Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic ...clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases.
Summary
This paper addresses stability and l2‐gain for discrete‐time switched systems with unstable modes based on slow/fast mode‐dependent average dwell time (MDADT) switching strategies. Firstly, ...by employing a class of multiple discontinuous Lyapunov functions (MDLFs) and developing a kind of alternative switching signals, the sufficient conditions on stability are established for the system without external disturbances under a slow/fast MDADT switching scheme with a tighter bounds on the dwell time. Furthermore, by defining indicator functions and exploring the features of slow/fast MDADT switching, the weighted l2‐gain conditions are achieved for the system with external disturbances. Particularly, the criteria of stability and l2‐gain are also established for the corresponding discrete‐time switched linear systems with unstable modes via the MDLFs method and the slow/fast MDADT switching strategy. Finally, two numerical examples are presented to illustrate the advantages of the proposed methods.
In this article, a load-modulation enhanced wideband compact high-efficiency millimeter-wave (mm-wave) gallium nitride (GaN) monolithic microwave integrated circuit (MMIC) synchronous Doherty power ...amplifier (DPA) is presented. A synchronous DPA architecture is used to ensure the optimal saturation performance at the mm-wave band. Based on the analysis of load-modulation behavior, the bandwidth of the DPA can be extended by decreasing the phase dispersion factor <inline-formula> <tex-math notation="LaTeX">\alpha </tex-math></inline-formula>. A simple optimal tuning-based method is proposed to design an equivalent <inline-formula> <tex-math notation="LaTeX">\lambda </tex-math></inline-formula>/4 transmission line (EQWTL) with the minimal <inline-formula> <tex-math notation="LaTeX">\alpha </tex-math></inline-formula> for a given topology. Furthermore, the influence of the power division ratio <inline-formula> <tex-math notation="LaTeX">\sigma </tex-math></inline-formula> on the proposed DPA's load-modulation behavior has also been analyzed and a proper load modulation can be realized by splitting more power to the peaking branch properly. For verification, a 24-28-GHz GaN MMIC synchronous DPA has been designed using a 0.15-<inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula> GaN on silicon carbide high-electron-mobility transistor process. Both the load modulation and the matching of the fundamental and the second harmonic load impedances can be realized by a modified bandpass-type EQWTL with a minimal <inline-formula> <tex-math notation="LaTeX">\alpha </tex-math></inline-formula> easily. Experimental results show that the fabricated DPA can achieve the output power of 35.4-36 dBm and the power-added efficiency (PAE) of 27.8%-36.8% at saturation. The PAE at 6-dB power back-off (PBO) is 18.3%-30.1% and the 9-dB PBO PAE is higher than 14.3% in the whole frequency band. An average PAE of 27.4% with good linearity is obtained when excited by a 400-MHz modulated signal after linearization.
In this paper, the analysis on stability and -gain is presented for switched systemswith unstable modes. To solve the problem, an improved mode-dependent average dwell time (MDADT) tradeoff switching ...method is developed by a time subsequence technique. Based on a general multiple discontinuous Lyapunov functions (MDLFs), stability conditions are acquired for switched nonlinear systems with unstable modes. Whereafter, the stability result is extended to the weighted -gain analysis for the system with external disturbance. Moreover, in light of the quadratic MDLFs, the stability and weighted -gain criteria are also presented for the liner systems under the obtained switching scheme. Due to the time subsequence technique, the proposed switching method is more convenient in practice. Particularly, under the switching scheme, the tighter bounds are provided for MDADT, and the MDADT on unstable modes is not restricted by upper bounds. Finally, numerical examples show that the proposed methods are effective.
Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of ...biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance.
Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets.
Through gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76, and SYK) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC. CCNE1 and TPX2 were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC. CCNE1 amplification was associated with poor overall survival in patients with metastatic TNBC.
CCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.
