Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment.

The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study.

Background: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses.

Methods: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median).

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis.

Alpha-smooth muscle actin expression in rat and mouse mesenteric wounds after transforming growth factor-beta1 treatment.

Rat mesenteric perforations heal by contraction within 5 to 7 days, whereas mouse mesenteric perforations seldom close within 3 weeks unless stimulated by transforming growth factor-beta1. In this article, we quantified the expression of alpha-smooth muscle actin by quantitative-reverse transcription-polymerase chain reaction and the orientation of actin filaments at the wound margin by Fourier transformation image analysis after treatment with transforming growth factor-beta1. The expression of transforming growth factor-beta1 and its type II receptor was also assessed.

Vacancy engineered ceria nanostructures for protection from radiation-induced cellular damage.

The ability of engineered cerium oxide nanoparticles to confer radioprotection was examined. Human normal and tumor cells were treated with nanoceria and irradiated, and cell survival was measured. Treatment of normal cells conferred almost 99% protection from radiation-induced cell death, whereas the same concentration showed almost no protection of tumor cells.

Differential expression of stress response genes in the H-Tx rat model of congenital hydrocephalus.

cDNA rat stress microarrays were used to test the general hypothesis that atypical gene expression patterns exist in the brains of Hydrocephalic-Texas (H-Tx) compared to normal Sprague-Dawley (SD) rats on embryonic day 18. Sixty-two percent of the 216 target transcripts were detected in at least 2 of 3 replicates, with maximum mean fold change (MFC) ratios (H-Tx:SD) in Bcl-2-related ovarian killer protein (BOK, 3.07) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha, 0.

Neonatal aphakia retards ocular growth and alters scleral gene expression in rhesus monkeys.

Purpose: We hypothesize that remodeling of the scleral extracellular matrix, involving collagen and proteoglycan synthesis and turnover, is a key process involved in ocular growth. Decreased axial elongation is observed following neonatal removal of the crystalline lens in a rhesus monkey model of congenital cataract. We wanted to determine changes in gene expression in the operated and companion eye following lensectomy, especially for extracellular matrix in the sclera.

Fibronectin fragments promote human retinal endothelial cell adhesion and proliferation and ERK activation through alpha5beta1 integrin and PI 3-kinase.

Purpose: Extracellular matrix degradation is associated with neovascularization in diabetic retinas. Fibronectin fragments (Fn-fs) are generated during vascular remodeling. The effects of cellular fibronectin (Fn) and selected Fn-fs on adhesion, proliferation, and signal transduction in human retinal endothelial cells (HRECs) were characterized.

Matrix metalloproteinase inhibition modulates fibroblast-mediated matrix contraction and collagen production in vitro.

Purpose: To investigate the effect of matrix metalloproteinase (MMP) inhibition on fibroblast-mediated matrix contraction and production.

Methods: Free-floating fibroblast-populated type I collagen lattices were prepared with human Tenon's capsule fibroblasts. Lattice areas were photographed and digitally analyzed to indicate the degree of lattice contraction.

Effects of tenascin-C on normal and diabetic retinal endothelial cells in culture.

Purpose: Tenascin-C (TN-C) is expressed in embryogenesis, tissue remodeling, and healing. It is up-regulated in retinas of patients affected by diabetic retinopathy (DR). Because TN-C may promote neovascularization, its potential angiogenic effects were examined in vitro in normal and diabetic retinal endothelial cells (RECs).

Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flight.

The mechanism of the loss of skeletal muscle mass that occurs during spaceflight is not well understood. Myostatin has been proposed as a negative modulator of muscle mass, and IGF-I and IGF-II are known positive regulators of muscle differentiation and growth. We investigated whether muscle loss associated with spaceflight is accompanied by increased levels of myostatin and a reduction in IGF-I and -II levels in the muscle, and whether these changes correlate with an increase in muscle proteolysis and apoptosis.

Insulin-like growth factor: receptor and binding proteins in human retinal endothelial cell cultures of diabetic and non-diabetic origin.

Human retinal endothelial cell (HREC) cultures of diabetic and non-diabetic origin were examined for the production of insulin-like growth factor I (IGF-I), IGF-I receptor and IGF-binding proteins (IGFBPs) using colloidal gold quantitative immunocytochemistry and quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR). The levels of immunoreactivity for IGF-I receptor and for four IGFBPs (IGFBP-1, -2, -3 and -5) were significantly increased in diabetic HREC cultures. Moreover, diabetic HREC cultures showed significantly less immunoreactivity for IGF-I and for IGFBP-4 as compared to non-diabetic HREC cultures.

Expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases in laryngeal and pharyngeal squamous cell carcinoma: A quantitative analysis.

Squamous cell carcinomas of the head and neck are known for their aggressive growth and propensity to metastasize. Invasion is facilitated by matrix metalloproteineases (MMPs). Tissue inhibitors of MMPs (TIMPs) negatively regulate MMP activity.

