Nuclear Overhauser Enhancement Mediated Chemical Exchange Saturation Transfer Imaging at 7 Tesla in Glioblastoma Patients

Background and Purpose

Nuclear Overhauser Enhancement (NOE) mediated chemical exchange saturation transfer (CEST) is a novel magnetic resonance imaging (MRI) technique on the basis of saturation transfer between exchanging protons of tissue proteins and bulk water. The purpose of this study was to evaluate and compare the information provided by three dimensional NOE mediated CEST at 7 Tesla (7T) and standard MRI in glioblastoma patients.

Patients and Methods

Twelve patients with newly diagnosed histologically proven glioblastoma were enrolled in this prospective ethics committee–approved study. NOE mediated CEST contrast was acquired with a modified three-dimensional gradient-echo sequence and asymmetry analysis was conducted at 3.3ppm (B1 = 0.7 µT) to calculate the magnetization transfer ratio asymmetry (MTR_asym). Contrast enhanced T1 (CE-T1) and T2-weighted images were acquired at 3T and used for data co-registration and comparison.

Results

Mean NOE mediated CEST signal based on MTR_asym values over all patients was significantly increased (p<0.001) in CE-T1 tumor (−1.99±1.22%), tumor necrosis (−1.36±1.30%) and peritumoral CEST hyperintensities (PTCH) within T2 edema margins (−3.56±1.24%) compared to contralateral normal appearing white matter (−8.38±1.19%). In CE-T1 tumor (p = 0.015) and tumor necrosis (p<0.001) mean MTR_asym values were significantly higher than in PTCH. Extent of the surrounding tumor hyperintensity was smaller in eight out of 12 patients on CEST than on T2-weighted images, while four displayed at equal size. In all patients, isolated high intensity regions (0.40±2.21%) displayed on CEST within the CE-T1 tumor that were not discernible on CE-T1 or T2-weighted images.

Conclusion

NOE mediated CEST Imaging at 7T provides additional information on the structure of peritumoral hyperintensities in glioblastoma and displays isolated high intensity regions within the CE-T1 tumor that cannot be acquired on CE-T1 or T2-weighted images. Further research is needed to determine the origin of NOE mediated CEST and possible clinical applications such as therapy assessment or biopsy planning.     

Mouse studies to shape clinical trials for mitochondrial diseases: high fat diet in Harlequin mice

Background

Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD.

Methods and Findings

Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice.

Conclusions

These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients.     

Keratin 20 - a diagnostic and prognostic marker in colorectal cancer?

Colorectal cancer cells characteristically show strong expression of keratin 20 (K20) and lack expression of keratin 7 (K7). The biological significance of reduced K20 expression, however, is unclear. 381 colorectal cancers with 148 corresponding metastases were evaluated for K20 and K7 expression by immunohistochemistry using a tissue microarray technique. K20 immunoreactivity was assessed semiquantitatively as either negative, low (<50% of cancer cells) or high (≥50% of cancer cells). Progression-free and cancer-specific survivals were determined using the Kaplan-Meier method. Expression of K20 was observed in 348 out of 372 (94%) evaluable primary tumors, with 135 (36%) cases showing low K20 and 213 (57%) cases high K20 expression, while 24 (6%) tumors completely lacked K20 immunoreactivity. Reduced K20 expression (lack of staining or low expression) was significantly associated with poor differentiation, large tumor size and mismatch repair deficiency, but did not significantly affect patients' outcome. Immunoreactivity of K20 and K7 in metastatic tissues matched well with that of corresponding primary tumors, with high concordance for lymph node (p<0.001) and distant metastases (p<0.001), respectively. In conclusion, our data illustrate the value of keratin subtyping in carcinoma of unknown primary (CUP) syndrome: K20 expression is common in colorectal cancer and the K20 high / K7 negative immunoprofile represents the predominant phenotype. Reduced K20 expression may, however, lead to false-negative assessment of metastatic deposits if only small amounts of tissue are obtained (e.g. in needle biopsies), particularly in poorly differentiated cancers. Reduced expression of K20 may be used to select tumors for microsatellite instability testing.     

Prognostic impact of vitamin B6 metabolism in lung cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.     

Elements of metacommunity structure in Amazonian Zygoptera among streams under different spatial scales and environmental conditions

An important aspect of conservation is to understand the founding elements and characteristics of metacommunities in natural environments, and the consequences of anthropogenic disturbance on these patterns. In natural Amazonian environments, the interfluves of the major rivers play an important role in the formation of areas of endemism through the historical isolation of species and the speciation process. We evaluated elements of metacommunity structure for Zygoptera (Insecta: Odonata) sampled in 93 Amazonian streams distributed in two distinct biogeographic regions (areas of endemism). Of sampled streams, 43 were considered to have experienced negligible anthropogenic impacts, and 50 were considered impacted by anthropogenic activities. Our hypothesis was that preserved (“negligible impact”) streams would present a Clementsian pattern, forming clusters of distinct species, reflecting the biogeographic pattern of the two regions, and that anthropogenic streams would present random patterns of metacommunity, due to the loss of more sensitive species and dominance of more tolerant species, which have higher dispersal ability and environmental tolerance. In negligible impact streams, the Clementsian pattern reflected a strong biogeographic pattern, which we discuss considering the areas of endemism of Amazonian rivers. As for communities in human‐impacted streams, a biotic homogenization was evident, in which rare species were suppressed and the most common species had become hyper‐dominant. Understanding the mechanisms that trigger changes in metacommunities is an important issue for conservation, because they can help create mitigation measures for the impacts of anthropogenic activities on biological communities, and so should be expanded to studies using other taxonomic groups in both tropical and temperate systems, and, wherever possible, at multiple spatial scales.     

Identification of acidic heterocycle-substituted 1H-pyrazolo[3,4-b]pyridines as soluble guanylate cyclase stimulators

Novel guanylate cyclase stimulators are disclosed. Design, synthesis, SAR, and pharmacological profile of the compounds are discussed.     

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.     

CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures

Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.