Validation and clinical discovery demonstration of breast cancer data from a real-world data extraction platform.

Objective: To validate and demonstrate the clinical discovery utility of a novel patient-mediated, medical record collection and data extraction platform developed to improve access and utilization of real-world clinical data.

Materials And Methods: Clinical variables were extracted from the medical records of 1011 consented patients with breast cancer. To validate the extracted data, case report forms completed using the structured data output of the platform were compared to manual chart review for 50 randomly-selected patients with metastatic breast cancer.

Wrestling with Chromosomes: The Roles of SUMO During Meiosis.

Meiosis is a specialized form of cell division required for the formation of haploid gametes and therefore is essential for successful sexual reproduction. Various steps are exquisitely coordinated to ensure accurate chromosome segregation during meiosis, thereby promoting the formation of haploid gametes from diploid cells. Recent studies are demonstrating that an important form of regulation during meiosis is exerted by the post-translational protein modification known as sumoylation.

SPR-5 is a histone H3K4 demethylase with a role in meiotic double-strand break repair.

Regulation of histone methylation levels has long been implicated in multiple cellular processes, many of which involve transcription. Here, however, we report a unique role for the Caenorhabditis elegans histone demethylase SPR-5 in meiotic DNA double-strand break repair (DSBR). SPR-5 shows enzymatic activity toward H3K4me2 both in vitro and in the nematode germline, and spr-5 mutants show several phenotypes indicating a perturbation of DSBR, including increased p53-dependent germ cell apoptosis, increased levels of the DSBR marker RAD-51, and sensitivity toward DSB-inducing treatments.

A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage.

Many proteins that respond to DNA damage are recruited to DNA lesions. We used a proteomics approach that coupled isotopic labeling with chromatin fractionation and mass spectrometry to uncover proteins that associate with damaged DNA, many of which are involved in DNA repair or nucleolar function. We show that polycomb group members are recruited by poly(ADP ribose) polymerase (PARP) to DNA lesions following UV laser microirradiation.

Developmental roles of the histone lysine demethylases.

Since the discovery of the first histone lysine demethylase in 2004, two protein families with numerous members have been identified that demethylate various histone lysine residues. Initial studies of the histone lysine demethylases focused on their in vitro enzymatic activity but, more recently, model organisms have been used to examine the roles of these enzymes in vivo. Here, we review recent insights into the roles of the histone lysine demethylases in multiple aspects of development across various species, including in germline maintenance and meiosis, in early embryonic development and differentiation, and in hormone receptor-mediated transcriptional regulation.

Mechanisms involved in the regulation of histone lysine demethylases.

Since the first histone lysine demethylase KDM1 (LSD1) was discovered in 2004, a great number of histone demethylases have been recognized and shown to play important roles in gene expression, as well as cellular differentiation and animal development. The chemical mechanisms and substrate specificities have already been extensively discussed elsewhere. This review focuses primarily on regulatory mechanisms that modulate demethylase recruitment and activity.

Redox sensor CtBP mediates hypoxia-induced tumor cell migration.

The rapid growth and poor vascularization of solid tumors expose cancer cells to hypoxia, which promotes the metastatic phenotype by reducing intercellular adhesion and increasing cell motility and invasiveness. In this study, we found that hypoxia increased free NADH levels in cancer cells, promoting CtBP recruitment to the E-cadherin promoter. This effect was blocked by pyruvate, which prevents the NADH increase.

Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases.

Histone methylation regulates chromatin structure, transcription, and epigenetic state of the cell. Histone methylation is dynamically regulated by histone methylases and demethylases such as LSD1 and JHDM1, which mediate demethylation of di- and monomethylated histones. It has been unclear whether demethylases exist that reverse lysine trimethylation.

Homeodomain-interacting protein kinase-2 mediates CtBP phosphorylation and degradation in UV-triggered apoptosis.

Homeodomain-interacting protein kinase-2 (HIPK2) is a serine/threonine kinase involved in transcriptional regulation and apoptosis. The transcriptional corepressor CtBP (carboxyl-terminal binding protein) also plays a fundamental role in these processes. Our previous studies indicate that HIPK2 participates in a pathway of UV-triggered CtBP clearance that results in cell death.