We conducted a systematic review and meta-analysis to dissect the association between PIK3CA mutations and resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) ...according to PIK3CA exon of mutations in metastatic colorectal cancer (mCRC).
We systematically identified studies exploring the association between PIK3CA mutations and clinical outcomes of mCRC patients treated with anti-EGFR MoAbs. The primary clinical outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed effect model or random effect model according to heterogeneity between studies.
Thirteen studies were considered eligible, with 576 mCRC patients included. In KRAS wild-type mCRC patients, we observed a lower ORR in patients with PIK3CA exon 20 mutations 3 studies, 377 patients; ORR = 0% versus 37%; RR = 0.25; 95% confidence interval (CI) 0.05–1.19; P = 0.082, although the result was not statistically significant because of the small sample size. Only one study provided survival data according to the PIK3CA exon of the mutations, in which PIK3CA exon 20 mutations were statistically significantly associated with shorter PFS (HR = 2.52; 95% CI 1.33–4.78; P = 0.013) and OS (HR = 3.29; 95% CI 1.60–6.74; P = 0.006) in KRAS wild-type mCRC patients treated with anti-EGFR MoAbs. The predictive power of exon 20 mutation is greater than exon 9 mutations and all exons mutations in terms of ORR, PFS, and OS.
These analyses suggest that PIK3CA exon 20 mutations may be a potential biomarker for resistance to anti-EGFR MoAbs in KRAS wild-type mCRC.
The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, ...corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt+ developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development.
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•All human innate lymphoid cell subsets express RORγt•RORγt is expressed in a subset of CD34+CD45RA+ progenitors found in human SLT•The human RORγt+CD34+CD45RA+ progenitor is restricted to ILC development
Human innate lymphoid cells (ILCs) mediate responses against pathogens and cancer; how they develop is unclear. Freud and colleagues identify a human RORγt+ progenitor that selectively resides in secondary lymphoid tissues and exclusively generates all ILCs, including NK cells. These findings help define the pathways involved in human ILC development.
It is of great practical significance to improve the traditional particle swarm optimization (PSO) for the production management of multi-objective flexible job-shop. However, the current studies ...have not solved the problem that the traditional PSO cannot apply to the production and processing environment with numerous uncertain changes. Therefore, this paper improves the PSO for the production management of multi-objective flexible job-shop under different conditions. Firstly, the author modelled the production management of high-dimensional dynamic multiobjective flexible job-shop, and explained the pre-reaction dynamic rescheduling method for production management. Then, the PSO was improved in terms of inertial weight, learning factors, global search ability, and local search ability, and the dynamic response mechanism was presented for the improved algorithm. The feasibility of the improved PSO was demonstrated through experiments. The research provides a reference for applying the improved PSO to the optimization in other fields. 27 refs.
Trapped ions are one of the leading platforms in quantum information science. For quantum computing with large circuit depth and quantum simulation with long evolution time, it is of crucial ...importance to cool large ion crystals at runtime without affecting the internal states of the computational qubits, thus the necessity of sympathetic cooling. Here, we report multi-ion sympathetic cooling on a long ion chain using a narrow cooling beam focused on two adjacent ions, and optimize the choice of the cooling ions according to the collective oscillation modes of the chain. We show that, by cooling a small fraction of ions, cooling effects close to the global Doppler cooling limit can be achieved. This experiment therefore demonstrates an important enabling step for quantum information processing with large ion crystals.
Using first-principles calculations based on density functional theory (DFT), the structural, elastic and electronic properties of two typical strengthening precipitates, namely θ (Al2Cu) and S ...(Al2CuMg), in Al–Cu–Mg series alloys are investigated. The optimized structural parameters including lattice constants and atomic coordinates are in good agreement with experimental values. The calculated cohesive energies and formation enthalpies show that θ phase exhibits a higher structural stability relative to S phase, while the latter presents a stronger alloying ability relative to the former. Additionally, the single-crystal elastic constants Cij of the two phases are calculated, and the bulk modulus B, shear modulus G, Young's modulus E, Poisson ratio v and anisotropy factor A of polycrystalline materials are deduced. It is suggested that θ and S phases appear ductile and brittle characteristic respectively. Comparatively, θ phase has a better isotropy in compression, while S phase is more isotopic in shear and stiffness. Further analysis of electronic structures indicates that the higher structural stability of θ relative to S can be attributed to its more bonding electron numbers below Fermi level.
► θ has a higher structural stability relative to S. ► S presents a stronger alloying ability relative to θ. ► θ and S exhibit ductile and brittle characteristic, respectively. ► θ is more isotopic in compression, while S is more isotopic in shear and stiffness. ► The more bonding electron numbers below EF of θ explain its higher stability.
