Fractal Dimension and Localization of DNA Knots

The scaling properties of DNA knots of different complexities were studied by atomic force microscope. Following two different protocols DNA knots are adsorbed onto a mica surface in regimes of (i) strong binding, that induces a kinetic trapping of the three-dimensional (3D) configuration, and of (ii) weak binding, that permits (partial) relaxation on the surface. In (i) the gyration radius of the adsorbed DNA knot scales with the 3D Flory exponent $\nu\approx 0.58$ within error. In (ii), we find $\nu\approx 0.66$, a value between the 3D and 2D ($\nu=3/4$) exponents, indicating an incomplete 2D relaxation or a different polymer universality class. Compelling evidence is also presented for the localization of the knot crossings in 2D.Comment: 4 pages, 3 figure

Numerical study of linear and circular model DNA chains confined in a slit: metric and topological properties

Advanced Monte Carlo simulations are used to study the effect of nano-slit confinement on metric and topological properties of model DNA chains. We consider both linear and circularised chains with contour lengths in the 1.2--4.8 $\mu$m range and slits widths spanning continuously the 50--1250nm range. The metric scaling predicted by de Gennes' blob model is shown to hold for both linear and circularised DNA up to the strongest levels of confinement. More notably, the topological properties of the circularised DNA molecules have two major differences compared to three-dimensional confinement. First, the overall knotting probability is non-monotonic for increasing confinement and can be largely enhanced or suppressed compared to the bulk case by simply varying the slit width. Secondly, the knot population consists of knots that are far simpler than for three-dimensional confinement. The results suggest that nano-slits could be used in nano-fluidic setups to produce DNA rings having simple topologies (including the unknot) or to separate heterogeneous ensembles of DNA rings by knot type.Comment: 12 pages, 10 figure

Structure and dynamics of ring polymers: entanglement effects because of solution density and ring topology

The effects of entanglement in solutions and melts of unknotted ring polymers have been addressed by several theoretical and numerical studies. The system properties have been typically profiled as a function of ring contour length at fixed solution density. Here, we use a different approach to investigate numerically the equilibrium and kinetic properties of solutions of model ring polymers. Specifically, the ring contour length is maintained fixed, while the interplay of inter- and intra-chain entanglement is modulated by varying both solution density (from infinite dilution up to \approx 40 % volume occupancy) and ring topology (by considering unknotted and trefoil-knotted chains). The equilibrium metric properties of rings with either topology are found to be only weakly affected by the increase of solution density. Even at the highest density, the average ring size, shape anisotropy and length of the knotted region differ at most by 40% from those of isolated rings. Conversely, kinetics are strongly affected by the degree of inter-chain entanglement: for both unknots and trefoils the characteristic times of ring size relaxation, reorientation and diffusion change by one order of magnitude across the considered range of concentrations. Yet, significant topology-dependent differences in kinetics are observed only for very dilute solutions (much below the ring overlap threshold). For knotted rings, the slowest kinetic process is found to correspond to the diffusion of the knotted region along the ring backbone.Comment: 17 pages, 11 figure

Principles of Modular Tumor Therapy

Nature is interwoven with communication and is represented and reproduced through communication acts. The central question is how may multimodal modularly acting and less toxic therapy approaches, defined as modular therapies, induce an objective response or even a continuous complete remission, although single stimulatory or inhibitingly acting drugs neither exert mono-activity in the respective metastatic tumor type nor are they directed to potentially ‘tumor-specific’ targets. Modularity in the present context is a formal pragmatic communicative systems concept, describing the degree to which systems objects (cells, pathways etc.) may be communicatively separated in a virtual continuum, and recombined and rededicated to alter validity and denotation of communication processes in the tumor. Intentional knowledge, discharging in reductionist therapies, disregards the risk-absorbing background knowledge of the tumor’s living world including the holistic communication processes, which we rely on in every therapy. At first, this knowledge constitutes the validity of informative intercellular processes, which is the prerequisite for therapeutic success. All communication-relevant steps, such as intentions, understandings, and the appreciation of messages, may be modulated simultaneously, even with a high grade of specificity. Thus, modular therapy approaches including risk-absorbing and validity-modifying background knowledge may overcome reductionist idealizations. Modular therapies show modular events assembled by the tumor’s living world as an additional evolution-constituting dimension. This way, modular knowledge may be acquired from the environment, either incidentally or constitutionally. The new communicatively defined modular coherency of environment, i.e. the tumor-associated microenvironment, and tumor cells open novel ways for the scientific community in ‘translational medicine’

