Immunological aspects of conventional and new treatments for cervical cancer, an immunopharmacological approach

<span style="font-size:12.0pt;font-family:"Times New Roman","serif"; mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;mso-ansi-language: NL;mso-fareast-language:NL;mso-bidi-language:AR-SA">Conventional therapies as chemotherapy and radiotherapy impact immune populations and immune responses in cervical cancer patients. This led to new perspectives into the important role of the immune system and possibilities to optimally implement immunotherapy in the treatment of cervical cancer. Immunotherapy with HPV16-SLP vaccination is a suitable candidate for combined therapy with chemotherapy, when administered within the optimal time window, as it maximizes vaccination efficacy while tumor-induces immune suppression is tackled. To eventually improve clinical outcome in cervical cancer patients, multimodality treatment approaches need further exploration. Within that approach, the assignment of treatment dose, timing and route of administration of both immunotherapy and the classic conventional therapies are important. In addition, individualization of patients therapy based on immune markers prior to treatment should be a goal to optimize combination therapy, minimize side effects and improve clinical outcomes. LUMC / Geneeskunde Repositoriu

Orbital Magnetism and Current Distribution of Two-Dimensional Electrons under Confining Potential

The spatial distribution of electric current under magnetic field and the resultant orbital magnetism have been studied for two-dimensional electrons under a harmonic confining potential V(\vecvar{r})=m \omega_0^2 r^2/2 in various regimes of temperature and magnetic field, and the microscopic conditions for the validity of Landau diamagnetism are clarified. Under a weak magnetic field (\omega_c\lsim\omega_0, \omega_c being a cyclotron frequency) and at low temperature (T\lsim\hbar\omega_0), where the orbital magnetic moment fluctuates as a function of the field, the currents are irregularly distributed paramagnetically or diamagnetically inside the bulk region. As the temperature is raised under such a weak field, however, the currents in the bulk region are immediately reduced and finally there only remains the diamagnetic current flowing along the edge. At the same time, the usual Landau diamagnetism results for the total magnetic moment. The origin of this dramatic temperature dependence is seen to be in the multiple reflection of electron waves by the boundary confining potential, which becomes important once the coherence length of electrons gets longer than the system length. Under a stronger field (\omega_c\gsim\omega_0), on the other hand, the currents in the bulk region cause de Haas-van Alphen effect at low temperature as T\lsim\hbar\omega_c. As the temperature gets higher (T\gsim\hbar\omega_c) under such a strong field, the bulk currents are reduced and the Landau diamagnetism by the edge current is recovered.Comment: 15 pages, 11 figure

Spin-orbit Scattering and the Kondo Effect

The effects of spin-orbit scattering of conduction electrons in the Kondo regime are investigated theoretically. It is shown that due to time-reversal symmetry, spin-orbit scattering does not suppress the Kondo effect, even though it breaks spin-rotational symmetry, in full agreement with experiment. An orbital magnetic field, which breaks time-reversal symmetry, leads to an effective Zeeman splitting, which can be probed in transport measurements. It is shown that, similar to weak-localization, this effect has anomalous magnetic field and temperature dependence.Comment: 10 pages, RevTex, one postscript figure available on request from [email protected]

Kondo resonances and Fano antiresonances in transport through quantum dots

The transmission of electrons through a non-interacting tight-binding chain with an interacting side quantum dot (QD) is analized. When the Kondo effect develops at the dot the conductance presents a wide minimum, reaching zero at the unitary limit. This result is compared to the opposite behaviour found in an embedded QD. Application of a magnetic field destroys the Kondo effect and the conductance shows pairs of dips separated by the charging energy U. The results are discussed in terms of Fano antiresonances and explain qualitatively recent experimental results.Comment: 4 pages including 4 figure

Correlation and symmetry effects in transport through an artificial molecule

Spectral weights and current-voltage characteristics of an artificial diatomic molecule are calculated, considering cases where the dots connected in series are in general different. The spectral weights allow us to understand the effects of correlations, their connection with selection rules for transport, and the role of excited states in the experimental conductance spectra of these coupled double dot systems (DDS). An extended Hubbard Hamiltonian with varying interdot tunneling strength is used as a model, incorporating quantum confinement in the DDS, interdot tunneling as well as intra- and interdot Coulomb interactions. We find that interdot tunneling values determine to a great extent the resulting eigenstates and corresponding spectral weights. Details of the state correlations strongly suppress most of the possible conduction channels, giving rise to effective selection rules for conductance through the molecule. Most states are found to make insignificant contributions to the total current for finite biases. We find also that the symmetry of the structure is reflected in the I-V characteristics, and is in qualitative agreement with experiment.Comment: 25 figure files - REVTEX - submitted to PR

