A spatially resolved mechanistic growth law for cancer drug development.

Mathematical models used in pre-clinical drug discovery tend to be empirical growth laws. Such models are well suited to fitting the data available, mostly longitudinal studies of tumour volume, however, they typically have little connection with the underlying physiological processes. This lack of a mechanistic underpinning restricts their flexibility and inhibits their direct translation across studies including from animal to human. Here we present a mathematical model describing tumour growth for the evaluation of single agent cytotoxic compounds that is based on mechanistic principles. The model can predict spatial distributions of cell subpopulations, tumour growth fraction as well as include spatial drug distribution effects within tumours. Importantly, we demonstrate the model can be reduced to a growth law similar in form to the ones currently implemented in pharmaceutical drug development for pre-clinical trials so that it can integrated into the current workflow. We validate this approach for both cell-derived xenograft (CDX) and patient-derived xenograft (PDX) data. This shows that our theoretical model fits as well as the best performing and most widely used models. Our work opens up current pre-clinical modelling studies to also incorporating spatially resolved and multi-modal data without significant added complexity and creates the opportunity to improve translation and tumour response predictions.

A refinement of clinical tumour marker monitoring - why not use an inverse value of doubling time?

The aim of this study was to compare prostate specific antigen (PSA) kinetics – half life time (HT), doubling time (DT) and elimination rate PSA (ePSA) in prostate cancer monitoring. We report that implementation of inverse value (ePSA) rather than HT or DT has distinct advantages: (1) values are valid when PSA is unchanged (ePSA equals zero), (2) the concept of ePSA is easily comprehendible – it is a growth fraction, (3) ePSA fluctuates in a narrow range – easy to interpret, no large numbers, (4) no mathematical flaws (no positive skewing). Exploring ePSA norm as < 0% might help to timely spot a biochemical recurrence (BCR). Primary health care providers (PHCP) tend to habitually use an irrelevant PSA threshold – 4.0 ng/ml in postoperative follow-up. The delayed referrals of patients in remission might be reduced if PHCPs adopt an ePSA.

A New Mathematical Model for Controlling Tumor Growth Based on Microenvironment Acidity and Oxygen Concentration

Hypoxia and the pH level of the tumor microenvironment have a great impact on the treatment of tumors. Here, the tumor growth is controlled by regulating the oxygen concentration and the acidity of the tumor microenvironment by introducing a two-dimensional multiscale cellular automata model of avascular tumor growth. The spatiotemporal evolution of tumor growth and metabolic variations is modeled based on biological assumptions, physical structure, states of cells, and transition rules. Each cell is allocated to one of the following states: proliferating cancer, nonproliferating cancer, necrotic, and normal cells. According to the response of the microenvironmental conditions, each cell consumes/produces metabolic factors and updates its state based on some stochastic rules. The input parameters are compatible with cancer biology using experimental data. The effect of neighborhoods during mitosis and simulating spatial heterogeneity is studied by considering multicellular layer structure of tumor. A simple Darwinist mutation is considered by introducing a critical parameter ( Nmm ) that affects division probability of the proliferative tumor cells based on the microenvironmental conditions and cancer hallmarks. The results show that Nmm regulation has a significant influence on the dynamics of tumor growth, the growth fraction, necrotic fraction, and the concentration levels of the metabolic factors. The model not only is able to simulate the in vivo tumor growth quantitatively and qualitatively but also can simulate the concentration of metabolic factors, oxygen, and acidity graphically. The results show the spatial heterogeneity effects on the proliferation of cancer cells and the rest of the system. By increasing Nmm , tumor shrinkage and significant increasing in the oxygen concentration and the pH value of the tumor microenvironment are observed. The results demonstrate the model’s ability, providing an essential tool for simulating different tumor evolution scenarios of a patient and reliable prediction of spatiotemporal progression of tumors for utilizing in personalized therapy.

HGG-04. ZINC ENHANCES TEMOZOLOMIDE CYTOTOXICITY IN PEDIATRIC GLIOBLASTOMA MULTIFORME MODEL SYSTEM

BACKGROUND Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients respond to it positively. We have shown that zinc metal reestablishes chemosensitivity in adult GBM in vitro and also in vivo but this effect has not been tested with pediatric GBM. METHODS Using Human pediatric glioblastoma cell lines- KNS42 (mutant p53/ MGMT [+]) and SF188 (mutant p53/ MGMT [-]), we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. RESULTS In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and a decrease in growth fraction as manifested by low ki67. Beta gal analysis showed that most of the remaining cells after the combination therapy are in senescence state. In order to eliminate the senescent population created as a result of the combined treatment of TMZ and Zinc, we decided to use a senolytic agent Navitoclax (ABT-263) that was demonstrated to be effective in reducing senescent cells by specific inhibition of Bcl-2, Bcl-XL and Bcl-w. Following the addition of Navitoclax to the combined treatment, SF188 cells, but not KNS42, show a significance reduction in viability compare to the combination treatment. CONCLUSIONS Our results suggest that zinc may serve as a potentiator of TMZ therapy in pediatric GBM patients and using a second hit with senolytic drug in some cases may be even more beneficial.

