Keys to unblocking multilateral nuclear arms control

Includes bibliographical references (p. 9.) "July 2002"This article outlines the activities that must be undertaken and the issues that must be addressed in order for multilateral arms control to succeed in the 21st century, given the current US opposition to most international agreements.unpublishednot peer reviewe

B cell reductive therapy with rituximab in the treatment of rheumatoid arthritis.

The approach to treating autoimmune disorders is currently undergoing a significant change in focus. As therapies are developed that are more precise in targeting the pathogenesis for these diseases, patients experience significantly fewer side effects. At the same time, as more precise therapies are discovered, the etiologies of these diseases become further elucidated. It is now widely accepted that B-lymphocytes play a significant role in the pathogenesis of various autoimmune diseases, the extent of which continues to be the focus of ongoing research. Rheumatoid arthritis is one such disease process that has been the focus of various B-lymphocyte-directed therapeutic trials. In this paper we review the current research available on rituximab as treatment for rheumatoid arthritis. This review details results from four main studies, as well as others, which used rituximab in at least one of the arms in treatment of rheumatoid arthritis. The results are promising and will likely lead to longer term studies as well as a potential focus on B cell subsets

Primary fibroblasts from CSPα mutation carriers recapitulate hallmarks of the adult onset neuronal ceroid lipofuscinosis

AbstractMutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities. AFSM accumulation correlates with CSPα aggregation and both are susceptible to pharmacological modulation of ALP function. In addition, we demonstrate that endogenous CSPα is present in the lysosome-enriched fractions and co-localizes with lysosome markers in soma, neurites and synaptic boutons. Overexpression of CSPα wild-type (WT) decreases lysotracker signal, secreted lysosomal enzymes and SNAP23-mediated lysosome exocytosis. CSPα WT, mutant and aggregated CSPα are degraded mainly by the ALP but this disease-causing mutation exhibits a faster rate of degradation. Co-expression of both WT and mutant CSPα cause a block in the fusion of autophagosomes/lysosomes. Our data suggest that aggregation‐dependent perturbation of ALP function is a relevant pathogenic mechanism for AD-ANCL and supports the use of AFSM or CSPα aggregation as biomarkers for drug screening purposes.</jats:p

Targeting self-renewal pathways in myeloid malignancies

A fundamental property of hematopoietic stem cells (HSCs) is the ability to self-renew. This is a complex process involving multiple signal transduction cascades which control the fine balance between self-renewal and differentiation through transcriptional networks. Key activators/regulators of self-renewal include chemokines, cytokines and morphogens which are expressed in the bone marrow niche, either in a paracrine or autocrine fashion, and modulate stem cell behaviour. Increasing evidence suggests that the downstream signaling pathways induced by these ligands converge at multiple levels providing a degree of redundancy in steady state hematopoiesis. Here we will focus on how these pathways cross-talk to regulate HSC self-renewal highlighting potential therapeutic windows which could be targeted to prevent leukemic stem cell self-renewal in myeloid malignancies