L1 Retrotransposons in Human Cancers

Retrotransposons like L1 are silenced in somatic cells by a variety of mechanisms acting at different levels. Protective mechanisms include DNA methylation and packaging into inactive chromatin to suppress transcription and prevent recombination, potentially supported by cytidine deaminase editing of RNA. Furthermore, DNA strand breaks arising during attempted retrotranspositions ought to activate cellular checkpoints, and L1 activation outside immunoprivileged sites may elicit immune responses. A number of observations indicate that L1 sequences nevertheless become reactivated in human cancer. Prominently, methylation of L1 sequences is diminished in many cancer types and full-length L1 RNAs become detectable, although strong expression is restricted to germ cell cancers. L1 elements have been found to be enriched at sites of illegitimate recombination in many cancers. In theory, lack of L1 repression in cancer might cause transcriptional deregulation, insertional mutations, DNA breaks, and an increased frequency of recombinations, contributing to genome disorganization, expression changes, and chromosomal instability. There is however little evidence that such effects occur at a gross scale in human cancers. Rather, as a rule, L1 repression is only partly alleviated. Unfortunately, many techniques commonly used to investigate genetic and epigenetic alterations in cancer cells are not well suited to detect subtle effects elicited by partial reactivation of retroelements like L1 which are present as abundant, but heterogeneous copies. Therefore, effects of L1 sequences exerted on the local chromatin structure, on the transcriptional regulation of individual genes, and on chromosome fragility need to be more closely investigated in normal and cancer cells

Insights into cancer mechanisms from genomic research on urological cancers

Molecular mechanisms driving cancer development and progression are rarely unique to one cancer type. Rather, recent genomic studies of urological cancers suggest that common mechanisms recur with variations. Examples include alterations in hypoxia response regulation, epigenetic regulator proteins, and signal transduction pathways in renal, prostatic and urothelial carcinomas. Consideration of these variations alongside the common basic cancer mechanisms might be important for the successful development of targeted therapies

Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer

BACKGROUND: Amplifications at 6p22.3 are prevalent in advanced stage bladder cancer (TCC). Previous studies have identified SOX4, CDKAL, and E2F3 as targets of this amplification and therefore potential oncogenes, but the more telomeric DEK gene too has been reported as overexpressed and amplified. We have therefore investigated whether the intermediate region harboring the oncogene candidate ID4 is also part of the amplicon. RESULTS: Expression of E2F3, DEK, and ID4 was investigated by real-time RT-PCR in 28 TCC compared to 6 normal bladder tissues and in 15 TCC cell lines compared to cultured normal urothelial cells. Expression of E2F3 as well as DEK increased on average in tumor vs. normal tissues (3-fold and 2.5-fold, resp.), but only the increase for E2F3 was statistically significant (p = 0.039). ID4 overexpression was observed in selected specimens. Each of the three genes was overexpressed in several cell lines, up to 150-fold (ID4), 30-fold (E2F3), and 9-fold (DEK), but these increases were not correlated to each other. Instead, moderate (DEK) to excellent (ID4) correlations were observed with copy number increases of microsatellites near each gene. Microsatellite copy number increases were highly heterogeneous across the investigated several Mb region revealing at least three subregions of amplification. CONCLUSION: Extending previous reports, our data indicate that the 6p22.3 amplicon in TCC is highly heterogeneous and targets several genes in a variable fashion. Among these, expression of E2F3 and DEK appear to be generally increased in TCC, with additional increases caused by amplifications. In contrast, over-expression of ID4, which is normally predominantly expressed in testes and brain, appears to depend more strictly on gene amplification. Accordingly, the effect of amplifications at 6p22.3 in bladder cancer is expected to be non-uniform, thereby contributing to the highly variable biological and clinical behavior of advanced stage tumors. ID4 is a potential oncogene in a small subset of bladder cancers

Visible-to-telecom quantum frequency conversion of light from a single quantum emitter

Quantum frequency conversion (QFC), a nonlinear optical process in which the frequency of a quantum light field is altered while conserving its non-classical correlations, was first demonstrated 20 years ago. Meanwhile, it is considered an essential tool for the implementation of quantum repeaters since it allows for interfacing quantum memories with telecom-wavelength photons as quantum information carriers. Here we demonstrate efficient (>30%) QFC of visible single photons (711 nm) emitted by a quantum dot (QD) to a telecom wavelength (1,313 nm). Analysis of the first and second-order coherence before and after wavelength conversion clearly proves that important properties, such as the coherence time and photon antibunching, are fully conserved during the frequency translation process. Our findings underline the great potential of single photon sources on demand in combination with QFC as a promising technique for quantum repeater schemes.Comment: 11 pages, 4 figure

Pseudo‐ Para ‐Substituted [2.2]Paracyclophanes for Hole Transport in Perovskite Solar Cells

