Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models.

This study investigated the antitumour effects of two dual mTOR/PI3K inhibitors, gedatolisib (WYE-129587/PKI-587/PF-05212384) and PF-04691502 against a panel of six human patient derived ovarian cancer xenograft models. Both dual mTOR/PI3K inhibitors demonstrated antitumour activity against all xenografts tested. The compounds produced tumour stasis during the treatment period and upon cessation of treatment, tumours re-grew.

Comparative gene expression profiling identifies common molecular signatures of NF-κB activation in canine and human diffuse large B cell lymphoma (DLBCL).

We present the first comparison of global transcriptional changes in canine and human diffuse large B-cell lymphoma (DLBCL), with particular reference to the nuclear factor-kappa B (NF-κB) pathway. Microarray data generated from canine DLBCL and normal lymph nodes were used for differential expression, co-expression and pathway analyses, and compared with analysis of microarray data from human healthy and DLBCL lymph nodes. The comparisons at gene level were performed by mapping the probesets in canine microarrays to orthologous genes in humans and vice versa.

Characterisation of tumour-infiltrating macrophages: impact on response and survival in patients receiving primary chemotherapy for breast cancer.

The role of the tumour microenvironment and complex cellular interactions has attracted interest in responses to primary chemotherapy. Of particular interest are tumour-infiltrating T cells and tumour-infiltrating macrophages (TIMs). We evaluated TIMs and their key activation markers in patients with breast cancer undergoing primary chemotherapy related to response and survival.

Stoichiometric quantification of Akt phosphorylation using LC-MS/MS.

The Ptdlns-3-kinase (PI3-K) signaling pathway plays a vital role in cell survival, proliferation, apoptosis and differentiation in normal cells, as well as in diseases such as cancer and diabetes. Quantification of phospho-Akt is a standard way of assessing the activity of the PI3-K signaling pathway in both cells and tumors. This measurement is traditionally performed semiquantitatively using immunoassays such as Western blot.

Expression of ovarian tumour suppressor OPCML in the female CD-1 mouse reproductive tract.

Opioid binding protein/cell adhesion molecule-like gene (OPCML) is frequently inactivated in epithelial ovarian cancer, but the role of this membrane protein in normal reproductive function is unclear. The ovarian surface epithelium (OSE) is thought to be the cell of origin of most epithelial ovarian cancers, some of which arise after transformation of OSE cells lining ovarian inclusion cysts, formed during ovulation. We used immunohistochemistry, immunoblotting and quantitative RT-PCR (qRT-PCR) to investigate OPCML expression in the uteri and ovaries of cycling 3-month CD-1 mice, as well as in ovaries from older mice containing inclusion cysts derived from rete ovarii tubules.

OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.

Background: Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction.

Opportunities posed by novel patient selection biomarker approaches in oncology drug development: going beyond the cytotoxics.

An area of unmet medical need in clinical oncology has been optimizing patient selection for a given therapeutic with the goal of getting the right drug to the right patient. Recent studies have developed preclinical approaches to identifying molecular 'signatures of resistance' for cytotoxic therapies and prospective validation of this strategy is ongoing in the clinic. New challenges in this setting include identifying approaches to patient selection for cytostatic compounds such as signaling pathway inhibitors and stem cell targets.

Experimental verification and theory for an eight-element multiple-aperture equal-gain coherent laser receiver for laser communications.

The detection and processing of laser communication signals are affected by the fading induced onto these signals by atmospheric turbulence. One method of reducing this fading is to use an array of detectors in which each of the detector outputs are added together coherently. We present experimental verification and theory of a 1.

Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus.

The tissue-specific translation elongation factor eEF1A2 is a potential oncogene that is overexpressed in human ovarian cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-alpha) making analysis with commercial antibodies difficult. We wanted to establish the expression pattern of eEF1A2 in ovarian cancer of defined histological subtypes at both the RNA and protein level, and to establish the mechanism for the overexpression of eEF1A2 in tumours.

Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours.

The four GPI-anchored cell adhesion molecules that exemplify the IgLON family are most highly expressed in the nervous system and associate to form up to six different heterodimeric 'Diglons' that can modify cell adhesion and inhibit axon migration. Recently, two members, OPCML and LSAMP, were identified as putative tumour suppressor genes in ovarian and renal carcinomas respectively. In this study, we investigated OPCML expression in nonneoplastic brain tissue and 35 brain tumours (18 glioblastoma multiformes, five anaplastic gliomas, five meningiomas, six metastases and one medulloblastoma) and four glioma cell lines using quantitative reverse transcriptase polymerase chain reaction (RT-PCR).

The IgLON family in epithelial ovarian cancer: expression profiles and clinicopathologic correlates.

Purpose: The IgLON family of cell adhesion molecules, comprising OPCML, HNT, LSAMP, and NEGR1, has recently been linked to cancer, through two of its members being proposed as tumor suppressors. We examined the expression profile of the family in human sporadic epithelial ovarian cancer and the normal ovary.

Experimental Design: We determined the expression level of each IgLON in a panel comprising 57 tumor and 11 normal ovarian samples by quantitative real-time reverse transcription-PCR.

Chx10 repression of Mitf is required for the maintenance of mammalian neuroretinal identity.

