Kinase inhibitors have limited success in cancer treatment because tumors circumvent their action. Using a quantitative proteomics approach, we assessed kinome activity in response to MEK inhibition ...in triple-negative breast cancer (TNBC) cells and genetically engineered mice (GEMMs). MEK inhibition caused acute ERK activity loss, resulting in rapid c-Myc degradation that induced expression and activation of several receptor tyrosine kinases (RTKs). RNAi knockdown of ERK or c-Myc mimicked RTK induction by MEK inhibitors, and prevention of proteasomal c-Myc degradation blocked kinome reprogramming. MEK inhibitor-induced RTK stimulation overcame MEK2 inhibition, but not MEK1 inhibition, reactivating ERK and producing drug resistance. The C3Tag GEMM for TNBC similarly induced RTKs in response to MEK inhibition. The inhibitor-induced RTK profile suggested a kinase inhibitor combination therapy that produced GEMM tumor apoptosis and regression where single agents were ineffective. This approach defines mechanisms of drug resistance, allowing rational design of combination therapies for cancer.
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► Inhibition of the MEK-ERK pathway rapidly reprograms kinome activity in tumors ► c-Myc degradation induces expression and activation of receptor tyrosine kinases ► Receptor tyrosine kinase activation overcomes MEK inhibition, causing resistance ► Kinome inhibitor response profiling rationally predicts combination therapies
Chemical proteomics reveals the dynamic rewiring of kinase networks in response to treatment with MEK inhibitors, uncovering how resistance to these inhibitors emerges in tumors and highlighting combination therapy approaches for bypassing drug resistance.
The Laser Interferometer Gravitational Wave Observatory (LIGO) has been directly detecting gravitational waves from compact binary mergers since 2015. We report on the first use of squeezed vacuum ...states in the direct measurement of gravitational waves with the Advanced LIGO H1 and L1 detectors. This achievement is the culmination of decades of research to implement squeezed states in gravitational-wave detectors. During the ongoing O3 observation run, squeezed states are improving the sensitivity of the LIGO interferometers to signals above 50 Hz by up to 3 dB, thereby increasing the expected detection rate by 40% (H1) and 50% (L1).
For the majority of patients with pancreas cancer, the high metastatic proclivity is life limiting. Some patients, however, present with and succumb to locally destructive disease. A molecular ...understanding of these distinct disease manifestations can critically inform patient management. Using genetically engineered mouse models, we show that heterozygous mutation of Dpc4/Smad4 attenuates the metastatic potential of KrasG12D/+;Trp53R172H/+ pancreatic ductal adenocarcinomas while increasing their proliferation. Subsequent loss of heterozygosity of Dpc4 restores metastatic competency while further unleashing proliferation, creating a highly lethal combination. Expression levels of Runx3 respond to and combine with Dpc4 status to coordinately regulate the balance between cancer cell division and dissemination. Thus, Runx3 serves as both a tumor suppressor and promoter in slowing proliferation while orchestrating a metastatic program to stimulate cell migration, invasion, and secretion of proteins that favor distant colonization. These findings suggest a model to anticipate likely disease behaviors in patients and tailor treatment strategies accordingly.
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•DPC4 dosage regulates RUNX3 levels in a biphasic manner•RUNX3 controls the balance between local growth and dissemination in PDA•RUNX3 functions as both tumor suppressor and tumor promoter in PDA•DPC4 and RUNX3 levels can jointly inform clinical decision making
RUNX3 regulates the balance between proliferation and dissemination of pancreas cancer cells in response to gene dosage of DPC4/SMAD4. Evaluating the levels of DPC4 and RUNX3 can help predict patterns of relapse and response to therapies in patients, informing clinical disease management.
The measurement of minuscule forces and displacements with ever greater precision is inhibited by the Heisenberg uncertainty principle, which imposes a limit to the precision with which the position ...of an object can be measured continuously, known as the standard quantum limit
. When light is used as the probe, the standard quantum limit arises from the balance between the uncertainties of the photon radiation pressure applied to the object and of the photon number in the photoelectric detection. The only way to surpass the standard quantum limit is by introducing correlations between the position/momentum uncertainty of the object and the photon number/phase uncertainty of the light that it reflects
. Here we confirm experimentally the theoretical prediction
that this type of quantum correlation is naturally produced in the Laser Interferometer Gravitational-wave Observatory (LIGO). We characterize and compare noise spectra taken without squeezing and with squeezed vacuum states injected at varying quadrature angles. After subtracting classical noise, our measurements show that the quantum mechanical uncertainties in the phases of the 200-kilowatt laser beams and in the positions of the 40-kilogram mirrors of the Advanced LIGO detectors yield a joint quantum uncertainty that is a factor of 1.4 (3 decibels) below the standard quantum limit. We anticipate that the use of quantum correlations will improve not only the observation of gravitational waves, but also more broadly future quantum noise-limited measurements.
