RESUMEN
Sixteen oncology drugs have been approved with a companion diagnostic (CDx) test by the FDA. These represent only 9.6% of the 167 oncology drug approvals since 1998, the year the first CDx test for Herceptin was approved. The great majority of CDx tests are for drugs that inhibit signal transduction pathways by either inhibiting the intracellular kinase activity with a small molecule or preventing ligand-induced receptor activation with a monoclonal antibody. In most of these cases, prospective patient selection for the biomarker-positive subpopulation was initiated in or before Phase II. The development of CDx tests for emerging immunotherapies will be more complicated because they are not dependent on driver mutations in the drug target, the mechanism of action is often pleiotropic, and will require both protein and cell-based assays to evaluate the interaction of the tumor with the immune system. Consequently, we will need to develop new biomarker strategies for the development of immunotherapies and to determine whether the optimum strategy is to release a prior checkpoint blockade in patients with a suppressed immune response, or to prime a new immune response to the tumor.
Asunto(s)
Antineoplásicos/uso terapéutico , Inmunoterapia , Neoplasias/terapia , Transducción de Señal/efectos de los fármacos , Biomarcadores/análisis , Pruebas Diagnósticas de Rutina , Humanos , Neoplasias/inmunología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
There is an urgent need for effective genomics education for healthcare professionals. Recent analysis of an experimental genomics curriculum showed that medical students' examinations of their own genotypes provide a valuable learning experience. Such experiential learning has a long tradition in medical education and its application to genomics is enabled by increasingly powerful and decreasingly costly genome science and technology. Personal genotyping is an important option to consider when designing educational programs for healthcare professionals.
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Genoma Humano , Programas Nacionales de Salud , Patología Molecular/tendencias , Medicina de Precisión/tendencias , Adulto , Técnicas de Laboratorio Clínico/tendencias , Análisis Costo-Beneficio , Predicción , Proyecto Genoma Humano , Humanos , Recién Nacido , Patología Molecular/economía , Medicina de Precisión/economía , Análisis de Secuencia , Estados UnidosRESUMEN
Genomics and "medical sequencing" will revolutionize clinical laboratory diagnostics as the foundation for the new era of personalized medicine. However, the medical profession lags far behind the technology and business communities in recognizing and preparing for this change. Pathologists must take the lead in the application of genomics technologies, including whole-genome sequencing, to laboratory diagnostics and personalized medicine. As a critical first step in leading this change, we have established a first-in-the-nation resident curriculum in genomics and personalized medicine. Our goal is to catalyze the adoption of similar training modules in every pathology residency in North America. If we succeed in the widespread implementation of this type of training as a core competency in pathology, we will ensure that the discipline of pathology will lead rather than follow in the coming era of personalized medicine.
Asunto(s)
Genómica/educación , Internado y Residencia , Patología Clínica/educación , Medicina de Precisión , Competencia Clínica , Curriculum , HumanosRESUMEN
Applications of next-generation nucleic acid sequencing technologies will lead to the development of precision diagnostics that will, in turn, be a major technology enabler of precision medicine. Terabyte-scale, multidimensional data sets derived using these technologies will be used to reverse engineer the specific disease networks that underlie individual patients' conditions. Modeling and simulation of these networks in the presence of virtual drugs, and combinations of drugs, will identify the most efficacious therapy for precision medicine and customized care. In coming years the practice of medicine will routinely employ network biology analytics supported by high-performance supercomputing.
RESUMEN
Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of approximately 20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function.
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Encéfalo/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genoma/genética , Animales , Encéfalo/anatomía & histología , Encéfalo/citología , Biología Computacional , Genómica , Hipocampo/anatomía & histología , Hipocampo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Neurogenomics is the study of how the genome as a whole contributes to the evolution, development, structure and function of the nervous system. It includes investigations of how genome products (transcriptomes and proteomes) vary in time and space. Neurogenomics differs markedly from the application of genome sciences to other systems, particularly in the spatial category, because anatomy and connectivity are paramount to our understanding of function in the nervous system. We focus here on some of the influences of genomics and its associated technologies on neuroscience. We discuss comparative genomics, gene expression atlases of the brain, network genetics and applications to behavioral phenotypes, and consider the culture, organization and funding of genome-scale projects.
