Molekular zielgerichtete Therapie

Zusammenfassung: Bis vor knapp 10Jahren stützte sich die Tumortherapie auf 3Säulen: die Chirurgie, die Strahlentherapie und die zytostatische Chemotherapie. Eine definitive Heilung im Bereich der soliden Tumoren versprach meist nur eine vollständige Entfernung des Tumors durch den Chirurgen. Radiotherapeuten und Onkologen konnten nur einem kleinen Teil ihrer Patienten langfristig helfen. Antikörpertherapien, Antitumorvakzinierungen oder gar genspezifische, individualisierte Therapieformen existierten zwar als Visionen, diese schienen Mitte der 90er-Jahre von einer klinischer Anwendung noch weit entfernt. Mit der Einführung des Antikörpers Rituximab (1997) und des Tyrosinkinaseinhibitors Imatinib (2001) in die klinische Praxis kamen 2 neuartige Substanzen auf den Markt, die Denken und Vorstellungen in der Onkologie grundsätzlich veränderten. Diese Therapeutika ließen aus Visionen Realitäten werden, die der Pharmaindustrie, den Klinikern und Patienten neue Perspektiven bezüglich Machbarkeit und kommender Möglichkeiten im Bereich der Tumortherapie eröffnet haben. Im Folgenden soll ein Überblick über die Entwicklung der 4.Säule der Tumortherapie, der sog. "targeted therapy", gegeben werde

Microscopic dynamics of thin hard rods

Based on the collision rules for hard needles we derive a hydrodynamic equation that determines the coupled translational and rotational dynamics of a tagged thin rod in an ensemble of identical rods. Specifically, based on a Pseudo-Liouville operator for binary collisions between rods, the Mori-Zwanzig projection formalism is used to derive a continued fraction representation for the correlation function of the tagged particle's density, specifying its position and orientation. Truncation of the continued fraction gives rise to a generalised Enskog equation, which can be compared to the phenomenological Perrin equation for anisotropic diffusion. Only for sufficiently large density do we observe anisotropic diffusion, as indicated by an anisotropic mean square displacement, growing linearly with time. For lower densities, the Perrin equation is shown to be an insufficient hydrodynamic description for hard needles interacting via binary collisions. We compare our results to simulations and find excellent quantitative agreement for low densities and qualtitative agreement for higher densities.Comment: 21 pages, 6 figures, v2: clarifications and improved readabilit

Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM × anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimen

Dynamics of gelling liquids: a short survey

The dynamics of randomly crosslinked liquids is addressed via a Rouse- and a Zimm-type model with crosslink statistics taken either from bond percolation or Erdoes-Renyi random graphs. While the Rouse-type model isolates the effects of the random connectivity on the dynamics of molecular clusters, the Zimm-type model also accounts for hydrodynamic interactions on a preaveraged level. The incoherent intermediate scattering function is computed in thermal equilibrium, its critical behaviour near the sol-gel transition is analysed and related to the scaling of cluster diffusion constants at the critical point. Second, non-equilibrium dynamics is studied by looking at stress relaxation in a simple shear flow. Anomalous stress relaxation and critical rheological properties are derived. Some of the results contradict long-standing scaling arguments, which are shown to be flawed by inconsistencies.Comment: 21 pages, 3 figures; Dedicated to Lothar Schaefer on the occasion of his 60th birthday; Changes: added comments on the gel phase and some reference

Granular cooling of hard needles

We have developed a kinetic theory of hard needles undergoing binary collisions with loss of energy due to normal and tangential restitution. In addition, we have simulated many particle systems of granular hard needles. The theory, based on the assumption of a homogeneous cooling state, predicts that granular cooling of the needles proceeds in two stages: An exponential decay of the initial configuration to a state where translational and rotational energies take on a time independent ratio (not necessarily unity), followed by an algebraic decay of the total kinetic energy $\sim t^{-2}$. The simulations support the theory very well for low and moderate densities. For higher densities, we have observed the onset of the formation of clusters and shear bands.Comment: 7 pages, 8 figures; major changes, extended versio

Pre-treatment comorbidities, C-reactive protein and eosinophil count, and immune-related adverse events as predictors of survival with checkpoint inhibition for multiple tumour entities

