Cross-platform assessment of genomic imbalance confirms the clinical relevance of genomic complexity and reveals loci with potential pathogenic roles in diffuse large B-cell lymphoma.

Genomic copy number alterations (CNAs) in diffuse large B-cell lymphoma (DLBCL) have roles in disease pathogenesis, but overall clinical relevance remains unclear. Herein, an unbiased algorithm was uniformly applied across three genome profiling datasets comprising 392 newly-diagnosed DLBCL specimens that defined 32 overlapping CNAs, involving 36 minimal common regions (MCRs). Scoring criteria were established for 50 aberrations within the MCRs while considering peak gains/losses.

Genomic imbalance defines three prognostic groups for risk stratification of patients with chronic lymphocytic leukemia.

Array comparative genomic hybridization (aCGH) has yet to be fully leveraged in a prognostic setting in chronic lymphocytic leukemia (CLL). Genomic imbalance was assessed in 288 CLL specimens using a targeted array. Based on 20 aberrations in a hierarchical manner, all 228 treatment-naive specimens were classified into a group with poor outcome (20.

Genomic deregulation during metastasis of renal cell carcinoma implements a myofibroblast-like program of gene expression.

Clear cell renal cell carcinoma (RCC) is the most common and invasive adult kidney cancer. The genetic and biological mechanisms that drive metastatic spread of RCC remain largely unknown. We have investigated the molecular signatures and underlying genomic aberrations associated with RCC metastasis, using an approach that combines a human xenograft model; expression profiling of RNA, DNA, and microRNA (miRNA); functional verification; and clinical validation.

SMAD3 functions as a transcriptional repressor of acid-sensing ion channel 3 (ASIC3) in nucleus pulposus cells of the intervertebral disc.

The goal of this investigation was to study the regulation of acid-sensing ion channel (ASIC)3 expression by TGFbeta in the nucleus pulposus cells of the intervertebral disc. Analysis of human nucleus pulposus tissue indicated decreased ASIC3 and elevated TGFbeta expression in the degenerate state. In a parallel study, treatment of nucleus pulposus cells with TGFbeta resulted in decreased expression of ASIC3 mRNA and protein.

Evidence for skeletal progenitor cells in the degenerate human intervertebral disc.

Study Design: To identify and characterize endogenous progenitor cell population from intervertebral disc.

Objective: To determine if progenitor cells exist in degenerate human discs.

Summary Of Background Data: Back pain, a significant source of morbidity in our society, is directly linked to the pathology of the intervertebral disc.

Normoxic stabilization of HIF-1alpha drives glycolytic metabolism and regulates aggrecan gene expression in nucleus pulposus cells of the rat intervertebral disk.

The nucleus pulposus is an aggrecan-rich, avascular tissue that permits the intervertebral disk to resist compressive loads. In the disk, nucleus pulposus cells express hypoxia-inducible factor (HIF)-1alpha, a transcription factor that responds to oxygen tension and regulates glycolysis. The goal of the present study was to examine the importance of HIF-1alpha in rat nucleus pulposus cells and to probe the function of this transcription factor in terms of regulating aggrecan gene expression.

MEK/ERK signaling controls osmoregulation of nucleus pulposus cells of the intervertebral disc by transactivation of TonEBP/OREBP.

Unlabelled: Earlier studies have shown that intervertebral disc cells express TonEBP, a transcription factor that permits adaptation to osmotic stress and regulates aggrecan gene expression. However, the mechanism of hyperosmotic activation of TonEBP in disc cells is not known. Results of this study show that hypertonic activation of ERK signaling regulates transactivation activity of TonEBP, modulating its function.

Fibroblast growth factor-2 maintains the differentiation potential of nucleus pulposus cells in vitro: implications for cell-based transplantation therapy.

Study Design: To investigate effects of FGF-2 on nucleus pulposus cell growth and differentiation.

Objectives: To elucidate the phenotypic changes that occur during expansion of nucleus pulposus cells in monolayer culture, and to investigate the effects of fibroblast growth factor (FGF)-2 on cell growth and differentiation.

Summary Of Background Data: Nucleus pulposus cells would have a limited application for autologous cell transplantation if phenotypic dedifferentiation takes place during culture expansion.

Galectin-3 expression in the intervertebral disc: a useful marker of the notochord phenotype?

Study Design: Galectin-3 expression in rat intervertebral disc at different stages in postnatal life is evaluated.

