pwc-archive/papers-with-abstracts huggingface dataset:
Modeling and simulation of vascular tumors embedded in evolving capillary networks
Authors: Marvin Fritz, Prashant K. Jha, Tobias Köppl, J. Tinsley Oden, Andreas Wagner, Barbara Wohlmuth
Date: 2021-01-22 00:00:00

In this work, we present a coupled 3D-1D model of solid tumor growth within a dynamically changing vascular network to facilitate realistic simulations of angiogenesis. Additionally, the model includes erosion of the extracellular matrix, interstitial flow, and coupled flow in blood vessels and tissue. We employ continuum mixture theory with stochastic Cahn--Hilliard type phase-field models of tumor growth. The interstitial flow is governed by a mesoscale version of Darcy's law. The flow in the blood vessels is controlled by Poiseuille flow, and Starling's law is applied to model the mass transfer in and out of blood vessels. The evolution of the network of blood vessels is orchestrated by the concentration of the tumor angiogenesis factors (TAFs); blood vessels grow towards the increasing TAFs concentrations. This process is not deterministic, allowing random growth of blood vessels and, therefore, due to the coupling of nutrients in tissue and vessels, makes the growth of tumors stochastic. We demonstrate the performance of the model by applying it to a variety of scenarios. Numerical experiments illustrate the flexibility of the model and its ability to generate satellite tumors. Simulations of the effects of angiogenesis on tumor growth are presented as well as sample-independent features of cancer.
Stability bounds of a delay visco-elastic rheological model with substrate friction
Authors: Malik A Dawi, Jose J Munoz
Date: 2021-01-18 00:00:00
Tasks: Friction

Cells and tissues exhibit oscillatory deformations during remodelling, migration or embryogenesis. Although it has been shown that these oscillations correlate with cell biochemical signalling, it is yet unclear the role of these oscillations in triggering drastic cell reorganisation events or instabilities, and the coupling of this oscillatory response with tested visco-elastic properties. We here present a rheological model that incorporates elastic, viscous and frictional components, and that is able to generate oscillatory response through a delay adaptive process of the rest-length. We analyse its stability properties as a function of the model parameters and deduce analytical bounds of the stable domain. While increasing values of the delay and remodelling rate render the model unstable, we also show that increasing friction with the substrate destabilise the oscillatory response. Furthermore, we numerically verify that the extension of the model to non-linear strain measures is able to generate sustained oscillations that alternate between stable and unstable regions.
A mutual information-based in vivo monitoring of adaptive response to targeted therapies in melanoma
Authors: Aurore Bugi-Marteyn, Fanny Noulet, Nicolas Liaudet, Rastine Merat
Date: 2021-01-10 00:00:00

The mechanisms of adaptive resistance to genetic-based targeted therapies of solid malignancies have been the subject of intense research. These studies hold great promise for finding co-targetable hub/pathways which in turn would control the downstream non-genetic mechanisms of adaptive resistance. Many such mechanisms have been described in the paradigmatic BRAF-mutated melanoma model of adaptive response to BRAF inhibition. Currently, a major challenge for these mechanistic studies is to confirm in vivo, at the single-cell proteomic level, the existence of dependencies between the co-targeted hub/pathways and their downstream effectors. Moreover, the drug-induced in vivo modulation of these dependencies needs to be demonstrated. Here, we implement such single-cell-based in vivo expression dependency quantification using immunohistochemistry (IHC)-based analyses of sequential biopsies in two xenograft models. These mimic phase 2 and 3 trials in our own therapeutic strategy to prevent the adaptive response to BRAF inhibition. In this mechanistic model, the dependencies between the targeted Li2CO3-inducible hub HuR and the resistance effectors are more likely time-shifted and transient since the minority of HuRLow cells, which act as a reservoir of adaptive plasticity, switch to a HuRHigh state as they paradoxically proliferate under BRAF inhibition. Nevertheless, we show that a copula/kernel density estimator (KDE)-based quantification of mutual information (MI) efficiently captures, at the individual level, the dependencies between HuR and two relevant resistance markers pERK and EGFR, and outperforms classic expression correlation coefficients. Ultimately, the validation of MI as a predictive IHC-based metric of response to our therapeutic strategy will be carried in clinical trials.
An injectable, self-healing and MMP-inhibiting hyaluronic acid gel via iron coordination
Authors: Ziyu Gao, Xuebin Yang, Elena Jones, Paul A. Bingham, Alex Scrimshire, Paul D. Thornton, Giuseppe Tronci
Date: 2021-01-07 00:00:00

