The third-generation
tyrosine kinase inhibitor osimertinib is approved to treat patients with
T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance to earlier-generation ...drugs. Acquired
C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown.
We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients.
experiments were conducted to functionally study the secondary
mutations identified.
G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC
) of osimertinib
, among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these
mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as
, and
were also discovered, potentially contributing to the osimertinib-resistance in patients without
secondary mutations.
We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of
L718 and L792 residues confer osimertinib resistance, both
and
, and are of great clinical and pharmaceutical relevance.
.
The persistence of HIV-infected cells in individuals on suppressive combination antiretroviral therapy (cART) presents a major barrier for curing HIV infections. HIV integrates its DNA into many ...sites in the host genome; we identified 2410 integration sites in peripheral blood lymphocytes of five infected individuals on cART. About 40% of the integrations were in clonally expanded cells. Approximately 50% of the infected cells in one patient were from a single clone, and some clones persisted for many years. There were multiple independent integrations in several genes, including MKL2 and BACH2; many of these integrations were in clonally expanded cells. Our findings show that HIV integration sites can play a critical role in expansion and persistence of HIV-infected cells.
Summary Objective To determine whether autophagy contributes to the pathogenesis of degenerative disc disease (DDD) or retards the intervertebral disc (IVD) degeneration, and investigate the possible ...relationship between compression-induced autophagy and intracellular reactive oxygen species (ROS) in nucleus pulposus (NP) cells in vitro. Methods The autophagosome and autophagy-related markers were used to explore the role of autophagy in rat NP cells under compressive stress, which were measured directly by electronic microscopy, monodansylcadaverine (MDC) staining, immunofluorescence, western blot, and indirectly by analyzing the impact of pharmacological inhibitors of autophagy such as 3-methyladenine (3-MA) and chloroquine (CQ). And the relationship between autophagy and apoptosis was investigated by Annexin-V/propidium iodide (PI)-fluorescein staining. In addition, ROS were measured to determine whether these factors are responsible for the development of compression-induced autophagy. Results Our results indicated that rat NP cells activated autophagy in response to the same strong apoptotic stimuli that triggered apoptosis by compression. Autophagy and apoptosis were interconnected and coordinated in rat NP cells exposed to compression stimuli. Compression-induced autophagy was closely related to intracellular ROS production. Conclusions Enhanced degradation of damaged components of NP cells by autophagy may be a crucial survival response against mechanical overload, and extensive autophagy may trigger autophagic cell death. Regulating autophagy and reducing the generation of intracellular ROS may retard IVD degeneration.
Cancer is a disease of complex genetic alterations, and comprehensive genetic diagnosis is beneficial to match each patient to appropriate therapy. However, acquisition of representative tumor ...samples is invasive and sometimes impossible. Circulating tumor DNA (ctDNA) is a promising tool to use as a non-invasive biomarker for cancer mutation profiling. Here we implemented targeted next generation sequencing (NGS) with a customized gene panel of 382 cancer-relevant genes on 605 ctDNA samples in multiple cancer types. Overall, tumor-specific mutations were identified in 87% of ctDNA samples, with mutation spectra highly concordant with their matched tumor tissues. 71% of patients had at least one clinically-actionable mutation, 76% of which have suggested drugs approved or in clinical trials. In particular, our study reveals a unique mutation spectrum in Chinese lung cancer patients which could be used to guide treatment decisions and monitor drug-resistant mutations. Taken together, our study demonstrated the feasibility of clinically-useful targeted NGS-based ctDNA mutation profiling to guide treatment decisions in cancer.
The genetic basis of many brain and spinal arteriovenous malformations is unclear. Hong et al. reveal a causative role for somatic tumour-related mutations in KRAS/BRAF in the majority of patients ...tested. This homogeneity supports therapeutic targeting of the RAS/RAF/MAPK pathway without the need for tissue genetic diagnosis.
Abstract
Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 ± 298×. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.
