Comparison of [18F]-Tracers in Various Experimental Tumor Models by PET Imaging and Identification of an Early Response Biomarker for the Novel Microtubule Stabilizer Patupilone

Purpose: The suitability of [18F]FDG, [18F]FLT, [18F]FET, and [18F]FCH as non-invasive positron emission tomography (PET) biomarkers for monitoring response to chemotherapy was analyzed in various experimental tumor models. Procedures: Tracer uptake into three syngeneic rodent tumor models and ten human xenograft models was evaluated using semiquantitative analysis of small-animal PET data. Murine RIF-1 fibrosarcomas and [18F]FLT were selected to monitor the effects of the novel cytotoxic patupilone. Results: Except [18F]FCH, all tracers provided good tumor visualization. Highest [18F]FDG uptake was identified in syngeneic tumors. Xenograft models, however, showed low [18F]FDG SUVs and were better visualized by [18F]FLT. Monitoring the effects of patupilone on [18F]FLT uptake in RIF-1 tumors revealed a significant decrease of tracer uptake after 24h, which strongly negatively correlated with apoptosis. Conclusion: [18F]FLT PET of experimental tumors is a viable complement to [18F]FDG for preclinical drug development. [18F]FLT may be an excellent biomarker for patupilone-induced apoptosi

Variola virus in a 300-year-old Siberian mummy.

International audienceNo abstract available

Mutations specific to the Rac-GEF domain of <i>TRIO</i> cause intellectual disability and microcephaly

Background: Neurodevelopmental disorders have challenged clinical genetics for decades, with over 700 genes implicated and many whose function remains unknown. The application of whole-exome sequencing is proving pivotal in closing the genotype/phenotype gap through the discovery of new genes and variants that help to unravel the pathogenic mechanisms driving neuropathogenesis. One such discovery includes TRIO, a gene recently implicated in neurodevelopmental delay. Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a major regulator of neuronal development, controlling actin cytoskeleton dynamics by activating the GTPase Rac1.Methods: Whole-exome sequencing was undertaken on a family presenting with global developmental delay, microcephaly and mild dysmorphism. Father/daughter exome analysis was performed, followed by confirmatory Sanger sequencing and segregation analysis on four individuals. Three further patients were recruited through the deciphering developmental disorders (DDD) study. Functional studies were undertaken using patient-specific Trio protein mutations.Results: We identified a frameshift deletion in TRIO that segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations in TRIO. Biochemical studies demonstrated that in three out of four families, the Trio mutations led to a markedly reduced Rac1 activation.Conclusions: We describe an inherited global developmental delay phenotype associated with a frameshift deletion in TRIO. Additionally, we identify pathogenic de novo missense mutations in TRIO associated with the same consistent phenotype, intellectual disability, microcephaly and dysmorphism with striking digital features. We further functionally validate the importance of the GEF domain in Trio protein function. Our study demonstrates how genomic technologies are yet again proving prolific in diagnosing and advancing the understanding of neurodevelopmental disorders.<br/

A historical overview of the classification, evolution, and dispersion of Leishmania parasites and sandflies

Background The aim of this study is to describe the major evolutionary historical events among Leishmania, sandflies, and the associated animal reservoirs in detail, in accordance with the geographical evolution of the Earth, which has not been previously discussed on a large scale. Methodology and Principal Findings Leishmania and sandfly classification has always been a controversial matter, and the increasing number of species currently described further complicates this issue. Despite several hypotheses on the origin, evolution, and distribution of Leishmania and sandflies in the Old and New World, no consistent agreement exists regarding dissemination of the actors that play roles in leishmaniasis. For this purpose, we present here three centuries of research on sandflies and Leishmania descriptions, as well as a complete description of Leishmania and sandfly fossils and the emergence date of each Leishmania and sandfly group during different geographical periods, from 550 million years ago until now. We discuss critically the different approaches that were used for Leishmana and sandfly classification and their synonymies, proposing an updated classification for each species of Leishmania and sandfly. We update information on the current distribution and dispersion of different species of Leishmania (53), sandflies (more than 800 at genus or subgenus level), and animal reservoirs in each of the following geographical ecozones: Palearctic, Nearctic, Neotropic, Afrotropical, Oriental, Malagasy, and Australian. We propose an updated list of the potential and proven sandfly vectors for each Leishmania species in the Old and New World. Finally, we address a classical question about digenetic Leishmania evolution: which was the first host, a vertebrate or an invertebrate? Conclusions and Significance We propose an updated view of events that have played important roles in the geographical dispersion of sandflies, in relation to both the Leishmania species they transmit and the animal reservoirs of the parasites

Lipoprotein and metabolite associations to breast cancer risk in the HUNT2 study

Background The aim of this study was to gain an increased understanding of the aetiology of breast cancer, by investigating possible associations between serum lipoprotein subfractions and metabolites and the long-term risk of developing the disease. Methods From a cohort of 65,200 participants within the Trøndelag Health Study (HUNT study), we identified all women who developed breast cancer within a 22-year follow-up period. Using nuclear magnetic resonance (NMR) spectroscopy, 28 metabolites and 89 lipoprotein subfractions were quantified from prediagnostic serum samples of future breast cancer patients and matching controls (n = 1199 case–control pairs). Results Among premenopausal women (554 cases) 14 lipoprotein subfractions were associated with long-term breast cancer risk. In specific, different subfractions of VLDL particles (in particular VLDL-2, VLDL-3 and VLDL-4) were inversely associated with breast cancer. In addition, inverse associations were detected for total serum triglyceride levels and HDL-4 triglycerides. No significant association was found in postmenopausal women. Conclusions We identified several associations between lipoprotein subfractions and long-term risk of breast cancer in premenopausal women. Inverse associations between several VLDL subfractions and breast cancer risk were found, revealing an altered metabolism in the endogenous lipid pathway many years prior to a breast cancer diagnosis.acceptedVersio

