A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting.

In response to a defined panel of stimuli, immature macrophages can be classified into two major phenotypes: proinflammatory (M1) and anti-inflammatory (M2). Although both phenotypes have been implicated in several chronic inflammatory diseases, their direct role in bone resorption remains unclear. The present study investigated the possible effects of M1 and M2 macrophages on RANKL-induced osteoclastogenesis. In osteoclastogenesis assays using RAW264.7 cells or bone marrow cells as osteoclast precursors, addition of M1 macrophages significantly suppressed RANKL-induced osteoclastogenesis compared to nonstimulated conditions (M0), addition of M2 macrophages, or no macrophage addition (P < 0.05), suggesting that M1 macrophages can downregulate osteoclastogenesis. This effect was maintained when direct contact between M1 and osteoclast precursors was interrupted by cell culture insertion, indicating engagement of soluble factors released from M1. Macrophages which originate from monocytes not only are the key effector cells in innate immunity but also play a pivotal role in the initiation of adaptive immunity (1). It is well documented that polarized macrophages can be classified mainly into two different phenotypes: proinflammatory (M1) and antiinflammatory (M2). The production of inflammatory cytokines, such as tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), by M1 macrophages promotes inflammation in the context of innate immune response, whereas the production of antiinflammatory cytokines and arginase by M2 macrophages leads to the resolution of inflammation (2). On the other hand, it is also true that osteoclasts that are engaged in bone resorption also belong to monocyte-lineage cells. Although macrophages and osteoclasts share the same precursor, macrophage colony-stimulating factor (M-CSF)-stimulated monocytes, the possible influence of macrophages, and especially the difference between M1 and M2, on osteoclastogenesis is largely unknown.Bone is a unique mineralized tissue which constantly undergoes a physiological remodeling process, and its homeostasis is achieved by the tuned balance between osteoclasts and boneforming cells (osteoblasts). As such, aberrantly promoted osteoclastogenesis is attributed to the bone destruction found in bone lytic diseases such as periodontitis and rheumatoid arthritis, which affects more than 50 million people in the United States alone (3). Of importance to this study, recent research has revealed that osteoclastogenesis is regulated by the immune system. For instance, a recent study (4) revealed that ␥␦-T cells inhibit osteoclastogenesis by their production of interferon gamma (IFN-␥), whereas B and T cells can produce RANKL under inflammatory conditions, thus working toward the promotion of osteoclastogenesis (5). However, in the context of bone lytic diseases involving chronic inflammation, such as periodontitis and rheumatoid arthritis, infiltrations of not only B and T cells but also of macrophages are observed (6, 7). It is true that macrophages are t...

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The nucleotide sequence of the gene for cyclodextrin glucanotransferase of alkalophilic Bacillus sp. strain 1011 was determined. The deduced amino acid sequence at the NH2-terminal side of the enzyme showed a high homology with the sequences of alpha-amylase in the three regions which constitutes the active centers of alpha-amylases.

Insertional mutagenesis is an important risk with all genetically modified cell therapies, including chimeric antigen receptor (CAR)-T cell therapy used for hematological malignancies. Here we describe a new tagmentation-assisted PCR (tag-PCR) system that can determine the integration sites of transgenes without using restriction enzyme digestion (which can potentially bias the detection) and allows library preparation in fewer steps than with other methods. Using this system, we compared the integration sites of CD19-specific CAR genes in final T cell products generated by retrovirus-based and lentivirus-based gene transfer and by the piggyBac transposon system. The piggyBac system demonstrated lower preference than the retroviral system for integration near transcriptional start sites and CpG islands and higher preference than the lentiviral system for integration into genomic safe harbors. Integration into or near proto-oncogenes was similar in all three systems. Tag-PCR mapping is a useful technique for assessing the risk of insertional mutagenesis.

These findings indicate that the regular application of an APM-containing dentifrice could reduce gingival inflammation.

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The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteinases termed gingipains that comprises Arg-gingipain (Rgp) and Lys-gingipain (Kgp). Growing evidence indicates that these 2 types of gingipains synergistically contribute to the entire virulence of the organism and increase the risk of periodontal disease (PD) by disrupting the host immune system and degrading the host tissue and plasma proteins. Therefore, a dual inhibitor of both gingipains would have attractive clinical potential for PD therapy. In this study, a novel, potent, dual inhibitor of Rgp and Kgp was developed through structure-based drug design, and its biological potency was evaluated in vitro and in vivo. This inhibitor had low nanomolar inhibitory potency (Ki=40 nM for Rgp, Ki=0.27 nM for Kgp) and good selectivity for host proteases and exhibited potent antibacterial activity against P. gingivalis by abrogating its manifold pathophysiological functions. The therapeutic potential of this inhibitor in vivo was also verified by suppressing the vascular permeability that was enhanced in guinea pigs by the organism and the gingival inflammation in beagle dog PD models. These findings suggest that a dual inhibitor of Rgp and Kgp would exhibit noteworthy anti-inflammatory activity in the treatment of PD.