Regulating the activity of matrix metalloproteinases (MMPs) is a potential strategy for osteoarthritis (OA) therapy, although delivering this effect in a spatially and temporally localised fashion remains a challenge. Here, we report an injectable and self-healing hydrogel enabling factor-free MMP regulation and biomechanical competence in situ. The hydrogel is realised within one minute upon room temperature coordination between hyaluronic acid (HA) and a cell-friendly iron-glutathione complex in aqueous environment. The resultant gel displayed up to 300% in shear strain and tolerance towards ATDC 5 chondrocytes, in line with the elasticity and biocompatibility requirements for connective tissue application. Significantly enhanced inhibition of MMP-13 activity was achieved after 12 hours in vitro, compared with a commercial HA injection (OSTENIL PLUS). Noteworthy, 24-hour incubation of a clinical synovial fluid sample collected from a late-stage OA patient with the reported hydrogel was still shown to downregulate synovial fluid MMP activity (100.0 +/- 17.6 % --> 81.0 +/- 7.5 %), with at least comparable extent to the case of the OSTENIL PLUS-treated SF group (100.0 +/- 17.6 % --> 92.3 +/- 27.3 %). These results therefore open up new possibilities in the use of HA as both mechanically-competent hydrogel as well as a mediator of MMP regulation for OA therapy.
Induced Periosteum-Mimicking Membrane with Cell Barrier and Multipotential Stromal Cell (MSC) Homing Functionalities
Authors: Heather E. Owston, Katrina M. Moisley, Giuseppe Tronci, Stephen J. Russell, Peter V. Giannoudis, Elena Jones
Date: 2021-01-05 00:00:00
Tasks: Management

The current management of critical size bone defects (CSBDs) remains challenging and requires multiple surgeries. To reduce the number of surgeries, wrapping a biodegradable fibrous membrane around the defect to contain the graft and carry biological stimulants for repair is highly desirable. Poly(epsilon-caprolactone) (PCL) can be utilised to realise nonwoven fibrous barrier-like structures through free surface electrospinning (FSE). Human periosteum and induced membrane (IM) samples informed the development of an FSE membrane to support platelet lysate (PL) absorption, multipotential stromal cells (MSC) growth, and the prevention of cell migration. Although thinner than IM, periosteum presented a more mature vascular system with a significantly larger blood vessel diameter. The electrospun membrane (PCL3%-E) exhibited randomly configured nanoscale fibres that were successfully customised to introduce pores of increased diameter, without compromising tensile properties. Additional to the PL absorption and release capabilities needed for MSC attraction and growth, PCL3%-E also provided a favourable surface for the proliferation and alignment of periosteum- and bone marrow derived-MSCs, whilst possessing a barrier function to cell migration. These results demonstrate the development of a promising biodegradable barrier membrane enabling PL release and MSC colonisation, two key functionalities needed for the in situ formation of a transitional periosteum-like structure, enabling movement towards single-surgery CSBD reconstruction.
Hydrolytic Degradability, Cell Tolerance and On-Demand Antibacterial Effect of Electrospun Photodynamically Active Fibres
Authors: Amy Contreras, Michael J. Raxworthy, Simon Wood, Giuseppe Tronci
Date: 2021-01-05 00:00:00
Tasks: Cultural Vocal Bursts Intensity Prediction

