A computational analysis of the long-term regulation of arterial pressure

The asserted dominant role of the kidneys in the chronic regulation of blood pressure and in the etiology of hypertension has been debated since the 1970s. At the center of the theory is the observation that the acute relationships between arterial pressure and urine production—the acute pressure-diuresis and pressure-natriuresis curves—physiologically adapt to perturbations in pressure and/or changes in the rate of salt and volume intake. These adaptations, modulated by various interacting neurohumoral mechanisms, result in chronic relationships between water and salt excretion and pressure that are much steeper than the acute relationships. While the view that renal function is the dominant controller of arterial pressure has been supported by computer models of the cardiovascular system known as the “Guyton-Coleman model”, no unambiguous description of a computer model capturing chronic adaptation of acute renal function in blood pressure control has been presented. Here, such a model is developed with the goals of: 1. representing the relevant mechanisms in an identifiable mathematical model; 2. identifying model parameters using appropriate data; 3. validating model predictions in comparison to data; and 4. probing hypotheses regarding the long-term control of arterial pressure and the etiology of primary hypertension. The developed model reveals: long-term control of arterial blood pressure is primarily through the baroreflex arc and the renin-angiotensin system; and arterial stiffening provides a sufficient explanation for the etiology of primary hypertension associated with ageing. Furthermore, the model provides the first consistent explanation of the physiological response to chronic stimulation of the baroreflex

The genotype-phenotype relationship in multicellular pattern-generating models - the neglected role of pattern descriptors

Background: A deep understanding of what causes the phenotypic variation arising from biological patterning processes, cannot be claimed before we are able to recreate this variation by mathematical models capable of generating genotype-phenotype maps in a causally cohesive way. However, the concept of pattern in a multicellular context implies that what matters is not the state of every single cell, but certain emergent qualities of the total cell aggregate. Thus, in order to set up a genotype-phenotype map in such a spatiotemporal pattern setting one is actually forced to establish new pattern descriptors and derive their relations to parameters of the original model. A pattern descriptor is a variable that describes and quantifies a certain qualitative feature of the pattern, for example the degree to which certain macroscopic structures are present. There is today no general procedure for how to relate a set of patterns and their characteristic features to the functional relationships, parameter values and initial values of an original pattern-generating model. Here we present a new, generic approach for explorative analysis of complex patterning models which focuses on the essential pattern features and their relations to the model parameters. The approach is illustrated on an existing model for Delta-Notch lateral inhibition over a two-dimensional lattice. Results: By combining computer simulations according to a succession of statistical experimental designs, computer graphics, automatic image analysis, human sensory descriptive analysis and multivariate data modelling, we derive a pattern descriptor model of those macroscopic, emergent aspects of the patterns that we consider of interest. The pattern descriptor model relates the values of the new, dedicated pattern descriptors to the parameter values of the original model, for example by predicting the parameter values leading to particular patterns, and provides insights that would have been hard to obtain by traditional methods. Conclusion: The results suggest that our approach may qualify as a general procedure for how to discover and relate relevant features and characteristics of emergent patterns to the functional relationships, parameter values and initial values of an underlying pattern-generating mathematical model

Wearable technology and the cardiovascular system: the future of patient assessment

The past decade has seen a dramatic rise in consumer technologies able to monitor a variety of cardiovascular parameters. Such devices initially recorded markers of exercise, but now include physiological and health-care focused measurements. The public are keen to adopt these devices in the belief that they are useful to identify and monitor cardiovascular disease. Clinicians are therefore often presented with health app data accompanied by a diverse range of concerns and queries. Herein, we assess whether these devices are accurate, their outputs validated, and whether they are suitable for professionals to make management decisions. We review underpinning methods and technologies and explore the evidence supporting the use of these devices as diagnostic and monitoring tools in hypertension, arrhythmia, heart failure, coronary artery disease, pulmonary hypertension, and valvular heart disease. Used correctly, they might improve health care and support research

Understanding signaling cascades in melanoma

Understanding regulatory pathways involved in melanoma development and progression has advanced significantly in recent years. It is now appreciated that melanoma is the result of complex changes in multiple signaling pathways that affect growth control, metabolism, motility and the ability to escape cell death programs. Here we review the major signaling pathways currently known to be deregulated in melanoma with an implication to its development and progression. Among these pathways are Ras, B-Raf, MEK, PTEN, phosphatidylinositol-3 kinase (PI3Ks) and Akt which are constitutively activated in a significant number of melanoma tumors, in most cases due to genomic change. Other pathways discussed in this review include the [Janus kinase/signal transducer and activator of transcription (JAK/STAT), transforming growth factor-beta pathways which are also activated in melanoma, although the underlying mechanism is not yet clear. As a paradigm for remodeled signaling pathways, melanoma also offers a unique opportunity for targeted drug development.Fil: Lopez Bergami, Pablo Roberto. Sanford-burnham Medical Research Institute; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fitchmann, B. Sanford-burnham Medical Research Institute; Estados UnidosFil: Ronai, Ze´ev. Sanford-burnham Medical Research Institute; Estados Unido

