Metaplastic breast carcinoma (MBC) is a rare histological type of breast cancer, which commonly shows resistance to standard therapies and is associated with poor prognosis. The immune ...microenvironment in MBC and its significance has not been well established due to its low incurrence rate and complex components. We aimed to investigate the diversity of immune parameters including subsets of TILs and PDL1/PD1 expression in MBC, as well as its correlation with prognosis.
A total of 60 patients diagnosed with MBC from January 2006 to December 2017 were included in our study. The percentage (%) and quantification (per mm
) of TILs and presence of tertiary lymphoid structures (TLS) were evaluated by hematoxylin and eosin staining (HE). The quantification of CD4+, CD8+ TILs (per mm
), and PD-1/PDL1 expression were evaluated through immunohistochemistry and analyzed in relation to clinicopathological characteristics. A ≥ 1% membranous or cytoplasmatic expression of PD1 and PDL1 was considered a positive expression.
We found squamous cell carcinoma MBC (33/60, 55%) exhibiting most TILs of all the MBC subtypes (p = 0.043). Thirty-three of 60 (50%) of the patients had coexisting invasive ductal carcinoma of no special type (IDC-NST), and the average percentage of TILs in MBC components was lower compared with NST components (p < 0.001). Thirty (50%) patients exhibited positive (≥ 1%) PDL1 expression in their tumor cells, while 36 (60%) had positive (≥ 1%) PDL1 expression in their TILs. Twenty-seven (45%) of all the patients had positive (≥ 1%) PD1 expression in their tumor cells and 33 (55%) had PD1-positive (≥ 1%) stromal TILs. More CD8+ TILs were associated with positive PDL1 expression of tumor cells as well as positive PD1 expression in stromal cells. Greater number of stromal TILS (> 300/mm
, 20%), CD4+ TILs (> 250/mm
), and CD8+ TILs (> 70/mm
) in MBC were found associated with longer disease-free survival. Positive expression of PDL1 in tumor cells (≥ 1%) and PD1 in stromal cells (≥ 1%) were also associated with longer survival.
The immune characteristics differ in various subtypes as well as components of MBC. Immune parameters are key predictive factors of MBC and provide the clinical significance of applying immune checkpoint therapies in patients with MBC.
Small interfering RNA (siRNA) shows excellent pharmaceutical prospects in treating diverse life-threatening diseases. Photodynamic therapy (PDT) is a clinically employed noninvasive treatment method ...that can trigger selective damage toward targeted tissue and cells. However, insufficient delivery of siRNA and photosensitizer to cancer cells remarkably hindered the application of siRNA and PDT in the treatment of cancer. In this study, a unique reactive oxygen species (ROS)-activatable polyplex, which consists of the PEGylated cationic polymer, ROS-cleavable linker, photosensitizer Ce6, and RRM2-against siRNA, termed PPTC/siRNA, was engineered. Upon irradiation of near-infrared (NIR) light, the polyplex efficiently generated ROS, which triggered degradation of the ROS-sensitive linker, disassembling the complex, destabilization of the cell membrane, and significantly accelerated cellular entry and endosomal escape of siRNA. Besides achieving effective siRNA internalization and gene silence in cancer cells in vitro, PPTC/siRNA synergistically inhibited tumor growth in both cell line-derived xenograft and patient-derived xenograft hepatocellular carcinoma murine models by repressing the RRM2 expression (reducing cell proliferation) and triggering photodynamic killing (enhancing cell apoptosis). The proposed polyplex also showed ideal safety profiles both in cell line and in animal. It provides a novel strategy for NIR-triggered RNAi and PDT combinational cancer treatment.
MicroRNAs have been appreciated in various cellular functions, including the regulation of angiogenesis. Mesenchymal-stem-cells (MSCs) transplanted to the MI heart improve cardiac function through ...paracrine-mediated angiogenesis. However, whether microRNAs regulate MSC induced angiogenesis remains to be clarified. Using microRNA microarray analysis, we identified a microRNA expression profile in hypoxia-treated MSCs and observed that among all dysregulated microRNAs, microRNA-377 was decreased the most significantly. We also validated that vascular endothelial growth factor (VEGF) is a target of microRNA-377 using dual-luciferase reporter assay and Western-blotting. Knockdown of endogenous microRNA-377 promoted tube formation in human umbilical vein endothelial cells. We then engineered rat MSCs with lentiviral vectors to either overexpress microRNA-377 (MSC miR-377) or knockdown microRNA-377 (MSC Anti-377) to investigate whether microRNA-377 regulated MSC-induced myocardial angiogenesis, using MSCs infected with lentiviral empty vector to serve as controls (MSC Null). Four weeks after implantation of the microRNA-engineered MSCs into the infarcted rat hearts, the vessel density was significantly increased in MSC Anti-377-hearts, and this was accompanied by reduced fibrosis and improved myocardial function as compared to controls. Adverse effects were observed in MSC miR-377-treated hearts, including reduced vessel density, impaired myocardial function, and increased fibrosis in comparison with MSC Null-group. These findings indicate that hypoxia-responsive microRNA-377 directly targets VEGF in MSCs, and knockdown of endogenous microRNA-377 promotes MSC-induced angiogenesis in the infarcted myocardium. Thus, microRNA-377 may serve as a novel therapeutic target for stem cell-based treatment of ischemic heart disease.