Objective: To determine if galectin-3 expression is confined to cells of the nucleus pulposus in the postnatal rat intervertebral disc.

Summary Of Background Data: During embryonic development, the anulus fibrosus is derived from the sclerotome, whereas the nucleus pulposus is notochordal.

TonEBP/OREBP is a regulator of nucleus pulposus cell function and survival in the intervertebral disc.

The nucleus pulposus is an aggrecan-rich hydrated tissue that permits the intervertebral disc to resist compressive loads. Adaptation to loading is achieved through an elevation in disc osmolarity mediated by the numerous charged glycosoaminoglycan side chains of the aggrecan molecule. The goal of this investigation was to determine the functional role of the osmo-regulatory protein, TonEBP, in cells of the nucleus pulposus.

Toward an optimum system for intervertebral disc organ culture: TGF-beta 3 enhances nucleus pulposus and anulus fibrosus survival and function through modulation of TGF-beta-R expression and ERK signaling.

Study Design: Rat lumbar discs comprising nucleus pulposus, annulus fibrosus, and cartilaginous endplates were cultured for 1 week in a specialized media containing either TGF-beta1 or TGF-beta3. Role of TGF-beta isoforms on cell function was evaluated.

Objective: To develop an in vitro organ culture of rat intervertebral disc and evaluate effects of TGF-beta3 on disc cell function.

Nucleus pulposus cells express HIF-1 alpha under normoxic culture conditions: a metabolic adaptation to the intervertebral disc microenvironment.

Nucleus pulposus (NP) cells of the intervertebral disc reside in an environment that has a limited vascular supply and generate energy through anaerobic glycolysis. The goal of the present study was to examine the expression and regulation of HIF-1alpha, a transcription factor that regulates oxidative metabolism in nucleus pulposus cells. Nucleus pulposus cells were isolated from rat, human, and sheep disc and maintained at either 21% or 2% oxygen for various time periods.

Anticancer effects of fenretinide in human medulloblastoma.

N-(4-hydroxyphenyl) retinamide (4-HPR, fenretinide) a synthetic retinoid is in clinical trials for the treatment of several malignancies. However, its biological effects and therapeutic value in childhood brain tumor medulloblastoma (MB) has not been investigated. In this study, we report for the first time that fenretinide (2.

Osteogenic potential of adult human stem cells of the lumbar vertebral body and the iliac crest.

Study Design: Marrow was aspirated from the vertebral body (VB) and iliac crest (IC) of patients undergoing lumbar spinal surgery, following an approved protocol. Progenitor cells were isolated using standard culture conditions and their osteogenic potential evaluated.

Objective: To evaluate the osteogenic potential of mesenchymal stem cells (MSCs) isolated from the bone marrow of the human VB.

Hypoxia activates MAPK activity in rat nucleus pulposus cells: regulation of integrin expression and cell survival.

Objective: The aim of the present study was to investigate whether activation of MAPK subtypes ERK and p38 influences integrin expression and promotes nucleus pulposus cell survival in hypoxia.

Summary Of Background Data: We have recently shown that in a low oxygen environment, rat nucleus pulposus cells activate phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. However, the role of these signaling pathways in regulating cell matrix interactions is not known.

Anticancer effects of the novel 1alpha, 25-dihydroxyvitamin D3 hybrid analog QW1624F2-2 in human neuroblastoma.

Vitamin D3 analogs are potential anti-cancer agents with theoretically wide therapeutic index, but there have been limited studies directed towards human neuroblastoma. The antiproliferative ability of the novel vitamin D3 hybrid analog QW-1624F2-2 (QW, 1-hydroxymethyl-16-ene-24, 24-F2-26, 27-bishomo-25-hydroxyvitamin D3) was examined in two human neuroblastoma-derived cell-lines. Analog QW inhibited cell-cycle progression of IMR5 cells with accumulation in G1 phase.

Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy.

Objective: Because mesenchymal stem cells can differentiate into chondrocyte-like cells, we ask the question, can mesenchymal stem cells commit to the nucleus pulposus phenotype?

Background: Back pain, a significant source of morbidity in our society, is linked to degenerative changes of the intervertebral disc. Absence of suitable graft tissue limits therapeutic approaches for repair of disc tissue. For this reason, there is considerable interest in developing "tissue engineering" strategies for the regeneration of the nucleus pulposus.