Identification of PIK3CA multigene mutation patterns associated with superior prognosis in stomach cancer.

BACKGROUND: PIK3CA is the second most frequently mutated gene in cancers and is extensively studied for its role in promoting cancer cell resistance to chemotherapy or targeted therapy. However, PIK3CA functions have mostly been investigated at a lower-order genetic level, and therapeutic strategies targeting PIK3CA mutations have limited effects. Here, we explore crucial factors interacting with PIK3CA mutations to facilitate a significant marginal survival effect at the higher-order level and identify therapeutic strategies based on these marginal factors. METHODS: Mutations in stomach adenocarcinoma (STAD), breast adenocarcinoma (BRCA), and colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) database were top-selected and combined for Cox proportional-hazards model analysis to calculate hazard ratios of mutation combinations according to overall survival data and define criteria to acquire mutation combinations with considerable marginal effects. We next analyzed the PIK3CA + HMCN1 + LRP1B mutation combination with marginal effects in STAD patients by Kaplan-Meier, transcriptomic differential, and KEGG integrated pathway enrichment analyses. Lastly, we adopted a connectivity map (CMap) to find potentially useful drugs specifically targeting LRP1B mutation in STAD patients. RESULTS: Factors interacting with PIK3CA mutations in a higher-order manner significantly influenced patient cohort survival curves (hazard ratio (HR) = 2.93, p-value = 2.63 × 10- 6). Moreover, PIK3CA mutations interacting with higher-order combination elements distinctly differentiated survival curves, with or without a marginal factor (HR = 0.26, p-value = 6.18 × 10- 8). Approximately 3238 PIK3CA-specific higher-order mutational combinations producing marginal survival effects were obtained. In STAD patients, PIK3CA + HMCN1 mutation yielded a substantial beneficial survival effect by interacting with LRP1B (HR = 3.78 × 10- 8, p-value = 0.0361) and AHNAK2 (HR = 3.86 × 10- 8, p-value = 0.0493) mutations. We next identified 208 differentially expressed genes (DEGs) induced by PIK3CA + HMCN1 compared with LRP1B mutation and mapped them to specific KEGG modules. Finally, small-molecule drugs such as geldanamycin (connectivity score = - 0.4011) and vemurafenib (connectivity score = - 0.4488) were selected as optimal therapeutic agents for targeting the STAD subtype with LRP1B mutation. CONCLUSIONS: Overall, PIK3CA-induced marginal survival effects need to be analyzed. We established a framework to systematically identify crucial factors responsible for marginal survival effects, analyzed mechanisms underlying marginal effects, and identified related drugs.

Single-cell profiling of the microenvironment in decidual tissue from women with missed abortions.

OBJECTIVE: To define the decidual microenvironment in euploid and aneuploid missed abortions and elective termination of pregnancies. DESIGN: Prospective, multicenter, observational study. SETTING: Tertiary hospital and descriptive analysis of transcriptomic data. PATIENT(S): A total of 34 patients experienced abortions, including 6 women who underwent elective terminations of pregnancy of unplanned pregnancies and 28 cases with missed abortions. All patients underwent their operations from Sep, 2021 to Sep, 2022. INTERVENTION(S): All women underwent villous copy number variation sequencing. Meanwhile, single-cell RNA sequencing were performed in the decidual tissues of 16 women, and reverse transcription quantitative polymerase chain reaction were performed in the decidual tissues of 18 women. MAIN OUTCOME MEASURE(S): Single-cell RNA sequencing was used to explore the changes in the microenvironment of decidual tissues in abortions. RESULT(S): Single-cell RNA sequencing indicated that the microenvironment of the decidual tissue of the missed-abortion group was altered, and that the stromal cells (SCs), natural killer cells, macrophages, and epithelial cells all reflected functional imbalances compared with the elective terminations of pregnancy group. We also noted a correlation between the proportion of senescent SCs and chromosomal abnormalities in missed-abortion embryos. The proportion of senescent decidual SCs in the decidual tissue of missed-abortion patients with common chromosomal abnormalities of the fetus was higher, and this was not conducive to fetal growth and was closely related to missed abortion. In addition, we ascertained that the strength of the HLA-KIR interaction between NK1 and NK2 subsets and non-senescent stromal cell subsets in the missed abortion decidual tissues was weakened, potentially playing a role in the occurrence of missed abortion. CONCLUSION(S): The decidualization of SCs in the missed-abortion decidual tissues was impaired, the clearance of senescent SCs by NK cells was weakened, the killing toxicity of non-senescent SCs was enhanced, macrophages were insufficiently resident at the maternal-fetal interface, and epithelial cell differentiation was unbalanced-all creating a maternal microenvironment that was not conducive to fetal growth. We posit that interfering with the expression of dysregulated genes in the missed-abortion decidual tissues and reversing the maternal microenvironment might constitute an effective means toward improving the clinical outcome of missed abortions. Intriguingly, we observed a correlation between stromal cell senescence and embryonic chromosomal abnormalities. Thus, we hypothesize that the DIO2 marker of senescent SCs can be used as a risk indicator for the occurrence of missed miscarriages with chromosomal abnormalities of the embryos, and that it can be applied to guide the clinical diagnosis and treatment of recurrent abortion. CLINICAL TRIAL REGISTRATION NUMBER: NCT04425317.

