Multiple myeloma (MM) is a common hematological malignancy. Drug resistance remains to be a major clinical challenge in MM therapy. In this study, we aim to investigate the functional roles of bone ...marrow mesenchymal stem cells (BMSC)-derived exosomal miR-182 on the carfilzomib resistance of MM and its underlying mechanism.
qRT-PCR and Western blot methods were utilized to confirm the gene or protein expressions. CCK-8 and transwell assays were performed to measure the capabilities of proliferation, migration, and invasion. The molecular interactions were validated through ChIP and Dual luciferase assay.
Our findings indicated that miR-182 expression was upregulated in serum, BMSCs and BMSC-derived exosomes from MM patients. Hypoxia-inducible factor-1α (HIF-1α), a key transcriptional factor in tumor microenvironment, could boost miR-182 expression by directly binding to its promoter, thus favoring exosomal secretion. Moreover, exosomal miR-182 from BMSCs could be transferred to MM cells and was able to promote malignant proliferation, metastasis, and invasion, as well as decrease the sensitivity of MM cells against carfilzomib. Additionally, SOX6 was identified as a downstream target of miR-182 in MM cells, and its expression was negatively regulated by miR-182. Rescue experiments proved that loss of SOX6 in MM cells dramatically reversed the promoting roles of BMSC-secreted exosomal miR-182 on proliferation, metastasis, and carfilzomib resistance in MM cells.
Collectively, our findings indicated that exosomal miR-182 derived from BMSCs contributed to the metastasis and carfilzomib resistance of MM cells by targeting SOX6. This study sheds light on the pathogenesis of the BMSC-derived exosome containing miR-182 in the malignant behaviors of MM cells and carfzomib resistance.
•The evaluation index system is set by the engineering and supply chain perspectives.•The interval-valued intuitionistic fuzzy set (IVIFS) to express the performances.•The IVIFS entropy weight method ...is applied to improve the objectivity of weights.
The selection of appropriate photovoltaic module is of extremely high importance for the solar power station project; however the comprehensive problem of evaluation index system, the information loss problem and the lack-objectivity problem in the selection process will decrease the reasonability of the selection result. The innovation points of this paper are as follows: first, the comprehensive evaluation index system of photovoltaic module is established from the engineering management and supply chain management perspectives to solve the comprehensive problem; second, the interval-valued intuitionistic fuzzy set (IVIFS) are introduced into the photovoltaic modules selection process to express the alternatives’ performances to solve the information loss problem; third, the IVIFS entropy weight method is applied to improve the objectivity of the criteria’s weights. According to the aforementioned solutions, the decision framework of photovoltaic module selection under interval-valued intuitionistic fuzzy environment are established and used in a case study to demonstrate its effectiveness. Therefore, from the theoretical modeling and empirical demonstration, the decision framework proposed in this paper can effectively handle such a complicated problem and lead to an outstanding result.
In the domain of optimal control for building HVAC systems, the performance of model-based control has been widely investigated and validated. However, the performance of model-based control highly ...depends on an accurate system performance model and sufficient sensors, which are difficult to obtain for certain buildings. To tackle this problem, a model-free optimal control method based on reinforcement learning is proposed to control the building cooling water system. In the proposed method, the wet bulb temperature and system cooling load are taken as the states, the frequencies of fans and pumps are the actions, and the reward is the system COP (i.e., the comprehensive COP of chillers, cooling water pumps, and cooling towers). The proposed method is based on Q-learning. Validated with the measured data from a real central chilled water system, a three-month measured data-based simulation is conducted under the supervision of four types of controllers: basic controller, local feedback controller, model-based controller, and the proposed model-free controller. Compared with the basic controller, the model-free controller can conserve 11% of the system energy in the first applied cooling season, which is greater than that of the local feedback controller (7%) but less than that of the model-based controller (14%). Moreover, the energy saving rate of the model-free controller could reach 12% in the second applied cooling season, after which the energy saving rate gets stabilized. Although the energy conservation performance of the model-free controller is inferior to that of the model-based controller, the model-free controller requires less a priori knowledge and sensors, which makes it promising for application in buildings for which the lack of accurate system performance models or sensors is an obstacle. Moreover, the results suggest that for a central chilled water system with a designed peak cooling load close to 2000 kW, three months of learning during the cooling season is sufficient to develop a good model-free controller with an acceptable performance.
