DW-MRI as a Biomarker to Compare Therapeutic Outcomes in Radiotherapy Regimens Incorporating Temozolomide or Gemcitabine in Glioblastoma

The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf−/− PtenloxP/loxP/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/− ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials

Sedimentary recycling in arc magmas: geochemical and U–Pb–Hf–O constraints on the Mesoproterozoic Suldal Arc, SW Norway

The Hardangervidda-Rogaland Block within southwest Norway is host to ~1.52 to 1.48 Ga continental building and variable reworking during the ~1.1 to 0.9 Ga Sveconorwegian orogeny. Due to the lack of geochronological and geochemical data, the timing and tectonic setting of early Mesoproterozoic magmatism has long been ambiguous. This paper presents zircon U–Pb–Hf–O isotope data combined with whole-rock geochemistry to address the age and petrogenesis of basement units within the Suldal region, located in the centre of the Hardangervidda-Rogaland Block. The basement comprises variably deformed grey gneisses and granitoids that petrologically and geochemically resemble mature volcanic arc lithologies. U–Pb ages confirm that magmatism occurred from ~1,521 to 1,485 Ma, and conspicuously lack any xenocrystic inheritance of distinctly older crust. Hafnium isotope data range from εHf(initial) +1 to +11, suggesting a rather juvenile magmatic source, but with possible involvement of late Palaeoproterozoic crust. Oxygen isotope data range from mantle-like (δ18O ~5 ‰) to elevated (~10 ‰) suggesting involvement of low-temperature altered material (e.g., supracrustal rocks) in the magma source. The Hf–O isotope array is compatible with mixing between mantle-derived material with young low-temperature altered material (oceanic crust/sediments) and older low-temperature altered material (continent-derived sediments). This, combined with a lack of xenoliths and xenocrysts, exposed older crust, AFC trends and S-type geochemistry, all point to mixing within a deep-crustal magma-generation zone. A proposed model comprises accretion of altered oceanic crust and the overlying sediments to a pre-existing continental margin, underthrusting to the magma-generation zone and remobilisation during arc magmatism. The geodynamic setting for this arc magmatism is comparable with that seen in the Phanerozoic (e.g., the Sierra Nevada and Coast Range batholiths), with compositions in the Suldal Sector reaching those of average upper continental crust. As within these younger examples, factors that drive magmatism towards the composition of the average continental crust include the addition of sedimentary material to magma source regions, and delamination of cumulate material. Underthrusting of sedimentary materials and their subsequent involvement in arc magmatism is perhaps a more widespread mechanism involved in continental growth than is currently recognised. Finally, the Suldal Arc magmatism represents a significant juvenile crustal addition to SW Fennoscandia

Substrate cycles and drug resistance to 1-beta-D-arabinofuranosylcytosine (araC)

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. After diagnosis, patients with AML are mainly treated with standard induction chemotherapy combining cytarabine (araC) and anthracyclines. The majority of them achieve complete remission (CR) (65-80%). However, prospects for long-term survival are poor for the majority of patients. Resistance to chemotherapy therefore remains a major obstacle in the effective treatment of patients with AML. In this review, we highlight the current knowledge of substrate cycles involved in normal deoxynucleoside triphosphate (dNTPs) metabolism and their possible role in drug resistance to araC. © 2005 Taylor & Francis Group Ltd.Fil: Fernandez Calotti, Paula. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Jordheim, Lars Petter. Université Claude Bernard Lyon 1; FranciaFil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Dumontet, Charles. Université Claude Bernard Lyon 1; FranciaFil: Galmarini, Carlos Maria. Université Claude Bernard Lyon 1; Franci