Identification of nonproliferating but viable hypoxic tumor cells in vivo

We have used the combination of pimonidazole labeling of hypoxic cells, bromodeoxyuridine labeling of proliferating cells, and cell sorting based on Hoechst 33342 perfusion to directly study hypoxia and proliferation in human tumor xenografts and transplantable murine tumors in vivo. Hypoxia was largely confined to cells in regions with the least perfusion, although in tumors exhibiting transient blood flow, hypoxic cells were not as highly localized. Similarly, proliferation and hypoxia were mutually exclusive except in areas of a tumor subjected to transient changes in perfusion. By determining the clonogenic potential, pimonidazole labeling intensity, and radiosensitivity of sorted tumor cell subpopulations, we have provided direct evidence that pimonidazole identifies hypoxic tumor cells of therapeutic relevance in vivo. Given that pimonidazole exhibits few diffusion or delivery problems and no apparent cytotoxicity, it appears to be a versatile and useful label for hypoxic cells in solid tumors.     

Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes

Interleukin 10 (IL-10) has recently been shown to induce normal human B lymphocytes to proliferate and differentiate into immunoglobulin (Ig)-secreting cells. Herein, we show that IL-10 also promotes DNA synthesis and IgM production by anti-CD40 activated B cell chronic lymphocytic leukemia (B-CLL). Most strikingly, IL-2 and IL-10 were found to synergize to induce the proliferation and differentiation of B-CLL cells. This synergy between IL-2 and IL-10 was also observed with normal B cells which proliferated strongly and secreted large amounts of IgM, IgG, and IgA. The observed synergy is likely to be due to the IL-10-induced increase of high affinity IL-2 receptors on both normal and leukemic B cells. This increase of high affinity receptor is associated to an increase of Tac/CD25 expression that can be detected by flow cytometric analysis. Taken together, these results indicate that IL-10 permits anti-CD40 activated B cells to respond to IL-2 through an induction of high affinity IL-2 receptors. This effect of IL-10 may partly explain how T cells, which activate B cells in a CD40-dependent fashion, induce B cell proliferation and differentiation mostly through IL-2.     

Effect of surface boundary on neuronal magnetic stimulation

The effect of the surface boundary between free space and a conducting medium on the excitation properties of neurons by magnetic fields are analyzed. The electric field and the spatial derivative of the induced field generated by a coil mounted both parallel and perpendicular to the surface of a semi-infinite conducting medium were calculated using the method of images. An imaginary axon is located in the same relative position from the coil in both configurations and the excitation properties are compared. The calculations are expressed in terms of the activating function for the electrical stimulation of axons. The calculations indicate that the activating function for magnetic stimulation is biphasic as opposed to triphasic for electrical stimulation. The large spatial extent of the magnetically induced electric field compared to the electric field generated by point source electrode suggests a different mode of excitation for neuronal structures in the CNS. The field distribution have been verified experimentally and are important for the understanding of the mechanisms of magnetic stimulation of neural tissue.     

Error rate measurements of a Josephson single flux quantum binaryripple counter

Single-flux quantum devices are used in superconductive analog-to-digital converters (ADCs), shift registers, and memory cells. They have been proposed for logic applications. The authors report the performance of high-speed superconducting, single-flux quantum (SFQ) ripple counters. Both memory and logic functions of the counter are investigated. Errors in logic operation produce bit error rates (BERs) as low as 0.22 errors per million binary operations, measured while counting 100-MHz pseudorandom input pulses. Errors in memory function do not occur on the time scale of the measurements. The BER is shown to be nearly independent of input bit rate and pattern, but strongly dependent on the counter cell operating point     

DNA methylation and developmental genes in lymphomagenesis--more questions than answers?

There is now considerable evidence suggesting that alterations in the DNA methylating machinery play an important role in tumorigenesis and tumour progression. For example, focal hypermethylation and generalised genomic demethylation are features of many different types of neoplasms. It is thought that tumorigenesis and tumour progression may be caused by hypermethylation induced mutational events and silencing of genes which control cellular proliferation and/or demethylation induced reactivation of genes which may only be required during embryological development. Consequently, we have begun to investigate the role of DNA methylation and developmental genes in malignant lymphoproliferative diseases. Previously, in all cases of non-Hodgkins lymphoma and leukemia studied, we have shown that the myogenic developmental gene Myf-3 is abnormally hypermethylated. In this review we discuss the possible significance of these findings since in vitro studies suggest that Myf-3 may play an important role in control of the cell cycle and therefore lymphomagenesis. In vitro and in vivo evidence suggests that PAX genes may also have oncogenic potential. The PAX family of developmental genes are involved in cellular differentiation, proliferation and cell migration. Expression of PAX3 in particular is associated with cellular mobility. Our previous studies have indicated that alternate regional expression of PAX genes may be controlled by DNA methylation. Therefore, we have proposed that abnormal methylation profiles of PAX3 may be associated with neoplastic transformation and/or metastatic potential. Results thus far reveal that the paired box of PAX3 is abnormally hypermethylated and the homeobox abnormally hypomethylated in lymphomas and leukemias. These new findings are consistent with our postulate and support the idea that inappropriate methylation induced activation or inactivation of developmental genes such as Myf-3 and PAX3 play an important role in lymphomagenesis and disease progression and that inspection of the methylation status of other developmental genes is warranted.     

Internet user behavior: compared study of the access traces and application to the discovery of communities

With an ever-increasing emphasis on human activity (idea exchange, shopping, gaming, etc.) being mediated through the data network, the understanding of Internet users' behavior has become a rising challenge. Research dealing with the analysis and modeling of Internet user behavior can be roughly split in to two main approaches. The first is based on sociocognitive observation of users' practices in a standardized context. The second approach focuses on the analysis of productions and the traces of users' activity. This paper relates to the latter approach and presents a comparative analysis of Internet navigation traces (URLs versus keywords) to characterize individual or group-of-users' behavior when accessing the Web. The proposed models are based on the study of accesses redundancy seen as global static parameters and from the angle of time evolution. We also study the use of these models, in particular, to categorize a population of users in communities of interests. This study enables us to draw some conclusions on the compared performances of the two kinds of trace exploitation, as raw information, as well as the self-similar properties of the models.