Colorectal cancer (CRC), the second leading cause of cancer-related deaths in the US, has been treated with targeted therapies. However, the mechanisms of differential responses and resistance of ...CRCs to targeted therapies are not well understood. In this study, we found that genetic alterations of FBW7, an E3 ubiquitin ligase and a tumor suppressor frequently mutated in CRCs, contribute to resistance to targeted therapies. CRC cells containing FBW7-inactivating mutations are insensitive to clinically used multi-kinase inhibitors of RAS/RAF/MEK/ERK signaling, including regorafenib and sorafenib. In contrast, sensitivity to these agents is not affected by oncogenic mutations in KRAS, BRAF, PIK3CA or p53. These cells are defective in apoptosis owing to blocked degradation of Mcl-1, a pro-survival Bcl-2 family protein. Deleting FBW7 in FBW7-wild-type CRC cells abolishes Mcl-1 degradation and recapitulates the in vitro and in vivo drug-resistance phenotypes of FBW7-mutant cells. CRC cells selected for regorafenib resistance have progressive enrichment of pre-existing FBW7 hotspot mutations, and are cross-resistant to other targeted drugs that induce Mcl-1 degradation. Furthermore, a selective Mcl-1 inhibitor restores regorafenib sensitivity in CRC cells with intrinsic or acquired resistance. Together, our results demonstrate FBW7 mutational status as a key genetic determinant of CRC response to targeted therapies, and Mcl-1 as an attractive therapeutic target.
Abstract
Engineering multiphoton resources is of importance in quantum metrology, quantum lithography, and biological sensing. Here we propose a concept of dynamical emission of
N
strongly-correlated ...photons. This is realized in a circuit quantum electrodynamical system driven by two Gaussian-pulse sequences. The underlying physical mechanism relies on the stimulated Raman adiabatic passage that allows efficient and selective preparation of target multiphoton states. Assisted by the photon decay, a highly pure
N
-photon bundle emission takes place in this system. In particular, the dynamical
N
-photon bundle emission can be tuned by controlling the time interval between consecutive pulses so that the device behaves as an
N
-photon gun, which can be triggered on demand. Our work opens up a route to achieve multiphoton source devices, which have wide potential applications in quantum information processing and quantum metrology.
The interaction between an incident shock wave and a wavy end-wall in a three-dimensional geometry is numerically simulated by using a high-order finite-difference solver with a ghost-cell immersed ...boundary method. The aim is to discover the differences of the unsteady propagation characteristics of triple bifurcation points and transverse waves at different incident shock Mach numbers (
M
1
)
and wavy wall amplitudes (
A
ww
). For a benchmark case with
M
1
=
1.5
and
A
ww
=
1
mm, the simulated results are in a good agreement with other studies, indicating the reliability of the current simulation technique. The numerical results at
M
1
=
1.5
, 1.9, 2.5, and 3.5 show that the Mach numbers of the transverse shock waves issued from the triple bifurcation points decrease with time according to a power function. It indicates that the deformation of the shock wave attenuates with time and its flat shape is gradually recovered. The stronger the incident shock wave is, the faster the deformation decays. In the central region, a petal-like vortex structure is observed near the wavy wall and its advancing speed with periodic fluctuation correlates with the cycle of the transverse motion of the triple bifurcation point. With the increase of
M
1
, the petal-like vortex gradually grows up in size, and a faster rate can be observed in the normal direction. By comparing the propagation characteristics of transverse waves at different wavy wall amplitudes, it is discovered that the cellular pattern becomes more diverse as the wall amplitude increases. This is due to the multiple collisions of the transverse waves on the wavy wall, which leads to the multi-modal waves system in the shocked gas.
In this paper, the issue of malicious URL detection is investigated. Firstly a P system is proposed. Then the new P system is introduced to design the optimization algorithm of BP neural network to ...achieve the malicious URL detection with better performance. In the end some examples are included and corresponding experimental results display the advantage and effectiveness of the optimization algorithm proposed.
