FOXM1 Expression and Contribution to Genomic Instability and Chemoresistance in High-Grade Serous Ovarian Cancer

High-grade serous ovarian cancer (HGSC) is the most common and deadly subtype of epithelial ovarian cancer. Understanding the molecular basis of HGSC will improve diagnosis and treatment approaches. The Cancer Genome Atlas (TCGA) discovered that Forkhead Box M1 (FOXM1) transcription factor activation is the second most frequent molecular alteration in HGSC (84% of cases), second only to mutations of TP53 (100%). We subsequently defined several genetic mechanisms that underlie increased FOXM1 expression in HGSC, including genomic amplifications and RB-E2F deregulation, and showed that FOXM1 promotes cell cycle progression in cell models relevant to HGSC. TCGA analyses revealed that genomic instability, consisting of frequent copy number alterations, as key defining molecular features of HGSC and basal breast, more than any other TCGA cancer type. DNA replication stress results from uncoupling of the replicative helicase and polymerase and is a key mechanism of genomic instability. FOXM1 expression is linked to genomic instability but the underlying mechanism is unclear; induction of DNA replication stress could explain this association. In this context, we revealed novel functions of FOXM1 using fallopian tube epithelial (FTE) cells, an HGSC precursor cell model. We showed that FOXM1 increased DNA fork rate, origin firing, and DNA damage. Furthermore, Cyclin E1 cooperated with FOXM1 to increase its transcriptional activity, which promoted cell cycle progression and genomic instability. In agreement, TCGA HGSC tumors with both FOXM1 and CCNE1 copy number gain show increased FOXM1 and CCNE1 expression and genomic instability. FOXM1 shares a bidirectional promoter with RHNO1 but this genetic interaction has never been studied in any context. Knowledge of this interaction is important for understanding the molecular mechanism of HGSC. We investigated FOXM1 and RHNO1 expression using large-scale genomic datasets from normal and pan-cancer tissues and validated these findings with HGSC cell lines and tissues. FOXM1 and RHNO1 showed a highly significant correlation in all comparisons suggesting a potential for cooperativity. Importantly, we showed that FOXM1 and RHNO1 cooperate to promote cell survival and chemoresistance in HGSC cells. Collectively, these studies support in vivo studies focusing on the cooperativity of FOXM1 and RHNO1 bidirectional gene partners, to further understand their contribution to HGSC development and progression

Test of the Dimopouos-Hall-Raby Ansatz for Fermion Mass Matrices

By evolution of fermion mass matrices of the Fritzsch and the Georgi-Jarlskog forms from the supersymmetric grand unified scale, DHR obtained predictions for the quark masses and mixings. Using Monte Carlo methods we test these predictions against the latest determinations of the mixings, the CP-violating parameter epsilon_K and the B_d^0--Bbar_d^0 mixing parameter r_d. The acceptable solutions closely specify the quark masses and mixings, but lie at the edges of allowed regions at 90% confidence level.Comment: 11 pages, 1 figure (not included

AEGIS-X: The Chandra Deep Survey of the Extended Groth Strip

We present the AEGIS-X survey, a series of deep Chandra ACIS-I observations of the Extended Groth Strip. The survey comprises pointings at 8 separate positions, each with nominal exposure 200ks, covering a total area of approximately 0.67 deg2 in a strip of length 2 degrees. We describe in detail an updated version of our data reduction and point source detection algorithms used to analyze these data. A total of 1325 band-merged sources have been found to a Poisson probability limit of 4e-6, with limiting fluxes of 5.3e-17 erg/cm2/s in the soft (0.5-2 keV) band and 3.8e-16 erg/cm2/s in the hard (2-10 keV) band. We present simulations verifying the validity of our source detection procedure and showing a very small, <1.5%, contamination rate from spurious sources. Optical/NIR counterparts have been identified from the DEEP2, CFHTLS, and Spitzer/IRAC surveys of the same region. Using a likelihood ratio method, we find optical counterparts for 76% of our sources, complete to R(AB)=24.1, and, of the 66% of the sources that have IRAC coverage, 94% have a counterpart to a limit of 0.9 microJy at 3.6 microns (m(AB)=23.8). After accounting for (small) positional offsets in the 8 Chandra fields, the astrometric accuracy of the Chandra positions is found to be 0.8 arcsec RMS, however this number depends both on the off-axis angle and the number of detected counts for a given source. All the data products described in this paper are made available via a public website.Comment: 17 pages, 9 figures. Accepted for publication in ApJS. Data products are available at http://astro.imperial.ac.uk/research/aegis