Photodynamically active fibres (PAFs) are a novel class of stimulus-sensitive systems capable of triggering antibiotic-free antibacterial effect on-demand when exposed to light. Despite their relevance in infection control, however, the broad clinical applicability of PAFs has not yet been fully realised due to the limited control in fibrous microstructure, cell tolerance and antibacterial activity in the physiologic environment. We addressed this challenge by creating semicrystalline electrospun fibres with varying content of poly[(L-lactide)-co-(glycolide)] (PLGA), poly(epsilon-caprolactone) (PCL) and methylene blue (MB), whereby the effect of polymer morphology, fibre composition and photosensitiser (PS) uptake on wet state fibre behaviour and functions was studied. The presence of crystalline domains and PS-polymer secondary interactions proved key to accomplishing long-lasting fibrous microstructure, controlled mass loss and controlled MB release profiles (37 degC, pH 7.4, 8 weeks). PAFs with equivalent PLGA:PCL weight ratio successfully promoted attachment and proliferation of L929 cells over a 7-day culture with and without light activation, while triggering up to 2.5 and 4 log reduction in E. coli and S. mutans viability, respectively. These results support the therapeutic applicability of PAFs for frequently encountered bacterial infections, opening up new opportunities in photodynamic fibrous systems with integrated wound healing and infection control capabilities.
A new parsimonious method for classifying Cancer Tissue-of-Origin Based on DNA Methylation 450K data
Authors: Shen Jia, Yulin Zhang, Yiming Mao, Jiawei Gao, Yixuan Chen, YuXuan Jiang, Haochen Luo, Kebo Lv, Jionglong Su
Date: 2021-01-03 00:00:00
Tasks: Cancer Classification, Diagnostic, Dimensionality Reduction, feature selection

DNA methylation is a well-studied genetic modification that regulates gene transcription of Eukaryotes. Its alternations have been recognized as a significant component of cancer development. In this study, we use the DNA methylation 450k data from The Cancer Genome Atlas to evaluate the efficacy of DNA methylation data on cancer classification for 30 cancer types. We propose a new method for gene selection in high dimensional data(over 450 thousand). Variance filtering is first introduced for dimension reduction and Recursive feature elimination (RFE) is then used for feature selection. We address the problem of selecting a small subsets of genes from large number of methylated sites, and our parsimonious model is demonstrated to be efficient, achieving an accuracy over 91%, outperforming other studies which use DNA micro-arrays and RNA-seq Data . The performance of 20 models, which are based on 4 estimators (Random Forest, Decision Tree, Extra Tree and Support Vector Machine) and 5 classifiers (k-Nearest Neighbours, Support Vector Machine, XGboost, Light GBM and Multi-Layer Perceptron), is compared and robustness of the RFE algorithm is examined. Results suggest that the combined model of extra tree plus catboost classifier offers the best performance in cancer identification, with an overall validation accuracy of 91% , 92.3%, 93.3% and 93.5% for 20, 30, 40 and 50 features respectively. The biological functions in cancer development of 50 selected genes is also explored through enrichment analysis and the results show that 12 out of 16 of our top features have already been identified to be specific with cancer and we also propose some more genes to be tested for future studies. Therefore, our method may be utilzed as an auxiliary diagnostic method to determine the actual clinicopathological status of a specific cancer.
Influence of shear rate and surface chemistry on thrombus formation in micro-crevice
Authors: Mansur Zhussupbekov, Wei-Tao Wu, Megan A. Jamiolkowski, Mehrdad Massoudi, James F. Antaki
Date: 2020-11-20 00:00:00
Tasks: Management

Thromboembolic complications remain a central issue in management of patients on mechanical circulatory support. Despite the best practices employed in design and manufacturing of modern ventricular assist devices, complexity and modular nature of these systems often introduces internal steps and crevices in the flow path which can serve as nidus for thrombus formation. Thrombotic potential is influenced by multiple factors including the characteristics of the flow and surface chemistry of the biomaterial. This study explored these elements in the setting of blood flow over a micro-crevice using a multi-constituent numerical model of thrombosis. The simulations reproduced the platelet deposition patterns observed experimentally and elucidated the role of flow, shear rate, and surface chemistry in shaping the deposition. The results offer insights for design and operation of blood-contacting devices.
Harnessing subcellular-resolved organ distribution of cationic copolymer-functionalized fluorescent nanodiamonds for optimal delivery of therapeutic siRNA to a xenografted tumor in mice
Authors: Sandra Claveau, Marek Kindermann, Alexandre Papine, Zamira Díaz-Riascos, Xavier Delen, Patrick Georges, Roser López-Alemany, Òscar Tirado Martínez, Jean-Rémi Bertrand, Ibane Abasolo Olaortua, Petr Cigler, François Treussart
Date: 2020-12-29 00:00:00