BACKGROUND The development of immune-related adverse events (irAEs) may be associated with clinical efficacy of checkpoint inhibitors (CPIs) in patients with cancer. We therefore investigated the effect of irAEs and pre-treatment parameters on outcome in a large, real-life patient cohort. METHODS We performed a single-centre, retrospective, observational study including patients who received CPIs from 2011 to 2018 and followed until 2021. The primary outcome was overall survival, and the secondary outcome was the development of irAEs. RESULTS In total, 229 patients with different tumour entities (41% non-small cell lung cancer [NSCLC], 29% melanoma) received a total of 282 CPI treatment courses (ipilimumab, nivolumab, pembrolizumab or atezolizumab). Thirty-four percent of patients developed irAEs (of these 17% had CTCAE Grade ≥3). Factors independently associated with mortality were pre-treatment CRP ≥10 mg/L (hazard ratio [HR] 2.064, p = 0.0003), comorbidity measured by Charlson comorbidity index (HR 1.149, p = 0.014) and irAEs (HR 0.644, p = 0.036) (age-adjusted, n = 216). Baseline eosinophil count ≤0.2 × 10$^{9}$ /L was a further independent predictor of mortality (age-, CRP-, CCI- and irAE-adjusted HR = 2.252, p = 0.002, n = 166). Anti-CTLA-4 use (p < 0.001), and pre-treatment CRP <10 mg/L were independently associated with irAE occurrence (p = 0.037). CONCLUSIONS We found an independent association between irAE occurrence and improved overall survival in a real-life cohort spanning multiple tumour entities and treatment regimens. Pre-treatment comorbidities, CRP and eosinophil count represent potential markers for predicting treatment response

Force-extension relation of cross-linked anisotropic polymer networks

Cross-linked polymer networks with orientational order constitute a wide class of soft materials and are relevant to biological systems (e.g., F-actin bundles). We analytically study the nonlinear force-extension relation of an array of parallel-aligned, strongly stretched semiflexible polymers with random cross-links. In the strong stretching limit, the effect of the cross-links is purely entropic, independent of the bending rigidity of the chains. Cross-links enhance the differential stretching stiffness of the bundle. For hard cross-links, the cross-link contribution to the force-extension relation scales inversely proportional to the force. Its dependence on the cross-link density, close to the gelation transition, is the same as that of the shear modulus. The qualitative behavior is captured by a toy model of two chains with a single cross-link in the middle.Comment: 7 pages, 4 figure

Energy landscape of a Lennard-Jones liquid: Statistics of stationary points

Molecular dynamics simulations are used to generate an ensemble of saddles of the potential energy of a Lennard-Jones liquid. Classifying all extrema by their potential energy u and number of unstable directions k, a well defined relation k(u) is revealed. The degree of instability of typical stationary points vanishes at a threshold potential energy, which lies above the energy of the lowest glassy minima of the system. The energies of the inherent states, as obtained by the Stillinger-Weber method, approach the threshold energy at a temperature close to the mode-coupling transition temperature Tc.Comment: 4 RevTeX pages, 6 eps figures. Revised versio

Cooling dynamics of a dilute gas of inelastic rods: a many particle simulation

We present results of simulations for a dilute gas of inelastically colliding particles. Collisions are modelled as a stochastic process, which on average decreases the translational energy (cooling), but allows for fluctuations in the transfer of energy to internal vibrations. We show that these fluctuations are strong enough to suppress inelastic collapse. This allows us to study large systems for long times in the truely inelastic regime. During the cooling stage we observe complex cluster dynamics, as large clusters of particles form, collide and merge or dissolve. Typical clusters are found to survive long enough to establish local equilibrium within a cluster, but not among different clusters. We extend the model to include net dissipation of energy by damping of the internal vibrations. Inelatic collapse is avoided also in this case but in contrast to the conservative system the translational energy decays according to the mean field scaling law, E(t)\propto t^{-2}, for asymptotically long times.Comment: 10 pages, 12 figures, Latex; extended discussion, accepted for publication in Phys. Rev.

Coefficient of restitution for elastic disks

We calculate the coefficient of restitution, $\epsilon$, starting from a microscopic model of elastic disks. The theory is shown to agree with the approach of Hertz in the quasistatic limit, but predicts inelastic collisions for finite relative velocities of two approaching disks. The velocity dependence of $\epsilon$ is calculated numerically for a wide range of velocities. The coefficient of restitution furthermore depends on the elastic constants of the material via Poisson's number. The elastic vibrations absorb kinetic energy more effectively for materials with low values of the shear modulus.Comment: 25 pages, 12 Postscript figures, LaTex2