Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor

Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.     

'Infotaxis' as a strategy for searching without gradients

Chemotactic bacteria rely on local concentration gradients to guide them towards the source of a nutrient. Such local cues pointing towards the location of the source are not always available at macroscopic scales because mixing in a flowing medium breaks up regions of high concentration into random and disconnected patches. Thus, animals sensing odours in air or water detect them only intermittently as patches sweep by on the wind or currents. A macroscopic searcher must devise a strategy of movement based on sporadic cues and partial information. Here we propose a search algorithm, which we call 'infotaxis', designed to work under such conditions. Any search process can be thought of as acquisition of information on source location; for infotaxis, information plays a role similar to concentration in chemotaxis. The infotaxis strategy locally maximizes the expected rate of information gain. We demonstrate its efficiency using a computational model of odour plume propagation and experimental data on mixing flows. Infotactic trajectories feature 'zigzagging' and 'casting' paths similar to those observed in the flight of moths. The proposed search algorithm is relevant to the design of olfactory robots, but the general idea of infotaxis can be applied more broadly in the context of searching with sparse information.     

Human metabolic individuality in biomedical and pharmaceutical research

Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.     

Institutional experience of PTH evaluation on fine-needle washing after aspiration biopsy to locate hyperfunctioning parathyroid tissue

Assaying parathyroid hormone (PTH) in the washing liquid after fine-needle aspiration biopsy (FNAB) seems to be a valid approach to locate parathyroid tissue. PTH-FNAB was evaluated in 47 patients with a clinical picture of primary hyperparathyroidism (PHP) and ultrasonography (US) suggestive of parathyroid lesion. The patients were subdivided into two groups on the basis of the absence or presence of US thyroid alterations. The result of PTH-FNAB was compared with those of cytology, scintigraphy and, in 24 patients, surgical outcome. PTH-FNAB samples with a value higher than that recorded in the serum and higher than our institutional cut-off were deemed to be probable samples of parathyroid tissue. Cytology proved diagnostic for benign thyroid lesions, non-diagnostic for thyroid lesions, hyperplastic parathyroid tissue, undetermined or malignant thyroid lesions and other lesions in 45%, 30%, 17%, 4%, and 4% of cases, respectively. In 47% of cases, PTH-FNAB indicated that the sample had been taken in parathyroid tissue. In patients without US alterations, the diagnostic accuracy of PTH-FNAB was greater than that of scintigraphy. After surgery, comparison between the results of PTH-FNAB and scintigraphy, in terms of positive predictive value (PPV), revealed the superiority of PTH-FNAB; PPV was 94% for FNAB and 71% for scintigraphy, while sensitivity was 83% and 69%, respectively. PTH-FNAB evaluation after FNAB appears to be more diagnostic than cytology and scintigraphy. Of all the procedures used, PTH-FNAB appears to be the method of choice when the target is US suggestive and reachable. PTH-FNAB appears to be a useful method of guiding surgical intervention.     

Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency

An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.