Diamond nanoparticles (nanodiamonds) can transport active drugs in cultured cells as well as in vivo. However, in the latter case, methods allowing to determine their bioavailability accurately are still lacking. Nanodiamond can be made fluorescent with a perfectly stable emission and a lifetime ten times longer than the one of tissue autofluorescence. Taking advantage of these properties, we present an automated quantification method of fluorescent nanodiamonds (FND) in histological sections of mouse organs and tumor, after systemic injection. We use a home-made time-delayed fluorescence microscope comprising a custom pulsed laser source synchronized on the master clock of a gated intensified array detector. This setup allows to obtain ultra-high-resolution images 120 Mpixels of whole mouse organs sections, with subcellular resolution and single-particle sensitivity. As a proof-of-principle experiment, we quantified the biodistribution and aggregation state of new cationic FNDs able to transport small interfering RNA inhibiting the oncogene responsible for Ewing sarcoma. Image analysis showed a low yield of nanodiamonds in the tumor after intravenous injection. Thus, for the in vivo efficacy assay we injected the nanomedicine into the tumor. We achieved a 28-fold inhibition of the oncogene. This method can readily be applied to other nanoemitters with $\approx$100 ns lifetime.
An insight into acupoints and meridians in human body based on interstitial fluid circulation
Authors: Li Hongyi, Yin Yajun, Hu Jun, Li Hua, Wang Fang, Ji Fusui, Ma Chao
Date: 2020-12-25 00:00:00

The atlas of human acupoints and meridians has been utilized in clinical practice for almost a millennium although the anatomical structures and functions remain to be clarified. It has recently been reported that a long-distance interstitial fluid (ISF) circulatory pathway may originate from the acupoints in the extremities. As observed in living human subjects, cadavers and animals using magnetic resonance imaging and fluorescent tracers, the ISF flow pathways include at least 4 types of anatomical structures: the cutaneous-, perivenous-, periarterial-, and neural-pathways. Unlike the blood or lymphatic vessels, these ISF flow pathways are composed of highly ordered and topologically connected interstitial fibrous connective tissues that may work as guiderails for the ISF to flow actively over long distance under certain driving forces. Our experimental results demonstrated that most acupoints in the extremity endings connect with one or more ISF flow pathways and comprise a complex network of acupoint-ISF-pathways. We also found that this acupoint-ISF-pathway network can connect to visceral organs or tissues such as the pericardium and epicardium, even though the topographical geometry in human extremities does not totally match the meridian lines on the atlas that is currently used in traditional Chinese medicine. Based on our experimental data, the following working hypotheses are proposed. A comprehensive atlas will be constructed to systemically reveal the detailed anatomical structures of the acupoints-originated ISF circulation. Such an atlas may shed light on the mysteries shrouding the visceral correlations of acupoints and meridians, and inaugurate a new frontier for innovative medical applications.
Letter to the Editor and Comments on: Intravital dynamic and correlative imaging reveals diffusion-dominated canalicular and flow-augmented ductular bile flux
Authors: Lutz Brusch, Yannis Kalaidzidis, Kirstin Meyer, Ivo F. Sbalzarini, Marino Zerial
Date: 2020-12-22 00:00:00

Bile, the central metabolic product of the liver, is secreted by hepatocytes into bile canaliculi (BC), tubular subcellular structures of 0.5-2 $\mu$m diameter which are formed by the apical membranes of juxtaposed hepatocytes. BC interconnect to build a highly ramified 3D network that collects and transports bile towards larger interlobular bile ducts (IBD). The transport mechanism of bile is of fundamental interest and the current text-book model of "osmotic canalicular bile flow", i.e. enforced by osmotic water influx, has recently been quantitatively verified based on flux measurements and BC contractility (Meyer et al., 2017) but challenged in the article entitled "Intravital dynamic and correlative imaging reveals diffusion-dominated canalicular and flow-augmented ductular bile flux" (Vartak et al., 2020). We feel compelled to share a series of arguments that question the key conclusions of this study (Vartak et al., 2020), particularly because it risks to be misinterpreted and misleading for the field in view of potential clinical applications. We summarized the arguments in the following 8 points.
Invading and receding sharp-fronted travelling waves
Authors: Maud El-Hachem, Scott W McCue, Matthew J Simpson
Date: 2020-08-03 00:00:00