FGF2 modulates simultaneously the mode, the rate of division and the growth fraction in cultures of radial glia

ABSTRACTRadial glial progenitors in the mammalian developing neocortex have been shown to follow a deterministic differentiation program restricted to an asymmetric-only mode of division. This feature seems incompatible with their well-known ability to increase in number when cultured in vitro, driven by fibroblast growth factor 2 and other mitogenic signals. The changes in their differentiation dynamics that allow this transition from in vivo asymmetric-only division mode to an in vitro self-renewing culture have not been fully characterized. Here, we combine experiments of radial glia cultures with numerical models and a branching process theoretical formalism to show that fibroblast growth factor 2 has a triple effect by simultaneously increasing the growth fraction, promoting symmetric divisions and shortening the length of the cell cycle. These combined effects partner to establish and sustain a pool of rapidly proliferating radial glial progenitors in vitro. We also show that, in conditions of variable proliferation dynamics, the branching process tool outperforms other commonly used methods based on thymidine analogs, such as BrdU and EdU, in terms of accuracy and reliability.

Chaos and Pattern Formation in Spatial Phytoplankton Dynamics

In this paper the dynamics of spatially extended infected phytoplankton with the Holling type II functional response and logistically growing susceptible phytoplankton system is studied. The proposed model is an extension of temporal model available [6], in spatiotemporal domain. The reaction diffusion system exhibits spatiotemporal chaos in phytoplankton dynamics. This is particularly important for the spatially extended systems that are studied in this paper as they display a wide spectrum of ecologically relevant behavior, including chaos. In this system stability of the system is studied with respect to disease contact rate and the growth fraction of infected phytoplankton indirectly rejoin the susceptible phytoplankton population. The results of numerical experiments in one dimension and two dimensions in space as well as time series in temporal models are presented using MATLAB simulation. Moreover, the stability of the corresponding temporal model is studied analytically. Finally, the comparison of the three types of numerical experimentations are discussed in conclusion.

Prognostic value of Ki-67 and prediction in patients with hypertension and prostate cancer: A Real-World Study of Chinese Group for Prostate Cancer Party

Purpose Prostate cancer is the second most common malignancy with high mortality among males around the world, especially combine with hypertension. Ki-67 is one of the most reliable markers for growth fraction of neoplastic human cell populations. However, the prognostic value and prediction of Ki-67 in patients with hypertension and prostate cancer remain unclear. Materials and methods We launched a retrospective analysis of 296 patients with hypertension and prostate cancer from May 1, 2012, to Oct 1, 2015. The overall survival was evaluated using Cox regression models and Kaplan-Meier analysis. A nomogram was established. The accuracy of the model was assessed by calibration curve. Results Multivariate analysis showed that the Ki-67 (+) class was associated with an over 5-fold increase in the risk of death (HR 5.83, 95% CI 3.35-10.14, p<0.001) and a 2-fold increase in the risk of progression (HR 2.06, 95% CI 1.37-3.10, p<0.001). Multivariate Lasso regression showed that smoking, heart failure, ACS, Ki-67 expression, serum albumin, prognostic nutritional index, surgery, Gealson score, and stage were positively associated with prognosis in patients with prostate cancer. To quantify the contribution of each covariate to the prognosis, a nomogram of the Cox model was generated and displayed. The nomogram demonstrated excellent accuracy in estimating the risk of death, with a bootstrap-corrected C index of 0.829. There was also a suitable calibration curve for risk estimation.Conclusions Ki-67(+) predicts worsened outcomes of OM. A cross-validated multivariate score, including Ki-67(+), showed excellent concordance and efficacy of predicting prostate cancer.

FGF2 modulates simultaneously the mode, the rate of division and the growth fraction in cultures of Radial Glia

ABSTRACTRadial Glial progenitors in the mammalian developing neocortex have been shown to follow a deterministic differentiation program restricted to an asymmetric-only mode of division. This feature seems incompatible with their well known ability to expand in number when cultured in vitro, driven by Fibroblast Growth Factor 2 and other mitogenic signals. The changes in their differentiation dynamics that allow this transition from in vivo asymmetric-only division mode to an in vitro self-renewing culture have not been fully characterized. Here we combine experiments of Radial Glia cultures with theory and numerical models to show that Fibroblast Growth Factor 2 has a triple effect by simultaneously increasing the growth fraction, promoting symmetric divisions and shortening the length of the cell cycle. This combined effect of Fibroblast Growth Factor 2 in the differentiation dynamics of Radial Glial progenitors partner to establish and sustain a pool of rapidly proliferating in vitro pool of Radial Glial progenitors.

Ki-67 index as a predictor of vestibular schwannoma regrowth or recurrence

BackgroundKi-67 is a monoclonal antibody that provides a means of evaluating the growth fraction of normal and neoplastic human cell populations. A Ki-67 index of less than 3 per cent is expected for a typical schwannoma. Vestibular schwannomas with an index of greater than 3 per cent are presumed to be actively proliferating and pose a theoretically higher risk for regrowth or recurrence.MethodsA retrospective chart review was conducted. Ki-67 staining was performed and specimens were divided into two groups according to Ki-67 activity: less than 3 per cent (low index), and 3 per cent or greater (elevated index).ResultsEight patients (53.3 per cent) with elevated Ki-67 had recurrence or regrowth, versus five (8.5 per cent) in the low Ki-67 group. Among the 13 patients with recurrence or regrowth, the average Ki-67 value was 4.3 per cent. Among the 61 patients without recurrence or regrowth, the average Ki-67 value was 1.0 per cent.ConclusionThe Ki-67 labelling index reliably identifies vestibular schwannomas with an elevated potential for recurrence or regrowth in subtotal or total resection cases. In patients with a Ki-67 index greater than 3 per cent, more frequent clinical examination and radiological follow up are recommended.