Activating mutations in RAS genes are associated with approximately 20% of all human cancers. New targeted therapies show preclinical promise in inhibiting the KRAS G12C variant. However, concerns ...exist regarding the effectiveness of such therapies in vivo given the possibilities of existing intratumor heterogeneity or de novo mutation leading to treatment resistance. We performed deep sequencing of 27 KRAS G12-positive lung tumors to determine the prevalence of other oncogenic mutations within KRAS or within commonly mutated downstream genes that could confer resistance at the time of treatment. We also passaged patient-derived xenografts to assess the potential for novel KRAS mutation to arise during subsequent tumor evolution. Furthermore, we estimate the de novo mutation rate in KRAS position 12 and in genes downstream of KRAS. Finally, we present an approach for estimation of the selection intensity for these point mutations that explains their high prevalence in tumors. We find no evidence of heterogeneity that may compromise KRAS G12C targeted therapy within sequenced lung tumors or passaged xenografts. We find that mutations that confer resistance are even less likely to occur downstream of KRAS than to occur within KRAS. Our approach predicts that BRAF V600E would provide the highest fitness advantage for de novo-resistant subclones. Overall, our findings suggest that resistance to targeted therapy of KRAS G12C-positive tumors is unlikely to be present at the time of treatment and, among the de novo mutations likely to confer resistance, mutations in BRAF, a gene with targeted inhibitors presently available, result in subclones with the highest fitness advantage.
Two types of amphoteric calixnarene carboxylic acid (CnCA) derivative, i.e., calix6arene hexa-carboxylic acid (C6HCA) and calix8arene octo-carboxylic acid (C8OCA), were synthesized by introducing ...acetoxyls into the hydroxyls of calixnarene (n=6, 8). C6HCA and C8OCA nanoparticles (NPs) were prepared successfully using the dialysis method. CnCA NPs had regular spherical shapes with an average diameter of 180–220 nm and possessed negative charges of greater than −30 mV. C6HCA and C8OCA NPs were stable in 4.5% bovine serum albumin solutions and buffers (pH 5–9), with a low critical aggregation concentration value of 5.7 mg·L−1 and 4.0 mg·L−1, respectively. C6HCA and C8OCA NPs exhibited good paclitaxel (PTX) loading capacity, with drug loading contents of 7.5% and 8.3%, respectively. The overall in vitro release behavior of PTX from the CnCA NPs was sustained, and C8OCA NPs had a slower release rate compared with C6HCA NPs. These favorable properties of CnCA NPs make them promising nanocarriers for tumor-targeted drug delivery.
In this paper, the finite-time boundedness (FTB) and H∞ control are discussed for a class of uncertain switched port-controlled Hamiltonian (PCH) systems via adaptive control strategies. In view of ...the mode-dependent matching principle, the energy-based multiple Lyapunov functions method and the mode-dependent average dwell time (MDADT) approach, sufficient conditions on the FTB are obtained for uncertain switched PCH systems by employing a set of adaptive mode-dependent state feedback controllers. Furthermore, to solve the finite-time H∞ control for the system under consideration, a new set of mode-dependent state feedback controllers are designed to restrain both the structured uncertainties and disturbances, and sufficient conditions on the H∞ control problem are derived for the system under a new MDADT scheme. Finally, the numerical simulations are presented to illustrate the effectiveness of the proposed finite-time adaptive control methods.
•The finite-time boundedness and H∞ control criteria are given for uncertain switched port-controlled Hamiltonian systems via energy-based multiple Lyapunov functions methods and mode-dependent average dwell time approaches.•The finite-time adaptive control strategies proposed in this paper can be extended to general uncertain switched nonlinear systems via generalized Hamiltonian realization principles.
This brief firstly presents a monolithically microwave integrated circuit (MMIC) load-modulated balanced amplifier (LMBA) developed in 0.15 <inline-formula> <tex-math notation="LaTeX">\mu {\mathrm{ ...m}} </tex-math></inline-formula> GaN process. In this brief, the asymmetric output coupler is applied for further enhancing output power and output back-off (OBO) efficiency over a larger OBO range. This MMIC LMBA operating mode is dependent on a three-ways active load modulation process by modifying the coupling coefficient of output coupler which can provide more design parameters and freedom. To validate the proposed LMBA at millimeter wave (mm-wave), a 24.7-25.7 GHz MMIC LMBA is demonstrated, fabricated and tested. Measurements show that this MMIC LMBA can deliver a 35.2-dBm saturated output power with a peak drain efficiency of 37.7%. At 6-dB/8-dB/10-dB OBO, 23.8-30%, 24.2-27% and 20-24% power added efficiencies (PAE) can be obtained, respectively. The measured <inline-formula> <tex-math notation="LaTeX">S_{21} </tex-math></inline-formula> is 15-dB with a ±0.4-dB gain variation. When driven by a 100MHz 64-QAM OFDM modulation signal with a PAPR of 9.2-dB, the measured ACPR is improved to −45.04 dBc with DPD. In this case, the PA achieves an average efficiency of 25.2% and a 26.2-dBm average output power.
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