CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Chemotherapy in cancer patients can be associated with serious short- and long-term adverse neurological effects, such as leukoencephalopathy and cognitive impairment, even when therapy is delivered systemically. The underlying cellular basis for these adverse effects is poorly understood.</p> <p>Results</p> <p>We found that three mainstream chemotherapeutic agents – carmustine (BCNU), cisplatin, and cytosine arabinoside (cytarabine), representing two DNA cross-linking agents and an antimetabolite, respectively – applied at clinically relevant exposure levels to cultured cells are more toxic for the progenitor cells of the CNS and for nondividing oligodendrocytes than they are for multiple cancer cell lines. Enhancement of cell death and suppression of cell division were seen <it>in vitro </it>and <it>in vivo</it>. When administered systemically in mice, these chemotherapeutic agents were associated with increased cell death and decreased cell division in the subventricular zone, in the dentate gyrus of the hippocampus and in the corpus callosum of the CNS. In some cases, cell division was reduced, and cell death increased, for weeks after drug administration ended.</p> <p>Conclusion</p> <p>Identifying neural populations at risk during any cancer treatment is of great importance in developing means of reducing neurotoxicity and preserving quality of life in long-term survivors. Thus, as well as providing possible explanations for the adverse neurological effects of systemic chemotherapy, the strong correlations between our <it>in vitro </it>and <it>in vivo </it>analyses indicate that the same approaches we used to identify the reported toxicities can also provide rapid <it>in vitro </it>screens for analyzing new therapies and discovering means of achieving selective protection or targeted killing.</p

The Representation of Mosuo People and Mosuo Culture in Chinese Tourism Websites

Past research has shown that because tourism itself is a product of a gendered society, its processes are gendered in terms of construction, presentation, and consumption. This study examines how these websites shape the image of the Mosuo people and the Mosuo culture by analyzing texts in Chinese tourism websites. Ten representative Chinese tourism websites were selected for this study, and all relevant texts that could be retrieved were analyzed manually. All samples selected were officially published and represent only the attitudes of the tourism websites. The results of the study show that there are a large number of feminized or sexualized descriptions in the texts about the Mosuo people and the Mosuo culture provided by Chinese tourism websites. The language used on tourism websites is shaped by discourses of patriarchy and sexuality and is intended for heterosexual male tourists

The Representation of Mosuo People and Mosuo Culture in Chinese Tourism Websites

Past research has shown that because tourism itself is a product of a gendered society, its processes are gendered in terms of construction, presentation, and consumption. This study examines how these websites shape the image of the Mosuo people and the Mosuo culture by analyzing texts in Chinese tourism websites. Ten representative Chinese tourism websites were selected for this study, and all relevant texts that could be retrieved were analyzed manually. All samples selected were officially published and represent only the attitudes of the tourism websites. The results of the study show that there are a large number of feminized or sexualized descriptions in the texts about the Mosuo people and the Mosuo culture provided by Chinese tourism websites. The language used on tourism websites is shaped by discourses of patriarchy and sexuality and is intended for heterosexual male tourists

Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system

<p>Abstract</p> <p>Background</p> <p>Cancer treatment with a variety of chemotherapeutic agents often is associated with delayed adverse neurological consequences. Despite their clinical importance, almost nothing is known about the basis for such effects. It is not even known whether the occurrence of delayed adverse effects requires exposure to multiple chemotherapeutic agents, the presence of both chemotherapeutic agents and the body's own response to cancer, prolonged damage to the blood-brain barrier, inflammation or other such changes. Nor are there any animal models that could enable the study of this important problem.</p> <p>Results</p> <p>We found that clinically relevant concentrations of 5-fluorouracil (5-FU; a widely used chemotherapeutic agent) were toxic for both central nervous system (CNS) progenitor cells and non-dividing oligodendrocytes <it>in vitro </it>and <it>in vivo</it>. Short-term systemic administration of 5-FU caused both acute CNS damage and a syndrome of progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology. Functional analysis also provided the first demonstration of delayed effects of chemotherapy on the latency of impulse conduction in the auditory system, offering the possibility of non-invasive analysis of myelin damage associated with cancer treatment.</p> <p>Conclusions</p> <p>Our studies demonstrate that systemic treatment with a single chemotherapeutic agent, 5-FU, is sufficient to cause a syndrome of delayed CNS damage and provide the first animal model of delayed damage to white-matter tracts of individuals treated with systemic chemotherapy. Unlike that caused by local irradiation, the degeneration caused by 5-FU treatment did not correlate with either chronic inflammation or extensive vascular damage and appears to represent a new class of delayed degenerative damage in the CNS.</p

Co-analysis of BrdU incorporation with antigen expression indicates that division of both DCXneuronal progenitors and Olig2oligodendrocyte precursors is reduced by systemic exposure to cytarabine

