DNA repair in cancer stem cells as a factor for glioma resistance to radiotherapy

Gliomas are brain tumors originating from glial cells and their precursor cells. In spite of currently used therapy, patient survival remains very poor. The main reason for dismal prognosis is the high level of tumor recurrence because of resistance to different ways of treatment. Currently, it is believed that glioma development is connected with the existence of cancer stem cells (CSCs), or tumor-initiating cells. The theory of hierarchal tumor structure is now commonly accepted. It accounts for characteristics of these cells, namely, the capability of self-renewal and differentiation into astrocytes, oligodendrocytes, and neurons. Moreover, these cells bear multiple genetic lesions typical of cancer cells. Thus, the presence of these cells after surgery and further treatment allows the tumor to recur. The data obtained in recent years confirm the important role of CSCs in the development of tumor resistance to chemo- and radiotherapy. In this review, we present general information about classification and treatment of gliomas and consider results of research connected with the influence of radiation therapy. Some authors show that DNA repair enables CSCs to survive even after treatment. To sum up, it is shown that DNA repair contributes to the development of tumor resistance to ionizing radiation. In addition, our work confirms the hypothesis that inhibition of DNA repair processes in these cells leads to tumor sensitization to radiotherapy

Nonlinear wavelength conversion in photonic crystal fibers with three zero dispersion points

In this theoretical study, we show that a simple endlessly single-mode photonic crystal fiber can be designed to yield, not just two, but three zero-dispersion wavelengths. The presence of a third dispersion zero creates a rich phase-matching topology, enabling enhanced control over the spectral locations of the four-wave-mixing and resonant-radiation bands emitted by solitons and short pulses. The greatly enhanced flexibility in the positioning of these bands has applications in wavelength conversion, supercontinuum generation and pair-photon sources for quantum optics

NEIL1 excises 3′ end proximal oxidative DNA lesions resistant to cleavage by NTH1 and OGG1

Base excision repair is the major pathway for the repair of oxidative DNA damage in human cells that is initiated by a damage-specific DNA glycosylase. In human cells, the major DNA glycosylases for the excision of oxidative base damage are OGG1 and NTH1 that excise 8-oxoguanine and oxidative pyrimidines, respectively. We find that both enzymes have limited activity on DNA lesions located in the vicinity of the 3′ end of a DNA single-strand break, suggesting that other enzymes are involved in the processing of such lesions. In this study, we identify and characterize NEIL1 as a major DNA glycosylase that excises oxidative base damage located in close proximity to the 3′ end of a DNA single-strand break

AKT regulates NPM dependent ARF localization and p53mut stability in tumors

Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53(mut) stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53(mut) status

Controlling pulse propagation in optical fibers through nonlinearity and dispersion management

In case of the nonlinear Schr\"odinger equation with designed group velocity dispersion, variable nonlinearity and gain/loss; we analytically demonstrate the phenomenon of chirp reversal crucial for pulse reproduction. Two different scenarios are exhibited, where the pulses experience identical dispersion profiles, but show entirely different propagation behavior. Exact expressions for dynamical quasi-solitons and soliton bound-states relevant for fiber communication are also exhibited.Comment: 4 pages, 5 eps figure

Understanding the dynamics of photoionization-induced solitons in gas-filled hollow-core photonic crystal fibers

We present in detail our developed model [Saleh et al., Phys. Rev. Lett. 107] that governs pulse propagation in hollow-core photonic crystal fibers filled by an ionizing gas. By using perturbative methods, we find that the photoionization process induces the opposite phenomenon of the well-known Raman self-frequency red-shift of solitons in solid-core glass fibers, as was recently experimentally demonstrated [Hoelzer et al., Phys. Rev. Lett. 107]. This process is only limited by ionization losses, and leads to a constant acceleration of solitons in the time domain with a continuous blue-shift in the frequency domain. By applying the Gagnon-B\'{e}langer gauge transformation, multi-peak `inverted gravity-like' solitary waves are predicted. We also demonstrate that the pulse dynamics shows the ejection of solitons during propagation in such fibers, analogous to what happens in conventional solid-core fibers. Moreover, unconventional long-range non-local interactions between temporally distant solitons, unique of gas plasma systems, are predicted and studied. Finally, the effects of higher-order dispersion coefficients and the shock operator on the pulse dynamics are investigated, showing that the resonant radiation in the UV [Joly et al., Phys. Rev. Lett. 106] can be improved via plasma formation.Comment: 9 pages, 10 figure

Coherent Control of Ultra-High Frequency Acoustic Resonances in Photonic Crystal Fibers

Ultra-high frequency acoustic resonances ($\backsim$2 GHz) trapped within the glass core ($\backsim$1 $\mu$m diameter) of a photonic crystal fiber are selectively excited through electrostriction using laser pulses of duration 100 ps and energy 500 pJ. Using precisely timed sequences of such driving pulses, we achieve coherent control of the acoustic resonances by constructive or destructive interference, demonstrating both enhancement and suppression of the vibrations. A sequence of 27 resonantly-timed pulses provides a 100-fold increase in the amplitude of the vibrational mode. The results are explained and interpreted using a semi-analytical theory, and supported by precise numerical simulations of the complex light-matter interaction.Comment: 4 pages, 3 figures, 3 avi movies (external link) - accepted in PR