The morphologies and orientation relationships of Cu6Sn5 grains formed between Sn and (0 0 1), (0 1 1), (1 1 1) and (1 23) Cu single crystals under liquid- and solid-state aging conditions were ...systematically investigated. The regular prism-type Cu6Sn5 grains formed on (0 0 1) and (1 1 1) Cu single crystals are elongated either along two perpendicular directions or along three preferential directions with an angle of 60 deg between each pair of directions. The orientation relationships between Cu and Cu6Sn5 lattice structures were determined by electron backscatter diffraction and were explained in terms of their minimum misfit. However, on (0 1 1) and (1 2 3) Cu single crystal surfaces, the Cu6Sn5 grains were mainly scallop-type, with only a few regular prism-type grains. Furthermore, the regular prism-type Cu6Sn5 grains will change into scallop-type after long reflow or aging times. Meanwhile it is considered that the growth of the scallop-type grains is supplied by two fluxes: the flux of the interfacial reaction and the flux of ripening. However, the growth of the prism-type grains is only supplied by the flux of the interfacial reaction. The kinetics of IMCs growth between Sn and Cu single crystals was also investigated.
Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation ...associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492,900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.
Recent evidence indicates that long noncoding RNAs (lncRNAs) have a critical role in the regulation of cellular processes such as differentiation, proliferation, and metastasis. These lncRNAs are ...dysregulated in a variety of cancers and many function as tumor suppressors; however, the regulatory factors involved in silencing lncRNA transcription are poorly understood. In this study, we showed that epigenetic silencing of lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) occurs in non-small-cell lung cancer (NSCLC) cells through direct transcriptional repression mediated by the Polycomb group protein enhancer of zeste homolog 2 (EZH2). SPRY4-IT1 is derived from an intron within SPRY4, and is upregulated in melanoma cells; knockdown of its expression leads to cell growth arrest, invasion inhibition, and elevated rates of apoptosis. Upon depletion of EZH2 by RNA interference, SPRY4-IT1 expression was restored, and transfection of SPRY4-IT1 into NSCLC cells resulted in a significant antitumoral effect, both in culture and in xenografted nude mice. Moreover, overexpression of SPRY4-IT1 was found to have a key role in the epithelial-mesenchymal transition through the regulation of E-cadherin and vimentin expression. In EZH2-knockdown cells, which characteristically showed impaired cell proliferation and metastasis, the induction of SPRY4-IT1 depletion partially rescued the oncogenic phenotype, suggesting that SPRY4-IT1 repression has an important role in EZH2 oncogenesis. Of most relevance, translation of these findings into human NSCLC tissue samples demonstrated that patients with low levels of SPRY4-IT1 expression had a shorter overall survival time, suggesting that SPRY4-IT1 could be a biomarker for poor prognosis of NSCLC.
Low back pain (LBP) is an extremely common disorder and is a major cause of disability globally. Intervertebral disc degeneration (IVDD) is the main contributor to LBP. Nevertheless, the specific ...mechanisms underlying the pathogenesis of IVDD remain unclear. Mitochondria are highly dynamic organelles that continuously undergo fusion and fission, known as mitochondrial dynamics. Accumulating evidence has revealed that aberrantly activated mitochondrial fission leads to mitochondrial fragmentation and dysfunction, which are involved in the development and progression of IVDD. To date, research into mitochondrial dynamics in IVDD is at an early stage. The present narrative review aims to summarize the most recent findings about the role of mitochondrial fission in the pathogenesis of IVDD.
Background
Controversy remains regarding whether closed-loop (CL) insulin delivery or insulin sensor-augmented pump (SAP) delivery is more efficient for clinical treatment. Therefore, we aimed to ...compare the efficacy and safety of CL insulin delivery systems versus insulin SAP delivery for adults with type 1 diabetes (T1D).
