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Published: 25 September 2020
by MDPI
Sensors, Volume 20; doi:10.3390/s20195484

Abstract:
Scattering hyperspectral technology is a nondestructive testing method with many advantages. Here, we propose a method to improve the accuracy of egg freshness, research the influence of incident angles of light source on the accuracy, and explain its mechanism. A variety of weak classifiers classify eggs based on the spectra after preprocessing and feature wavelength extraction to obtain three classifiers with the highest accuracy. The three classifiers are used as metamodels of stacking ensemble learning to improve the highest accuracy from 96.25% to 100%. Moreover, the highest accuracy of scattering, reflection, transmission, and mixed hyperspectral of eggs are 100.00%, 88.75%, 95.00%, and 96.25%, respectively, indicating that the scattering hyperspectral for egg freshness detection is better than that of the others. In addition, the accuracy is inversely proportional to the angle of incidence, i.e., the smaller the incident angle, the camera collects a larger proportion of scattering light, which contains more biochemical parameters of an egg than that of reflection and transmission. These results are very important for improving the accuracy of non-destructive testing and for selecting the incident angle of a light source, and they have potential applications for online non-destructive testing.
Published: 25 September 2020
by MDPI
Brain Sciences, Volume 10; doi:10.3390/brainsci10100666

Abstract:
Background: Neuroinvasion of severe acute respiratory syndrome coronavirus (SARS-CoV) is well documented and, given the similarities between this virus and SARS-CoV-2, it seems that the neurological impairment that is associated with coronavirus disease 2019 (COVID-19) is due to SARS-CoV-2 neuroinvasion. Hypothalamic circuits are exposed to the entry of the virus via the olfactory bulb and interact centrally with crucial respiratory nuclei. Hypothalamic microRNAs are considered as potential biomarkers and modulators for various diseases and future therapeutic targets. The present study aims to investigate the microRNAs that regulate the expression of hypothalamic angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), essential elements for SARS-CoV-2 cell entry. Methods: To determine potential hypothalamic miRNAs that can directly bind to ACE2 and TMPRSS2, multiple target bioinformatics prediction algorithms were used, including miRBase, Target scan, and miRWalk2.029. Results: Our in silico analysis has revealed that, although there are over 5000 hypothalamic miRNAs, around 31 miRNAs and 29 miRNAs have shown binding sites and strong binding capacity against ACE2 and TMPRSS2, respectively. Conclusion: These novel potential hypothalamic miRNAs can be used to identify new therapeutic targets to treat neurological symptoms in COVID-19 patients via regulation of ACE2 and TMPRSS2 expression.
Published: 25 September 2020
by MDPI
Applied Sciences, Volume 10; doi:10.3390/app10196697

Abstract:
In this research work, thermal foaming of bottom ash and sodium silicate geopolymer is proposed as a production process for light weight bricks. The composition and temperatures were studied and optimized to get the most suitable intumescence properties for the lightweight construction applications. For this purpose, four different compositions (i.e., 10%, 20%, 30%, and 40% bottom ash (BA)) were cured at four different curing temperatures (CT) (i.e., 200, 400, 500, and 600 °C). Sodium silicate (SS) to sodium hydroxide (SH) ratio was kept constant in order to keep the activation capacity of the solution constant in all the samples so that the effect of composition and CT could be studied effectively. All samples were characterized by bulk density, foamability, compression test, XRD, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), water absorption index (WAI), and weight loss index (WLI). These characterizations finally led to the optimized parameters to get the most appropriate intumescence properties. It was found that bottom ash and sodium silicate geopolymer foams have good potential to produce lightweight aerated blocks.
Lifeng Li, Wenhua Xue, Zhibo Shen, Jie Liu, Min Hu, Zhenyong Cheng, Yuxing Wang, Yulu Chen, Hao Chang, Yingyi Liu, et al.
Published: 25 September 2020
Molecular Therapy - Oncolytics, Volume 18, pp 215-225; doi:10.1016/j.omto.2020.06.013

Abstract:
Therapeutic targeting of advanced or metastatic non-small-cell lung cancer (NSCLC) represents a major goal of clinical treatment. Polo-like kinase 1 (PLK1) is an essential mitotic kinase in cell cycle progression and is associated with oncogenesis in a large spectrum of cancer types, including NSCLC. Volasertib (BI 6727) is a potent, selective, PLK1 inhibitor that is currently under phase 2 clinical trials with modest antitumor activity against solid tumors. As the combination of volasertib with pemetrexed does not improve efficacy for NSCLC treatment, it is crucial to identify compounds that could enhance efficacy with volasertib. Immunomodulatory drugs (IMiDs) bind to E3 ligase CRBN and repurposes it to ubiquitinate other proteins as neo-substrates, representing an effective treatment for hematologic malignancies. In this study, by screening IMiDs, we found that a novel CRBN modulator, CC-885, can synergistically inhibit NSCLC with volasertib both in vitro and in vivo. This synergistic effect overcomes volasertib resistance caused by PLK1 mutations and is compromised in CRBN-or p97-depleted cells. Mechanistically, CC-885 selectively promotes CRBN- and p97-dependent PLK1 ubiquitination and degradation, thereby enhancing the sensitivity of NSCLC to volasertib. In conclusion, our findings reveal that PLK1 is a neo-substrate of CUL4-CRBN induced by CC-885 and represent a combinational approach for treating NSCLC.
Angelique Sao-Mai Sy Do, Takayuki Amano, Lincoln A. Edwards, Lei Zhang, Mariza De Peralta-Venturina, Sciprofile linkJohn S. Yu
Published: 25 September 2020
Molecular Therapy - Oncolytics, Volume 18, pp 295-303; doi:10.1016/j.omto.2020.06.019

