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Furge K.A.,Laboratory of Computational Biology | MacKeigan J.P.,Laboratory of Systems Biology | Teh B.T.,Laboratory of Cancer Genetics | Teh B.T.,National Cancer Center
The Lancet Oncology | Year: 2010

Renal-cell carcinoma is a heterogeneous group of tumours that arise in the adult kidneys. Irrespective of the type of renal tumour, traditional chemotherapeutic and radiation-based therapies have been largely ineffective at treating advanced tumours, with long-term survival being very low. Molecularly-targeted inhibitors of protein kinases are effective in delaying progression of advanced renal tumours. These therapies revolve around inhibition of the vascular endothelial growth factor receptor tyrosine kinase and the mammalian target of rapamycin serine or threonine kinase signalling pathways. The genetic complexity of renal tumours revealed by gene-expression profiling and other molecular-genetic technologies indicate that inhibition of additional kinase-associated pathways could also prevent renal tumour growth. In this review, we discuss the use of molecularly-targeted kinase inhibitors in the treatment of renal-cell carcinoma and identify the next generation of kinase inhibitors that show promise for treatment. © 2010 Elsevier Ltd. Source

Gemayel R.,Laboratory of Systems Biology | Chavali S.,University of Cambridge | Pougach K.,Laboratory of Systems Biology | Legendre M.,Aix - Marseille University | And 9 more authors.
Molecular Cell | Year: 2015

Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington's disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator's innate function, with the inherent risk of pathogenic repeat expansions. © 2015 The Authors. Source

Itoh S.,Stanford University | Kimura N.,Stanford University | Axtell R.C.,Stanford University | Velotta J.B.,Stanford University | And 18 more authors.
Circulation | Year: 2011

Background-Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice. Methods and Results-Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17) or-wild-type mice. Allograft survival was significantly prolonged in IL-17 recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17 recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17 recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4 and CD8 T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2 recipient mice engrafted with either wild-type or IL-17 CD4 and CD8 T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls. Conclusions-During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4 and CD8 T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection. © 2011 American Heart Association, Inc. Source

Aslankoohi E.,Laboratory of Systems Biology | Aslankoohi E.,Catholic University of Leuven | Rezaei M.N.,AMD Inc | Vervoort Y.,Laboratory of Systems Biology | And 4 more authors.
PLoS ONE | Year: 2015

Glycerol is the main compatible solute in yeast Saccharomyces cerevisiae. When faced with osmotic stress, for example during semi-solid state bread dough fermentation, yeast cells produce and accumulate glycerol in order to prevent dehydration by balancing the intracellular osmolarity with that of the environment. However, increased glycerol production also results in decreased CO2 production, which may reduce dough leavening. We investigated the effect of yeast glycerol production level on bread dough fermentation capacity of a commercial bakery strain and a laboratory strain. We find that Δgpd1 mutants that show decreased glycerol production show impaired dough fermentation. In contrast, overexpression of GPD1 in the laboratory strain results in increased fermentation rates in high-sugar dough and improved gas retention in the fermenting bread dough. Together, our results reveal the crucial role of glycerol production level by fermenting yeast cells in dough fermentation efficiency as well as gas retention in dough, thereby opening up new routes for the selection of improved commercial bakery yeasts. © 2015 Aslankoohi et al. Source

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