Time Dependent Current Oscillations Through a Quantum Dot

Time dependent phenomena associated to charge transport along a quantum dot in the charge quantization regime is studied. Superimposed to the Coulomb blockade behaviour the current has novel non-linear properties. Together with static multistabilities in the negative resistance region of the I-V characteristic curve, strong correlations at the dot give rise to self-sustained current and charge oscillations. Their properties depend upon the parameters of the quantum dot and the external applied voltages.Comment: 4 pages, 3 figures; to appear in PR

Restoration of endogenous wild-type p53 activity in a glioblastoma cell line with intrinsic temperature-sensitive p53 induces growth arrest but not apoptosis.

p53 protein is a transcription factor involved in multiple tumor-suppressor activities including cell cycle control and apoptosis. TP53 gene is frequently mutated in glioblastoma, suggesting the importance of inactivation of this gene product in gliomagenesis. Restoration of p53 function in glioblastoma cell lines deficient for p53 has shown that p53 induces growth arrest or apoptosis depending on the cell line and vector used to transduce wild-type TP53 alleles. Considering that astrocytes grow and express p53, it is not clear whether these results reflect physiologic responses or the result of p53 overexpression in combination with cellular responses to viral vector infection. Here, we reassessed this issue using a glioblastoma cell line (LN382) that expresses an endogenous temperature-sensitive mutant p53. This cell line expresses TP53 alleles (100% as determined by a p53 transcriptional assay in yeast) mutated at codon 197 GTG (Val) &amp;gt; CTG (Leu). We found that the p53 protein in these cells acted as an inactive mutant at 37 degrees C and as a functional wild-type p53 below 34 degrees C as demonstrated by several lines of evidence, including (i) restoration of transactivating ability in yeast, (ii) induction of p53-modulated genes such as CDKN1(p21) and transforming growth factor-alpha, (iii) disappearance of accumulated p53 protein in the nucleus and (iv) decrease in steady state p53 protein levels. This temperature switch allowed p53 levels, which were close to physiological levels to dramatically reduce LN382 cell proliferation by inducing a G(1)/S cell cycle block, but not to induce apoptosis. The lack of apoptosis was considered to be a result of the low level p53 expression, because increasing wild-type p53 levels by adenoviral-mediated gene transfer caused apoptosis in these cells. The LN382 cell line will be extremely useful for investigations into the roles of p53 in cellular responses to a variety of stimuli or damages

Gradient descent learning in and out of equilibrium

Relations between the off thermal equilibrium dynamical process of on-line learning and the thermally equilibrated off-line learning are studied for potential gradient descent learning. The approach of Opper to study on-line Bayesian algorithms is extended to potential based or maximum likelihood learning. We look at the on-line learning algorithm that best approximates the off-line algorithm in the sense of least Kullback-Leibler information loss. It works by updating the weights along the gradient of an effective potential different from the parent off-line potential. The interpretation of this off equilibrium dynamics holds some similarities to the cavity approach of Griniasty. We are able to analyze networks with non-smooth transfer functions and transfer the smoothness requirement to the potential.Comment: 08 pages, submitted to the Journal of Physics

Aharonov-Bohm Interferometry with Interacting Quantum Dots: Spin Configurations, Asymmetric Interference Patterns, Bias-Voltage-Induced Aharonov-Bohm Oscillations, and Symmetries of Transport Coefficients

We study electron transport through multiply-connected mesoscopic geometries containing interacting quantum dots. Our formulation covers both equilibrium and non-equilibrium physics. We discuss the relation of coherent transport channels through the quantum dot to flux-sensitive Aharonov-Bohm oscillations in the total conductance of the device. Contributions to transport in first and second order in the intrinsic line width of the dot levels are addressed in detail. We predict an interaction-induced asymmetry in the amplitude of the interference signal around resonance peaks as a consequence of incoherence associated with spin-flip processes. This asymmetry can be used to probe the total spin of the quantum dot. Such a probe requires less stringent experimental conditions than the Kondo effect, which provides the same information. We show that first-order contributions can be partially or even fully coherent. This contrasts with the sequential-tunneling picture, which describes first-order transport as a sequence of incoherent tunneling processes. We predict bias-voltage induced Aharonov-Bohm oscillations of physical quantities which are independent of flux in the linear-response regime. Going beyond the Onsager relations we analyze the relations between the space symmetry group of the setup and the flux-dependent non-linear conductance.Comment: 22 pages, 11 figure

Resonant transmission through an open quantum dot

We have measured the low-temperature transport properties of a quantum dot formed in a one-dimensional channel. In zero magnetic field this device shows quantized ballistic conductance plateaus with resonant tunneling peaks in each transition region between plateaus. Studies of this structure as a function of applied perpendicular magnetic field and source-drain bias indicate that resonant structure deriving from tightly bound states is split by Coulomb charging at zero magnetic field.Comment: To be published in Phys. Rev. B (1997). 8 LaTex pages with 5 figure