The first detection of gravitational waves by the Laser Interferometer Gravitational-Wave Observatory (LIGO) in 2015 launched the era of gravitational-wave astronomy. The quest for gravitational-wave ...signals from objects that are fainter or farther away impels technological advances to realize ever more sensitive detectors. Since 2019, one advanced technique, the injection of squeezed states of light, is being used to improve the shot-noise limit to the sensitivity of the Advanced LIGO detectors, at frequencies above ∼50 Hz. Below this frequency, quantum backaction, in the form of radiation pressure induced motion of the mirrors, degrades the sensitivity. To simultaneously reduce shot noise at high frequencies and quantum radiation pressure noise at low frequencies requires a quantum noise filter cavity with low optical losses to rotate the squeezed quadrature as a function of frequency. We report on the observation of frequency-dependent squeezed quadrature rotation with rotation frequency of 30 Hz, using a 16-m-long filter cavity. A novel control scheme is developed for this frequency-dependent squeezed vacuum source, and the results presented here demonstrate that a low-loss filter cavity can achieve the squeezed quadrature rotation necessary for the next planned upgrade to Advanced LIGO, known as "A+."
The dynamic nature of the kinome Graves, Lee M; Duncan, James S; Whittle, Martin C ...
Biochemical journal,
02/2013, Letnik:
450, Številka:
1
Journal Article
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Odprti dostop
Recent advances in proteomics have facilitated the analysis of the kinome 'en masse'. What these studies have revealed is a surprisingly dynamic network of kinase responses to highly selective kinase ...inhibitors, thereby illustrating the complex biological responses to these small molecules. Moreover these studies have identified key transcription factors, such as c-Myc and FOXO (forkhead box O), that play pivotal roles in kinome reprogramming in cancer cells. Since many kinase inhibitors fail despite a high efficacy of blocking their intended targets, elucidating kinome changes at a more global level will be essential to understanding the mechanisms of kinase inhibitor pharmacology. The development of technologies to study the kinome, as well as examples of kinome resilience and reprogramming, will be discussed in the present review.
Noise due to scattered light has been a frequent disturbance in the advanced LIGO gravitational wave detectors, hindering the detection of gravitational waves. The non stationary scatter noise caused ...by low frequency motion can be recognized as arches in the time-frequency plane of the gravitational wave channel. In this paper, we characterize the scattering noise for LIGO and Virgo's third observing run O3 from April, 2019 to March, 2020. We find at least two different populations of scattering noise and we investigate the multiple origins of one of them as well as its mitigation. We find that relative motion between two specific surfaces is strongly correlated with the presence of scattered light and we implement a technique to reduce this motion. We also present an algorithm using a witness channel to identify the times this noise can be present in the detector.
A comprehensive photophysical investigation has been carried out on a series of eight complexes of the type (diimine)Pt(−C⋮C−Ar)2, where diimine is a series of 2,2‘-bipyridine (bpy) ligands and ...−C⋮C−Ar is a series of substituted aryl acetylide ligands. In one series of complexes, the energy of the Pt → bpy metal-to-ligand charge transfer (MLCT) excited state is varied by changing the substituents on the 4,4‘- and/or the 5,5‘-positions of the bpy ligand. In a second series of complexes the electronic demand of the aryl acetylide ligand is varied by changing the para substituent (X) on the aryl ring (X = −CF3, −CH3, −OCH3, and −N(CH3)2). The effect of variation of the substituents on the excited states of the complexes has been assessed by examining their UV−visible absorption, variable-temperature photoluminescence, transient absorption, and time-resolved infrared spectroscopy. In addition, the nonradiative decay rates of the series of complexes are subjected to a quantitative energy gap law analysis. The results of this study reveal that in most cases the photophysics of the complexes is dominated by the energetically low lying Pt → bpy 3MLCT state. Some of the complexes also feature a low-lying intraligand (IL) 3π,π* excited state that is derived from transitions between π- and π*-type orbitals localized largely on the aryl acetylide ligands. The involvement of the IL 3π,π* state in the photophysics of some of the complexes is signaled by unusual features in the transient absorption, time-resolved infrared, and photoluminescence spectra and in the excited-state decay kinetics. The time-resolved infrared difference spectroscopy indicates that Pt → bpy MLCT excitation induces a +25 to + 35 cm-1 shift in the frequency of the C⋮C stretching band. This is the first study to report the effect of MLCT excitation on the vibrational frequency of an acetylide ligand.
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