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Encéfalo , Genoma , Neurobiología , Animales , Evolución Biológica , Encéfalo/fisiología , Bases de Datos Genéticas , Perfilación de la Expresión Génica/métodos , Genómica , Humanos , Biología Molecular/métodos , Fenotipo , Proteoma , Apoyo a la Investigación como AsuntoRESUMEN
This article reviews recent advances in genomics and informatics relevant to cardiovascular research. In particular, we review the status of (1) whole genome sequencing efforts in human, mouse, rat, zebrafish, and dog; (2) the development of data mining and analysis tools; (3) the launching of the National Heart, Lung, and Blood Institute Programs for Genomics Applications and Proteomics Initiative; (4) efforts to characterize the cardiac transcriptome and proteome; and (5) the current status of computational modeling of the cardiac myocyte. In each instance, we provide links to relevant sources of information on the World Wide Web and critical appraisals of the promises and the challenges of an expanding and diverse information landscape.
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Biología Computacional/tendencias , Genómica/tendencias , Miocardio/metabolismo , Animales , Perros , Predicción , Humanos , Internet , Ratones , Modelos Cardiovasculares , Proteómica/tendencias , Ratas , Transcripción GenéticaRESUMEN
Success in proteomics depends upon careful study design and high-quality biological samples. Advanced information technologies, and also an ability to use existing knowledge to the full, will be crucial in making sense of the data. Despite its genome-scale potential, proteome analysis is at a much earlier stage of development than genomics and gene expression (microarray) studies. Fundamental issues involving biological variability, pre-analytic factors and analytical reproducibility remain to be resolved. Consequently, the analysis of proteomics data is currently informal and relies heavily on expert opinion. Databases and software tools developed for the analysis of molecular sequences and microarrays are helpful, but are limited owing to the unique attributes of proteomics data and differing research goals.
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Investigación Biomédica , Biología Computacional/métodos , Proteómica/métodos , Proteómica/normas , Biología Computacional/normas , Bases de Datos de Proteínas , Humanos , Proteínas/análisis , Control de Calidad , Reproducibilidad de los Resultados , Proyectos de InvestigaciónRESUMEN
BACKGROUND: As the rough draft of the human genome sequence nears a finished product and other genome-sequencing projects accumulate sequence data exponentially, bioinformatics is emerging as an important tool for studies of transposon biology. In particular, L1 elements exhibit a variety of sequence structures after insertion into the human genome that are amenable to computational analysis. We carried out a detailed analysis of the anatomy and distribution of L1 elements in the human genome using a new computer program, TSDfinder, designed to identify transposon boundaries precisely. RESULTS: Structural variants of L1 elements shared similar trends in the length and quality of their target site duplications (TSDs) and poly(A) tails. Furthermore, we found no correlation between the composition and genomic location of the pre-insertion locus and the resulting anatomy of the L1 insertion. We verified that L1 insertions with TSDs have the 5'-TTAAAA-3' cleavage site associated with L1 endonuclease activity. In addition, the second target DNA cut required for L1 insertion weakly matches the consensus pattern TTAAAA. On the other hand, the L1-internal breakpoints of deleted and inverted L1 elements do not resemble L1 endonuclease cleavage sites. Finally, the genome sequence data indicate that whereas singly inverted elements are common, doubly inverted elements are almost never found. CONCLUSIONS: The sequence data give no indication that the creation of L1 structural variants depends on characteristics of the insertion locus. In addition, the formation of 5' truncated and 5' inverted L1s are probably not due to the action of the L1 endonuclease.