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Sudarsanam S.,Emiliem Inc. | Johnson D.E.,Emiliem Inc.
Current Opinion in Drug Discovery and Development | Year: 2010

TOR (target of rapamycin) is a serine-threonine protein kinase that is conserved across a diverse range of species from fungi to mammals. The signaling pathway that is anchored by TOR is also conserved across species. In mammals, mTOR integrates growth factor, amino acid, nutrient and energy sensing signals, and thus plays a major role in cell growth and proliferation, protein synthesis and autophagy. As a result of the pivotal role of mTOR in signaling, the aberrant regulation of mTOR has been implicated in several disease processes, including cancer, diabetes, ocular diseases and neurodegenerative disorders, as well as in lifespan extension. More recently, rapamycin (sirolimus) analogs that antagonize the mTOR signaling pathway have been approved for the treatment of several cancers. This review describes some recent advances in the understanding of mTOR signaling, with an emphasis on the functional consequences ofmTOR inhibition and therapeutic intervention strategies. © Thomson Reuters (Scientific) Ltd.


Johnson D.E.,Emiliem Inc. | Sudarsanam S.,Emiliem Inc. | Bingham J.,Jivan Biologics | Srinivasan S.,Institute of Bioinformatics and Applied Biotechnology
Current Drug Discovery Technologies | Year: 2012

Genome-wide RNA splicing (with gene expression) can be used to discover variations that drive specific diseases and / or change the susceptibility in individuals to drug responses including tissue specific toxicities. Evidence linking causative SNPs to individual splicing differences between individuals is emerging and this may lead to a better understanding of susceptibilities related to rare drug-induced toxicities. The development of more sensitive genomics tools is expected to further the study of variations in molecular phenotype from alternative splicing of pre-mRNA. This report highlights a genomics platform developed to measure splicing changes that occur in response to drug exposures, and therefore is applicable for the study of drug-induced toxicity. The platform is applicable for humans, all toxicology species, and specialized model systems. For efficiency, multiple samples can be combined into a single sequencing run and individual sequences can be separated via informatics. Biobanked specimens from clinical trials, toxicology studies, from commercial sources, and/or from public 'omics' data resources such as in NCBI are the only sample or non-sample data requirements. © 2012 Bentham Science Publishers.


Larson H.,Emiliem Inc. | Chan E.,Emiliem Inc. | Sudarsanam S.,Emiliem Inc. | Johnson D.E.,Emiliem Inc.
Methods in Molecular Biology | Year: 2013

Biomarkers are characteristics objectively measured and evaluated as indicators of: normal biologic processes, pathogenic processes, or pharmacologic response(s) to a therapeutic intervention. In environmental research and risk assessment, biomarkers are frequently referred to as indicators of human or environmental hazards. Discovering and implementing new biomarkers for toxicity caused by exposure to a chemical either from a therapeutic intervention or accidentally through the environment continues to be pursued through the use of animal models to predict potential human effects, from human studies (clinical or epidemiologic) or biobanked human samples, or the combination of all such approaches. The key to discovering or inferring biomarkers through computational means involves the identification or prediction of the molecular target(s) of the chemical(s) and the association of these targets with perturbed biological pathways. Two examples are given in this chapter: (1) inferring potential human biomarkers from animal toxicogenomics data, and (2) the identification of protein targets through computational means and associating these in one example with potential drug interactions and in another case with increasing the risk of developing certain human diseases. © 2013 Springer Science+Business Media, LLC.


Johnson D.E.,Emiliem Inc. | Johnson D.E.,University of California at Berkeley
Expert Review of Clinical Pharmacology | Year: 2010

First-in-human dose-selection criteria for biotherapeutics are changing, primarily based on severe adverse events in a single monoclonal antibody trial in healthy volunteers. Spurred by new EMA guidance, the minimum anticipated biological-effect level (MABEL) for estimating a starting human dose from exposure-response preclinical data have been introduced and should help to create long overdue target mechanism-based models focused on exposure-response relationships. Even though clarity of its application is still developing, this has the potential to become the model for most biotherapeutics in the future. However, maximizing benefit from MABEL will require increased efforts to define and create assays for relevant biomarkers of biological activity and safety as pharmacodynamic end points. Currently, this has not been realized sufficiently to make the model applicable to a majority of biotherapeutics; however, this review suggests how it can be applied universally with monoclonal antibodies. © 2010 Expert Reviews Ltd.