Abstract:
Cancer stem cells are initiating cells of cancer and propagate its growth through self-renewal and differentiation of its daughter cells. CD133 is a cell surface antigen that is present on glioma stem cells and has been used to prospectively isolate glioma stem cells. We hypothesized that a major histocompatibility complex (MHC)-independent and long-lasting immune response against CD133 could be generated by transfecting CD133 mRNA into dendritic cells and vaccinating animals with experimental gliomas. To test this hypothesis, we developed a novel humanized mouse model using CD34-positive hematopoietic stem cells. We confirmed the robust simultaneous activation of CD8- and CD4-positive T cells by dendritic cell vaccination with modified CD133 mRNA leading to a potent and long-lived immune response, with subsequent abrogation of CD133-positive glioma stem cell propagation and tumor growth. This study for the first time demonstrates in both a humanized mouse model and in a syngeneic mouse model of glioblastoma that targeting a glioma stem cell-associated antigen is an effective strategy to target and kill glioma stem cells. This novel and simple humanized mouse model for immunotherapy is a significant advance in our ability to test human-specific immunotherapies for glioblastoma.
Jamal Alzubi, Viviane Dettmer-Monaco, Johannes Kuehle, Niko Thorausch, Maximilian Seidl, Sanaz Taromi, Wolfgang Schamel, Robert Zeiser, Hinrich Abken, Sciprofile linkToni Cathomen, et al.
Published: 25 September 2020
Molecular Therapy - Oncolytics, Volume 18, pp 226-235; doi:10.1016/j.omto.2020.06.014

Abstract:
While chimeric antigen receptor (CAR) T cell immunotherapy targeting CD19 has shown remarkable success in patients with lymphoid malignancies, the potency of CAR T cells in solid tumors is low so far. To improve the efficacy of CAR T cells targeting prostate carcinoma, we designed a novel CAR that recognizes a new epitope in the prostate-specific membrane antigen (PSMA) and established novel paradigms to apply CAR T cells in a preclinical prostate cancer model. In vitro characterization of the D7 single-chain antibody fragment-derived anti-PSMA CAR confirmed that the choice of the co-stimulatory domain is a major determinant of CAR T cell activation, differentiation, and exhaustion. In vivo, focal injections of the PSMA CAR T cells eradicated established human prostate cancer xenografts in a preclinical mouse model. Moreover, systemic intravenous CAR T cell application significantly inhibited tumor growth in combination with non-ablative low-dose docetaxel chemotherapy, while docetaxel or CAR T cell application alone was not effective. In conclusion, the focal application of D7-derived CAR T cells and their combination with chemotherapy represent promising immunotherapeutic avenues to treat local and advanced prostate cancer in the clinic.
Jia-Bao Yan, Chien-Cheng Lai, Jin-Wei Jhu, Brendan Gongol, Traci L. Marin, Shih-Chieh Lin, Hsiang-Yi Chiu, Chia-Jui Yen, Liang-Yi Wang, Sciprofile linkI-Chen Peng
Published: 25 September 2020
Molecular Therapy - Oncolytics, Volume 18, pp 282-294; doi:10.1016/j.omto.2020.06.010

Abstract:
Type 2 diabetes mellitus (T2DM) is a frequent comorbidity of cancer. Hyperinsulinemia secondary to T2DM promotes cancer progression, whereas antidiabetic agents, such as metformin, have anticancer effects. However, the detailed mechanism for insulin and metformin-regulated cancer cell proliferation remains unclear. This study identified a mechanism by which insulin upregulated the expression of c-Myc, sterol regulatory element-binding protein 1 (SREBP1), and acetyl-coenzyme A (CoA) carboxylase 1 (ACC1), which are important regulators of lipogenesis and cell proliferation. Thymine DNA glycosylase (TDG), a DNA demethylase, was transactivated by c-Myc upon insulin treatment, thereby decreasing 5-carboxylcytosine (5caC) abundance in the SREBP1 promoter. On the other hand, metformin-activated AMP-activated protein kinase (AMPK) increased DNA methyltransferase 3A (DNMT3A) activity to increase 5-methylcytosine (5mC) abundance in the TDG promoter. This resulted in decreased TDG expression and enhanced 5caC abundance in the SREBP1 promoter. These findings demonstrate that c-Myc activates, whereas AMPK inhibits, TDG-mediated DNA demethylation of the SREBP1 promoter in insulin-promoted and metformin-suppressed cancer progression, respectively. This study indicates that TDG is an epigenetic-based therapeutic target for cancers associated with T2DM.
Xiangyu Zhao, Junfang Yang, Xian Zhang, Xin-An Lu, Min Xiong, Jianping Zhang, Xiaosu Zhou, Feifei Qi, Ting He, Yanping Ding, et al.
Published: 25 September 2020
Molecular Therapy - Oncolytics, Volume 18, pp 272-281; doi:10.1016/j.omto.2020.06.016