Increasing evidence has revealed that microRNAs (miRNAs) are closely associated with multiple myeloma (MM) pathogenesis and progression. Therefore, an in-depth understanding of the biological ...functions of miRNAs in MM may be helpful for the identification of promising therapeutic techniques for patients with MM. miRNA-765 (miR-765) has been reported to be dysregulated in many types of human cancer. However, the expression pattern, specific roles and underlying mechanisms of miR-765 in MM remain largely unknown. In the present study, plasma miR-765 significantly increased in patients with MM and cell lines. The downregulation of miR-765 in MM cells attenuated proliferation and promoted apoptosis. Bioinformatics analysis predicted that SRY-Box 6 (SOX6) was a putative target of miR-765. This was experimentally verified using a luciferase reporter assay, reverse transcription-quantitative PCR and western blot analysis. Furthermore, plasma SOX6 was downregulated in patients with MM and the downregulation of SOX6 was inversely correlated with that of miR-765 expression. Furthermore, SOX6 knockdown markedly abrogated the effects of miR-765 underexpression on cell proliferation and apoptosis in MM. The current study demonstrated that miR-765 serves an oncogenic role in MM progression by directly targeting SOX6, suggesting that miR-765 may be a potential therapeutic target for MM prevention and treatment.
Glioma initiating cells (GICs), also known as glioma stem cells (GSCs), play an important role in the progression and recurrence of glioblastoma multiforme (GBM) due to their potential for ...self-renewal, multiple differentiation and tumor initiation. In the recent years, Notch1 has been found to be overexpressed in GICs. However, the regulatory mechanism of Notch1 in the self-renewal and invasion ability of GICs remains unclear. This study aims to explore the effect of Notch pathway on self-renewal and invasion of GICs and the underlying mechanisms.
Bioinformatic analysis and immunohistochemistry (IHC) were performed to evaluate the expression of Notch1 and Hes1 in GBM samples. Immunofluorescent (IF) staining was performed to observe the distribution of Notch1 and CXCR4 in GBM and GICs. Both pharmacological intervention and RNA interference were employed to investigate the role of Notch1 in GICs self-renewal, invasion and tumor growth in vitro or in vivo. The crosstalk effect of Notch1 and CXCL12/CXCR4 system on GIC self-renewal and invasion was explored by sphere formation assay, limiting dilution assay and Transwell assay. Western blots were used to verify the activation of Notch1/CXCR4/AKT pathway in self-renewal, invasion and tumor growth of GICs. Luciferase reporter assay was used to testify the potential binding site of Notch1 signaling and CXCR4. The orthotopic GICs implantations were established to analyze the role and the mechanism of Notch1 in glioma progression in vivo.
Notch1 signaling activity was elevated in GBM tissues. Notch1 and CXCR4 were both upregulated in GICs, compared to Notch1 positive glioma cells comprised a large proportion in the CD133+ glioma cell spheres, CXCR4 positive glioma cells which usually expressed Notch1 both and dispersed in the periphery of the sphere, only represent a small subset of CD133+ glioma cell spheres. Furthermore, downregulation of the Notch1 pathway by shRNA and MK0752 significantly inhibited the PI3K/AKT/mTOR signaling pathway via the decreased expression of CXCR4 in GICs, and weakened the self-renewal, invasion and tumor growth ability of GICs.
These findings suggest that the cross-talk between Notch1 signaling and CXCL12/CXCR4 system could contribute to the self-renewal and invasion of GICs, and this discovery could help drive the design of more effective therapies in Notch1-targeted treatment of GBMs.
Window application is the important aim for semitransparent solar cells (STPSC) investigation. Here, we demonstrate a method to achieve significantly improved color rendering index (CRI), depressed ...chromaticity difference (DC), and enhanced power conversion efficiency (PCE) simultaneously by introducing the one-dimensional photonic crystals (1DPCs) Bragg reflector structure onto the STPSC. The device performance is studied from aspects of color perception, electrical properties, and theoretical optical simulations. The STPSCs exhibit achromatic transparency nature color perceptions, especially for the STPSCs with 1DPCs (pairs ≥ 3) under AM 1.5G illumination light source, standard illuminant D65, and standard illuminant A. The excellent CRI is approaching 97 with lower DC about 0.0013 for the device with 5 pairs of 1DPC illumined by AM 1.5G illumination light source. At the same time, the PCE of STPSC devices with 5 pairs of 1DPC was improved from 4.87 ± 0.14% to 5.31 ± 0.13% compared to without. This method provides a facilitative approach to realizing excellent SPTSC window application.
Abstract
Background
To investigate the potential value of the pretreatment MRI-based radiomic model in predicting the overall survival (OS) of nasopharyngeal carcinoma (NPC) patients with local ...residual tumors after intensity-modulated radiotherapy (IMRT).
Methods
A total of 218 consecutive nonmetastatic NPC patients with local residual tumors after IMRT training cohort (n = 173) and validation cohort (n = 45) were retrospectively included in this study. Clinical and MRI data were obtained. Univariate Cox regression and the least absolute shrinkage and selection operator (LASSO) were used to select the radiomic features from pretreatment MRI. The clinical, radiomic, and combined models for predicting OS were constructed. The models’ performances were evaluated using Harrell’s concordance index (C-index), calibration curve, and decision curve analysis.