During vertebrate eye development, the cells of the optic vesicle (OV) become either neuroretinal progenitors expressing the transcription factor Chx10, or retinal pigment epithelium (RPE) progenitors expressing the transcription factor Mitf. Chx10 mutations lead to microphthalmia and impaired neuroretinal proliferation. Mitf mutants have a dorsal RPE-to-neuroretinal phenotypic transformation, indicating that Mitf is a determinant of RPE identity.

Identification of clinically relevant genes on chromosome 11 in a functional model of ovarian cancer tumor suppression.

Microcell-mediated transfer of normal chromosome 11 (chr 11) to a clonal derivative of the ovarian cancer cell line, OVCAR3, was performed and generated independent hybrids with a common set of phenotypes: inhibition of cell growth and of cellular migration in vitro; and inhibition of tumor growth in vivo. Differential display reverse transcriptase-PCR (RT-PCR), cDNA-representational difference analysis, and hybridization of cDNA high-density filter arrays identified altered mRNAs associated with these phenotypic alterations. Quantitative RT-PCR-based validation of each altered mRNA eliminated false positives to identify a reduced set of expression differences.

OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC), the leading cause of death from gynecological malignancy, is a poorly understood disease. The typically advanced presentation of EOC with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases are hallmarks of the disease. These features relate to the biology of the disease, which is a principal determinant of outcome.

The homeobox gene BARX2 can modulate cisplatin sensitivity in human epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most common cause of death from gynaecological malignancy. Resistance to platinum chemotherapy is a major reason for treatment failure and poor prognosis. The human homeobox gene BARX2 is located within a minimal region at 11q25 that is associated with frequent loss of heterozygosity (LOH) and adverse survival in EOC.

Expression of the serine protease matriptase and its inhibitor HAI-1 in epithelial ovarian cancer: correlation with clinical outcome and tumor clinicopathological parameters.

Purpose: Matriptase is a type II transmembrane serine protease expressed by cells of surface epithelial origin, including epithelial ovarian tumor cells. Matriptase cleaves and activates proteins implicated in the progression of ovarian cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine the expression of matriptase, and its inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1), in epithelial ovarian cancer and to assign clinicopathological correlations.

BARX2 induces cadherin 6 expression and is a functional suppressor of ovarian cancer progression.

The human homeobox BARX2 is located at 11q24-q25, within a minimal region associated with frequent loss of heterozygosity and adverse survival in epithelial ovarian cancer. BARX2 is a transcription factor that regulates transcription of specific cell adhesion molecules in the mouse. We show that BARX2 and cadherin 6 are expressed in normal human ovarian surface epithelium.

Differential display.

Differential display reverse transcriptase polymerase chain reaction (DDRT-PCR) is an extremely powerful method for analyzing differences in gene expression between matched tissue/cell samples. Liang and Pardee originally described the technique in 1992 in their seminal paper (1). DDRT-PCR is now firmly established as a widespread powerful and commonly used method for identifying differentially expressed genes.

A 700-kb physical map of a region of 16q23.2 homozygously deleted in multiple cancers and spanning the common fragile site FRA16D.

We have identified a >600-kb region at 16q23.2 that is homozygously deleted from malignant ovarian ascites using representational difference analysis. Overlapping homozygous deletions were also observed in the colon carcinoma cell line HCT116 and a xenograft established from the small cell lung cancer cell line WX330.

The incidence of PAX6 mutation in patients with simple aniridia: an evaluation of mutation detection in 12 cases.

Twelve aniridia patients, five with a family history and seven presumed to be sporadic, were exhaustively screened in order to test what proportion of people with aniridia, uncomplicated by associated anomalies, carry mutations in the human PAX6 gene. Mutations were detected in 90% of the cases. Three mutation detection techniques were used to determine if one method was superior for this gene.

The Xenopus laevis homologue of the 64-kDa subunit of cleavage stimulation factor.

Cleavage stimulation factor (CstF) is composed of three subunits of 50, 64 and 77 kDa, respectively. We report here the identification of a cDNA clone from Xenopus laevis encoding a homologue of the 64-kDa subunit of human CstF. Comparative sequence analysis reveals that these two proteins are highly conserved with the exception of a unique repeat structure found in the human, but not in the X.

ERWIN: an E-region wind interferometer.

A field-widened Michelson interferometer designed to measure upper atmospheric winds at three altitudes near the mesopause by using airglow emissions from O(1)S, OH, and O(2) is described. A very large path difference (11 cm) is used to suppress the fringes from the hot F-region emission of O(1)S and to facilitate accurate measurements. Field widening and thermal compensation are achieved over the large spectral range (557.

Organization of the region encompassing the human serum amyloid A (SAA) gene family on chromosome 11p15.1.

The four members of the human serum amyloid A protein (SAA) gene family are clustered on human chromosome 11p15.1. Three genes are differentially expressed and encode small apolipoproteins of M(r) 12-19 kDa: SAA1 and SAA2 encode the acute phase SAAs (A-SAAs), and SAA4 encodes the constitutively expressed SAA (C-SAA).

Characterization, expression and evolution of mouse beta 2-glycoprotein I (apolipoprotein H).

beta 2-glycoprotein I (beta 2I) is a 50kDa serum glycoprotein of ill defined function. Based upon its capacity to bind negatively charged phospholipids a number of possible inhibitory roles for beta 2I have been proposed. We have cloned and sequenced a full length mouse beta 2I cDNA clone and demonstrated that mouse beta 2I does not behave as an acute phase reactant following an experimentally induced inflammation.