Cell cycle times of short-term cultures of brain cancers as predictors of survival

Tumour cytokinetics estimated in vivo as potential doubling times (Tpot values) have been found to range in a variety of human cancers from 2 days to several weeks and are often related to clinical outcome. We have previously developed a method to estimate culture cycle times of short-term cultures of surgical material for several tumour types and found, surprisingly, that their range was similar to that reported for Tpot values. As Tpot is recognised as important prognostic variable in cancer, we wished to determine whether culture cycle times had clinical significance. Brain tumour material obtained at surgery from 70 patients with glioblastoma, medulloblastoma, astrocytoma, oligodendroglioma and metastatic melanoma was cultured for 7 days on 96-well plates, coated with agarose to prevent proliferation of fibroblasts. Culture cycle times were estimated from relative 3H-thymidine incorporation in the presence and absence of cell division. Patients were divided into two groups on the basis of culture cycle times of ⩽10 days and >10 days and patient survival was compared. For patients with brain cancers of all types, median survival for the ⩽10-day and >10-day groups were 5.1 and 12.5 months, respectively (P=0.0009). For 42 patients with glioblastoma, the corresponding values were 6.5 and 9.0 months, respectively (P=0.03). Lower grade gliomas had longer median culture cycle times (16 days) than those of medulloblastomas (9.9 days), glioblastomas (9.8 days) or melanomas (6.7 days). We conclude that culture cycle times determined using short-term cultures of surgical material from brain tumours correlate with patient survival. Tumour cells thus appear to preserve important cytokinetic characteristics when transferred to culture

Zinc in innate and adaptive tumor immunity

Zinc is important. It is the second most abundant trace metal with 2-4 grams in humans. It is an essential trace element, critical for cell growth, development and differentiation, DNA synthesis, RNA transcription, cell division, and cell activation. Zinc deficiency has adverse consequences during embryogenesis and early childhood development, particularly on immune functioning. It is essential in members of all enzyme classes, including over 300 signaling molecules and transcription factors. Free zinc in immune and tumor cells is regulated by 14 distinct zinc importers (ZIP) and transporters (ZNT1-8). Zinc depletion induces cell death via apoptosis (or necrosis if apoptotic pathways are blocked) while sufficient zinc levels allows maintenance of autophagy. Cancer cells have upregulated zinc importers, and frequently increased zinc levels, which allow them to survive. Based on this novel synthesis, approaches which locally regulate zinc levels to promote survival of immune cells and/or induce tumor apoptosis are in order

Understanding the core density profile in TCV H-mode plasmas

Results from a database analysis of H-mode electron density profiles on the Tokamak \`a Configuration Variable (TCV) in stationary conditions show that the logarithmic electron density gradient increases with collisionality. By contrast, usual observations of H-modes showed that the electron density profiles tend to flatten with increasing collisionality. In this work it is reinforced that the role of collisionality alone, depending on the parameter regime, can be rather weak and in these, dominantly electron heated TCV cases, the electron density gradient is tailored by the underlying turbulence regime, which is mostly determined by the ratio of the electron to ion temperature and that of their gradients. Additionally, mostly in ohmic plasmas, the Ware-pinch can significantly contribute to the density peaking. Qualitative agreement between the predicted density peaking by quasi-linear gyrokinetic simulations and the experimental results is found. Quantitative comparison would necessitate ion temperature measurements, which are lacking in the considered experimental dataset. However, the simulation results show that it is the combination of several effects that influences the density peaking in TCV H-mode plasmas.Comment: 23 pages, 12 figure

Magnetic Resonance Imaging of Tumors Colonized with Bacterial Ferritin-Expressing Escherichia coli

Background: Recent studies have shown that human ferritin can be used as a reporter of gene expression for magnetic resonance imaging (MRI). Bacteria also encode three classes of ferritin-type molecules with iron accumulation properties. Methods and Findings: Here, we investigated whether these bacterial ferritins can also be used as MRI reporter genes and which of the bacterial ferritins is the most suitable reporter. Bacterial ferritins were overexpressed in probiotic E. coli Nissle 1917. Cultures of these bacteria were analyzed and those generating highest MRI contrast were further investigated in tumor bearing mice. Among members of three classes of bacterial ferritin tested, bacterioferritin showed the most promise as a reporter gene. Although all three proteins accumulated similar amounts of iron when overexpressed individually, bacterioferritin showed the highest contrast change. By site-directed mutagenesis we also show that the heme iron, a unique part of the bacterioferritin molecule, is not critical for MRI contrast change. Tumor-specific induction of bacterioferritin-expression in colonized tumors resulted in contrast changes within the bacteria-colonized tumors. Conclusions: Our data suggest that colonization and gene expression by live vectors expressing bacterioferritin can be monitored by MRI due to contrast change

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Etude Hydrogéochimique des Eaux Souterraines dans la Formation Gréseuse de la Région de Berberati en République Centrafricaine

La population de la République Centrafricaine est inégalement repartie: les zones ouest et sud montrent une densité de population beaucoup plus haute que la partie Est. Pour parvenir à une meilleure connaissance des ressources en eau en présence, la compréhension des conditions de recharge des formations gréseuses et leur interrelation avec les cours d'eau environnants et leur reservoirs constituent les principales lacunes à combler par ce projet. L’étude porte donc sur l’évaluation des ressources en eaux dans la formation gréseuse de Berberati par l’utilisation des techniques hydrogéochimiques de et l’hydrologie isotopiques.The population of the Central African Republic is unevenly distributed: the western and southern zones show a much higher population density than the eastern part. To gain a better understanding of the water resources present, understanding the recharge conditions of grès formations and their interrelation with the surrounding watercourses and reservoirs are the main gaps to be filled by this project. The study therefore focuses on the evaluation of water resources in the Berberati grès formation through the use of hydrogeochemical techniques and isotopic hydrology