Funky But Nonetheless , Motivational Quotes On DHFR inhibitor

ten.1038/protex.2011.218(2011).
alongwithreducedCCL2secretion(Fig.4b),whereasPTENknock-
down selleck chemicals llc increased p65 nuclear translocation, an indicator of NF-kB
activation,andCCL2expression(Fig.4d,e),partlythroughAktactiva-
tion(ExtendedDataFig.7c).Moreover,CCL2mRNAandCCL2 14. Zhu,H.,Han,C.,Lu,D.&Wu,T.miR-17�C92clusterpromotescholangiocarcinoma
growth:evidenceforPTENasdownstreamtargetandIL-6/Stat3asupstream
activator.Am.J.Pathol.184,2828�C2839(2014).
15. Liu,S.-Q.,Jiang,S.,Li,C.,Zhang,B.&Li,Q.-J.miR-17�C92clustertargets
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17. Olive,V.,Jiang,I.&He,L.

mir-17-92,aclusterofmiRNAsinthemidstofthecancer
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proteinexpressioninbrain-seekingtumourcellswasinhibitedbythe
NF-kBinhibitorpyrrolidinedithiocarbamate(PDTC)(ExtendedData
Fig.7d�Cf),indicatingthatNF-kBactivationiscrucialforPTEN-loss-
inducedCCL2upregulation.
24
CCL2isachemo-attractantduringinflammation Aurora Kinase .CCL2receptor
(CCR2)-expressing brain-derived IBA1-positive (IBA11 ) primary
myeloid cells and BV2 microglial cells (Extended Data Fig. 8a, b)
migrate towards CCL2, which was blocked by CCR2 antagonists
25
18. Ventura,A.etal.Targeteddeletionrevealsessentialandoverlappingfunctionsof
themiR-17through92familyofmiRNAclusters.Cell132,875�C886(2008).
19. Mittelbrunn,M.etal.UnidirectionaltransferofmicroRNA-loadedexosomesfromT
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(ExtendedDataFig.8c,d).Functionally,co-culturingwithBV2cells
enhancedproliferationandinhibitedapoptosisofbreastcancercells
(Fig.4f,g).Invivo,CCL2-knockdownbrainmetastaseshaddecreased different 20. Suetsugu,A.etal.Imagingexosometransferfrombreastcancercellstostromaat
IBA11/CCR21 myeloid cellinfiltration (Fig.4h),corresponding to
their reduced proliferation and elevated apoptosis (Fig. 4i, j).
Additionally, IHC staining of human primary breast tumours and
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matched brain metastases for PTEN and CCL2 (Figs 1b and 4k, 22. Kesimer,M.

etal.Characterizationofexosome-likevesiclesreleasedfromhuman
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23. Peinado,H.etal.Melanomaexosomeseducatebonemarrowprogenitorcells
ion in brain metastases than in primary tumours (Extended Data
Fig. 9a). Importantly, severe PTEN loss in brain metastases corre-
sponded to higher CCL2 expression (Extended Data Fig. 9b),
whichsignificantlycorrelatedwithIBA11 myeloidcellrecruitment
(Extended Data Fig. 9c), validating that PTEN downregulation in
brainmetastatictumourcellscontributestoCCL2upregulationand
IBA11myeloidcellrecruitmentinclinicalbrainmetastases.
Ta