Novel subdomains of the mouse olfactory bulb defined by molecular heterogeneity in the nascent external plexiform and glomerular layers

<p>Abstract</p> <p>Background</p> <p>In the mouse olfactory system, the role of the olfactory bulb in guiding olfactory sensory neuron (OSN) axons to their targets is poorly understood. What cell types within the bulb are necessary for targeting is unknown. What genes are important for this process is also unknown. Although projection neurons are not required, other cell-types within the external plexiform and glomerular layers also form synapses with OSNs. We hypothesized that these cells are important for targeting, and express spatially differentially expressed guidance cues that act to guide OSN axons within the bulb.</p> <p>Results</p> <p>We used laser microdissection and microarray analysis to find genes that are differentially expressed along the dorsal-ventral, medial-lateral, and anterior-posterior axes of the bulb. The expression patterns of these genes divide the bulb into previously unrecognized subdomains. Interestingly, some genes are expressed in both the medial and lateral bulb, showing for the first time the existence of symmetric expression along this axis. We use a regeneration paradigm to show that several of these genes are altered in expression in response to deafferentation, consistent with the interpretation that they are expressed in cells that interact with OSNs.</p> <p>Conclusion</p> <p>We demonstrate that the nascent external plexiform and glomerular layers of the bulb can be divided into multiple domains based on the expression of these genes, several of which are known to function in axon guidance, synaptogenesis, and angiogenesis. These genes represent candidate guidance cues that may act to guide OSN axons within the bulb during targeting.</p

Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance.

Insulin resistance in muscle, adipocytes and liver is a gateway to a number of metabolic diseases. Here, we show a selective deficiency in mitochondrial coenzyme Q (CoQ) in insulin-resistant adipose and muscle tissue. This defect was observed in a range of in vitro insulin resistance models and adipose tissue from insulin-resistant humans and was concomitant with lower expression of mevalonate/CoQ biosynthesis pathway proteins in most models. Pharmacologic or genetic manipulations that decreased mitochondrial CoQ triggered mitochondrial oxidants and insulin resistance while CoQ supplementation in either insulin-resistant cell models or mice restored normal insulin sensitivity. Specifically, lowering of mitochondrial CoQ caused insulin resistance in adipocytes as a result of increased superoxide/hydrogen peroxide production via complex II. These data suggest that mitochondrial CoQ is a proximal driver of mitochondrial oxidants and insulin resistance, and that mechanisms that restore mitochondrial CoQ may be effective therapeutic targets for treating insulin resistance

Transcriptome, Methylome and Genomic Variations Analysis of Ectopic Thyroid Glands

Congenital hypothyroidism from thyroid dysgenesis (CHTD) is predominantly a sporadic disease characterized by defects in the differentiation, migration or growth of thyroid tissue. Of these defects, incomplete migration resulting in ectopic thyroid tissue is the most common (up to 80%). Germinal mutations in the thyroid-related transcription factors NKX2.1, FOXE1, PAX-8, and NKX2.5 have been identified in only 3% of patients with sporadic CHTD. Moreover, a survey of monozygotic twins yielded a discordance rate of 92%, suggesting that somatic events, genetic or epigenetic, probably play an important role in the etiology of CHTD.Journal ArticleResearch Support, Non-U.S. Gov'tValidation StudiesSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Discriminating lymphomas and reactive lymphadenopathy in lymph node biopsies by gene expression profiling

