第942回千葉医学会例会・第31回肺癌研究施設例会

Example of CellPD’s outputs. This folder contains two examples of the outputs generated by CellPD (using the data from Fig. 2 and Additional file 6). (ZIP 36462 kb

MultiCellDS: a community-developed standard for curating microenvironment-dependent multicellular data

Exchanging and understanding scientific data and their context represents a significant barrier to advancing research, especially with respect to information siloing. Maintaining information provenance and providing data curation and quality control help overcome common concerns and barriers to the effective sharing of scientific data. To address these problems in and the unique challenges of multicellular systems, we assembled a panel composed of investigators from several disciplines to create the MultiCellular Data Standard (MultiCellDS) with a use-case driven development process. The standard includes (1) digital cell lines, which are analogous to traditional biological cell lines, to record metadata, cellular microenvironment, and cellular phenotype variables of a biological cell line, (2) digital snapshots to consistently record simulation, experimental, and clinical data for multicellular systems, and (3) collections that can logically group digital cell lines and snapshots. We have created a MultiCellular DataBase (MultiCellDB) to store digital snapshots and the 200+ digital cell lines we have generated. MultiCellDS, by having a fixed standard, enables discoverability, extensibility, maintainability, searchability, and sustainability of data, creating biological applicability and clinical utility that permits us to identify upcoming challenges to uplift biology and strategies and therapies for improving human health

MultiCellDS: a standard and a community for sharing multicellular data

Cell biology is increasingly focused on cellular heterogeneity and multicellular systems. To make the fullest use of experimental, clinical, and computational efforts, we need standardized data formats, community-curated "public data libraries", and tools to combine and analyze shared data. To address these needs, our multidisciplinary community created MultiCellDS (MultiCellular Data Standard): an extensible standard, a library of digital cell lines and tissue snapshots, and support software. With the help of experimentalists, clinicians, modelers, and data and library scientists, we can grow this seed into a community-owned ecosystem of shared data and tools, to the benefit of basic science, engineering, and human health

17β-Estradiol Prevents Early-Stage Atherosclerosis in Estrogen Receptor-Alpha Deficient Female Mice

Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERα and ERβ. However, the role of the ERα in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERα-deficient (ERα−/−) and wild-type (ERα+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17β-estradiol (E2) from those of ERα on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 μg/day of exogenous 17β-estradiol (E2) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E2-deficient controls) were compared to mice with endogenous E2 (intact ovaries) and exogenous E2. Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p < 0.001) attenuated by E2 with 55–64% reduction in lesion area by endogenous E2 and >90% reduction by exogenous E2. Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E2. Lesion size, development, number, and distribution inversely correlated with circulating plasma E2 levels. However, atheroprotection was independent of ERα status, and E2 athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERα is not essential for endogenous/exogenous E2-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy

17β-Estradiol Prevents Early-Stage Atherosclerosis in Estrogen Receptor-Alpha Deficient Female Mice

Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERα and ERβ. However, the role of the ERα in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERα-deficient (ERα−/−) and wild-type (ERα+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17β-estradiol (E2) from those of ERα on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 μg/day of exogenous 17β-estradiol (E2) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E2-deficient controls) were compared to mice with endogenous E2 (intact ovaries) and exogenous E2. Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p &lt; 0.001) attenuated by E2 with 55–64% reduction in lesion area by endogenous E2 and &gt;90% reduction by exogenous E2. Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E2. Lesion size, development, number, and distribution inversely correlated with circulating plasma E2 levels. However, atheroprotection was independent of ERα status, and E2 athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERα is not essential for endogenous/exogenous E2-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy

Example depicting dose schedule definition for one cycle of treatment with <i>n</i> = 3 for all optimization classes.

<p>This schematic shows the process by which one cycle of treatment is defined for each optimization class with <i>n</i> = 3. A cycle in Class 1 or 3 contains a standard erlotinib dosing schedule of 150 mg/day, whereas a cycle in Class 2 contains a low-dose erlotinib schedule of 7 mg twice daily. When <i>n</i> = 3, each cycle has length <i>L</i> = 168 (one week). For Classes 1 and 2, the evofosfamide dose in each cycle is given 24 hours before the end of the week, and for Class 3 the evofosfamide dose in each cycle is given 6 hours before the end of the week. This is all depicted in step 1. Step 2 shows the removal of erlotinib doses required to satisfy the combination toxicity constraint. Each of these cycles is then repeated to form the entire dosing schedule.</p

Tumor evolutionary dynamics over time, given a variety of single-agent and combination therapies.

<p>Mean tumor size (A) and probability of resistance (B) are calculated up to recurrence time for a tumor with an initial population of 1.6 ⋅ 10⁶ sensitive cells undergoing treatment with each of the ten dosing schedules defined in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005077#pcbi.1005077.t003" target="_blank">Table 3</a>. Each labeled curve corresponds to the dosing schedule with the matching letter in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005077#pcbi.1005077.t003" target="_blank">Table 3</a>. For the sake of comparison, results due to dosing schedules using erlotinib alone are shown in red, results due to dosing schedules using evofosfamide alone are shown in blue, and results due to combination therapies are shown in green. Mean tumor size for one of each of these three types of dosing schedules is broken down into the means of sensitive and resistant cells in (C). (D) shows the expected tumor size for combination strategies, conditioned upon the event of developing resistance.</p

Tumor microenvironment modeling process.

<p>This schematic shows the process used to model the tumor microenvironment as a set of discrete compartments. A series of compartments is defined based on various distances from the nearest blood vessel, and the oxygen concentration in each compartment is calculated accordingly. The relative weights of the compartments are determined based on experimental observations of oxygen partial pressure distribution in solid tumors.</p