WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma.

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6%±8.7%, respectively (p<0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89%±2% vs. 57.4%±1.8% (p<0.01)). In contrast, ß-catenin mutation sensitized TP53 mutant cells to radiation (p<0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5%±1.5% in lithium treated cells vs. 56.6±3% (p<0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33%±8% for lithium treated cells vs. 27%±3% for untreated controls (p=0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.

Numerical simulation of a steam-injection pilot study for a PCP-contaminated aquifer.

The following study was focused on the simulation of a steam-injection field pilottest conducted in our past research. The scope of research contained two main subjects: heat transfer and contaminant transport when steam was injected into a pentachlorophenol (PCP)-contaminated aquifer. Numerical simulation of the heat transfer during the field test showed that vertical permeability is more influential to the distribution of water temperature than the horizontal permeability. If the vertical permeability is relatively high, the steam in the aquifer has a higher tendency to migrate upward and cause the aquifer temperature to rise faster. The simulation results also showed that heat convection is very sensitive to the soil permeability. Therefore, high permeability media makes the effect of heat convection more important on applying the steam-injection method. Heat conduction dominates the heat transfer within the hot aqueous zone. However, the hot aqueous zone is relatively smaller than the steam zone when steam is injected into the aquifer. Therefore, heat conduction is not as important as heat convection within the steam zone, which is the same result observed in the field test. Specific heat of soil media is also a sensitive factor. A numerical simulator, T2VOC, was utilized to simulate the PCP transport in the aquifer when steam was injected into the aquifer. The results showed that the shape of PCP distribution was identical to that of steam. It illustrated thatthe steam carried PCP upward and laterally. The high vertical soil permeability causes the steam to migrate upward with PCP easily. A low partitioning coefficient allows PCP to be desorbed easier, also an important factor. A majority of the PCP in the soil was transferred to the aqueous phase as the water temperature increased, showing similar results to those observed in the field test. According to the sensitivity analysis, PCP transport is more sensitive to the vertical permeability than the partitioning coefficient. The steam-injection rate is also an important operation parameter and may determine the success of the remediation work.

Desorption kinetics of PCP-contaminated soil: effect of temperature.

A thermally enhanced pump-and-treatment method for pentachlorophenol (PCP)-contaminated soil and groundwater has shown potential advantages over the traditional pump-and-treatment method. Studies on the desorption kinetics of PCP from aquifer soil are the first step toward quantitative assessment of the newly proposed method. Five series of desorption batch tests were conducted at different temperatures, and the test results were analyzed by linear regression to determine the best-fit kinetic model for PCP desorbed from the contaminated field soil under all temperature conditions. The first-order kinetic model, parabolic diffusion model, and modified Freundlich model were discussed in linear regression work. A modified Freundlich model was found to describe the PCP desorption kinetics from soil in consideration of a temperature effect.