<p><b>Copyright information:</b></p><p>Taken from "CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents and "</p><p>http://jbiol.com/content/5/7/22</p><p>Journal of Biology 2006;5(7):22-22.</p><p>Published online 30 Nov 2006</p><p>PMCID:PMC2000477.</p><p></p> In the CC, where there was an approximately 50% reduction in the number of BrdUcells (see Figure 11b), the proportion of BrdUcells that were Olig2was no different between controls and treated animals on either day 1 (control; cytarabine) or on day 56 (control; cytarabine) after completion of treatment. Thus, the reduction in apparent division of Olig2cells was proportionate to the overall reduction in all BrdUcells. In contrast with effects on Olig2populations in the corpus callosum, our analyses indicate an enhanced loss of DCXcells from among the BrdUpopulation in both the SVZ and DG. This was particularly striking in the DG, where at 56 days post-treatment the proportion of BrdUcells in the cytarabine-treated animals was < 40% of that seen in control animals. Data are means ± SEM; *< 0.05, **< 0.01, and ***< 0.001 in comparisons with control animals

Schematic representation of the lineage relationships of the cell types examined in these studies

<p><b>Copyright information:</b></p><p>Taken from "CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents and "</p><p>http://jbiol.com/content/5/7/22</p><p>Journal of Biology 2006;5(7):22-22.</p><p>Published online 30 Nov 2006</p><p>PMCID:PMC2000477.</p><p></p> Pluripotent neuroepithelial stem cells (NSC) give rise to glial-restricted precursor (GRP) cells and neuron-restricted precursor (NRP) cells. NRP cells can give rise to multiple populations of neurons, whereas GRP cells give rise to astrocytes and oligodendrocyte-type-2 astrocytes (O-2A/OPCs). The O-2A/OPCs in turn give rise to oligodendrocytes. The progenitor cells that lie between NSCs and differentiated cell types, and are the major dividing cell population in the CNS, appear to be exceptionally vulnerable to the effects of chemotherapeutic agents. Also sharing this vulnerability are nondividing oligodendrocytes

Low-dose cytarabine decreases division and promotes differentiation of O-2A/OPCs

<p><b>Copyright information:</b></p><p>Taken from "CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents and "</p><p>http://jbiol.com/content/5/7/22</p><p>Journal of Biology 2006;5(7):22-22.</p><p>Published online 30 Nov 2006</p><p>PMCID:PMC2000477.</p><p></p> Cells grown at clonal density were exposed 1 day after plating to low-dose cytarabine (0.01 μM for 24 h), a dosage that killed less than 5% of O-2A/OPCs in mass culture (Figure 9). The number of undifferentiated O-2A/OPCs and differentiated cells (oligodendrocytes) was determined in each individual clone from a total of 100 clones in each condition by morphological examination and by immunostaining with A2B5 and anti-GalC antibodies (to label O-2A/OPCs and oligodendrocytes, respectively), as in Figure 4. Composition of progenitors and oligodendrocytes in a representative experiment of control cultures analyzed 6 days after plating optic nerve-derived O-2A/OPCs cells at clonal density. In parallel cytarabine (Ara-C)-treated cultures analyzed 6 days after plating at clonal density (5 days after the start of cytarabine exposure), there was a marked increase in the representation of small clones consisting wholly of oligodendrocytes, a reduction in the representation of large clones, and a general shift of clone size towards smaller values. Experiments were performed in triplicate in at least two independent experiments

Primary CNS cells are equally or more vulnerable to cytarabine than cancer cells

<p><b>Copyright information:</b></p><p>Taken from "CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents and "</p><p>http://jbiol.com/content/5/7/22</p><p>Journal of Biology 2006;5(7):22-22.</p><p>Published online 30 Nov 2006</p><p>PMCID:PMC2000477.</p><p></p> Cells were plated on coverslips in 24-well plates at a density of 1,000 cells per well and allowed to grow for 24–48 h. On the basis of drug concentrations achieved in human patients, cells were exposed to cytarabine for 24 h. Cell survival and viability was determined after additional 24–48 h (see Materials and methods). Rat neural cell types studied included O-2A/OPCs, oligodendrocytes, GRP cells, NSCs and astrocytes. We also examined the T98 glioma cell line, a meningioma cell line, and the L1210 and EL-4 leukemia cell lines. To define the onset of cytarabine toxicity, cells were treated with cytarabine over a wide dose range (0.01–1 μM) extending downwards from the lower ranges achieved in high-dose therapy. Each experiment was carried out in quadruplicate and was repeated multiple times in independent experiments. Data represent mean of survival ± SEM, normalized to control values. There are no concentrations of cytarabine at which tumor cell lines were more sensitive O-2A/OPCs or oligodendrocytes