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Microglia arise from the yolk sac and enter the brain during early embryogenesis. Upon entry, microglia undergoin situproliferation and eventually colonize the entire brain by the third postnatal week in mice. However, the intricacies of their developmental expansion remain unclear. Here, we characterize the proliferative dynamics of microglia during embryonic and postnatal development using complementary fate-mapping techniques. We demonstrate that the developmental colonization of the brain is facilitated by clonal expansion of highly proliferative microglial progenitors that occupy spatial niches throughout the brain. Moreover, the spatial distribution of microglia switches from a clustered to a random pattern between embryonic and late postnatal development. Interestingly, the developmental increase in microglial numbers follows the proportional growth of the brain in an allometric manner until a mosaic distribution has been established. Overall, our findings offer insight into how the competition for space may drive microglial colonization by clonal expansion during development.

The development and usage of safe cell systems for testing agents which possess anti-HIV activity is a very important factor in the design of new drugs. We have described in detail a system we designed that is based on lentiviral vectors (Prokofjeva et. al.,Antiviral Therapy,in print) for swift and completely safe screening of potential HIV-1 replication inhibitors. The system enables one to test the efficiency of the inhibitory activity of compounds whose action is directed towards either wild-type HIV-1 reverse transcriptase or integrase, or mutant enzymes corresponding to the drug-resistant virus form. Testing results of a number of already known drugs, which correlate well with published data as well as data on newly synthesized compounds, were obtained. Application of this system substantially broadens the possibilities of preclinical anti-HIV drugs testing.

Previously we have shown that lentiviral vector mediated herpes simplex virus thymidine kinase (HSV-Tk) / ganciclovir (GCV) therapy is a very promising therapeutic option for GBM treatment. However, after long-term remission, tumor recurrence was observed in treated animals and interestingly a fraction of recurrent glioma cells expressed HSV-Tk. We hypothesized that short-term GCV treatment, which is used in clinical trials for suicide gene therapy of GBM, fails to eliminate a fraction of glioma cells which are slow-proliferating; thus, a longer period of prodrug administration might provide a better outcome. Here, we compared long-term treatment with the prodrug valganciclovir (valGCV), which is tailored for oral administration, to short-term treatment with GCV within the context of suicide gene therapy for experimental GBM. After orthotopic implantation of patient derived GBM spheroids and visible tumor growth on MRI, we injected lentiviral vectors expressing TK.007, a highly active mutant of HSV-tk. Animals were treated with either short-term GCV (3 weeks) or long-term valGCV (3 months). Although both treatment groups showed remission and subsequent tumor recurrence, animals in the valGCV treatment group survived significantly longer and had a longer recurrence-free time period. When analyzing the recurrent tumors, we observed that these were more invasive and less angiogenic compared to primary tumors in the control groups. Furthermore, recurrent tumors showed upregulation of tyrosine kinase receptor expression, in particular EGFR. These results open up the possibility for a combination treatment of lentiviral suicide gene therapy with tyrosine kinase receptor inhibitors in the future.

Objective: Neural stem cells (NSC) have an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive gliomas. Here, we demonstrate that the non-invasive intranasal administration of tumor-targeting NSC is able to deliver a novel suicide gene (TK007) to[for full text, please go to the a.m. URL], 65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Objective: The current study aimed at analyzing the molecular requirements for tumor initiation of EGFR-amplified, EGFRvIII-positive glioblastoma (GBM) cells in vitro and in vivo. Method: GBM-derived EGFR-amplified, EGFRvIII-positive BS153 cells were analyzed for their tumor-initiating capacity in[for full text, please go to the a.m. URL], 64. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Разработка безопасных клеточных систем, позволяющих тестировать соединения, обладающие антиВИЧ -активностью, весьма важна для создания новых противовирусных препаратов. Нами детально охарактеризована разработанная ранее на основе лентивирусных векторов система (Prokofjeva et. al., Antiviral Therapy, в печати) для быстрого и полностью безопасного скрининга потенциальных ингибиторов репликации ВИЧ-1. Система позволяет проводить испытания ингибиторной активности соединений, действие которых направлено как на обратную транскриптазу и интегразу ВИЧ-1 дикого типа, так и на мутантные ферменты, соответствующие лекарственно-устойчивым формам вируса. Получены результаты тестирования ряда известных препаратов, которые хорошо согласуются с опубликованными данными, а также вновь синтезированных соединений. Применение этой системы существенно расширяет возможности доклинических испытаний анти-ВИЧ-препаратов.

The cellular basis of cancer immune surveillance, already hypothesized in ancient times, was only demonstrated with the advent of HSCT. Indeed, the discovery of the nature of GVHD and its antileukemic effects (Weiden et al.