Model for in vivo progression of tumors based on co-evolving cell population and vasculature

With countless biological details emerging from cancer experiments, there is a growing need for minimal mathematical models which simultaneously advance our understanding of single tumors and metastasis, provide patient-personalized predictions, whilst avoiding excessive hard-to-measure input parameters which complicate simulation, analysis and interpretation. Here we present a model built around a co-evolving resource network and cell population, yielding good agreement with primary tumors in a murine mammary cell line EMT6-HER2 model in BALB/c mice and with clinical metastasis data. Seeding data about the tumor and its vasculature from in vivo images, our model predicts corridors of future tumor growth behavior and intervention response. A scaling relation enables the estimation of a tumor's most likely evolution and pinpoints specific target sites to control growth. Our findings suggest that the clinically separate phenomena of individual tumor growth and metastasis can be viewed as mathematical copies of each other differentiated only by network structure

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined

The Combined Dexamethasone/CRH Test (DEX/CRH Test) and Prediction of Acute Treatment Response in Major Depression

In this study the predictive value of the combined dexamethasone/CRH test (DEX/CRH test) for acute antidepressant response was investigated. In 114 depressed inpatients suffering from unipolar or bipolar depression (sample 1) the DEX/CRH test was performed at admission and shortly before discharge. During their stay in the hospital patients received different antidepressant treatment regimens. At admission, the rate of nonsuppression (basal cortisol levels >75.3 nmol/l) was 24.6% and was not related to the later therapeutic response. Moreover, 45 out of 114 (39.5%) patients showed an enhancement of HPA axis function at discharge in spite of clinical improvement. In a second sample, 40 depressed patients were treated either with reboxetine or mirtazapine for 5 weeks. The DEX/CRH test was performed before, after 1 week, and after 5 weeks of pharmacotherapy. Attenuation of HPA axis activity after 1 week was associated with a more pronounced alleviation of depressive symptoms after 5-week mirtazapine treatment, whereas downregulation of HPA system activity after 5 weeks was related to clinical response to reboxetine. However, early improvement of HPA axis dysregulation was not necessarily followed by a beneficial treatment outcome. Taken together, performance of a single DEX/CRH test does not predict the therapeutic response. The best predictor for response seems to be an early attenuation of HPA axis activity within 1 or 2 weeks. However, early improvement of HPA system dysfunction is not a sufficient condition for a favourable response. Since a substantial part of depressive patients display a persistence of HPA axis hyperactivity at discharge, downregulation of HPA system function is not a necessary condition for acute clinical improvement either. Our data underline the importance of HPA axis dysregulation for treatment outcome in major depression, although restoration of HPA system dysfunction seems to be neither a necessary nor a sufficient determinant for acute treatment response

Nocturnal secretion of TSH and ACTH in male patients with depression and healthy controls

profound alterations of the hypothalamic-pituitary-thyroid (HPT) and the hypothalamic-pituitary-adrenal (HPA) systems at the hypophyseal level have been described in affective disorder. To precisely characterize the basal alterations of both axes during sleep. we simultaneously investigated sleep EEG and the secretion of thyrotropin. ACTH and cortisol in nine drug-free male patients with depression in comparison to 10 healthy age and sex matched controls. In depressed patients the nearly diametrical nocturnal secretion of thyrotropin and ACTH was disturbed by significantly blunted thyrotropin values (TSH AUC 51.96+/-5.68 vs. 87.23+/-13.63. P<0.05) and elevated ACTH values (ACTH AUC 1804+/-161 vs. 1538+/-130. P<0.05) compared to controls. Moreover, cross correlation analysis revealed a highly negative association of 0 lag between thyrotropin and ACTH and between thyrotropin and cortisol in the control sample, indicating a physiological nocturnal negative correlation of HPT and HPA system. In the patients sample these associations were weak and reached not statistical significance. Therefore, as a descriptive tool, the ratio TSH/ACTH revealed a significant group difference between controls and patients in the first half of the night (TSH/ACTH AUC 6.50+/-0.42 vs. 3.35+/-0.31. P<0.05). Sleep-EEG analysis showed a shortened REM latency, a decrease of stage 2 and an increase of awake time in the patients. Our data support the hypothesis that both hypophyseal hormones reflect a common dysregulation of both systems in depression probably due to impaired action of TRH-related corticotropin-release- inhibiting-factor (CRIF). The ratio TSH/ACTH might be a tool to characterize alterations of both the HPT and HPA axis in depression during the first half of the night, (C), 2002 Elsevier Science Ltd. All rights reserv

Central but Not Systemic Administration of Ghrelin Induces Wakefulness in Mice

Ghrelin is a brain-gut peptide hormone widely known for its orexigenic and growth hormone-releasing activities. Findings from our and other laboratories indicate a role of ghrelin in sleep regulation. The effects of exogenous ghrelin on sleep-wake activity in mice are, however, unknown. The aim of the present study was to determine the sleep-modulating effects of ghrelin after central and systemic administrations in mice. Sleep-wake activity after intracerebroventricular (icv) administration of 0.2, 1 and 5 µg ghrelin and intraperitoneal injections of 40, 100, and 400 µg/kg ghrelin prior to light onset were determined in C57BL/6 mice. In addition, body temperature, motor activity and 1-hour food intake was measured after the systemic injections. Sleep effects of systemic ghrelin (40 and 400 µg/kg) injected before dark onset were also determined. Icv injection of ghrelin increased wakefulness and suppressed non-rapid-eye-movement sleep and electroencephalographic slow-wave activity in the first hour after injections. Rapid-eye-movement sleep was decreased for 2–4 hours after each dose of ghrelin. Sytemic administration of ghrelin did not induce changes in sleep-wake activity in mice at dark or light onset. Motor activity and body temperature remained unaltered and food intake was significantly increased after systemic injections of ghrelin given prior the light period. These findings indicate that the activation of central, but not peripheral, ghrelin-sensitive mechanisms elicits arousal in mice. The results are consistent with the hypothesis that the activation of the hypothalamic neuronal circuit formed by ghrelin, orexin, and neuropeptide Y neurons triggers behavioral sequence characterized by increased wakefulness, motor activity and feeding in nocturnal rodents

The role of cell lysis and matrix deposition in tumor growth modeling

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