2,2′,7,7′-Tetrakis(N,N-di-p-methoxyphenylamine)−9,9′-spirobifluorene (spiro-OMeTAD) is the prevalent hole transport layer in perovskite solar cells (PSCs) with regular device architecture. Yet, its spirobifluorene core and multistep synthesis make it rather expensive. For the further technological success of PSCs, novel scalable and inexpensive alternative hole transport layers are needed. Herein, a study of the structure-property relations of pseudo-para-substituted [2.2]paracyclophanes is presented. Eight different hole transport materials are synthesized via double CH activation, eliminating metal-containing substituents for cross-coupling reactions. The ionization potentials (IPs) of the disubstituted paracyclophanes (DiPCPs) are examined by photoelectron spectroscopy in air, cyclic voltammetry and theoretical calculations. Through variation of donor groups and π-linkers, IPs that span a range from 5.14 to 5.86 eV are achieved, demonstrating high customizability. From the eight novel materials, five showed good solubility and are implemented into PSCs. The solar cells with a hole transport layer of undoped 4,16-di(4-(2-thienyl)-N,N-bis(4-methoxyphenyl)aniline)[2.2]paracyclophane (DiPCP-2) exhibit a power conversion efficiency of 12.7% ± 0.4%. The facile synthesis of DiPCP-2 enables an estimated cost reduction by two thirds compared to spiro-OMeTAD

On the AC spectrum of one-dimensional random Schroedinger operators with matrix-valued potentials

We consider discrete one-dimensional random Schroedinger operators with decaying matrix-valued, independent potentials. We show that if the l^2-norm of this potential has finite expectation value with respect to the product measure then almost surely the Schroedinger operator has an interval of purely absolutely continuous (ac) spectrum. We apply this result to Schroedinger operators on a strip. This work provides a new proof and generalizes a result obtained by Delyon, Simon, and Souillard.Comment: (1 figure

Rashba precession in quantum wires with interaction

Rashba precession of spins moving along a one-dimensional quantum channel is calculated, accounting for Coulomb interactions. The Tomonaga--Luttinger model is formulated in the presence of spin-orbit scattering and solved by Bosonization. Increasing interaction strength at decreasing carrier density is found to {\sl enhance} spin precession and the nominal Rashba parameter due to the decreasing spin velocity compared with the Fermi velocity. This result can elucidate the observed pronounced changes of the spin splitting on applied gate voltages which are estimated to influence the interface electric field in heterostructures only little.Comment: now replaced by published versio

S6K1 and 4E-BP1 Are Independent Regulated and Control Cellular Growth in Bladder Cancer

Aberrant activation and mutation status of proteins in the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and the mitogen activated protein kinase (MAPK) signaling pathways have been linked to tumorigenesis in various tumors including urothelial carcinoma (UC). However, anti-tumor therapy with small molecule inhibitors against mTOR turned out to be less successful than expected. We characterized the molecular mechanism of this pathway in urothelial carcinoma by interfering with different molecular components using small chemical inhibitors and siRNA technology and analyzed effects on the molecular activation status, cell growth, proliferation and apoptosis. In a majority of tested cell lines constitutive activation of the PI3K was observed. Manipulation of mTOR or Akt expression or activity only regulated phosphorylation of S6K1 but not 4E-BP1. Instead, we provide evidence for an alternative mTOR independent but PI3K dependent regulation of 4E-BP1. Only the simultaneous inhibition of both S6K1 and 4E-BP1 suppressed cell growth efficiently. Crosstalk between PI3K and the MAPK signaling pathway is mediated via PI3K and indirect by S6K1 activity. Inhibition of MEK1/2 results in activation of Akt but not mTOR/S6K1 or 4E-BP1. Our data suggest that 4E-BP1 is a potential new target molecule and stratification marker for anti cancer therapy in UC and support the consideration of a multi-targeting approach against PI3K, mTORC1/2 and MAPK

APOBEC3B Activity Is Prevalent in Urothelial Carcinoma Cells and Only Slightly Affected by LINE-1 Expression

The most common mutational signature in urothelial carcinoma (UC), the most common type of urinary bladder cancer is assumed to be caused by the misdirected activity of APOBEC3 (A3) cytidine deaminases, especially A3A or A3B, which are known to normally restrict the propagation of exogenous viruses and endogenous retroelements such as LINE-1 (L1). The involvement of A3 proteins in urothelial carcinogenesis is unexpected because, to date, UC is thought to be caused by chemical carcinogens rather than viral activity. Therefore, we explored the relationship between A3 expression and L1 activity, which is generally upregulated in UC. We found that UC cell lines highly express A3B and in some cases A3G, but not A3A, and exhibit corresponding cytidine deamination activity in vitro. While we observed evidence suggesting that L1 expression has a weak positive effect on A3B and A3G expression and A3B promoter activity, neither efficient siRNA-mediated knockdown nor overexpression of functional L1 elements affected catalytic activity of A3 proteins consistently. However, L1 knockdown diminished proliferation of a UC cell line exhibiting robust endogenous L1 expression, but had little impact on a cell line with low L1 expression levels. Our results indicate that UC cells express A3B at levels exceeding A3A levels by far, making A3B the prime candidate for causing genomic mutations. Our data provide evidence that L1 activation constitutes only a minor and negligible factor involved in induction or upregulation of endogenous A3 expression in UC