An Accuracy Assessment of Absolute Gravimetric Observations in Fennoscandia

We compare a suite of absolute gravimeters used to monitor the temporal changes of gravity at a number of sites in Fennoscandia. Direct comparisons are made from simultaneous observations at selected sites within and outside of the postglacial uplift region. We also compare results at sites visited by two instruments with some separation in time. We conclude from four years of data that gravity differences are obtained within an rms error of ± 3 Gal. The data reveal no systematic biases between the instruments, but occasional shifts from one year to another are noted. We consider that annual instrument comparisons are required to ensure data integrity in a regional observing program that extends over more than a decade

A Theoretical Exploration of Birhythmicity in the p53-Mdm2 Network

Experimental observations performed in the p53-Mdm2 network, one of the key protein modules involved in the control of proliferation of abnormal cells in mammals, revealed the existence of two frequencies of oscillations of p53 and Mdm2 in irradiated cells depending on the irradiation dose. These observations raised the question of the existence of birhythmicity, i.e. the coexistence of two oscillatory regimes for the same external conditions, in the p53-Mdm2 network which would be at the origin of these two distinct frequencies. A theoretical answer has been recently suggested by Ouattara, Abou-Jaoudé and Kaufman who proposed a 3-dimensional differential model showing birhythmicity to reproduce the two frequencies experimentally observed. The aim of this work is to analyze the mechanisms at the origin of the birhythmic behavior through a theoretical analysis of this differential model. To do so, we reduced this model, in a first step, into a 3-dimensional piecewise linear differential model where the Hill functions have been approximated by step functions, and, in a second step, into a 2-dimensional piecewise linear differential model by setting one autonomous variable as a constant in each domain of the phase space. We find that two features related to the phase space structure of the system are at the origin of the birhythmic behavior: the existence of two embedded cycles in the transition graph of the reduced models; the presence of a bypass in the orbit of the large amplitude oscillatory regime of low frequency. Based on this analysis, an experimental strategy is proposed to test the existence of birhythmicity in the p53-Mdm2 network. From a methodological point of view, this approach greatly facilitates the computational analysis of complex oscillatory behavior and could represent a valuable tool to explore mathematical models of biological rhythms showing sufficiently steep nonlinearities

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma

B-RAF and N-RAS Mutations Are Preserved during Short Time In Vitro Propagation and Differentially Impact Prognosis

In melanoma, the RAS/RAF/MEK/ERK signalling pathway is an area of great interest, because it regulates tumor cell proliferation and survival. A varying mutation rate has been reported for B-RAF and N-RAS, which has been largely attributed to the differential source of tumor DNA analyzed, e.g., fixed tumor tissues or in vitro propagated melanoma cells. Notably, this variation also interfered with interpreting the impact of these mutations on the clinical course of the disease. Consequently, we investigated the mutational profile of B-RAF and N-RAS in biopsies and corresponding cell lines from metastatic tumor lesions of 109 melanoma patients (AJCC stage III/IV), and its respective impact on survival. 97 tissue biopsies and 105 biopsy-derived cell lines were screened for B-RAF and N-RAS mutations by PCR single strand conformation polymorphism and DNA sequencing. Mutations were correlated with patient survival data obtained within a median follow-up time of 31 months. B-RAF mutations were detected in 55% tissues and 51% cell lines, N-RAS mutations in 23% tissues and 25% cell lines, respectively. There was strong concordance between the mutational status of tissues and corresponding cell lines, showing a differing status for B-RAF in only 5% and N-RAS in only 6%, respectively. Patients with tumors carrying mutated B-RAF showed an impaired median survival (8.0 versus 11.8 months, p = 0.055, tissues; 7.1 versus 9.3 months, p = 0.068, cell lines), whereas patients with N-RAS-mutated tumors presented with a favorable prognosis (median survival 12.5 versus 7.9 months, p = 0.084, tissues; 15.4 versus 6.8 months, p = 0.0008, cell lines), each in comparison with wildtype gene status. Multivariate analysis qualified N-RAS (p = 0.006) but not B-RAF mutation status as an independent prognostic factor of overall survival. Our findings demonstrate that B-RAF and N-RAS mutations are well preserved during short term in vitro propagation and, most importantly, differentially impact the outcome of melanoma patients

Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

Background: VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings: Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion: Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab