Vacuum brazing between SiCp/6063 Al MMCs and Fe-Ni alloys

This research paper deals with the joining of different materials such as SiCp/6063Al MMCs and Fe-Ni alloys by means of vacuum brazing with active filler metal Ag47-Cu18-In17-Sn17-Ti1. With the optimal process parameters, i.e., brazing temperature 580 °C, soaking time of 30 min and vacuum degree of 6.5×10-3 Pa, the joint shear strength can achieve the maximum of 56 MPa. Once the brazing temperature of 580 °C has exceeded the solidus temperature of SiCp/6063Al MMCs, the specimen can still keep the original shape due to the stiffness of composites. Sufficient diffusion between brazing filler metal and SiCp/6063Al MMCs could occur across the interface in liquid phase considerably faster than that in solid phase. The component analysis indicates that the elements in filler metal such as Ag, Sn and In can diffuse into SiCp/6063Al MMCs, which is believed to be beneficial for the joint quality

Proteomics-derived basal biomarker DNA-PKcs is associated with intrinsic subtype and long-term clinical outcomes in breast cancer

Precise biomarkers are needed to guide better diagnostics and therapeutics for basal-like breast cancer, for which DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has been recently reported by the Clinical Proteomic Tumor Analysis Consortium as the most specific biomarker. We evaluated DNA-PKcs expression in clinically-annotated breast cancer tissue microarrays and correlated results with immune biomarkers (training set: n = 300; validation set: n = 2401). Following a pre-specified study design per REMARK criteria, we found that high expression of DNA-PKcs was significantly associated with stromal and CD8 + tumor infiltrating lymphocytes. Within the basal-like subtype, tumors with low DNA-PKcs and high tumor-infiltrating lymphocytes displayed the most favourable survival. DNA-PKcs expression by immunohistochemistry identified estrogen receptor-positive cases with a basal-like gene expression subtype. Non-silent mutations in PRKDC were significantly associated with poor outcomes. Integrating DNA-PKcs expression with validated immune biomarkers could guide patient selection for DNA-PKcs targeting strategies, DNA-damaging agents, and their combination with an immune-checkpoint blockade

The immune microenvironment and relation to outcome in patients with advanced breast cancer treated with docetaxel with or without gemcitabine

Preclinical studies suggest that some effects of conventional chemotherapy, and in particular, gemcitabine, are mediated through enhanced antitumor immune responses. The objective of this study was to use material from a randomized clinical trial to evaluate whether patients with preexisting immune infiltrates responded better to treatment with gemcitabine + docetaxel (GD) compared to docetaxel alone. Formalin fixed, paraffin-embedded breast cancer tissues from SBG0102 phase 3 trial patients randomly assigned to treatment with GD or docetaxel were used. Immunohistochemical staining for CD8, FOXP3, LAG3, PD-1, PD-L1 and CD163 was performed. Tumor infiltrating lymphocytes (TILs) and tumor associated macrophages were evaluated. Prespecified statistical analyses were performed in a formal prospective-retrospective design. Time to progression was primary endpoint and overall survival secondary endpoint. Correlations between biomarker status and endpoints were evaluated using the Kaplan-Meier method and Cox proportional hazards models. Biomarker data was obtained for 237 patients. There was no difference in treatment effect according to biomarker status for the whole cohort. In planned subgroup analysis by PAM50 subtype, in non-luminal (basal-like and HER2E) breast cancers FOXP3 was a significant predictor of treatment effect with GD compared to docetaxel, with a HR of 0.22 (0.09-0.52) for tumors with low FOXP3 compared to HR 0.92 (0.47-1.80) for high FOXP3 TILs (Pinteraction = 0.01). Immune biomarkers were not predictive of added benefit of gemcitabine in a cohort of mixed breast cancer subtypes. However, in non-luminal breast cancers, patients with low FOXP3+ TILs may have significant benefit from added gemcitabine

