knee osteoarthritis.

Osteoarthritis (OA) is a common disease worldwide with large unmet medical needs. To bring innovative treatments to OA patients, we at Merck have implemented a comprehensive strategy for drug candidate evaluation. We have a clear framework for decision-making in our preclinical pipeline, to design our clinical proof-of-concept trials for OA patients. We have qualified our strategy to define and refine dose and dosing regimen, for treatments administered either systemically or intra-articularly (IA). We do this through preclinical in vitro and in vivo studies, and by back-translating results from clinical studies in OA patients

Building resilience in CTLs: Reflections on practice

What are the qualities of the “now” that make teaching and learning an urgent, if not a moral, imperative? A group of faculty, administrators, and educational developers respond to this question with individual narratives bound together by a common theme of reflective practice in times of crises to help faculty become more resilient in preparing for ongoing upheavals and unexpected crises while pursuing more inclusive communities. Our personal narratives reflect on the subjects of flexibility in the face of crises, technology and ethics, study abroad exposure to ethical challenges, students’ growing anxiety and mental health, modeling metacognition with peers and students, and considerations of pedagogy in uncertain times. Our individual stories of practice will be helpful to teaching and learning center colleagues who work with faculty and to faculty themselves as they operate in times of crises

Building Resilience in CTLs: Reflections on Practice

What are the qualities of the “now” that make teaching and learning an urgent, if not a moral, imperative? A group of faculty, administrators, and educational developers respond to this question with individual narratives bound together by a common theme of reflective practice in times of crises to help faculty become more resilient in preparing for ongoing upheavals and unexpected crises while pursuing more inclusive communities. Our personal narratives reflect on the subjects of flexibility in the face of crises, technology and ethics, study abroad exposure to ethical challenges, students’ growing anxiety and mental health, modeling metacognition with peers and students, and considerations of pedagogy in uncertain times. Our individual stories of practice will be helpful to teaching and learning center colleagues who work with faculty and to faculty themselves as they operate in times of crises

A Critical Site in the Core of the CCR5 Chemokine Receptor Required for Binding and Infectivity of Human Immunodeficiency Virus Type 1

Like the CCR5 chemokine receptors of humans and rhesus macaques, the very homologous (∼98–99% identical) CCR5 of African green monkeys (AGMs) avidly binds β-chemokines and functions as a coreceptor for simian immunodeficiency viruses. However, AGM CCR5 is a weak coreceptor for tested macrophage-tropic (R5) isolates of human immunodeficiency virus type 1 (HIV-1). Correspondingly, gp120 envelope glycoproteins derived from R5 isolates of HIV-1 bind poorly to AGM CCR5. We focused on a unique extracellular amino acid substitution at the juncture of transmembrane helix 4 (TM4) and extracellular loop 2 (ECL2) (Arg for Gly at amino acid 163 (G163R)) as the likely source of the weak R5 gp120 binding and HIV-1 coreceptor properties of AGM CCR5. Accordingly, a G163R mutant of human CCR5 was severely attenuated in its ability to bind R5 gp120s and to mediate infection by R5 HIV-1 isolates. Conversely, the R163G mutant of AGM CCR5 was substantially strengthened as a coreceptor for HIV-1 and had improved R5 gp120 binding affinity relative to the wild-type AGM CCR5. These substitutions at amino acid position 163 had no effect on chemokine binding or signal transduction, suggesting the absence of structural alterations. The 2D7 monoclonal antibody has been reported to bind to ECL2 and to block HIV-1 binding and infection. Whereas 2D7 antibody binding to CCR5 was unaffected by the G163R mutation, it was prevented by a conservative ECL2 substitution (K171R), shared between rhesus and AGM CCR5s. Thus, it appears that the 2D7 antibody binds to an epitope that includes Lys-171 and may block HIV-1 infection mediated by CCR5 by occluding an HIV-1-binding site in the vicinity of Gly-163. In summary, our results identify a site for gp120 interaction that is critical for R5 isolates of HIV-1 in the central core of human CCR5, and we propose that this site collaborates with a previously identified region in the CCR5 amino terminus to enable gp120 binding and HIV-1 infections

Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation

<p>Abstract</p> <p>Objectives</p> <p>The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation.</p> <p>Methods</p> <p>The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs.</p> <p>Results</p> <p>MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009).</p> <p>Conclusion</p> <p>In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation.</p

211 Identifying lupus patient subsets and specific pharmacodynamic changes through immune cell deconvolution of gene expression data in atacicept-treated patients in the APRIL-SLE study

n/

Venice: An Aging City

This project initiated a study of the quality of life of older Venetians. Through observations as well as interviews with older Venetians and with representatives of service agencies, we learned that Venice is a city beloved by its elderly residents. Its distinctive setting provides numerous social opportunities, strong community ties, a relaxed lifestyle, and very rich culture and history. But for all its attributes, Venice is not perfect; challenges include the high cost of living, mobility for some, and the overabundance of tourists