526 research outputs found
PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer
PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for co-targeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future
Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased
survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a
variety of common efectors that can lead to the development of resistance to drug inhibitors. Most
current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase
PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the
PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein
expression, as well as their functional efcacy. We have determined that around 20% of prostate
cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a
high Gleason grade tumour (â„Gleason 8). A co-targeted inhibition approach ofered broader inhibition
of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition.
The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional
outcome compared with combined AZD-1208 +BEZ235, which have been investigated in clinical trials,
and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is
a viable therapeutic strategy that should be developed further in pre-clinical studies
The photon PDF from high-mass Drell Yan data at the LHC
Achieving the highest precision for theoretical predictions at the LHC requires the calculation of hard-scattering cross-sections that include perturbative QCD corrections up to (N)NNLO and electroweak (EW) corrections up to NLO. Parton distribution functions (PDFs) need to be provided with matching accuracy, which in the case of QED effects involves introducing the photon parton distribution of the proton, . In this work a determination of the photon PDF from fits to recent ATLAS measurements of high-mass Drell-Yan dilepton production at TeV is presented. This analysis is based on the xFitter framework, and has required improvements both in the APFEL program, to account for NLO QED effects, and in the aMCfast interface to account for the photon-initiated contributions in the EW calculations within MadGraph5_aMC@NLO. The results are compared with other recent QED fits and determinations of the photon PDF, consistent results are found
Search for astrophysical sources of neutrinos using cascade events in IceCube
The IceCube neutrino observatory has established the existence of a flux of
high-energy astrophysical neutrinos inconsistent with the expectation from
atmospheric backgrounds at a significance greater than . This flux has
been observed in analyses of both track events from muon neutrino interactions
and cascade events from interactions of all neutrino flavors. Searches for
astrophysical neutrino sources have focused on track events due to the
significantly better angular resolution of track reconstructions. To date, no
such sources have been confirmed. Here we present the first search for
astrophysical neutrino sources using cascades interacting in IceCube with
deposited energies as small as 1 TeV. No significant clustering was observed in
a selection of 263 cascades collected from May 2010 to May 2012. We show that
compared to the classic approach using tracks, this statistically-independent
search offers improved sensitivity to sources in the southern sky, especially
if the emission is spatially extended or follows a soft energy spectrum. This
enhancement is due to the low background from atmospheric neutrinos forming
cascade events and the additional veto of atmospheric neutrinos at declinations
.Comment: 14 pages, 9 figures, 1 tabl
Measurement of the multi-TeV neutrino cross section with IceCube using Earth absorption
Neutrinos interact only very weakly, so they are extremely penetrating.
However, the theoretical neutrino-nucleon interaction cross section rises with
energy such that, at energies above 40 TeV, neutrinos are expected to be
absorbed as they pass through the Earth. Experimentally, the cross section has
been measured only at the relatively low energies (below 400 GeV) available at
neutrino beams from accelerators \cite{Agashe:2014kda, Formaggio:2013kya}. Here
we report the first measurement of neutrino absorption in the Earth, using a
sample of 10,784 energetic upward-going neutrino-induced muons observed with
the IceCube Neutrino Observatory. The flux of high-energy neutrinos transiting
long paths through the Earth is attenuated compared to a reference sample that
follows shorter trajectories through the Earth. Using a fit to the
two-dimensional distribution of muon energy and zenith angle, we determine the
cross section for neutrino energies between 6.3 TeV and 980 TeV, more than an
order of magnitude higher in energy than previous measurements. The measured
cross section is (stat.) (syst.)
times the prediction of the Standard Model \cite{CooperSarkar:2011pa},
consistent with the expectation for charged and neutral current interactions.
We do not observe a dramatic increase in the cross section, expected in some
speculative models, including those invoking new compact dimensions
\cite{AlvarezMuniz:2002ga} or the production of leptoquarks
\cite{Romero:2009vu}.Comment: Preprint version of Nature paper 10.1038/nature2445
Search for astrophysical sources of neutrinos using cascade events in IceCube
The IceCube neutrino observatory has established the existence of a flux of
high-energy astrophysical neutrinos inconsistent with the expectation from
atmospheric backgrounds at a significance greater than . This flux has
been observed in analyses of both track events from muon neutrino interactions
and cascade events from interactions of all neutrino flavors. Searches for
astrophysical neutrino sources have focused on track events due to the
significantly better angular resolution of track reconstructions. To date, no
such sources have been confirmed. Here we present the first search for
astrophysical neutrino sources using cascades interacting in IceCube with
deposited energies as small as 1 TeV. No significant clustering was observed in
a selection of 263 cascades collected from May 2010 to May 2012. We show that
compared to the classic approach using tracks, this statistically-independent
search offers improved sensitivity to sources in the southern sky, especially
if the emission is spatially extended or follows a soft energy spectrum. This
enhancement is due to the low background from atmospheric neutrinos forming
cascade events and the additional veto of atmospheric neutrinos at declinations
.Comment: 14 pages, 9 figures, 1 tabl
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