Converis & VIVO in a Biomedical Research Institute: the Fred Hutchinson Cancer Research Center Experience

Description of the Arnold Library at the Fred Hutchinson Cancer Research Center project to develop a research information / profiles system using Converis and VIVO

Animal data

Animal dat

Human data

This is the human data of our study

Dexpramipexole Is Ineffective in Two Models of ALS Related Neurodegeneration

<div><p>Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy screening in high-copy B6-SJL-SOD1^G93A/Gur1 mice, and 2) high-content neuronal survival screening in primary rat cortical neurons transfected with wild-type human TDP43 or mutant human TDP43. In both cases, we exposed the test systems to RPPX levels approximating those achieved in human Phase II clinical investigations. In SOD1^G93A mice, no effect was observed on neuromotor disease progression or survival. In primary cortical neurons transfected with either mutant or wild-type human TDP43, a marginally significant improvement in a single indicator of neuronal survival was observed, and only at the 10 µM RPPX treatment. These systems reflect both mutant SOD1- and TDP43-mediated forms of neurodegeneration. The systems also reflect both complex non-cell autonomous and neuronal cell autonomous disease mechanisms. The results of these experiments, taken in context with results produced by other molecules tested in both screening systems, do not argue positively for further study of RPPX in ALS.</p></div

CRP impairs autophagy <i>in vivo</i>.

<p>(A) LC3 II/I and p62 levels in <i>PLC3</i> mice and <i>LC3</i> mice prior and post-IRI by immunoblotting. (B) GFP-LC3 punctae in <i>PLC3</i> mice and <i>LC3</i> mice prior and post-IRI by immunohistochemistry. (C) RFP-LC3 and GFP-LC3 punctae in <i>RG-LC3</i> mice and <i>PRG-LC3</i> mice prior and post-IRI by immunohistochemistry. (D) Representative TEM for autophagosomes and autolysosomes in the kidneys. Data are expressed as means ± SD of at least 4 mice from each group and statistical significance was assessed by one-way ANOVA followed by Newman-Keuls test. *: P<0.05, **: P<0.01, ***: P<0.0001 between two groups. A: autophagy; AL: autolysosome; and L: Lysosome.</p

Kaplan-Meier survival plot for age at death in SOD1^G93A mice.

<p>Left panel shows data from all animals (All); middle and right panels show data from females (F) and males (M), respectively. Vehicle control (CTRL) animals received 0.22 micron filtered animal facility drinking water. Dexpramipexole-treated (DRUG) animals received daily 200 mg/kg/day dexpramipexole (1.19 g/L) in filtered drinking water. Results of statistical analysis for these data are given in the lower portion of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091608#pone-0091608-t004" target="_blank">Table 4</a>.</p

CRP exacerbates acute kidney injury <i>in vivo</i>.

<p>(A) SCr and BUN of <i>PLC3</i> mice and <i>LC3</i> mice prior to and post-IRI. (B) Representative PAS stain of kidney sections at Day 1 and Day 2 after IRI. Tissue damage was scored by the percentage of damaged tubule. (C) NGAL protein levels in the kidney lysates of <i>PLC3</i> mice and <i>LC3</i> mice prior and post-IRI. Data are expressed as means ± SD of at least 4 mice from each group and statistical significance was assessed by one-way ANOVA followed by Newman-Keuls test. *: P<0.05, **: P<0.01, ***: P<0.0001 between two groups.</p

Cortical Neuron Survival Data, TDP43^A315T-EGFP with RPPX Treatment.

<p>Cortical Neuron Survival Data, TDP43^A315T-EGFP with RPPX Treatment.</p

Time-to-Event Analysis for Onset of Neurological Symptoms and for Survival Duration.^1–3

<p>Testing Terms: In Kaplan-Meier analysis the Log-Rank test places more weight on later event times; the Wilcoxon test places more weight on early event times and is the optimum rank test if the error distribution is logistic. Prob > ChiSq lists the probability of obtaining, by chance alone, a Chi-square value greater than the one computed if the time-to-event functions are the same for all groups. In Cox proportional hazards analysis the Effect Likelihood Test is the likelihood-ratio Chi-square test on the null hypothesis that the parameter estimate for the Treatment covariate is zero (no effect of treatment). Testing term descriptions are taken from the JMP 10.0.0 Help file. A neurological score of two in both hind limbs is taken to be the definitive onset of neurological symptoms. Animals that did not reach a neurological severity score of 2 prior to termination of the experiment at 180 days of age were right-censored in the onset analysis. Animals that did not die by 180 days of age were right-censored in the survival analysis.</p><p>Time-to-Event Analysis for Onset of Neurological Symptoms and for Survival Duration.^1–3</p

Autophagy modulators alter autophagic flux and severity of kidney injury in IRI model.

<p>(A) Rapamycin reduces SCr in <i>PLC3</i> mice post-IRI. (B) Representative PAS stain of kidney sections of <i>PLC3</i> mice with Baf A1 or rapamycin (rapa) or vehicle (Veh) injection at first day post IRI. Tubular damage was scored by the percentage of damaged tubule. (C) Rapamycin injection rescues autophagy flux and reduces NGAL expression in <i>PLC3</i> mice post-IRI. Data expressed as means ± SD of 4 mice from each group and statistical significance was assessed by one-way ANOVA followed by Newman-Keuls test. *: P<0.05, **: P<0.01 between two groups for A ~ C. Rapamycin treatment for 24 hours rescues autophagy flux and CRP/H₂O₂-induced cytotoxicity <i>ex vivo</i> (D) or <i>in vitro</i> (E). Data are expressed as means ± SD of at least 3 independent experiments for each group and statistical significance was assessed by one-way ANOVA followed by Newman-Keuls test for D and E. *: P<0.05, **: P<0.01 vs. CRP group; ^#: P<0.05, ^##: P<0.01, ^###: P<0.0001 vs. CRP + H₂O₂ group; ^$: P<0.05, ^$ $: P<0.05 vs. CRP + rapamycin group; ^θ: P<0.05, ^θθ: P<0.01 vs. CRP + rapamycin + H₂O₂ group.</p