Urinary metabolomics reveals glycemic and coffee associated signatures of thyroid function in two population-based cohorts

Triiodothyronine (T3) and thyroxine (T4) as the main secretion products of the thyroid affect nearly every human tissue and are involved in a broad range of processes ranging from energy expenditure and lipid metabolism to glucose homeostasis. Metabolomics studies outside the focus of clinical manifest thyroid diseases are rare. The aim of the present investigation was to analyze the cross-sectional and longitudinal associations of urinary metabolites with serum free T4 (FT4) and thyroid-stimulating hormone (TSH).Urine Metabolites of participants of the population-based studies Inter99 (n = 5620) and Health2006/Health2008 (n = 3788) were analyzed by 1H-NMR spectroscopy. Linear or mixed linear models were used to detect associations between urine metabolites and thyroid function.Cross-sectional analyses revealed positive relations of alanine, trigonelline and lactic acid with FT4 and negative relations of dimethylamine, glucose, glycine and lactic acid with log(TSH). In longitudinal analyses, lower levels of alanine, dimethylamine, glycine, lactic acid and N,N-dimethylglycine were linked to a higher decline in FT4 levels over time, whereas higher trigonelline levels were related to a higher FT4 decline. Moreover, the risk of hypothyroidism was higher in subjects with high baseline trigonelline or low lactic acid, alanine or glycine values.The detected associations mainly emphasize the important role of thyroid hormones in glucose homeostasis. In addition, the predictive character of these metabolites might argue for a potential feedback of the metabolic state on thyroid function. Besides known metabolic consequences of TH, the link to the urine excretion of trigonelline, a marker of coffee consumption, represents a novel finding of this study and given the ubiquitous consumption of coffee requires further research

Infestation by pyrethroids resistant bed bugs in the suburb of Paris, France

Bed bugs are hematophagous insects responsible for a re-emerging and challenging indoor pest in many countries. Bed bugs infestations may have health consequences including nuisance biting, cutaneous and systemic reactions. This resurgence can probably be attributed to factors such as increased international travel and development of resistance against insecticides. Resistance against pyrethroids has been reported several times from the USA and rarely in Europe. In France, very few data on bed bugs are available. The present study aimed to assess the infestation by bed bugs of a complex of two high-rise apartment buildings in the suburb of Paris and to evaluate their susceptibility to pyrethroid insecticides. We inspected for bed bugs 192 out of 198 apartments units (97%) and interviewed their residents. 76 (39.6%) apartments were infested. Among the 97 residents living in infested apartments, 53 (54.6%) reported bed bug bites. A total of 564 bed bugs were collected in the infested units. Bioassays showed that 54 out of 143 bed bugs were resistant to pyrethroids (37.8%; 95% confidence interval: 29.9-45.7%). DNA sequencing showed that all bed bugs tested (n = 124) had homozygous L925I kdr-like gene mutation. The level of pyrethroid resistance found indicates that this phenomenon was already established in the site and prompts the need to reevaluate the wide use of pyrethroids to control bed bugs

Does hyperphenylalaninemia induce brain glucose hypometabolism? Cerebral spinal fluid findings in treated adult phenylketonuric patients

Despite numerous studies in human patients and animal models for phenylketonuria (PKU; OMIM#261600), the pathophysiology of PKU and the underlying causes of brain dysfunction and cognitive problems in PKU patients are not well understood. In this study, lumbar cerebral spinal fluid (CSF) was obtained immediately after blood sampling from early-treated adult PKU patients who had fasted overnight. Metabolite and amino acid concentrations in the CSF of PKU patients were compared with those of non-PKU controls. The CSF concentrations and CSF/plasma ratios for glucose and lactate were found to be below normal, similar to what has been reported for glucose transporter1 (GLUT1) deficiency patients who exhibit many of the same clinical symptoms as untreated PKU patients. CSF glucose and lactate levels were negatively correlated with CSF phenylalanine (Phe), while CSF glutamine and glutamate levels were positively correlated with CSF Phe levels. Plasma glucose levels were negatively correlated with plasma Phe concentrations in PKU subjects, which partly explains the reduced CSF glucose concentrations. Although brain glucose concentrations are unlikely to be low enough to impair brain glucose utilization, it is possible that the metabolism of Phe in the brain to produce phenyllactate, which can be transported across the blood-brain barrier to the blood, may consume glucose and/or lactate to generate the carbon backbone for glutamate. This glutamate is then converted to glutamine and carries the Phe-derived ammonia from the brain to the blood. While this mechanism remains to be tested, it may explain the correlations of CSF glutamine, glucose, and lactate concentrations with CSF Phe

Antinuclear factors in murine alloantisera

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65479/1/j.1399-0039.1981.tb01357.x.pd