Citations

Olanzapine is an atypical antipsychotic agent of the thienobenzodiazepine class. Olanzapine blocks multiple neurotransmitter receptors, including dopaminergic (D 1 , D 2 , D 3 , and D 4 ), serotonergic (5-hydroxytryptamine 2A [5-HT 2A ], 5-HT 2C , 5-HT 3 , and 5-HT 6 ), adrenergic (α 1 ), histaminic (H 1 ), and muscarinic (M 1 , M 2 , M 3 , and M 4 ) receptors. Olanzapine has a high affinity for the 5HT 2A receptor, which is up to 5 times greater than the dopamine receptor, resulting in less propensity to the development of extrapyramidal side effects. The affinity of olanzapine for multiple receptors has lead to the identification of olanzapine as an important agent in the treatment of delirium, nausea, and vomiting. Olanzapine has been demonstrated to have opioid-sparing properties. Olanzapine is principally metabolized by glucuronidation, with a smaller metabolic contribution from the cytochrome oxidase system. Adverse effects of olanzapine include somnolence, postural hypotension, constipation, dizziness, restlessness, and weight gain. The purpose of this article is to outline the pharmacodynamics, pharmacology, and evidence for the use of olanzapine in palliative care.

Abstract Fusion genes and fusion gene products are widely employed as biomarkers and therapeutic targets in hematopoietic cancers, but their applications have yet to be appreciated in solid tumors. Here, we report the use of SnowShoes-FTD, a powerful new analytic pipeline that can identify fusion transcripts and assess their redundancy and tumor subtype-specific distribution in primary tumors. In a study of primary breast tumors, SnowShoes-FTD was used to analyze paired-end mRNA-Seq data from a panel of estrogen receptor (ER)+, HER2+, and triple-negative primary breast tumors, identifying tumor-specific fusion transcripts by comparison with mRNA-Seq data from nontransformed human mammary epithelial cell cultures plus the Illumina Body Map data from normal tissues. We found that every primary breast tumor that was analyzed expressed one or more fusion transcripts. Of the 131 tumor-specific fusion transcripts identified, 86 were “private” (restricted to a single tumor) and 45 were “redundant” (distributed among multiple tumors). Among the redundant fusion transcripts, 7 were unique to ER+ tumors and 8 were unique to triple-negative tumors. In contrast, none of the redundant fusion transcripts were unique to HER2+ tumors. Both private and redundant fusion transcripts were widely expressed in primary breast tumors, with many mapping to genomic loci implicated in breast carcinogenesis and/or risk. Our finding that some fusion transcripts are tumor subtype-specific suggests that these entities may be critical determinants in the etiology of breast cancer subtypes, useful as biomarkers for tumor stratification, or exploitable as cancer-specific therapeutic targets. Cancer Res; 72(8); 1921–8. ©2012 AACR.

Overexpression of the brain and acute leukemia, cytoplasmic ( BAALC ) gene is implicated in myeloid leukemogenesis and associated with poor outcome in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients. Additionally, high BAALC expression occurs in glioblastoma, melanoma, and childhood gastrointestinal stroma tumors, suggesting an oncogenic role for BAALC . However, the mechanisms underlying the deregulated expression are unknown. We hypothesized that a common heritable genetic feature located in cis might account for overexpression of BAALC in an allele-specific manner. By sequencing the genomic region of BAALC we identified nine informative single nucleotide polymorphisms (SNPs) and tested them for a possible association with BAALC expression levels. We show that BAALC overexpression occurs in the presence of the T allele of SNP rs62527607[GT], which creates a binding site for the activating RUNX1 transcription factor in the BAALC promoter region. The mechanism is demonstrated experimentally in vitro using luciferase reporter assays and electrophoretic mobility shift assay (EMSA) analysis. The association of high BAALC expression with the T allele and its correlations with RUNX1 expresser status are shown in vivo in a test set ( n = 253) and validation set ( n = 105) of samples from cytogenetically normal AML patients from different populations. Thus, we identify a heritable genomic feature predisposing to overexpression of an oncogene, thereby possibly leading to enhanced AML leukemogenesis. Our findings further suggest that genomic variants might become useful tools in the practice of personalized medicine.

ABSTRACT Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase‐1 (HO‐1) expression on vaccine response and outcome of influenza infection. HO‐1‐deficient and wild‐type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus ) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adeno‐viral‐based influenza vaccine. A genome‐wide association study evaluated the expression of single‐nucleotide polymorphisms (SNPs) in the HO‐1 gene and the response to influenza vaccination in healthy humans. HO‐1‐deficient mice had decreased survival after influenza infection compared to WT mice (median survival 5.5 vs. 6.5 d, P =0.016). HO‐1‐deficient mice had impaired production of antibody following influenza vaccination compared to WT mice (mean antibody titer 869 vs. 1698, P =0.02). One SNP in HO‐1 and one SNP in the constitutively expressed isoform HO‐2 were independently associated with decreased antibody production after influenza vaccination in healthy human volunteers ( P =0.017 and 0.014, respectively). HO‐1 deficient mice were paired with sex‐ and age‐matched WT controls. HO‐1 affects the immune response to both influenza infection and vaccination, suggesting that therapeutic induction of HO‐1 expression may represent a novel adjuvant to enhance influenza vaccine effectiveness.—Cummins, N. W., Weaver, E. A., May, S. M., Croatt, A. J., Foreman, O., Kennedy, R. B., Poland, G. A., Barry, M. A., Nath, K. A., Badley, A. D. Heme oxygenase‐1 regulates the immune response to influenza virus infection and vaccination in aged mice. FASEB J. 26, 2911–2918 (2012). www.fasebj.org