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Cold Spring Harbor, NY, United States

Mager E.M.,University of Miami | Brix K.V.,University of Miami | Gerdes R.M.,Cold Spring Harbor Laboratories | Ryan A.C.,Hydroqual Inc | Grosell M.,University of Miami
Ecotoxicology and Environmental Safety

As the first step toward parameterization of a chronic lead (Pb) biotic ligand model (BLM) for Ceriodaphnia dubia, 7-d toxicity tests were performed in waters modified to evaluate the influences of hardness, DOM (as Suwannee River NOM and Aldrich humic acid (HA)), pH (buffered with 4mM MOPS) and alkalinity on the chronic toxicity of Pb. Calculated EC20s for the control base water test and each of the most extreme modified test waters were as follows in γgL-1 Pb (95% confidence interval): base water control=45 (14-53), 5mM CaSO4=22 (12-30), 32mgL-1 DOM=523 (388-573), 2.5mM NaHCO3=73 (21-120) and pH 6.4 buffered with MOPS=3.9γgL-1 Pb (1-5). Results indicate that hardness does not protect against chronic toxicity of Pb to C. dubia, whereas HA does protect at the highest concentration tested (597γM). Additionally, our findings suggest that low pH increases the chronic toxicity of Pb whereas increased alkalinity is protective. The findings reported herein support the need for a chronic Pb BLM as an alternative approach to hardness-based regulations. © 2010 Elsevier Inc. Source

Kerr J.B.,Monash University | Hutt K.J.,Monash University | Hutt K.J.,Prince Henrys Institute of Medical Research | Michalak E.M.,Walter and Eliza Hall Institute of Medical Research | And 14 more authors.
Molecular Cell

Trp63, a transcription factor related to the tumor suppressor p53, is activated by diverse stimuli and can initiate a range of cellular responses. TAp63 is the predominant Trp53 family member in primordial follicle oocyte nuclei and is essential for their apoptosis triggered by DNA damage in vivo. After γ-irradiation, induction of the proapoptotic BH3-only members Puma and Noxa was observed in primordial follicle oocytes from WT and Trp53-/- mice but not in those from TAp63-deficient mice. Primordial follicle oocytes from mice lacking Puma or both Puma and Noxa were protected from γ-irradiation-induced apoptosis and, remarkably, could produce healthy offspring. Hence, PUMA and NOXA are critical for DNA damage-induced, TAp63-mediated primordial follicle oocyte apoptosis. Thus, blockade of PUMA may protect fertility during cancer therapy and prevent premature menopause, improving women's health. © 2012 Elsevier Inc. Source

Russnes H.G.,University of Oslo | Russnes H.G.,Dana-Farber Cancer Institute | Navin N.,University of Texas M. D. Anderson Cancer Center | Hicks J.,Cold Spring Harbor Laboratories | Borresen-Dale A.-L.,University of Oslo
Journal of Clinical Investigation

Rapid and sophisticated improvements in molecular analysis have allowed us to sequence whole human genomes as well as cancer genomes, and the findings suggest that we may be approaching the ability to individualize the diagnosis and treatment of cancer. This paradigmatic shift in approach will require clinicians and researchers to overcome several challenges including the huge spectrum of tumor types within a given cancer, as well as the cell-to-cell variations observed within tumors. This review discusses how next-generation sequencing of breast cancer genomes already reveals insight into tumor heterogeneity and how it can contribute to future breast cancer classification and management. Source

Karni-Schmidt O.,Columbia University | Castillo-Martin M.,Columbia University | HuaiShen T.,Columbia University | Gladoun N.,Columbia University | And 6 more authors.
American Journal of Pathology

The TP63 gene, a member of the TP53 tumor suppressor gene family, can be expressed as at least six isoforms due to alternative promoter use and alternative splicing. The lack of p63 isoform-specific antibodies has limited the analysis of the biological significance of p63. We report a novel set of well-defined antibodies to examine p63 isoforms in mouse and human urothelium during embryogenesis and tumor progression, respectively. We provide evidence that basal and intermediate urothelial cells express p63 isoforms, with the TAp63 variant the first to be detected during development, whereas umbrella cells are characterized by a p63-negative phenotype. Notably, we report that p63-null mice develop a bladder with an abnormal urothelium, constituted by a single layer of cells that express uroplakin II and low molecular weight cytokeratins, consistent with an umbrella cell phenotype. Finally, analysis of 202 human bladder carcinomas revealed a new categorization of invasive tumors into basal-like (positive for ΔNp63 and high molecular weight cytokeratins and negative for low molecular weight cytokeratins) versus luminal-like (negative for ΔNp63 and high molecular weight cytokeratins and positive for low molecular weight cytokeratins) phenotypes, with ΔNp63 expression associated with an aggressive clinical course and poor prognosis. This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ΔNp63 acting as an oncogene in certain invasive bladder tumors. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. Source

Cold Spring Harbor Laboratories and Philips | Date: 2010-01-25

Provided is a method for the analysis of breast cancer disorders, comprising determining the genomic methylation status of one or more CpG dinucleotides. Furthermore, a computer program product stored on a computer-readable medium comprising software code adapted to perform the steps of the method when executed on a data-processing apparatus is provided. A device comprising means for supporting a clinician is also provided.

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