Phospho-Ser784-VCP is required for DNA damage response and is associated with poor prognosis of chemotherapy-treated breast cancer

Spatiotemporal protein reorganization at DNA damage sites induced by genotoxic chemotherapies is crucial for DNA damage response (DDR), which influences treatment response by directing cancer cell fate. This process is orchestrated by valosin-containing protein (VCP), an AAA+ ATPase that extracts polyubiquinated chromatin proteins and facilitates their turnover. However, because of the essential and pleiotropic effects of VCP in global proteostasis, it remains challenging practically to understand and target its DDR-specific functions. We describe a DNA-damage-induced phosphorylation event (Se

High-temperature modification of steel slag using composite modifier containing silicon calcium slag, fly ash, and reservoir sediment

Steel slag (SS) is a kind of industrial solid waste, and its accumulation brings certain harm to the ecological environment. In order to promote the building material utilization of SS, high-temperature modification (HTM) of SS is performed using a composite modifier (CMSFR) containing silicon calcium slag (SCS), fly ash (FA), and reservoir sediment (RS). Then, the authors investigated the effect of CMSFR on the cementitious properties and volume soundness of SS mixture after HTM (SMHTM). After that, the mineral composition and microstructure of SMHTM were investigated through X-ray fluorescence analysis (XRF), X-ray diffraction (XRD), scanning electronic microscopy (SEM), energy dispersive spectrometry (EDS), and particle size analysis. It was found that the free CaO (f-CaO) content obviously decreased, and the cementitious properties improved in SMHTM. When the CMSFR content was 20% (SCS: FA: RS = 9:7:4), and the modification temperature (MT) was 1,250°C, the mass fraction of f-CaO in SMHTM dropped from 4.81% to 1.90%, down by 60.5%; the 28-day activity index of SMHTM increased to 85.4%, 14.3% higher than that of raw SS, which meets the technical requirement of Steel slag powder used for cement and concrete (GB/T 20491-2017): the activity index of grade I SS powder must be greater than or equal to 80%. As the mass fraction of CMSFR grew from 10% to 30%, new mineral phases formed in SMHTM, including diopside (CMS2), ceylonite (MgFe2O4), gehlenite (C2AS), tricalcium aluminate (C3A), and magnetite (Fe3O4). The HTM with CMSFR promotes the decomposition of RO phase (a continuous solid solution composed of divalent metal oxides like FeO, MgO, MnO, and CaO) in raw SS, turning the FeO in that phase into Fe3O4. The above results indicate that the SMHTM mixed with CMSFR can be applied harmless in cement and concrete, making low-energy fine grinding of SS a possibility

Combination of 4-1BB and DAP10 promotes proliferation and persistence of NKG2D(bbz) CAR-T cells

Chimeric antigen receptor (CAR)-T cell therapy has been shown to have considerable therapeutic effects in hematological malignancies, and NKG2D(z) CAR-T cell therapy has been verified to be safe based on clinical trials. However, due to the poor persistence of NKG2D(z) CAR-T cells, their therapeutic effect is not obvious. Here, we constructed NKG2D(bbz) CAR-T cells that can simultaneously activate 4-1BB and DAP10 costimulatory signaling. They were found to be cytotoxic to the target cells in vitro and in vivo. They exhibited low differentiation, low exhaustion, and good proliferation. Importantly, the proportions of central memory T (Tcm) and stem cell-like memory T (Tscm) cell subsets were strikingly increased. After long-term incubation with the target cells, they displayed reduced exhaustion compared to NKG2D(z) CAR-T cells. Further, in the presence of the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, they exhibited reduced exhaustion and apoptosis, upregulated Bcl2 expression, and an increased proportion of Tcm cell subsets. Finally, NKG2D(bbz) CAR-T cells had better antitumor effects in vivo. In summary, the results showed that NKG2D(bbz) CAR-T cells may be valuable for cellular immunotherapy of cancer

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

Aims The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI >= 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. Conclusions The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further