Heterochromia after pediatric cataract surgery.

Purpose: Changes in iris color have been noted anecdotally after cataract surgery in infants, but they have not been studied systematically. The mechanism for these iris color changes has not previously been reported in the biomedical literature.

Methods: Photographs were taken of both eyes of 15 children and 11 rhesus monkeys who had undergone unilateral cataract surgery.

TGF-beta1 expression is reduced in hydrocephalic H-Tx rat brain.

Transforming growth factor-beta1 (TGF-beta1) is a cytokine with diverse biological effects. Overexpression of TGF-beta1 in mice has been shown to induce progressive hydrocephalus. We have used a quantitative RT-PCR method to analyze the TGF-beta1 expression in the brains of H-Tx rat, a model of congenital hydrocephalus.

Expression of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases in mesothelial cells and their regulation by transforming growth factor-beta1.

Tissue injury and pelvic inflammation often results in peritoneal scar tissue formation. The objective of this study was to determine whether mesothelial cells which line the peritoneal cavity express matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs), and if their expression is regulated by transforming growth factor-beta1, a key regulator of tissue fibrosis. For this purpose we used Met-5A cells, a cell line derived from human normal mesothelial cells, and for comparative analysis we used U-937 cells, a human monocytic/macrophage cell line.

Molecular responses of human dermal fibroblasts to dual cues: contact guidance and mechanical load.

Fibroblast contraction in wound healing involves the interaction of several cell types, cytokines, and extracellular matrix molecules. We have previously developed fibroblast alignment models using precise uniaxial mechanical loads in 3D culture and using contact guidance on fibronectin strands. Our aim here was to use contact guidance to place fibroblasts in their potentially most sensitive configuration, i.

Adenosine receptor activation induces vascular endothelial growth factor in human retinal endothelial cells.

Adenosine, released in increased amounts by hypoxic tissues, is thought to be an angiogenic factor that links altered cellular metabolism caused by oxygen deprivation to compensatory angiogenesis. Adenosine interacts with 4 subtypes of G protein-coupled receptors, termed A(1), A(2A), A(2B), and A(3). We investigated whether adenosine causes proliferation of human retinal endothelial cells (HRECs) and synthesis of vascular endothelial growth factor (VEGF) and, if so, which adenosine receptor subtype mediates these effects.

Messenger RNA levels for genes involved in extracellular matrix from human corneal scrapings before and after photorefractive keratectomy.

Purpose: To measure the levels of mRNA for genes important in cellular and extracellular matrix regulation in human corneal epithelium before and after photorefractive keratectomy (PRK) in order to explain myopic regression following surgery.

Methods: Scrapings from 26 normal corneas before a first photorefractive keratectomy were randomly pooled in two samples of 16 and 10 scraping, respectively, and compared to another 23 scrapings from corneas with myopic regression after a previous photorefractive keratectomy, also randomly pooled in another 2 samples of 16 and 7 scrapings each. The scrapings were analysed for seven different messenger RNAs involved in extracellular matrix using competition-based quantitative reverse-transcription polymerase chain reaction.

Matrix metalloproteinase expression in human retinal microvascular cells.

The degree of hyperglycemia correlates with the development of diabetic retinopathy. We investigated the effect of glucose on the expression of matrix metalloproteinase (MMP)-2 and MMP-9 (72-kDa and 92-kDa type IV collagenases, respectively) by human retinal microvascular endothelial cells (HRECs). Cultured HRECs from nondiabetic and diabetic donors were exposed to 5 or 30 mmol/l glucose.

Changes in the expression of extracellular matrix (ECM) and matrix metalloproteinases (MMP) of proliferating rat parotid acinar cells.

Tissue morphogenesis, development, and maintenance of function are mediated by signals generated through the composition of the extracellular matrix. The regulation of the composition of matrix is determined by enzymes specific for their degradation, the matrix metalloproteinases. Chronic injections of the beta-adrenergic receptor agonist, isoproterenol, result in a non-neoplastic hypertrophy and hyperplasia of the rat parotid gland.

Age-related differences in the temporal and spatial regulation of matrix metalloproteinases (MMPs) in normal skin and acute cutaneous wounds of healthy humans.

Despite the association of increasing age with chronic wound-healing disorders and an impaired rate of healing of acute cutaneous wounds, the role of matrix metalloproteinases (MMPs) is unknown. To determine the spatial and temporal patterns and activities of MMP-1, -2, -3 and -9, 132 healthy humans aged between 19 and 96 years underwent 4-mm punch biopsies followed by wound excision between day 1 and day 180 post-wounding. Wounds showed an age-related increase in MMP-2 and MMP-9 immunostaining from day 3; this was associated with degradation of gelatin as shown by zymograms and with increased proteinase activity as shown by azocoll assays.