Methods
Embase, Ovid MEDLINE, PubMed, ScienceDirect, Scopus, the Cochrane Library, and other databases were searched for related articles, and we analyzed the average blood glucose (BG), time in range (TIR), and adverse effects (AEs) as primary endpoints to evaluate efficacy and safety.
Results
Of 1616 articles, 12 randomized-controlled trials (RCTs) were included in the final analysis. Regarding BG control efficacy, CL insulin delivery resulted better outcomes than SAP therapy with regard to the average BG value, which was detected and recorded by continuous glucose monitoring (mean difference MDmmol/L: − 0.25 95% confidence interval CI − 0.42 to − 0.08,
p
= 0.003); TIR 3.9–10 mmol/L (MD %: 7.91 95% CI 4.45–11.37,
p
< 0.00001). Similar results were observed for the secondary outcomes including low blood glucose index (LBGI) (MD: − 0.41 95% CI − 0.55 to − 0.26,
p
< 0.00001), high blood glucose index (HBGI) (MD: − 2.56 95% CI − 3.38 to − 1.74,
p
< 0.00001), and standard deviation (SD) of glucose variability (MD mmol/L: -0.25 95% CI − 0.44 to − 0.06,
p
= 0.01). Furthermore, SAP therapy was associated with more adverse effects (risk ratio: 0.20 95% CI 0.07–0.52,
p
= 0.001) than CL insulin delivery, and one of the most common adverse effects was hypoglycemia.
Conclusions
CL insulin delivery appears to be a better treatment method than SAP therapy for adults with T1D because of its increased BG control efficacy and decreased number of hypoglycemic events.
Context.
Galaxy clusters in the local universe descend from high-redshift overdense regions known as protoclusters. The large gas reservoirs and high rate of galaxy interaction in protoclusters are ...expected to enhance star-formation activity and trigger luminous supermassive black-hole accretion in the nuclear regions of the host galaxies.
Aims.
We investigated the active galactic nucleus (AGN) content of a gas-rich and starbursting protocluster at
z
= 4.002, known as the Distant Red Core (DRC). In particular, we search for luminous and possibly obscured AGN in 13 identified members of the structure, and compare the results with protoclusters at lower redshifts. We also test whether a hidden AGN can power the Ly
α
blob (LAB) detected with VLT/MUSE in the DRC.
Methods.
We observed all of the identified members of the structure with 139 ks of
Chandra
ACIS-S imaging. Being less affected by absorption than optical and IR bands, even in the presence of large column densities of obscuring material, X-ray observations are the best tools to detect ongoing nuclear activity in the DRC galaxies.
Results.
We detect obscured X-ray emission from the two most gas-rich members of the DRC, named DRC-1 and DRC-2. Both of them are resolved into multiple interacting clumps in high-resolution Atacama Large Millimeter Array and
Hubble
Space Telescope observations. In particular, DRC-2 is found to host a luminous (
L
2−10 keV
≈ 3 × 10
45
erg s
−1
) Compton-thick (
N
H
≳ 10
24
cm
−2
) quasar (QSO) candidate, comparable to the most luminous QSOs known at all cosmic times. The AGN fraction among DRC members is consistent with results found for lower redshift protoclusters. However, X-ray stacking analysis reveals that supermassive black hole (SMBH) accretion is likely also taking place in other DRC galaxies that are not detected individually by
Chandra
.
Conclusions.
The luminous AGN detected in the most gas-rich galaxies in the DRC and the widespread SMBH accretion in the other members, which is suggested by stacking analysis, point toward the presence of a strong link between large gas reservoirs, galaxy interactions, and luminous and obscured nuclear activity in protocluster members. The powerful and obscured QSO detected in DRC-2 is likely powering the nearby LAB detected with VLT/MUSE, possibly through photoionization; however, we propose that the diffuse Ly
α
emission may be due to gas shocked by a massive outflow launched by DRC-2 over a ≈10 kpc scale.
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