Biological invasion, whereby populations of motile and proliferative individuals lead to moving fronts that invade into vacant regions, are routinely studied using partial differential equation (PDE) models based upon the classical Fisher--KPP model. While the Fisher--KPP model and extensions have been successfully used to model a range of invasive phenomena, including ecological and cellular invasion, an often--overlooked limitation of the Fisher--KPP model is that it cannot be used to model biological recession where the spatial extent of the population decreases with time. In this work we study the \textit{Fisher--Stefan} model, which is a generalisation of the Fisher--KPP model obtained by reformulating the Fisher--KPP model as a moving boundary problem. The nondimensional Fisher--Stefan model involves just one single parameter, $\kappa$, which relates the shape of the density front at the moving boundary to the speed of the associated travelling wave, $c$. Using numerical simulation, phase plane and perturbation analysis, we construct approximate solutions of the Fisher--Stefan model for both slowly invading and slowly receding travelling waves, as well as for rapidly receding travelling waves. These approximations allow us to determine the relationship between $c$ and $\kappa$ so that commonly--reported experimental estimates of $c$ can be used to provide estimates of the unknown parameter $\kappa$. Interestingly, when we reinterpret the Fisher--KPP model as a moving boundary problem, many disregarded features of the classical Fisher--KPP phase plane take on a new interpretation since travelling waves solutions with $c < 2$ are not normally considered. This means that our analysis of the Fisher--Stefan model has both practical value and an inherent mathematical value.
Concurrent consideration of cortical and cancellous bone within continuum bone remodelling
Authors: Ina Schmidt, Areti Papastavrou, Paul Steinmann
Date: 2020-11-25 00:00:00

Continuum bone remodelling is an important tool for predicting the effects of mechanical stimuli on bone density evolution. While the modelling of only cancellous bone is considered in many studies based on continuum bone remodelling, this work presents an approach of modelling also cortical bone and the interaction of both bone types. The distinction between bone types is made by introducing an initial volume fraction. A simple point-wise example is used to study the behaviour of novel model options, as well as a proximal femur example, where the interaction of both bone types is demonstrated using initial density distributions. The results of the proposed model options indicate that the consideration of cortical bone remarkably changes the density evolution of cancellous bone, and should therefore not be neglected.
Multi-scale simulation of thrombus formation at LVAD inlet cannula connection: Importance of Virchow's triad
Authors: R. Mendez Rojano, M. Zhussupbekov, J. F. Antaki
Date: 2020-11-20 00:00:00

As pump thrombosis is reduced in current-generation ventricular assist devices (VAD), adverse events such as bleeding or stroke remain at unacceptable rates. Thrombosis around the VAD inlet cannula (IC) has been highlighted as a possible source of stroke events. Recent computational fluid dynamics (CFD) studies have attempted to characterize the thrombosis risk of different IC-ventricle configurations. However, purely CFD simulations relate thrombosis risk to ad-hoc criteria based on flow characteristics, with little consideration of biochemical factors. This study investigates the genesis of IC thrombosis including two elements of the Virchow's triad: Endothelial injury and Hypercoagulability. To this end a multi-scale thrombosis simulation that includes platelet activity and coagulation reactions was performed. Our results show significant thrombin formation in stagnation regions (|u|< 0.002 m/s) close to the IC wall. In addition, high shear-mediated platelet activation was observed over the leading-edge tip of the cannula which mirrors the thrombus deposition pattern observed clinically. The current study reveals the importance of biochemical factors to the genesis of thrombosis at the ventricular-cannula junction which can inform clinical decisions in terms of anticoagulation/antiplatelet therapy and guide engineers to develop more robust designs.