The role and impact of SNPs in pharmacogenomics and personalized medicine.

Over 10 million SNPs have been discovered to date as the result of both a private and public effort in the past two decades. Extensive investigations on SNPs have been performed to assess clinical applications for pharmacogenomics and Personalized Medicine. Recently, around the 10(th) anniversary of the first publication by the Human Genome Project, Hamburg and Collins addressed questions regarding the progress of the genomics field and its impact on pharmacogenomics / Personalized Medicine. Similar questions remain around the potential link of SNPs to Personalized Medicine applications, and the extent to which they have impacted "real world" clinical practices. Built upon these previous efforts, and to achieve our objectives of describing and assessing the role of SNPs and their impact on Personalized Medicine, this article analyzes and summarizes the clinical relevance, molecular mechanisms, clinical evidence, and preliminary regulatory and clinical guideline information of relevant SNPs. In addition, it focuses on two applications directly related to Personalized Medicine drug therapeutics: predictive biomarkers for patient stratification and dose selection. In summary, this article attempts to provide a general and comprehensive view of the role of SNPs in pharmacogenomics and Personalized Medicine, as well as a practical view of their impact on clinical practice today.

Natural course following pediatric tracheostomy.

OBJECTIVE: To describe the hospital course of pediatric posttracheostomy patients, their underlying diagnosis, and their demographic characteristics. DESIGN: Retrospective, descriptive record review. SETTINGS: Academic tertiary Pediatric Critical Care Unit. METHODS AND RESULTS: One hundred and forty-one patients 1 month to 20 years old identified and included in the study. The length of in-hospital stay ranged from 14 to 280 days. The most common indications for tracheostomy were ventilation of chronic lung disease (CLD), subglottic stenosis, or combination at 44.7% of the cases followed by neurological cases 26.2%. Patients requiring prolonged stay were more likely to have pulmonary hypertension (odds ratio [OR] = 5.43), gastrointestinal reflux (OR = 2.09), prior episodes of failure to thrive (OR = 4.17), feeding failure requiring feeding tube (OR = 3.32), and tracheitis (OR = 4.17). The chances for home ventilation requirement increased with long preoperative in-hospital ventilation time and high ventilator respiratory rate on the day of tracheostomy as 0.98 days for each preoperative day and 0.94 days for each set ventilator breath (set respiratory rate per minute). The survival rate was 98.9% for the first 30 days and 78% afterward. CONCLUSION: Chronic lung disease, subglottic stenosis, and combinations are the most common causes for tracheostomy at present followed for tracheostomy due to neurological problems. Children requiring tracheostomy have lengthy hospital stay. Establishing an accurate diagnosis helps predict the length of hospitalization and the need for home ventilation; however, in less clear cases, the length of stay can be predicted from the presence of pulmonary hypertension, reflux, and failure to thrive. The mortality rate is low at the postoperative period and increases depending upon the underline reason for tracheostomy referral.

JunD mediates survival signaling by the JNK signal transduction pathway.

The c-Jun NH(2)-terminal kinase (JNK) can cause cell death by activating the mitochondrial apoptosis pathway. However, JNK is also capable of signaling cell survival. The mechanism that accounts for the dual role of JNK in apoptosis and survival signaling has not been established. Here we demonstrate that JNK-stimulated survival signaling can be mediated by JunD. The JNK/JunD pathway can collaborate with NF-kappaB to increase antiapoptotic gene expression. This observation accounts for the ability of JNK to cause either survival or apoptosis in different cellular contexts. Furthermore, these data illustrate the general principal that signal transduction pathway integration is critical for the ability of cells to mount an appropriate biological response to a specific challenge.

Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts.

The c-Jun NH(2)-terminal kinase (JNK) is implicated in the apoptotic response of cells exposed to stress, but the JNK signal transduction pathway may not act exclusively in apoptosis. In some studies of tumor cells, JNK has been implicated in signaling cell survival. The possibility that JNK might mediate a survival signal in tumor cells is consistent with the observation that it is activated in response to some oncogenes, such as the leukemogenic oncogene BCR-ABL, which is created by a reciprocal translocation between human chromosomes 9 and 22 (ref. 2). The BCR-ABL protein activates the JNK signaling pathway in hematopoietic cells and increases transcriptional activity mediated by the transcription factor AP1 (ref. 3). Also, inhibition of c-Jun or JNK prevents BCR-ABL-induced cell transformation in vitro. Although this implicates the JNK signaling pathway in transformation by BCR-ABL, the possible role of JNK in this process is unclear. We find that disruption of the JNK ortholog Mapk8 (also known as Jnk1) in mice causes defective transformation of pre-B cells by BCR-ABL in vitro and in vivo. The Jnk1 protein is required for the survival of the transformed cells in the absence of stromal support. Failure to survive is associated with decreased expression of Bcl2, and the effect of Jnk1 deficiency can be rescued by transgenic expression of Bcl2. Our results show that Jnk1 signals cell survival in transformed B lymphoblasts and suggest that it may contribute to the pathogenesis of some proliferative diseases.

c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation.

The c-Jun NH(2)-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8(+) T cells. Unlike CD4(+) T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8(+) T cells. In contrast, JNK1-deficient CD8(+) T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor alpha chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8(+) T cells can account for the impaired IL-2 receptor alpha chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8(+) T cell activation and these roles differ from those in CD4(+) T cells.