QCD Corrections to Toponium Production at Hadron Colliders

Toponium production at future hadron colliders is investigated. Perturbative QCD corrections to the production cross section for gluon fusion are calculated as well as the contributions from gluon-quark and quark-antiquark collisions to the total cross section. The dependence on the renormalization and factorization scales and on the choice of the parton distribution functions is explored. QCD corrections to the branching ratio of $\eta_{t}$ into $\gamma\gamma$ are included and the two-loop QCD potential is used to predict the wave function at the origin. The branching ratio of $\eta_{t}$ into $\gamma Z$, $ZZ$, $HZ$ and $WW$ is compared with the $\gamma\gamma$ channel.Comment: 16 pages (latex) 9 figures (postscript) available upon request, TTP92-3

G515, Revisited. I. Stellar Populations And Evidence Of Nuclear Activity In A Luminous "E+A" Galaxy

We present multiwavelength observations of the very luminous "E+A" galaxy known as G515 (J152426.55+080906.7), including deep K_s imaging, spatially resolved H-alpha spectroscopy, and radio observations. The data, together with detailed spectral synthesis of the galaxy's integrated stellar population, show that G515 is a ~1 Gyr old post-merger, post-starburst galaxy. We detect no Balmer line emission in the galaxy, although there is a small amount of [NII]6548,6583A emission. The galaxy's H I mass has a 2-sigma upper limit of 1.0 * 10^9 solar masses. IRAS detections in the 60-micron and 100-micron bands indicate a far infrared luminosity of ~5.8 * 10^10 solar luminosities. A small amount (~3 mJy) of radio continuum flux, which appears to be variable, has been detected. The data suggest that G515 may have once been an ultraluminous infrared galaxy, and may harbor a weak, dust-obscured active nucleus.Comment: 25 pages, 7 figures, accepted to Ap

Testing the Standard Model and Schemes for Quark Mass Matrices with CP Asymmetries in B Decays

The values of $\sin (2 \alpha)$ and $\sin (2 \beta)$, where $\alpha$ and $\beta$ are angles of the unitarity triangle, will be readily measured in a B factory (and maybe also in hadron colliders). We study the standard model constraints in the $\sin (2 \alpha) - \sin (2 \beta)$ plane. We use the results from recent analyses of $f_B$ and $\tau_b|V_{cb}|^2$ which take into account heavy quark symmetry considerations. We find $\sin (2 \beta) \geq 0.15$ and most likely \sin (2 \beta) \roughly{>} 0.6, and emphasize the strong correlations between $\sin (2 \alpha)$ and $\sin (2 \beta)$. Various schemes for quark mass matrices allow much smaller areas in the $\sin (2 \alpha) - \sin (2 \beta)$ plane. We study the schemes of Fritzsch, of Dimopoulos, Hall and Raby, and of Giudice, as well as the ``symmetric CKM'' idea, and show how CP asymmetries in B decays will crucially test each of these schemes.Comment: 11 pages and 4 postscript figures available on request, LaTeX, WIS-92/52/Jun-PH, LBL-3256

BORIS expression in ovarian cancer precursor cells alters the CTCF cistrome and enhances invasiveness through GALNT14

