Genetics and rheumatoid arthritis susceptibility in Iran

Rheumatoid arthritis (RA) is an autoimmune disorder with a number of risk factors, including both genetic and environmental. A number of RA risk associated genomic loci has been identified. In this review, we summarize the association of genetic factors with RA reported in population studies in Iran. No significant association was found between the majority of genetic factors identified in other populations and risk for RA in the Iranian subjects. This conflicting result could be due to the ethnic differences and diversity that are present in Iran. We conclude that there is a need to investigate larger groups of Iranian subjects, encompassing different regions of Iran, to either prove or refute these initial findings.     

Pathology and diseases of great apes at the National Zoological Park

Knowledge of the diseases of great apes in captivity is essential for captive management of self-sustaining populations. This survey of medical and pathology records of orangutans, gorillas, and one chimpanzee at the National Zoological Park was conducted to provide a data base for improving health care of captive apes. Strongyloidiasis, balantidiasis, and entamoebiasis were recurrent problems in adult and juvenile apes of all species. Cardiac fibrosis also was prevalent in middle-aged apes and was a major cause of mortality. Bacterial infections were prevalent in perinatal orangutans and resulted in the death of two. For gorillas, rheumatoid arthritis associated with mycoplasma infections, and infertility were major problems. Because the pathogenesis of many of these lesions is unknown, survival of great ape populations in captivity may depend on future research on these problems.     

Identification of highly potent and selective PI3Kδ inhibitors

Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined.     

Interactions between cadherin-11 and platelet-derived growth factor receptor-alpha signaling link cell adhesion and proliferation

Cadherins are homophilic cell-to-cell adhesion molecules that help cells respond to environmental changes. Newly formed cadherin junctions are associated with increased cell phosphorylation, but the pathways driving this signaling response are largely unknown. Since cadherins have no intrinsic signaling activity, this phosphorylation must occur through interactions with other signaling molecules. We previously reported that cadherin-11 engagement activates joint synovial fibroblasts, promoting inflammatory and degradative pathways important in rheumatoid arthritis (RA) pathogenesis. Our objective in this study was to discover interacting partners that mediate cadherin-11 signaling. Protein array screening showed that cadherin-11 extracellular binding domains linked to an Fc domain (cad11Fc) induced platelet-derived growth factor (PDGFR)-α phosphorylation in synovial fibroblasts and glioblastoma cells. PDGFRs are growth factor receptor tyrosine kinases that promote cell proliferation, survival, and migration in mesodermally derived cells. Increased PDGFR activity is implicated in RA pathology and associates with poor prognosis in several cancers, including sarcoma and glioblastoma. PDGFRα activation by cadherin-11 signaling promoted fibroblast proliferation, a signaling pathway independent from cadherin-11-stimulated IL-6 or matrix metalloproteinase (MMP)-3 release. PDGFRα phosphorylation mediated most of the cad11Fc-induced phosphatidyl-3-kinase (PI3K)/Akt activation, but only part of the mitogen-activated protein kinase (MAPK) response. PDGFRα-dependent signaling did not require cell cadherin-11 expression. Rather, cad11Fc immunoprecipitated PDGFRα, indicating a direct interaction between cadherin-11 and PDGFRα extracellular domains. This study is the first to report an interaction between cadherin-11 and PDGFRα and adds to our growing understanding that cadherin-growth factor receptor interactions help balance the interplay between tissue growth and adhesion.     

pHLIP and acidity as a universal biomarker for cancer

Of great importance to clinical cancer diagnosis is the use of organic biomarkers. The detection of RNA, DNA, and protein antigen are all established methods for identifying specific cancer types and instrumental in promoting greater survivorship of the patient. Despite many decades of intense cancer research, we have yet to identify a "universal" protein or nucleic acid that allows us to diagnose more than a small subset of cancers at a time. In this review, we examine the use of localized cellular acidity as a universal marker for solid tumors, outlining some successes with a small peptide we call pHLIP, a pH-sensitive biosensor that allows us to label tumor tissue in live mice.