Abstract:
CD19-directed chimeric antigen receptor-T (CAR-T) cells with a 4-1BB or CD28 co-stimulatory domain have shown impressive antitumor activity against relapsed or refractory B cell acute lymphoblastic leukemia (r/r B-ALL). However, a parallel comparison of their performances in r/r B-ALL therapy has not been sufficiently reported. Here, we manufactured 4-1BB- and CD28-based CD19 CAR-T cells using the same process technology and evaluated their efficacy and safety in r/r B-ALL therapy based on pre-clinical and exploratory clinical investigations. In B-ALL-bearing mice, a similar antitumor effect and CAR-T kinetics in peripheral blood were observed at the CAR-T dose of 1 × 107/mouse. However, when the dose was decreased to 1 × 106/mouse, 4-1BB CAR-T cells were more potent in eradicating tumor cells and showed longer persistence than CD28 CAR-T cells. Retrospective analysis of an exploratory clinical study that used 4-1BB- or CD28-based CAR-T cells to treat r/r B-ALL was performed. Compared with CD28 CAR-T cells, 4-1BB CAR-T cells resulted in higher antitumor efficacy and less severe adverse events. This study demonstrated that the performance of 4-1BB CAR-T cells was superior to that of CD28 CAR-T cells in suppressing CD19+ B-ALL, at least under our manufacturing process.
Zhen-Jian Zhuo, Rui-Xi Hua, Zhen Chen, Jinhong Zhu, Mi Wang, Zhonghua Yang, Jiao Zhang, Yong Li, Li Li, Suhong Li, et al.
Published: 25 September 2020
Molecular Therapy - Oncolytics, Volume 18, pp 118-125; doi:10.1016/j.omto.2020.06.007

Abstract:
Hepatoblastoma is a rare disease, and its etiology remains to be revealed. Wilms tumor suppressor-1-associated protein (WTAP) plays a critical role in tumorigenesis. However, whether single nucleotide polymorphisms (SNPs) of the WTAP gene predispose to hepatoblastoma risk awaits to be investigated. With the use of the TaqMan assay, we evaluated the genotype frequencies of three WTAP SNPs (rs7766006 G > T, rs9457712 G > A, and rs1853259 A > G) in Chinese children with 313 hepatoblastoma patients and 1,446 controls. Among these three SNPs, only the rs7766006 T allele exhibited a significant association with hepatoblastoma risk (GT versus GG: adjusted odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.53–0.92, p = 0.009; GT/TT versus GG: adjusted OR = 0.73, 95% CI = 0.57–0.95, p = 0.017). Combined analysis indicated that subjects with two risk genotypes showed significantly higher hepatoblastoma risk, compared to individuals without a risk genotype (adjusted OR = 1.38, 95% CI = 1.02–1.88, p = 0.037). The stratified analysis revealed that the rs1853259 GG genotype, the rs7766006 GT/TT genotype, and two risk genotypes modified hepatoblastoma risk in certain subgroups. The significant results were validated by haplotype analyses and false-positive report probability analyses. Furthermore, the expression quantitative trait locus analysis indicated that rs7766006 T was associated with decreased expression of WTAP mRNA. Collectively, our results suggest that WTAP SNPs may be genetic modifiers for the development of hepatoblastoma.
Published: 25 September 2020
by MDPI
Sensors, Volume 20; doi:10.3390/s20195483

Abstract:
Most methods for sudden cardiac death (SCD) prediction require long-term (24 h) electrocardiogram recordings to measure heart rate variability (HRV) indices or premature ventricular complex indices (with the heartprint method). This work aimed to identify the best combinations of HRV and heartprint indices for predicting SCD based on short-term recordings (1000 heartbeats) through a support vector machine (SVM). Eleven HRV indices and five heartprint indices were measured in 135 pairs of recordings (one before an SCD episode and another without SCD as control). SVMs (defined with a radial basis function kernel with hyperparameter optimization) were trained with this dataset to identify the 13 best combinations of indices systematically. Through 10-fold cross-validation, the best area under the curve (AUC) value as a function of γ (gamma) and cost was identified. The predictive value of the identified combinations had AUCs between 0.80 and 0.86 and accuracies between 80 and 86%. Further SVM performance tests on a different dataset of 68 recordings (33 before SCD and 35 as control) showed AUC = 0.68 and accuracy = 67% for the best combination. The developed SVM may be useful for preventing imminent SCD through early warning based on electrocardiogram (ECG) or heart rate monitoring.
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