Ambient Oxygen Promotes Tumorigenesis

Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ∼50% increase in the median tumor-free survival time of p53−/− mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53−/− mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo

BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions

Investigations into brain function and disease depend on the precise classification of neural cell types. Cells of the oligodendrocyte lineage differ greatly in their morphology, but accurate identification has thus far only been possible for oligodendrocyte progenitor cells and mature oligodendrocytes in humans. We find that breast carcinoma amplified sequence 1 (BCAS1) expression identifies an oligodendroglial subpopulation in the mouse and human brain. These cells are newly formed, myelinating oligodendrocytes that segregate from oligodendrocyte progenitor cells and mature oligodendrocytes and mark regions of active myelin formation in development and in the adult. We find that BCAS1+ oligodendrocytes are restricted to the fetal and early postnatal human white matter but remain in the cortical gray matter until old age. BCAS1+ oligodendrocytes are reformed after experimental demyelination and found in a proportion of chronic white matter lesions of patients with multiple sclerosis (MS) even in a subset of patients with advanced disease. Our work identifies a means to map ongoing myelin formation in health and disease and presents a potential cellular target for remyelination therapies in MS

Reproductive capability in dogs with canine leukocyte adhesion deficiency treated with nonmyeloablative conditioning prior to allogeneic hematopoietic stem cell transplantation

Nonmyeloablative conditioning regimens are increasingly replacing myeolablative conditioning prior to allogeneic hematopoietic stem cell transplantation (SCT). The recent advent of these conditioning regimens has limited the assessment of the long-term effects of this treatment, including analysis of reproductive function. To address the question of reproductive function after nonmyeloablative transplantation, we analyzed a cohort of young dogs with the genetic disease canine leukocyte adhesion deficiency that were treated with a nonmyeloablative dose of 200 cGy total body irradiation followed by matched-littermate SCT. Five males and 5 females entered puberty; all 5 males and 4 females subsequently sired or delivered litters following transplantation. We demonstrate that fertility is intact and dogs have uncomplicated parturitions following nonmyeloablative conditioning for SCT. These results are encouraging for children and adults of childbearing age who receive similar conditioning regimens prior to allogeneic transplantation

NPC1 deficiency in mice is associated with fetal growth restriction, neonatal lethality and abnormal lung pathology

The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of NPC1, which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various Npc1 mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a Npc1 mouse model, Npc1em1Pav, and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. Npc1em1Pav/em1Pav mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in Npc1em1Pav/em1Pav mice. The phenotypic severity of the Npc1em1Pav model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients

Late Multiple Organ Surge in Interferon-Regulated Target Genes Characterizes Staphylococcal Enterotoxin B Lethality

<div><p>Background</p><p>Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB) challenge was investigated in six tissues.</p><p>Results</p><p>The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC), spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RT-PCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN)/antiviral-response and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN)-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature.</p><p>Conclusion</p><p>Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes.</p></div

Tissue-specific parallel plots of the 103 probesets that met selection criteria.

<p>Expression levels were normalized to the time 0 h control condition to emphasize change over time from baseline. Probesets with peak expression before 24 h in any tissue are displayed in red. Notably, 12 probesets representing 11 unique genes (Cxcl9, Cxcl10, Cxcl11, Cd274, Fam26f, Irf1, Irf8, Irgm2, Parp14, Serpina3g, and Stat1) peaked at 5 h post-staphylococcal enterotoxin B (SEB) challenge in PBMCs and/or spleen as indicated. Gene symbols (in red) are displayed vertically from highest to lowest fold-change at 5 h.</p

Quantitative real-time PCR (qRT-PCR) confirmation of tissue-wide changes in gene expression.

<p>Nine genes were quantitated by qRT-PCR across all 6 tissues at 24 h. (A) Scatter plot of all genes and tissues tested comparing microarray and qRT-PCR fold-change from control. As shown by the line of identify (x  =  y), qRT-PCR typically returned higher fold-change results than microarray. Gene specific results, colored by tissue (see Legend), are shown as follows: (B) Cxcl11; (C) Herc6; (D) Irf1; (E) Irf8; (F) Irgm1; (G) Parp12; (H) Stat1; (I) Xaf1; and (J) Zbp1. All qRT-PCR results met the >1.5 fold-change cut-off for gene selection, except for measurements of Irf8 in PBMCs and spleen. However, Irf8 similarly failed selection by microarray in these tissues at 24 h. Four samples were tested per tissue. Each PBMC sample represented a pool of multiple mice while each organ sample came from an individual mouse.</p

Top eleven promoter regulatory matrices identified using the F-match module in ExPlain 3.1 (BioBase Knowledge Library) (see Methods).

a<p>Ratio of the abundance of each promoter matrix in genes differentially regulated across all six tissues compared to 492 mouse housekeeping genes (see Methods).</p>b<p>Prdm1 (Blimp1), a transcriptional repressor essential for B- and T-cell differentiation and homeostasis, is regulated by Irf4. Prdm1 and interferon regulatory factors bind to similar DNA sequences. Some promoters contain overlapping motifs where Prdm1 and Irf family members may competitively interact.</p

Thematic analysis, interferon (IFN) response subtype classification, and promoter analysis for binding matrices responsive to IFN.

<p>(A) Canonical pathways significantly associated with the all-tissue response to staphylococcal enterotoxin B (SEB) challenge. Seventy-nine unique genes were recognized by the Ingenuity Pathway Analysis® (IPA®) database and mapped to IFN signaling, antigen presentation, and activation of IFN regulatory factor (IRF) by cytosolic pattern recognition receptors, among the other canonical pathways shown. (B) Classification of genes significantly up-regulated across all tissues by IFN response subtype. Note that for <i>Mus musculus</i>, the Interferome v2.01 database contained 1655 Type I genes, 1413 Type II genes, and no Type III genes. (C) IFN pathway-driven regulatory binding sites identified in the promoters of genes regulated across all tissues. Of 81 promoter regions analyzed (from +500 to −1500 bp), 68 were found to contain IFN-driven regulatory matrices as shown. Results generated by Interferome v2.01 using TRANSFAC® Professional (2012) matrices and the MATCH™ algorithm.</p