INT254816

Context Info Confidence 0.55 First Reported 2008 Last Reported 2010 Negated 0 Speculated 4 Reported most in Body Documents 20 Total Number 24 Disease Relevance 9.24 Pain Relevance 0.34

cell differentiation (Tgfbr1) signal transduction (Tgfbr1) cell motility (Tgfbr1) plasma membrane (Tgfbr1) embryo development (Tgfbr1) protein complex (Tgfbr1)

Anatomy Link Frequency Notch 2 endothelial cell 1 fibroblast 1 mesenchymal cells 1 Tgfbr1 (Mus musculus)

Pain Link Frequency Relevance Heat Osteoarthritis 91 94.08 Inflammation 36 73.44 fibrosis 21 71.32 agonist 6 61.32 anesthesia 12 50.04 metalloproteinase 16 5.00 cytokine 14 5.00 palliative 13 5.00 Immobilon 13 5.00 ketamine 6 5.00

Disease Link Frequency Relevance Heat Lung Cancer 2 99.64 Malignant Neoplastic Disease 2 99.38 Keloid Scars 54 98.96 Cancer 546 98.80 Death 84 97.88 Toxicity 11 97.88 Apoptosis 481 97.44 Glaucoma 18 97.44 Hematological Disease 7 97.32 Myelodysplastic Syndromes 1 95.08

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

Inhibition of ALK5 was achieved by adding the SB431542 compounds to the spheroids-containing gels at 10 µM final concentration.

Negative_regulation (Inhibition) of ALK5

1) Confidence 0.55 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0 Pain Relevance 0

Notch inhibition, alone or in combination with ALK5 inhibition, however did not rescue the proliferation defect.

Negative_regulation (inhibition) of ALK5 in Notch

2) Confidence 0.55 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.08 Pain Relevance 0

The inhibition of ALK5 was performed by adding SB431542 at 10 µM in the medium 1 day before the radiation and the inhibitor containing medium was refreshed every 2 days.

Negative_regulation (inhibition) of ALK5

3) Confidence 0.55 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.24 Pain Relevance 0

ALK5 inhibition prevents radiation-induced inhibition of angiogenesis in vivo

Negative_regulation (inhibition) of ALK5

4) Confidence 0.55 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.16 Pain Relevance 0

In our model ALK5 inhibition, however, did not rescue the proliferation defect.

Negative_regulation (inhibition) of ALK5

5) Confidence 0.55 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.06 Pain Relevance 0

To examine effects of ALK5 inhibition, 10 µM SB-431542 was added for 72 hr in DMEM containing 1% FBS.

Spec (examine) Negative_regulation (inhibition) of ALK5

6) Confidence 0.41 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2659748 Disease Relevance 0.18 Pain Relevance 0

type I receptor/activin receptor-like kinase-5 (ALK5) pathway and pharmacological ALK5 inhibition prevents radiation-induced suppression of endothelial cell migration and sprouting in vitro, and impairment of angiogenesis in vivo.

Negative_regulation (inhibition) of ALK5 in endothelial cell

7) Confidence 0.41 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.32 Pain Relevance 0.04

ALK5 inhibition, however, did not rescue deficient proliferation.

Negative_regulation (inhibition) of ALK5

8) Confidence 0.41 Published 2010 Journal PLoS ONE Section Abstract Doc Link PMC2884035 Disease Relevance 0.23 Pain Relevance 0

Inhibitors of ALK5 are in clinical development, including as anti-cancer agents [60] and results generated by these trials will be very informative on this matter.

Negative_regulation (Inhibitors) of ALK5 associated with cancer

9) Confidence 0.41 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.69 Pain Relevance 0

type I receptor/ALK5 signaling and that inhibition of ALK5 kinase activity rescues deficient migration and sprouting in vitro and angiogenesis in vivo.

Negative_regulation (inhibition) of ALK5

10) Confidence 0.41 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.30 Pain Relevance 0

Notch signaling, known to hinder angiogenesis, was activated by radiation but its inhibition, alone or in combination with ALK5 inhibition, did not rescue suppressed proliferation.

Negative_regulation (inhibition) of ALK5 in Notch

11) Confidence 0.41 Published 2010 Journal PLoS ONE Section Abstract Doc Link PMC2884035 Disease Relevance 0.21 Pain Relevance 0

Furthermore, ALK5 inhibition led to a significant decrease in the number of mesenchymal cells associated with ECs in the 3-dimensional model, suggesting that TGF-?

Negative_regulation (inhibition) of ALK5 in mesenchymal cells

12) Confidence 0.40 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2659748 Disease Relevance 0.53 Pain Relevance 0

In both coculture systems, inhibition of ALK5 led to a significant increase in endothelial, but not 10T1/2, cell death.

Negative_regulation (inhibition) of ALK5 associated with death

13) Confidence 0.40 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2659748 Disease Relevance 0.47 Pain Relevance 0

RI/ALK5 pathway and ALK5 inhibition prevents radiation-induced suppression of migration and sprouting

Negative_regulation (inhibition) of ALK5

14) Confidence 0.40 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.11 Pain Relevance 0

Inhibition of ALK5 signaling was performed by the i.p. administration of SB431542 compound (10 mg/kg/mouse) daily starting one day before irradiation until the end of the experiment.

Negative_regulation (Inhibition) of ALK5

15) Confidence 0.40 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0 Pain Relevance 0

To test whether ALK5 inhibition was sufficient to restore angiogenesis in vivo, we performed a VEGF-driven Matrigel angiogenesis assays in non-irradiated mice and in locally pre-irradiated mice treated systemically with either the ALK5 inhibitor SB431542 or vehicle only.

Spec (whether) Negative_regulation (inhibition) of ALK5

16) Confidence 0.40 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2884035 Disease Relevance 0.16 Pain Relevance 0

In old animals, showing a decrease in the ALK5/ALK1 ratio, the protective effect of TGF?

Negative_regulation (decrease) of ALK5

17) Confidence 0.21 Published 2010 Journal Arthritis Res Ther Section Body Doc Link PMC2875624 Disease Relevance 0.58 Pain Relevance 0.18

action (in TFS and via a specific ALK5 inhibitor) showed TGF-?

Negative_regulation (inhibitor) of ALK5

18) Confidence 0.20 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597201 Disease Relevance 1.20 Pain Relevance 0.07

action, using a specific ALK5 inhibitor (ALK5i), significantly diminished simvastatin-induced VSMC death (Figure 2a).

Negative_regulation (inhibitor) of ALK5i associated with death

19) Confidence 0.14 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597201 Disease Relevance 0.66 Pain Relevance 0

action, using a specific ALK5 inhibitor (ALK5i), significantly diminished simvastatin-induced VSMC death (Figure 2a).

Negative_regulation (inhibitor) of ALK5 associated with death

20) Confidence 0.14 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597201 Disease Relevance 0.66 Pain Relevance 0

General Comments

This test has worked.