Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

Objective: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. Results: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0

IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2–dependent mechanisms with implications for psoriasis pathogenesis

Aberrant cytokine expression has been proposed as an underlying cause of psoriasis, although it is unclear which cytokines play critical roles. Interleukin (IL)-23 is expressed in human psoriasis and may be a master regulator cytokine. Direct intradermal administration of IL-23 in mouse skin, but not IL-12, initiates a tumor necrosis factor–dependent, but IL-17A–independent, cascade of events resulting in erythema, mixed dermal infiltrate, and epidermal hyperplasia associated with parakeratosis. IL-23 induced IL-19 and IL-24 expression in mouse skin, and both genes were also elevated in human psoriasis. IL-23–dependent epidermal hyperplasia was observed in IL-19−/− and IL-24−/− mice, but was inhibited in IL-20R2−/− mice. These data implicate IL-23 in the pathogenesis of psoriasis and support IL-20R2 as a novel therapeutic target

Global Chromatin Architecture Reflects Pluripotency and Lineage Commitment in the Early Mouse Embryo

An open chromatin architecture devoid of compact chromatin is thought to be associated with pluripotency in embryonic stem cells. Establishing this distinct epigenetic state may also be required for somatic cell reprogramming. However, there has been little direct examination of global structural domains of chromatin during the founding and loss of pluripotency that occurs in preimplantation mouse development. Here, we used electron spectroscopic imaging to examine large-scale chromatin structural changes during the transition from one-cell to early postimplantation stage embryos. In one-cell embryos chromatin was extensively dispersed with no noticeable accumulation at the nuclear envelope. Major changes were observed from one-cell to two-cell stage embryos, where chromatin became confined to discrete blocks of compaction and with an increased concentration at the nuclear envelope. In eight-cell embryos and pluripotent epiblast cells, chromatin was primarily distributed as an extended meshwork of uncompacted fibres and was indistinguishable from chromatin organization in embryonic stem cells. In contrast, lineage-committed trophectoderm and primitive endoderm cells, and the stem cell lines derived from these tissues, displayed higher levels of chromatin compaction, suggesting an association between developmental potential and chromatin organisation. We examined this association in vivo and found that deletion of Oct4, a factor required for pluripotency, caused the formation of large blocks of compact chromatin in putative epiblast cells. Together, these studies show that an open chromatin architecture is established in the embryonic lineages during development and is sufficient to distinguish pluripotent cells from tissue-restricted progenitor cells

Transcription termination factor TTF-I exhibits contrahelicase activity during DNA replication

In mammals, sequence-specific termination of DNA replication within the ribosomal RNA genes is catalyzed by a defined DNA–protein complex that includes transcription termination factor I (TTF-I). Here we show that TTF-I acts as a polar contrahelicase contrary to the intrinsic 3′→5′ helicase activity of SV40 large T antigen. The contrahelicase activity requires binding of TTF-I to its cognate recognition site and the presence of an auxiliary GC-rich sequence, which is able to form a specific secondary structure. Mutations in the GC-rich sequence lead to a loss of folding into correct secondary structure and abrogate contrahelicase activity. The finding suggests that a specific interaction between the Sal box-bound TTF-I and the GC-rich sequence is essential for the inhibition of T antigen helicase. Analyses of N-terminally truncated mutants of TTF-I showed inhibition of helicase by the same domain of TTF-I, which is also responsible for replication fork arrest

Interactions Between Hemopoietically Derived TNF and Central Nervous System-Resident Glial Chemokines Underlie Initiation of Autoimmune Inflammation in the Brain

Tumor necrosis factor is a proinflammatory cytokine that induces directly many of the components required for inflammation to proceed rapidly. We show in this study that the interplay between TNF and chemokines, now recognized to be essential for normal secondary lymphoid tissue development, is also a feature of CNS inflammation, and that the two apparently dissimilar biological processes share many properties. Thus, induction of seven chemokines, including T cell activation gene 3 (TCA3), monocyte chemoattractant protein-1, and IFN-{gamma}-inducible protein-10 within the CNS during experimental autoimmune encephalomyelitis fails to occur early in the inflammatory process in TNF-deficient mice, despite local expression of monokines and IFN-{gamma}. The critical source of TNF in CNS inflammation is the infiltrating hemopoietic cell, and, in its absence, chemokine expression by irradiation-resistant CNS-resident cells fails. The CCR8 ligand, TCA3, is shown to be produced predominantly by resident microglia of the CNS in response to TNF. Using CCR8-/- mice, evidence is provided that TCA3-CCR8 interactions contribute to rapid-onset CNS inflammation. Thus, through TNF production, the hemopoietic compartment initiates the signals for its own movement into tissues, although the tissue ultimately defines the nature of that movement. Chemokines are a major, although not exclusive, mechanism by which tissues regulate leukocyte movement in response to TNF