<p>Abstract</p> <p>Background</p> <p>Diagnostic accuracy of lymphoma, a heterogeneous cancer, is essential for patient management. Several ancillary tests including immunophenotyping, and sometimes cytogenetics and PCR are required to aid histological diagnosis. In this proof of principle study, gene expression microarray was evaluated as a single platform test in the differential diagnosis of common lymphoma subtypes and reactive lymphadenopathy (RL) in lymph node biopsies.</p> <p>Methods</p> <p>116 lymph node biopsies diagnosed as RL, classical Hodgkin lymphoma (cHL), diffuse large B cell lymphoma (DLBCL) or follicular lymphoma (FL) were assayed by mRNA microarray. Three supervised classification strategies (global multi-class, local binary-class and global binary-class classifications) using diagonal linear discriminant analysis was performed on training sets of array data and the classification error rates calculated by leave one out cross-validation. The independent error rate was then evaluated by testing the identified gene classifiers on an independent (test) set of array data.</p> <p>Results</p> <p>The binary classifications provided prediction accuracies, between a subtype of interest and the remaining samples, of 88.5%, 82.8%, 82.8% and 80.0% for FL, cHL, DLBCL, and RL respectively. Identified gene classifiers include LIM domain only-2 (<it>LMO2</it>), Chemokine (C-C motif) ligand 22 (<it>CCL22</it>) and Cyclin-dependent kinase inhibitor-3 (<it>CDK3</it>) specifically for FL, cHL and DLBCL subtypes respectively.</p> <p>Conclusions</p> <p>This study highlights the ability of gene expression profiling to distinguish lymphoma from reactive conditions and classify the major subtypes of lymphoma in a diagnostic setting. A cost-effective single platform "mini-chip" assay could, in principle, be developed to aid the quick diagnosis of lymph node biopsies with the potential to incorporate other pathological entities into such an assay.</p

Clonal evolution in liver cancer at single-cell and single-variant resolution.

Genetic heterogeneity of tumor is closely related to its clonal evolution, phenotypic diversity and treatment resistance, and such heterogeneity has only been characterized at single-cell sub-chromosomal scale in liver cancer. Here we reconstructed the single-variant resolution clonal evolution in human liver cancer based on single-cell mutational profiles. The results indicated that key genetic events occurred early during tumorigenesis, and an early metastasis followed by independent evolution was observed in primary liver tumor and intrahepatic metastatic portal vein tumor thrombus. By parallel single-cell RNA-Seq, the transcriptomic phenotype of HCC was found to be related with genetic heterogeneity. For the first time we reconstructed the single-cell and single-variant clonal evolution in human liver cancer, and dissection of both genetic and phenotypic heterogeneity will facilitate better understanding of their relationship

Increased Phosphorylation of Vimentin in Noninfiltrative Meningiomas

International audienceBACKGROUND: Tissue invasion or tissue infiltration are clinical behaviors of a poor-prognosis subset of meningiomas. We carried out proteomic analyses of tissue extracts to discover new markers to accurately distinguish between infiltrative and noninfiltrative meningiomas. METHODOLOGY/PRINCIPAL FINDINGS: Protein lysates of 64 different tissue samples (including two brain-invasive and 32 infiltrative tumors) were submitted to SELDI-TOF mass spectrometric analysis. Mass profiles were used to build up both unsupervised and supervised hierarchical clustering. One marker was found at high levels in noninvasive and noninfiltrative tumors and appeared to be a discriminative marker for clustering infiltrative and/or invasive meningiomas versus noninvasive meningiomas in two distinct subsets. Sensitivity and specificity were 86.7% and 100%, respectively. This marker was purified and identified as a multiphosphorylated form of vimentin, a cytoskeletal protein expressed in meningiomas. CONCLUSIONS/SIGNIFICANCE: Specific forms of vimentin can be surrogate molecular indicators of the invasive/infiltrative phenotype in tumors

A Mouse Stromal Response to Tumor Invasion Predicts Prostate and Breast Cancer Patient Survival

Primary and metastatic tumor growth induces host tissue responses that are believed to support tumor progression. Understanding the molecular changes within the tumor microenvironment during tumor progression may therefore be relevant not only for discovering potential therapeutic targets, but also for identifying putative molecular signatures that may improve tumor classification and predict clinical outcome. To selectively address stromal gene expression changes during cancer progression, we performed cDNA microarray analysis of laser-microdissected stromal cells derived from prostate intraepithelial neoplasia (PIN) and invasive cancer in a multistage model of prostate carcinogenesis. Human orthologs of genes identified in the stromal reaction to tumor progression in this mouse model were observed to be expressed in several human cancers, and to cluster prostate and breast cancer patients into groups with statistically different clinical outcomes. Univariate Cox analysis showed that overexpression of these genes is associated with shorter survival and recurrence-free periods. Taken together, our observations provide evidence that the expression signature of the stromal response to tumor invasion in a mouse tumor model can be used to probe human cancer, and to provide a powerful prognostic indicator for some of the most frequent human malignancies