Multifunctional N, Fe-doped carbon dots (N, Fe-CDs) were synthesized by the one-step hydrothermal method using ferric ammonium citrate and dicyandiamide as raw materials. The N, Fe-CDs exhibited ...peroxidase-like (POD) activity by catalyzing the oxidization of 3,3′,5,5′-tetramethylbenzidine (TMB) to the green oxidation state ox-TMB in the presence of hydrogen peroxide (H
2
O
2
). Subsequently, based on the POD activity of N, Fe-CDs, an efficient and sensitive colorimetric method for the detection of H
2
O
2
and ascorbic acid (AA) was established with a limit of detection of 0.40 µM and 2.05 µM. The proposed detection method has been successfully applied to detect AA in fruit juice, vitamin C tablets, and human serum samples and has exhibited excellent application prospects in biotechnology and food fields. Furthermore, N, Fe-CDs also showed a protective effect on the cell damage caused by H
2
O
2
and could be used as an antioxidant agent.
Graphical Abstract
Coalbed methane (CBM) is high-quality clean energy and accurate prediction of daily gas production of CBM is critical for CBM engineering. However, the production process of CBM is a non-stable ...dynamic with significant fluctuation, and it is hard to predict by traditional statistical methods. This study processes a deep learning model T-DGCN considering time, space, and geological features for predicting complex long gas production sequences. T-DGCN innovatively measures the similarity of geological features between wells with Dynamic Time Warping (DTW), and merges geological and spatial features to dynamically correct the weight matrix in a multilayer neural network with multiple aggregations. Then, the model uses the Gated Recurrent Unit (GRU) to extract the temporal features of gas production and predict the daily gas production sequence. The experiments with the data set from Shanxi Province showed that T-DGCN achieves an accuracy of 0.9298 in short-term production prediction, which is higher than the baseline models. In addition, the geological similarity calculated by DTW in T-DGCN significantly improves the performance of the model. And T-DGCN can still have better performance in long-term prediction tasks with accuracy above 0.9. This study provides a new method for the theoretical guidance for adjusting development schemes of CBM and the prediction of long-time series in geoscience.
•A multi-feature deep learning model T-DGCN for coalbed methane production prediction.•T-DGCN integrates time, space and geological features for increasing accuracy.•The inter-well interference caused by space proximity was integrated into T-DGCN.•The similarity of geological features was measured by the Dynamic Time Warping.•T-DGCN's accuracy exceeds the baseline models' on unstable long-time series.
Atherosclerosis is a leading cause of death worldwide. Recent studies have emphasized the significance of gut microbiota and lipid metabolism in the development of atherosclerosis. Herein, the ...effects and molecular mechanisms involving ferulic acid (FA) was examined in atherosclerosis using the ApoE-knockout (ApoE
, c57BL/6 background) mouse model. Eighteen male ApoE
mice were fed a high-fat diet (HFD) for 12 weeks and then randomly divided into three groups: the model group, the FA (40 mg/kg/day) group and simvastatin (5 mg/kg/day) group. As results, FA could significantly alleviate atherosclerosis and regulate lipid levels in mice. Liver injury and hepatocyte steatosis induced by HFD were also mitigated by FA. FA improved lipid metabolism involving up-regulation of AMPKα phosphorylation and down-regulation of SREBP1 and ACC1 expression. Furthermore, FA induced marked structural changes in the gut microbiota and fecal metabolites and specifically reduced the relative abundance of
,
and
which were positively correlated with serum lipid levels in atherosclerosis mice. In conclusion, we demonstrate that FA could significantly ameliorate atherosclerotic injury, which may be partly by modulating gut microbiota and lipid metabolism via the AMPKα/SREBP1/ACC1 pathway.
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•A novel strontium-doped small intestinal submucosa (SIS) scaffold was investigated.•Sr2+ bound to the SIS scaffold via coordination.•Sr/SIS complexes enhanced SIS scaffolds’ ...mechanical properties and released Sr2+ persistently.•Sr/SIS scaffolds enhanced proliferation and osteogenic differentiation of BMSCs.