Community engagement and professionalization: Emerging tensions

© 2019 by Emerald Publishing Limited. An increase in community engagement by governments across Australia’s three-tiered federal polity conforms to international trends. It represents a multidimensional institutionalization of participatory democracy designed to involve the public in decision-making. Increasingly, it is a practice which displays the markers of professionalization, including (self-described) professionals, professional associations and a code of ethics. The individuals who design, communicate, and facilitate community engagement are placed in a unique position, whereas most professions claim to serve both their client or employer and a greater public good, community engagement practitioners play these roles while also claiming to serve as “guardians” of democratic processes. Yet the claimed professionalization of community engagement is raising some questions: Is community engagement really a profession – and by what criteria ought this be assessed? What tensions do community engagement practitioners face by “serving multiple masters,” and how do they manage these? More pointedly, how can ethics inform our understanding of community engagement and its professionalization? This chapter examines the case for the practice of community engagement as a profession using Noordegraaf’s (2007) pillars of pure professionalism as a guide. It then explores some practical examples of the tensions practitioners may experience. The chapter concludes by reflecting on the future direction of community engagement given its positioning

The Prognostic PDE4D7 Score in a Diagnostic Biopsy Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

Purpose. To further validate the prognostic power of the biomarker PDE4D7, we investigated the correlation of PDE4D7 scores adjusted for presurgical clinical variables with longitudinal postsurgical biological outcomes. Methods. RNA was extracted from biopsy punches of resected tumors (550 patients; RP cohort) and diagnostic needle biopsies (168 patients; DB cohort). Cox regression and survival were applied to correlate PDE4D7 scores with patient outcomes. Logistic regression was used to combine the clinical CAPRA score with PDE4D7. Results. In univariate analysis, the PDE4D7 score was significantly associated with PSA recurrence after prostatectomy in both studied patient cohorts' analysis (HR 0.53; 95% CI 0.41-0.67; p<1.0E-04 and HR 0.47; 95% CI 0.33-0.65; p<1.0E-04, respectively). After adjustment for the presurgical clinical variables preoperative PSA, PSA density, biopsy Gleason, clinical stage, percentage tumor in the biopsy (data only available for RP cohort), and percentage of positive biopsies, the HR was 0.49 (95% CI 0.38-0.64; p<1.0E-04) and 0.43 (95% CI 0.29-0.63; p<1.0E-04), respectively. The addition of the PDE4D7 to the clinical CAPRA score increased the AUC by 5% over the CAPRA score alone (0.82 versus 0.77; p=0.004). This combination model stratified 14.6% patients of the DB cohort to no risk of biochemical relapse (NPV 100%) over a follow-up period of up to 15 years. Conclusions. The PDE4D7 score provides independent risk information for pretreatment risk stratification. Combining CAPRA with PDE4D7 scores significantly improved the clinical risk stratification before surgery

Angiotensin II Facilitates Breast Cancer Cell Migration and Metastasis

Breast cancer metastasis is a leading cause of death by malignancy in women worldwide. Efforts are being made to further characterize the rate-limiting steps of cancer metastasis, i.e. extravasation of circulating tumor cells and colonization of secondary organs. In this study, we investigated whether angiotensin II, a major vasoactive peptide both produced locally and released in the bloodstream, may trigger activating signals that contribute to cancer cell extravasation and metastasis. We used an experimental in vivo model of cancer metastasis in which bioluminescent breast tumor cells (D3H2LN) were injected intra-cardiacally into nude mice in order to recapitulate the late and essential steps of metastatic dissemination. Real-time intravital imaging studies revealed that angiotensin II accelerates the formation of metastatic foci at secondary sites. Pre-treatment of cancer cells with the peptide increases the number of mice with metastases, as well as the number and size of metastases per mouse. In vitro, angiotensin II contributes to each sequential step of cancer metastasis by promoting cancer cell adhesion to endothelial cells, trans-endothelial migration and tumor cell migration across extracellular matrix. At the molecular level, a total of 102 genes differentially expressed following angiotensin II pre-treatment were identified by comparative DNA microarray. Angiotensin II regulates two groups of connected genes related to its precursor angiotensinogen. Among those, up-regulated MMP2/MMP9 and ICAM1 stand at the crossroad of a network of genes involved in cell adhesion, migration and invasion. Our data suggest that targeting angiotensin II production or action may represent a valuable therapeutic option to prevent metastatic progression of invasive breast tumors

Cancer: evolutionary, genetic and epigenetic aspects

There exist two paradigms about the nature of cancer. According to the generally accepted one, cancer is a by-product of design limitations of a multi-cellular organism (Greaves, Nat Rev Cancer 7:213–221, 2007). The essence of the second resides in the question “Does cancer kill the individual and save the species?” (Sommer, Hum Mutat 3:166–169, 1994). Recent data on genetic and epigenetic mechanisms of cell transformation summarized in this review support the latter point of view, namely that carcinogenesis is an evolutionary conserved phenomenon—a programmed death of an organism. It is assumed that cancer possesses an important function of altruistic nature: as a mediator of negative selection, it serves to preserve integrity of species gene pool and to mediate its evolutionary adjustment. Cancer fulfills its task due apparently to specific killer function, understanding mechanism of which may suggest new therapeutic strategy