Summary
Hepatitis B virus surface antigen (HBsAg) plays an important role in maintaining the tolerance and may interfere with host innate and adaptive immune responses; therefore, novel therapeutic ...strategies to reduce HBsAg loads in patients infected with hepatitis B virus (HBV) are emerging as an attractive but challenging issue. Metformin could regulate hepatic metabolism while the latter interacts with HBV infection. We hypothesized that metformin could affect HBsAg expression and HBV replication and may work synergistically when combined with current antivirals. In our study, a notably inhibitory effect on HBsAg production, as well as a moderate inhibition in HBV replication and HBeAg expression was observed following metformin treatment. The 50% effective concentration (EC50) for extracellular HBsAg and intracellular HBsAg in HBV‐producing HepG2.2.15 cells was 2.85 mm and 2.75 mm, respectively, with a similarly selective index of about 18. When administered in combination, metformin enhanced the inhibitory effects of interferon‐α2b on HBsAg expression and HBV replication and provided a complimentary role in HBsAg expression for lamivudine (LMV). This novel action of metformin derives partially from its inhibition on multiple HBV cis‐acting elements. By the virtues of preferably hepatocyte distribution and safety profile, collectively, our results suggest that metformin would be potentially clinically helpful as an HBsAg production inhibitor.
Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for ...self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5(+) HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5(+) cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5(+) CICs. Mechanistically, LSD1 promotes β-catenin activation by inhibiting the expression of several suppressors of β-catenin signaling, especially Prickle1 and APC in Lgr5(+) CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the β-catenin signaling is essential for maintaining the activity of Lgr5(+) CICs. Together, our findings unravel the LSD1/Prickle1/APC/β-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5(+) CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.
We use quantum coherence in a system consisting of one metallic nanorod and one semiconductor quantum dot to investigate a plasmonic nanosensor capable of digital optical detection and recognition of ...single biological molecules. In such a sensor the adsorption of a specific molecule to the nanorod turns off the emission of the system when it interacts with an optical pulse having a certain intensity and temporal width. The proposed quantum sensors can count the number of molecules of the same type or differentiate between molecule types with digital optical signals that can be measured with high certainty. We show that these sensors are based on the ultrafast upheaval of coherent dynamics of the system and the removal of coherent blockage of energy transfer from the quantum dot to the nanorod once the adsorption process has occurred.
The data assimilation scheme used in the Met Office's Operational Sea Surface Temperature and Ice Analysis (OSTIA) system has been updated from an Optimal Interpolation (OI)‐type scheme to a ...variational assimilation scheme. The updated system includes a dual length‐scale background error correlation operator, and a flow‐dependent component to adjust the length‐scale combination in favour of the short scale in regions of high sea surface temperature (SST) variability. The variational assimilation scheme improves both the analysis performance and the representation of SST features in the OSTIA analysis compared to the OI scheme of the original system. The results of spectral analysis, assessment of horizontal SST gradients and the response of an atmospheric model to the OSTIA SST analysis as a boundary condition indicate that the flow‐dependent formulation successfully contributes to improvements in the feature resolution capability of the analysis. Overall, using a short length‐scale of 15 km and including a flow‐dependent adjustment component produces the best results compared to using either 40 km or the first Rossby radius of deformation as the short length‐scale. The new system successfully captures realistic ocean variability without introducing noise into the analysis, allowing the feature resolution capability of the new system to out‐perform that of other comparable SST analysis products.
The data assimilation scheme used in the Met Office's OSTIA (Operational Sea Surface Temperature and Ice Analysis) system has been updated from an OI‐type scheme to a variational assimilation scheme, NEMOVAR. Updates include a flow‐dependent component to the background error correlation operator, which shortens the length‐scale in regions of high sea surface temperature (SST) variability. The analysis performance and representation of SST features (as demonstrated in the figure) are improved using the updated system.
Mitochondrial DNA maintenance and segregation are dependent on the actin cytoskeleton in budding yeast. We found two cytoskeletal proteins among six proteins tightly associated with rat liver ...mitochondrial DNA: non-muscle myosin heavy chain IIA and β-actin. In human cells, transient gene silencing of MYH9 (encoding non-muscle myosin heavy chain IIA), or the closely related MYH10 gene (encoding non-muscle myosin heavy chain IIB), altered the topology and increased the copy number of mitochondrial DNA; and the latter effect was enhanced when both genes were targeted simultaneously. In contrast, genetic ablation of non-muscle myosin IIB was associated with a 60% decrease in mitochondrial DNA copy number in mouse embryonic fibroblasts, compared to control cells. Gene silencing of β-actin also affected mitochondrial DNA copy number and organization. Protease-protection experiments and iodixanol gradient analysis suggest some β-actin and non-muscle myosin heavy chain IIA reside within human mitochondria and confirm that they are associated with mitochondrial DNA. Collectively, these results strongly implicate the actomyosin cytoskeleton in mammalian mitochondrial DNA maintenance.
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