10.1093/brain/awy307_video1
awy307media1
5978667388001
The effect of preferential flow on the stability of landslides is studied through numerical simulation of two types of rainfall events on a hypothetical hillslope. A model is developed that consists ...of two parts. The first part is a model for combined saturated/unsaturated subsurface flow and is used to compute the spatial and temporal water pressure response to rainfall. Preferential flow is simulated with a dual-permeability continuum model consisting of a matrix domain coupled to a preferential flow domain. The second part is a soil mechanics model and is used to compute the spatial and temporal distribution of the local factor of safety based on the water pressure distribution computed with the subsurface flow model. Two types of rainfall events were considered: long-duration, low-intensity rainfall, and short-duration, high-intensity rainfall. The effect of preferential flow on slope stability is assessed through comparison of the failure area when subsurface flow is simulated with the dual-permeability model as compared to a single-permeability model (no preferential flow). For the low-intensity rainfall case, preferential flow has a positive effect on drainage of the hillslope resulting in a smaller failure area. For the high-intensity rainfall case, preferential flow has a negative effect on the slope stability as the majority of rainfall infiltrates into the preferential flow domain when rainfall intensity exceeds the infiltration capacity of the matrix domain, resulting in larger water pressure and a larger failure area.
Hot deformation behavior of delta-processed superalloy 718 Wang, Y.; Shao, W.Z.; Zhen, L. ...
Materials science & engineering. A, Structural materials : properties, microstructure and processing,
03/2011, Letnik:
528, Številka:
7
Journal Article
Recenzirano
▶ The peak stress for hot deformation can be described by the
Z parameter. ▶ The grain size of DRX was inversely proportional to the
Z parameter. ▶ The dissolution of δ phases was greatly accelerated ...under hot deformation. ▶The δ phase stimulated nucleation can serve as the main DRX mechanism.
Flow stress behavior and microstructures during hot compression of delta-processed superalloy 718 at temperatures from 950 to 1100
°C with strain rates of 10
−3 to 1
s
−1 were investigated by optical microscopy (OM), electron backscatter diffraction (EBSD) technique and transmission electron microscopy (TEM). The relationship between the peak stress and the deformation conditions can be expressed by a hyperbolic-sine type equation. The activation energy for the delta-processed superalloy 718 is determined to be 467
kJ/mol. The change of the dominant deformation mechanisms leads to the decrease of stress exponent and the increase of activation energy with increasing temperature. The dynamically recrystallized grain size is inversely proportional to the Zener–Hollomon (
Z) parameter. It is found that the dissolution rate of δ phases under hot deformation conditions is much faster than that under static conditions. Dislocation, vacancy and curvature play important roles in the dissolution of δ phases. The main nucleation mechanisms of dynamic recrystallization (DRX) for the delta-processed superalloy 718 include the bulging of original grain boundaries and the δ phase stimulated DRX nucleation, which is closely related to the dissolution behavior of δ phases under certain deformation conditions.
Flow behavior and microstructures of superalloy 718 were investigated by hot compression tests performed at temperatures ranging from 950 to 1100
°C with strain rates of 10
−3 to 1
s
−1. The ...dependence of the peak stress on deformation temperature and strain rate can be expressed by a hyperbolic-sine type equation. The activation energy for superalloy 718 is determined to be 443.2
kJ
mol
−1. A power exponent relationship between the peak strain and the
Z parameter is obtained. Microstructure analysis shows that the dynamically recrystallized grain size is inversely proportional to the
Z parameter. The nucleation mechanisms of DRX are closely related to the value of
Z parameter. Under low
Z conditions, DRX nucleation and development are mainly assisted by the formation of twins near the original grain boundaries.
It is widely known that corrective switching, including transmission line switching, bus-bar switching, and shunt element switching, may change the states of the power systems, and consequently, ...affect the distribution of power flows, transmission losses, short circuit currents, voltage profiles as well as transient stability of power systems. In this paper, a new algorithm is developed to find the best line and bus-bar switching action for relieving overloads and voltage violations caused by system contingencies based on a sparse inverse technique and fast decoupled power flow with limited iteration count. A general model of bus-bar switching action is also presented such that the new algorithm can simulate any kind of complicated bus-bar switching action. Furthermore, on the basis of a newly proposed voltage distribution factor by multiple iterations in power flow calculation, a novel algorithm for corrective voltage control by shunt switching is developed. These two algorithms are then integrated into a corrective switching algorithm. Simulation results on the WECC 179-bus system indicate that the new corrective switching algorithm proposed in this paper can effectively solve certain problems of line overloads and voltage violations. The computation time required is also satisfactory.
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