Development of Y2O3 Dispersion-Strengthened Copper Alloy by Sol-Gel Method.

In this study, oxide dispersion-strengthened Cu alloy with a Y2O3 content of 1 wt.% was fabricated through citric acid sol-gel synthesis and spark plasma sintering (SPS). The citric acid sol-gel method provides molecular mixing for the preparation of precursor powders, which produces nanoscale and uniformly distributed Y2O3 particles in an ultrafine-grained Cu matrix. The effects of nanoscale Y2O3 particles on the microstructure, mechanical properties and thermal conductivity of the Cu-1wt.%Y2O3 alloy were investigated. The average grain size of the Cu-1wt.%Y2O3 alloy is 0.42 µm, while the average particle size of Y2O3 is 16.4 nm. The unique microstructure provides excellent mechanical properties with a tensile strength of 572 MPa and a total elongation of 6.4%. After annealing at 800 °C for 1 h, the strength of the alloy does not decrease obviously, showing excellent thermal stability. The thermal conductivity of Cu-1wt.%Y2O3 alloy is about 308 Wm-1K-1 at room temperature and it decreases with increasing temperature. The refined grain size, high strength and excellent thermal stability of Cu-1wt.%Y2O3 alloys can be ascribed to the pinning effects of nanoscale Y2O3 particles dispersed in the Cu matrix. The Cu-Y2O3 alloys with high strength and high thermal conductivity have potential applications in high thermal load components of fusion reactors.

Microstructures and Tensile Properties of 9Cr-F/M Steel at Elevated Temperatures.

Tensile properties and microstructure changes under different stress states of tempered 9Cr-F/M steel were characterized using a transmission electron microscope (TEM), electron backscatter diffraction (EBSD), scanning electron microscopy (SEM), Vickers hardness tester, and tensile tester. This tempered steel has a typical lath martensite structure with only a few polygonal ferrites embedded, and M23C6 and MX phases nucleated on the lath boundaries or within the sub-grains. At elevated temperatures, the strength of the steel decreases. However, the elongation at 400 °C is lower than that at room temperature. For the necking zone, tensile deformation made the grain elongated to the direction of applied stress and thus the grain's cross-section becomes smaller. For samples with rectangular working area cross-section, the deformation in the TD direction was more severe than that in the ND direction, which made the grain elongated in the TD direction. These results can provide some guidance for composition optimization of the 9Cr-F/M steel and facilitate a better understanding of the fracture mechanism under different stress states.

Effect of Nano-Y2O3 Content on Microstructure and Mechanical Properties of Fe18Cr Films Fabricated by RF Magnetron Sputtering.

In this work, FeCr-based films with different Y2O3 contents were fabricated using radio frequency (RF) magnetron sputtering. The effects of Y2O3 content on their microstructure and mechanical properties were investigated through scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), inductive coupled plasma emission spectrometer (ICP) and a nanoindenter. It was found that the Y2O3-doped FeCr films exhibited a nanocomposite structure with nanosized Y2O3 particles uniformly distributed into a FeCr matrix. With the increase of Y2O3 content from 0 to 1.97 wt.%, the average grain size of the FeCr films decreased from 12.65 nm to 7.34 nm, demonstrating a grain refining effect of Y2O3. Furthermore, the hardness of the Y2O3-doped FeCr films showed an increasing trend with Y2O3 concentration, owing to the synergetic effect of dispersion strengthening and grain refinement strengthening. This work provides a beneficial guidance on the development and research of composite materials of nanocrystalline metal with a rare earth oxide dispersion phase.

Enhanced Erosion-Corrosion Resistance of Tungsten by Carburizing Using Spark Plasma Sintering Technique.

The biggest obstacle for the application of tungsten as the target materials in the spallation neutron source is its serious corrosion in the coolant of flowing water. For this reason, W-Cr-C clad tungsten was developed by tungsten carburizing in a spark plasma sintering device, with superior corrosion resistance in the static immersion and electrochemical corrosion test. This work focused on its erosion and corrosion performance in a flowing water system, based upon test parameters simulated under the service conditions. W-Cr-C clad tungsten showed superior corrosion resistance to that of bare tungsten due to the corrosion form changing from the intergranular corrosion of bare tungsten to pitting corrosion of W-Cr-C coating. The corrosion rate of tungsten was as high as tenfold that of the coated sample at 20 °C, and at most fourfold at 60 °C after testing for 360 h. Effects of water velocity and temperature on pitting and intergranular corrosion were investigated in detail and their corresponding corrosion mechanisms were analyzed and discussed.

Nb-doped and Al2O3 + B2O3-coated granular secondary LiMn2O4 particles as cathode materials for lithium-ion batteries.

In this work, to improve the cyclability and high-temperature performance of cubic spinel LiMn2O4 (LMO) as cathode materials, Nb5+-doped LiMn2O4 powders coated and uncoated with Al2O3 and/or B2O3 were synthesized via the modified solid-state reaction method. It was found that Nb5+-doped and B2O3 + Al2O3-coated LMO powders comprising 5 µm granular agglomerated fine primary particles smaller than 350 nm in diameter exhibited superior electrochemical properties with initial discharge capacity of 101.68 mA h g-1; we also observed capacity retention of 96.31% after 300 cycles at room temperature (RT) and that of 98% after 50 cycles at 55 °C and 1C rate.