Johnson D.E.,Emiliem Inc. | Johnson D.E.,University of California at Berkeley | Johnson D.E.,University of Michigan
Expert Opinion on Orphan Drugs | Year: 2014

In June 2013, US FDA finalized changes to the Orphan Drug Regulation, clarifying the potential of using a single drug for multiple indications that would cause the total patient population to be > 200,000, but maintaining orphan drug status for a 'subset' of a disease where each patient population is < 200,000. In this editorial, an example is presented where drug candidates targeting biological pathways with the potential for multiple indications could capitalize on orphan indications, while maintaining a broader development strategy. The mammalian target of rapamycin pathway is highlighted with potential orphan indications in ocular diseases, tuberous sclerosis complex-related diseases and rare cancers. © Informa UK, Ltd.


PubMed | Emiliem Inc.
Type: Journal Article | Journal: Current drug discovery technologies | Year: 2012

Genome-wide RNA splicing (with gene expression) can be used to discover variations that drive specific diseases and / or change the susceptibility in individuals to drug responses including tissue specific toxicities. Evidence linking causative SNPs to individual splicing differences between individuals is emerging and this may lead to a better understanding of susceptibilities related to rare drug-induced toxicities. The development of more sensitive genomics tools is expected to further the study of variations in molecular phenotype from alternative splicing of pre-mRNA. This report highlights a genomics platform developed to measure splicing changes that occur in response to drug exposures, and therefore is applicable for the study of drug-induced toxicity. The platform is applicable for humans, all toxicology species, and specialized model systems. For efficiency, multiple samples can be combined into a single sequencing run and individual sequences can be separated via informatics. Biobanked specimens from clinical trials, toxicology studies, from commercial sources, and/or from public omics data resources such as in NCBI are the only sample or non-sample data requirements.


PubMed | Emiliem Inc.
Type: Journal Article | Journal: Current opinion in drug discovery & development | Year: 2010

TOR (target of rapamycin) is a serine-threonine protein kinase that is conserved across a diverse range of species from fungi to mammals. The signaling pathway that is anchored by TOR is also conserved across species. In mammals, mTOR integrates growth factor, amino acid, nutrient and energy sensing signals, and thus plays a major role in cell growth and proliferation, protein synthesis and autophagy. As a result of the pivotal role of mTOR in signaling, the aberrant regulation of mTOR has been implicated in several disease processes, including cancer, diabetes, ocular diseases and neurodegenerative disorders, as well as in lifespan extension. More recently, rapamycin (sirolimus) analogs that antagonize the mTOR signaling pathway have been approved for the treatment of several cancers. This review describes some recent advances in the understanding of mTOR signaling, with an emphasis on the functional consequences of mTOR inhibition and therapeutic intervention strategies.


PubMed | Emiliem Inc.
Type: Journal Article | Journal: Expert review of clinical pharmacology | Year: 2011

First-in-human dose-selection criteria for biotherapeutics are changing, primarily based on severe adverse events in a single monoclonal antibody trial in healthy volunteers. Spurred by new EMA guidance, the minimum anticipated biological-effect level (MABEL) for estimating a starting human dose from exposure-response preclinical data have been introduced and should help to create long overdue target mechanism-based models focused on exposure-response relationships. Even though clarity of its application is still developing, this has the potential to become the model for most biotherapeutics in the future. However, maximizing benefit from MABEL will require increased efforts to define and create assays for relevant biomarkers of biological activity and safety as pharmacodynamic end points. Currently, this has not been realized sufficiently to make the model applicable to a majority of biotherapeutics; however, this review suggests how it can be applied universally with monoclonal antibodies.


PubMed | Emiliem Inc.
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2012

Biomarkers are characteristics objectively measured and evaluated as indicators of: normal biologic processes, pathogenic processes, or pharmacologic response(s) to a therapeutic intervention. In environmental research and risk assessment, biomarkers are frequently referred to as indicators of human or environmental hazards. Discovering and implementing new biomarkers for toxicity caused by exposure to a chemical either from a therapeutic intervention or accidentally through the environment continues to be pursued through the use of animal models to predict potential human effects, from human studies (clinical or epidemiologic) or biobanked human samples, or the combination of all such approaches. The key to discovering or inferring biomarkers through computational means involves the identification or prediction of the molecular target(s) of the chemical(s) and the association of these targets with perturbed biological pathways. Two examples are given in this chapter: (1) inferring potential human biomarkers from animal toxicogenomics data, and (2) the identification of protein targets through computational means and associating these in one example with potential drug interactions and in another case with increasing the risk of developing certain human diseases.

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