Results
The C-index of the radiomic model was higher than that of the clinical model, with the C-index of 0.788 (95% CI 0.724–0.852) versus 0.672 (95% CI 0.599–0.745) in the training cohort and 0.753 (95% CI 0.604–0.902) versus 0.634 (95% CI 0.593–0.675) in the validation cohort. Calibration curves showed good agreement between the radiomic model-predicted probability of 2- and 3-year OS and the actual observed probability in the training and validation groups. Decision curve analysis showed that the radiomic model had higher clinical usefulness than the clinical model. The discrimination of the combined model improved significantly in the training cohort (
P
< 0.01) but not in the validation cohort, with the C-index of 0.834 and 0.734, respectively. The radiomic model divided patients into high- and low-risk groups with a significant difference in OS in both the training and validation cohorts.
Conclusions
Pretreatment MRI-based radiomic model may improve OS prediction in NPC patients with local residual tumors after IMRT and may assist in clinical decision-making.
•A new attempt to introduce CO2 into the RH decarburization of ultra-low carbon steel.•Carburization and decarburization at the surface of CO2 bubbles were analyzed.•Industrial tests were carried out ...for the decarburization with pure CO2 injection.•It is practicable to replace Ar by CO2 in decarburization of ultra-low carbon steel.
In this work, carbon dioxide (CO2) was investigated as a lifting gas in the Ruhrstahl–Heraeus (RH) decarburization process of ultra-low carbon steel. The main challenge was to determine whether the local carburization reaction leads to the carburization of molten steel with ultra-low carbon content. Thermodynamic analysis of the reaction of the Fe-C-O melt with CO2 demonstrated that compared with traditional Ar injection, the decarburization rate can be improved during the early stage of the decarburization process. This occurs because oxygen that is present not only in molten steel but also produced by CO2 dissociation can react with dissolved carbon to remove the carbon from molten steel. However, it is difficult to determine whether the decarburization rate can be influenced during the later stage by injecting CO2. This is because the carburization reaction at the surface of CO2 bubbles in the up-snorkel and the decarburization reaction at other reaction sites can occur simultaneously. Industrial test results demonstrated that compared with Ar injection, the decarburization rate was not significantly affected by CO2 injection at the early stage, whereas it was reduced during the middle and later stages. Nevertheless, the average carbon content in molten steel after the RH treatment with CO2 injection was only 2.6 ppm higher compared with that in Ar injection. Therefore, Ar can potentially be replaced by CO2 in the RH decarburization process of ultra-low carbon steel based on economic and environmental considerations.
We fabricate ITO-free bulk-heterojunction polymer solar cells (PSCs) with the structure glass/WO3/Ag/WO3/P3HT:PCBM/LiF/Al. According to the J–V characterization, the device efficiency is improved by ...27.4% for the ITO-free device with a 70nm-thick active layer but reduced by 19.9% for the device with a 150nm-thick active layer, when compared with that of the PSC device with an ITO transparent electrode. Further investigation based on IPCE spectra test and transfer matrix simulations reveals that it is the optical resonance effect of the metal-mirror-microcavity (MMC) constructed between the semitransparent Ag electrode and top Al electrode that leads to the efficiency improvement for the device with 70nm-thick active layer. Meanwhile, the efficiency reduction of the device with a 150nm-thick active layer is caused by the off-resonance suppression of the MMC structure. It demonstrates that the MMC structure is an important element to be considered when the WO3/Ag/WO3 multilayer is used to substitute the ITO electrode as a transparent electrode of the PSC devices.
► Metal-mirror-microcavity was constructed between the semitransparent Ag electrode and top Al electrode. ► The microcavity effect on device performance varied with the thickness of active layer. ► Distribution of normalized modulus square of the optical electric field reveals microcavity resonance effects.
Autophagy is a vital process that involves degradation of long-lived proteins and dysfunctional organelles and contributes to cellular metabolism. Glioma-initiating cells (GICs) have the ability to ...self-renew, differentiate into heterogeneous types of tumor cells, and sustain tumorigenicity; thus, GICs lead to tumor recurrence. Accumulating evidence indicates that autophagy can induce stem cell differentiation and increase the lethality of temozolomide against GICs. However, the mechanism underlying the regulation of GIC self-renewal by autophagy remains uncharacterized. In the present study, autophagy induced by AZD8055 and rapamycin treatment suppressed GIC self-renewal in vitro. We found that autophagy inhibited Notch1 pathway activation. Moreover, autophagy activated Notch1 degradation, which is associated with maintenance of the self-renewal ability of GICs. Furthermore, autophagy abolished the tumorigenicity of CD133 + U87-MG neurosphere cells in an intracranial model. These findings suggest that autophagy regulating GICs self-renewal and tumorigenicity is probably bound up with Notch1 degradation. The results of this study could aid in the design of autophagy-based clinical trials for glioma treatments, which may be of great value.
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