High-grade serous carcinoma (HGSC) is the most aggressive and predominant form of epithelial ovarian cancer and the leading cause of gynecological cancer death. We have previously shown that CTCFL (also known as BORIS, Brother of the Regulator of Imprinted Sites) is expressed in most ovarian cancers, and is associated with global and promoter-specific DNA hypomethylation, advanced tumor stage, and poor prognosis. To explore its role in HGSC, we expressed BORIS in human fallopian tube secretory epithelial cells (FTSEC), the presumptive cells of origin for HGSC. BORIS-expressing cells exhibited increased motility and invasion, and BORIS expression was associated with alterations in several cancer-associated gene expression networks, including fatty acid metabolism, TNF signaling, cell migration, and ECM-receptor interactions. Importantly, GALNT14, a glycosyltransferase gene implicated in cancer cell migration and invasion, was highly induced by BORIS, and GALNT14 knockdown significantly abrogated BORIS-induced cell motility and invasion. In addition, in silico analyses provided evidence for BORIS and GALNT14 co-expression in several cancers. Finally, ChIP-seq demonstrated that expression of BORIS was associated with de novo and enhanced binding of CTCF at hundreds of loci, many of which correlated with activation of transcription at target genes, including GALNT14. Taken together, our data indicate that BORIS may promote cell motility and invasion in HGSC via upregulation of GALNT14, and suggests BORIS as a potential therapeutic target in this malignancy

Characterization of CDK(5) Inhibitor, 20-223 (aka CP668863) for Colorectal Cancer Therapy

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for patients suffering from CRC, none of which focus on the cell signaling mechanisms controlled by the popular kinase family, cyclin dependent kinases (CDKs). Here we evaluate a Pfizer developed compound, CP668863, that inhibits cyclin-dependent kinase 5 (CDK5) in neurodegenerative disorders. CDK5 has been implicated in a number of cancers, most recently as an oncogene in colorectal cancers. Our lab synthesized and characterized CP668863 – now called 20-223. In our established colorectal cancer xenograft model, 20-223 reduced tumor growth and tumor weight indicating its value as a potential anti-CRC agent. We subjected 20-223 to a series of cell-free and cell-based studies to understand the mechanism of its anti-tumor effects. In our hands, in vitro 20-223 is most potent against CDK2 and CDK5. The clinically used CDK inhibitor AT7519 and 20-223 share the aminopyrazole core and we used it to benchmark the 20-223 potency. In CDK5 and CDK2 kinase assays, 20-223 was ~3.5-fold and ~65.3-fold more potent than known clinically used CDK inhibitor, AT7519, respectively. Cell-based studies examining phosphorylation of downstream substrates revealed 20-223 inhibits the kinase activity of CDK5 and CDK2 in multiple CRC cell lines. Consistent with CDK5 inhibition, 20-223 inhibited migration of CRC cells in a wound-healing assay. Profiling a panel of CRC cell lines for growth inhibitory effects showed that 20-223 has nanomolar potency across multiple CRC cell lines and was on an average \u3e2-fold more potent than AT7519. Cell cycle analyses in CRC cells revealed that 20-223 phenocopied the effects associated with AT7519. Collectively, these findings suggest that 20-223 exerts anti-tumor effects against CRC by targeting CDK 2/5 and inducing cell cycle arrest. Our studies also indicate that 20-223 is a suitable lead compound for colorectal cancer therapy

Leading Charm Production in the Interacting Gluon Model

We discuss leading charm production in connection with energy deposition in the central rapidity region. Special attention is given to the correlation between production in central and fragmentation regions. If the fraction of the reaction energy released in the central region increases the asymmetry in the $x_F$ distributions of charmed mesons will become smaller. We illustrate this quantitatively with simple calculations performed using the Interacting Gluon Model. Leading beauty production is also considered.Comment: 13 pages in Latex file and 7 uuencoded ps-figure

Long-Lived Quarks?

Several lines of reasoning suggest that there might exist a non-sequential fourth generation of heavy quarks having very small mixing with light quarks and hence exceptionally long lifetime.Comment: 10 pages, Late