This paper describes a novel natural extracellular matrix-derived scaffold composite prepared through a coordination reaction between small intestinal submucosa (SIS) and strontium (Sr) ions. The physicochemical and biological properties of the Sr/SIS composite scaffold were investigated. The Sr/SIS complex had a porous structure and a uniform distribution of Sr2+. The coordination bond of Sr-SIS provides the Sr/SIS scaffolds with improved mechanical properties and sustained Sr2+ release.Controlled release of Sr2+ enhanced cell proliferation and osteogenic differentiation. The 1.5 wt% Sr/SIS scaffold had the best osteogenesis effect among the experimental groups, indicating its potential as a biomaterial for bone tissue engineering.
The effects of irradiating blue, UV-A, UV-B and a combination of the lights on anthocyanin accumulation at different hypocotyl positions were investigated in seedlings of the purple top turnip ...'Tsuda'. The location of anthocyanin accumulation varied depending on different light spectra. Stronger accumulation of anthocyanin was induced (i) at the upper hypocotyl positions by blue light; (ii) mainly at the upper position, but also at the middle position by UV-B light; and (iii) at the upper to lower position by UV-A light. There were synergistic effects between blue and UV-B, while such effects were not observed for the other light combinations. Among the six chalcone synthase (CHS) genes identified in the 'Tsuda' turnip, BrCHS1, 4 and 5 exhibited light-dependent expression patterns, while the other three showed no apparent light responses. The expression of BrCHS1, 4 and 5 was increased particularly by UV-A and blue + UV-B irradiation at the middle to lower hypocotyl positions, in accordance with anthocyanin accumulation patterns. The highest induction of gene expression was observed for BrCHS4 upon blue + UV-B co-irradiation. In contrast, CHS expression was induced only slightly at higher hypocotyl positions by blue light. The R2R3-type MYB transcription factor genes PAP1, MYB4, MYB12 and MYB111 exhibited differential expression patterns at different hypocotyl positions; these patterns were unique for different light spectra. These unique anthocyanin accumulation patterns and gene expression profiles depending on hypocotyl positions and light sources demonstrate that there is a distinct UV-A response, blue + UV-B synergistic response and blue/UV-A light response for anthocyanin biosynthesis in turnip. UV-A light-dependent anthocyanin biosynthesis appeared to be regulated in a manner that is distinct from that mediated by cryptochromes and UV-B photoreceptors.
Background
Microvascular invasion (MVI) is a risk factor for tumor recurrence after hepatectomy in hepatocellular carcinoma (HCC) patients.
Objective
This study aimed to investigate the efficacy and ...safety of postoperative adjuvant transarterial infusion chemotherapy (TAI) with the FOLFOX regimen for HCC patients with MVI.
Methods
In this prospective, phase III, randomized, open-label, controlled clinical trial, HCC patients with histologically confirmed MVI were randomly assigned (1:1) after hepatectomy to receive either one to two cycles of adjuvant TAI (AT group) or follow-up without any adjuvant treatment (FU group). The primary endpoint was disease-free survival (DFS), while secondary endpoints were overall survival (OS) and safety.
Results
Between June 2016 and April 2019, 127 patients were randomly assigned to the AT group (
n
= 63) or FU group (
n
= 64). Clinicopathological characteristics of the two groups were well-balanced. The 6-, 12-, and 18-month OS rates for the AT group were 100.0%, 97.7%, and 97.7%, respectively, and 94.5%, 89.6%, and 78.5% for the FU group, respectively. The 6-, 12-, and 18-month DFS rates for the AT and FU groups were 84.7%, 61.8%, and 58.7%, and 62.9%, 48.1%, and 38.6%, respectively. OS and DFS were significantly better in the AT group than in the FU group (
p
= 0.037 and 0.023, respectively). No patients in the AT group experienced grade 3 or more severe adverse events.
Conclusions
Adjuvant TAI after hepatectomy may bring survival benefits to HCC patients with MVI.
Trial registration
Trial number: NCT03192618.
•An energy-saving control strategy is proposed for multi-group lighting sources.•The proposed controller is designed to minimize the light-energy consumption.•It is designed to speed up the ...convergence rate without increasing the oscillation.•The minimal energy usage is guaranteed, while keeping the desired lighting level.•Experimental results shows the superiorities of the energy-saving control strategy.
In recent years, the energy problem has been a universal concern. In order to improve the lighting energy efficiency and reduce the electric energy consumption, this paper develops an energy-saving control strategy for the lighting system with multiple lighting sources. The control strategy presented in this paper includes two parts: a new multivariate extremum seeking control method with Newton algorithm is developed to minimize the light-energy consumption by separately manipulating the brightness of multiple lighting sources, and a proportion-integration-differentiation control approach is adopted to realize the desired lighting level. The proposed scheme can increase the convergence speed of the closed loop system toward the minimum light-energy consumption, meanwhile, the accuracy of the control strategy will be improved. Experimental results illustrate that the light-energy consumption via the proposed method can reach more rapidly to a smaller vicinity of the minimum energy point, so, the lighting energy efficiency is greatly increased accordingly.
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