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Pleiotrophin (PTN) is an important developmental cytokine that is highly expressed during embryogenesis but shows very limited expression in adult tissues, where it is largely restricted to the brain. High PTN serum levels are associated with a variety of solid tumors. We recently showed that patients with multiple myeloma (MM) also have elevated serum levels of this protein and the amount of PTN correlated with the patients' disease status and response to treatment. In this study, we demonstrate that MM cell lines and the malignant cells from MM patients' bone marrow produced PTN and secreted PTN protein into the supernatants during short-term culture. Moreover, Ptn gene expression correlated with the patients' disease status. Inhibition of PTN with a polyclonal anti-PTN antibody reduced growth and enhanced apoptosis of MM cell lines and freshly isolated bone marrow tumor cells from MM patients in vitro. Importantly, this antibody also markedly suppressed the growth of MM in vivo using a severe combined immunodeficiency (SCID)-hu murine model. This represents the first study showing the importance of PTN in the growth of any hematological disorder. Because the expression of this protein is very limited in normal adult tissues, PTN may represent a new target for the treatment of MM.

Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)-marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.

Doxorubicin has shown efficacy especially in combination treatment for the treatment of multiple myeloma; however, its side effects limit its use. INNO-206 is an albumin-binding prodrug of doxorubicin, which is released from albumin under acidic conditions. Because INNO-206 has not been previously evaluated in any hematologic malignancy, we determined its anti-multiple myeloma effects. The anti-multiple myeloma effect of INNO-206 at different pH levels on multiple myeloma cell proliferation using multiple myeloma cell lines with the MTS assay and antiangiogenic activity using the chorioallantoic membrane/feather bud assay were determined. The anti-multiple myeloma effects and toxicity of INNO-206 were also compared with conventional doxorubicin and PEGylated liposomal doxorubicin (PLD) alone, and in combination with bortezomib, using our multiple myeloma xenograft models. INNO-206 inhibited blood vessel formation and reduced multiple myeloma cell growth in a pH-dependent fashion. INNO-206 alone produced marked anti-multiple myeloma effects in vivo at doses that doxorubicin was toxic, and the combination of INNO-206 plus bortezomib produced increased anti-multiple myeloma effects compared with either agent alone. In contrast, all mice receiving bortezomib with doxorubicin or PLD died. These findings show that INNO-206 produces anti-multiple myeloma effects in vitro and in vivo. It also enhances the antitumor effects of bortezomib. These results suggest that INNO-206 may provide patients with multiple myeloma with an anthracycline that may be administered safely at higher doses compared with free doxorubicin, resulting in superior efficacy compared with the currently available anthracyclines to treat this B-cell malignancy.

The development of the plasma cell tumor (PCT) model was the first widely accepted in vivo model of multiple myeloma (MM). Potter and colleagues used this chemically induced PCT model to study the pathophysiology of malignant plasma cells and also used it to screen anti-MM agents. Two decades later the C57BL/KaLwRij mouse strain was found to spontaneously develop MM. Testing of pamidronate using this endogenously arising MM model revealed significant reductions in MM-associated bone disease, which was subsequently confirmed in human trials in MM patients. Transgenic models have also been developed in which the MM is localized in the bone marrow causing lytic bone lesions. Experiments in a transgenic model showed that a new oral proteasome inhibitor was effective at reducing MM burden. A clinical trial later confirmed this observation and validated the model. The xenograft model has been used to grow human MM in immunocompromised mice. The xenograft models of MM have been very useful in optimizing drug schedules and doses, which have helped in the treatments given to MM patients. However, in vivo models have been criticized for having a low clinical predictive power of new chemical entities (NCEs). Despite this, the knowledge gained from in vivo models of MM has without a doubt benefited MM patients.

ABSTRACT So far, a number of multi-channel MAC proto- cols have been proposed for wireless sensor networks (WSNs). It is imperative to get the following three im- portant parameters for design of multi-channel proto- cols in WSNs. One is the number of available orthogo- nal, another is the time required to switch between two channels, and the other is the total energy consumed to switch between two channels. But to the best of our knowledge little practical information is available about these three parameters. This paper describes our approaches to determine the above three parameters for the Mica2 node, which is equipped with a CC1000 ra- dio and set to work in the channel of 433 MHz by de- fault. Through extensive experiments, we find that for the Mica2 nodes (1) there are 48 channels available; (2) it requires about 50 ms to switch between two chan- nels; (3) it consumes about 1940 nJ energy to switch between two channels. At last, we also point out some implications of these results for design of multi-channel protocols. The approaches presented in this paper can be easily extended to determine the parameters for the Zigbee (CC2420) nodes, such as MicaZ and TelosB.