Thursday, September 15, 2016

Fly study points to importance and approaches for precision/personalized medicine in Ret fusion-associated cancers

Levinson S, Cagan RL. Drosophila Cancer Models Identify Functional Differences between Ret Fusions. Cell Rep. 2016 Sep 13;16(11):3052-3061. PMID: 27626672.

Abstract: "We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion."

Monday, September 12, 2016

Experiments in Drosophila contribute to characterization of links between kidney disease and salt stress

Mahajan A, Rodan AR, Le TH, Gaulton KJ, Haessler J, Stilp AM, Kamatani Y, Zhu G, Sofer T, Puri S, Schellinger JN, Chu PL, Cechova S, van Zuydam N; SUMMIT Consortium; BioBank Japan Project, Arnlov J, Flessner MF, Giedraitis V, Heath AC, Kubo M, Larsson A, Lindgren CM, Madden PA, Montgomery GW, Papanicolaou GJ, Reiner AP, Sundström J, Thornton TA, Lind L, Ingelsson E, Cai J, Martin NG, Kooperberg C, Matsuda K, Whitfield JB, Okada Y, Laurie CC, Morris AP, Franceschini N. Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity. Am J Hum Genet. 2016 Sep 1;99(3):636-46. PMID: 27588450.

From the abstract: "We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function ... We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci ... Loss-of-function mutations in ancestral orthologs of both [NFATC1 and RGS14] genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. ... Our study ... suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans."

Friday, August 19, 2016

Thursday, July 28, 2016

Uncovering the cellular function of Torsins -- relevance to DYT1 dystonia

Grillet M, Dominguez Gonzalez B, Sicart A, Pöttler M, Cascalho A, Billion K, Hernandez Diaz S, Swerts J, Naismith TV, Gounko NV, Verstreken P, Hanson PI, Goodchild RE. Torsins Are Essential Regulators of Cellular Lipid Metabolism. Dev Cell. 2016 Jul 14. PMID: 27453503.

From the abstract: "Torsins are developmentally essential AAA+ proteins, and mutation of human torsinA causes the neurological disease DYT1 dystonia. They localize in the ER membranes, but their cellular function remains unclear. We now show that dTorsin is required in Drosophila adipose tissue, where it suppresses triglyceride levels, promotes cell growth, and elevates membrane lipid content. We also see that human torsinA at the inner nuclear membrane is associated with membrane expansion and elevated cellular lipid content. ... These findings identify that torsins are essential regulators of cellular lipid metabolism and implicate disturbed lipid biology in childhood-onset DYT1 dystonia."

Monday, July 25, 2016

Exploring the relationship of metals to Friedreich's ataxia

Soriano S, Calap-Quintana P, Llorens JV, Al-Ramahi I, Gutiérrez L, Martínez-Sebastián MJ, Botas J, Moltó MD. Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease. PLoS One. 2016 Jul 19;11(7):e0159209. PMID: 27433942.

From the abstract: "Friedreich's ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. ... we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets."

Monday, July 18, 2016

If it sickens flies, do I want it in me? Using Drosophila to assess toxicity of plant extracts

Júnior FE, Macedo GE, Zemolin AP, Silva GF, Cruz LC, Boligon AA, de Menezes IR, Franco JL, Posser T. Oxidant effects and toxicity of Croton campestris in Drosophila melanogaster. Pharm Biol. 2016 Jul 14:1-10. PMID: 27417881.

From the abstract:  "... Croton campestris ... is a species native to Northeast Brazil used by traditional communities for the treatment of a variety of health problems. ... The potential toxicity of the hydroalcoholic extract of C. campestris leaves on Drosophila melanogaster ... were analysed in this study. ... Our data show important toxicological effects of C. campestris leading to increased mortality and impaired locomotor performance accompanied by induction of cell stress markers in flies. The study draws attention to the indiscriminate use of plant extracts."

Wednesday, June 15, 2016

Drosophila as a model for cancer drug development (review article)

Yadav AK, Srikrishna S, Gupta SC. Cancer Drug Development Using Drosophila as an in vivo Tool: From Bedside to Bench and Back. Trends Pharmacol Sci. 2016 Jun 10. pii: S0165-6147(16)30053-0. PMID: 27298020.

From the abstract: "The fruit fly Drosophila melanogaster has been used for modeling cancer and as an in vivo tool for the validation and/or development of cancer therapeutics. The impetus for the use of Drosophila in cancer research stems from the high conservation of its signaling pathways, lower genetic redundancy, short life cycle, genetic amenability, and ease of maintenance. Several cell signaling pathways in Drosophila have been used for cancer drug development. The efficacy of combination therapy and uptake/bioavailability of drugs have also been studied. ... The advantages and limitations of the model are discussed."