Interactively illustrating polymerization using three-level model fusion

Background: Research in cell biology is steadily contributing new knowledge about many aspects of physiological processes, both with respect to the involved molecular structures as well as their related function. Illustrations of the spatio-temporal development of such processes are not only used in biomedical education, but also can serve scientists as an additional platform for in-silico experiments. Results: In this paper, we contribute a new, three-level modeling approach to illustrate physiological processes from the class of polymerization at different time scales. We integrate physical and empirical modeling, according to which approach best suits the different involved levels of detail, and we additionally enable a form of interactive steering, while the process is illustrated. We demonstrate the suitability of our approach in the context of several polymerization processes and report from a first evaluation with domain experts. Conclusion: We conclude that our approach provides a new, hybrid modeling approach for illustrating the process of emergence in physiology, embedded in a densely filled environment. Our approach of a complementary fusion of three systems combines the strong points from the different modeling approaches and is capable to bridge different spatial and temporal scales

Trends & Opportunities in Visualization for Physiology: A Multiscale Overview

Combining elements of biology, chemistry, physics, and medicine, the science of human physiology is complex and multifaceted. In this report, we offer a broad and multiscale perspective on key developments and challenges in visualization for physiology. Our literature search process combined standard methods with a state-of-the-art visual analysis search tool to identify surveys and representative individual approaches for physiology. Our resulting taxonomy sorts literature on two levels. The first level categorizes literature according to organizational complexity and ranges from molecule to organ. A second level identifies any of three high-level visualization tasks within a given work: exploration, analysis, and communication. The findings of this report may be used by visualization researchers to understand the overarching trends, challenges, and opportunities in visualization for physiology and to provide a foundation for discussion and future research directions in this area.publishedVersio

A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors

BackgroundThe PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.ProcedureWe performed a standard 3+3 phase I, open‐label, dose‐escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25–75 mg/m2/day) and temsirolimus (25–75 mg/m2 IV weekly) were investigated.ResultsTwenty‐three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high‐grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose‐limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single‐agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high‐grade glioma; no partial or complete responses were achieved.ConclusionsThe combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137302/1/pbc26409.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137302/2/pbc26409_am.pd

A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors

<div><p>The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4–18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m²/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high-grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.</p></div

Perifosine dose level 2 (~50 mg/m²/day).

<p>Perifosine dose level 2 (~50 mg/m²/day).</p

Patient characteristics and responses.

<p>Patient characteristics and responses.</p

Perifosine dose level 5 (~125 mg/m²/day).

<p>Perifosine dose level 5 (~125 mg/m²/day).</p