Engineered Exosomes Carrying miR-588 for Treatment of Triple Negative Breast Cancer Through Remodeling the Immunosuppressive Microenvironment.

Background: The morbidity and mortality of triple-negative breast cancer (TNBC) are still high, causing a heavy medical burden. CCL5, as a chemokine, can be involved in altering the composition of the tumor microenvironment (TME) as well as the immunosuppressive degree, and has become a very promising target for the treatment of TNBC. Dysregulation of microRNAs (miRNAs) in tumor tissues is closely related to tumor progression, and its utilization can be used to achieve therapeutic purposes. Engineered exosomes can avoid the shortcomings of miRNAs and also enhance their targeting and anti-tumor effects through engineering. Therefore, we aimed to create a cRGD-modified exosome for targeted delivery of miR-588 and to investigate its effect in remodeling immunosuppressive TME by anchoring CCL5 in TNBC. Methods: In this study, we loaded miR-588 into exosomes using electroporation and modified it with cRGD using post insertion to obtain cRGD-Exos/miR-588. Transmission electron microscopy (TEM), nanoparticle tracking assay technique (NTA), Western Blots, qPCR, and flow cytometry were applied for its characterization. CCK-8, qPCR and enzyme-linked immunosorbent assay (ELISA), in vivo fluorescence imaging system, immunohistochemistry and H&E staining were used to explore the efficacy as well as the mechanism at the cellular level as well as in subcutaneous graft-tumor nude mouse model. Results: The cRGD-Exos/miR-588 was successfully constructed and had strong TNBC tumor targeting in vitro and in vivo. Meanwhile, it has significant efficacy on TME components affected by CCL5 and the degree of immunosuppression, which can effectively control TNBC with good safety. Conclusion: In this experiment, cRGD-Exos/miR-588 was prepared to remodel immunosuppressive TME by anchoring CCL5, which is affected by the vicious cycle of immune escape. Overall, cRGD-Exos/miR-588 explored the feasibility of targeting TME for the TNBC treatment, and provided a competitive delivery system for the engineered exosomes to deliver miRNAs for antitumor therapy drug.

MTX-PEG-modified CG/DMMA polymeric micelles for targeted delivery of doxorubicin to induce synergistic autophagic death against triple-negative breast cancer.

The chemotherapy of triple-negative breast cancer based on doxorubicin (DOX) regimens suffers from great challenges on toxicity and autophagy raised off-target. In this study, a conjugate methotrexate-polyethylene glycol (shorten as MTX-PEG)-modified CG/DMMA polymeric micelles were prepared to endue DOX tumor selectivity and synergistic autophagic flux interference to reduce systematic toxicity and to improve anti-tumor capacity. The micelles could effectively promote the accumulation of autophagosomes in tumor cells and interfere with the degradation process of autophagic flux, collectively inducing autophagic death of tumor cells. In vivo and in vitro experiments showed that the micelles could exert improved anti-tumor effect and specificity, as well as reduced accumulation and damage of chemotherapeutic drugs in normal organs. The potential mechanism of synergistic autophagic death exerted by the synthesized micelles in MDA-MB-231 cells has been performed by autophagic flux-related pathway.

InSAR time-series deformation forecasting surrounding Salt Lake using deep transformer models.

The free and open data policy of Sentinel-1 SAR images enables Radar interferometry (InSAR) to perform time series surface deformation monitoring over large areas. InSAR deformation monitoring and prediction can investigate the freeze-thaw cycles of permafrost on the Qinghai-Tibet Plateau. However, the convolutional and recurrent neural networks cannot accurately model long-term and complex relations in multivariate time series data, it is challenging to implement time series deformation prediction with high spatial resolution. In this paper, an innovative InSAR deformation prediction integrated algorithm based on the transformer models is proposed to predict time series deformation more accurately surrounding Salt Lake. Compared with the other solutions, the unique feature of the proposed method is that: 1) this method takes advantage of the self-attention mechanism to study complicated dynamic deformation features of permafrost caused by temperature and other variables from InSAR time series deformation. 2) The transformer-based model can more accurately simulate seasonal and non-seasonal deformation signals, and is effective for short-term prediction of surface deformation in permafrost areas. The InSAR deformation prediction results demonstrate that the InSAR deformation prediction method achieves better prediction performance in predicting the deformation trends of permafrost with a point scale compared with the prediction results of other models. Based on the predicted deformation and the water extraction results, the expansion trends surrounding Salt Lake are discussed and evaluated. The total area of Salt Lake increased by 57.32 km2 during the period 2015-2019. And Salt Lake maintained slowing expansion trend from 2019 to 2022. The time series deformation forecasting method can be used as a generic framework for modeling nonlinear deformation processes in complex permafrost areas, and it reveals the potential impact of the Salt Lake outburst event on the deformation processes and the degradation of permafrost.

Development of a 3D-printed pelvic CT phantom combined with fresh pathological tissues of bone tumor.

Background: Computed tomography (CT) imaging is the most important and common means of detecting and diagnosing pelvic bone tumors. While phantoms with sufficient flexibility and anatomical realism are useful in CT research, using phantoms has been difficult for pelvic bone tumors because of the tumors' relatively large size and highly variable shape. By combining medical 3D printing technology and fresh tumor specimens, this study aimed to design such a hybrid phantom, test its imaging properties, and demonstrate its usefulness in optimizing the CT protocols. Methods: Two phantoms were designed for 2 patients with pelvic bone tumors who underwent surgical resection. One phantom was scanned with a routine pelvic CT protocol and compared against the patient image to test the imaging properties. We optimized the imaging protocol by assessing a series of varied settings on tube voltage (80, 100, 120, and 140 kVp), tube current (80, 120, and 160 to 200 mAs), and pitch factor (0.5, 0.8, 1.1, and 1.4) using the other phantom. These were assessed in comparison to the clinical reference of 140 kVp, 240 mAs, and 1.0 pitch, respectively. Image quality was quantified in terms of CT value, image noise, signal to noise ratio (SNR), and contrast to noise ratio (CNR) in various regions of interest. Results: With the routine protocol, the phantom image showed no significant difference in CT values of the bone and soft tissues and image noise compared to the patient image (all P values >0.05). With a lower tube voltage (80, 100, and 120 kVp) than the reference protocol, the CT value of bone tissue showed significant differences (all P values <0.001). No significant difference was found when applying a reduced tube current (all P values >0.05). With an increased helical pitch, pitches of 0.5, 0.8 and 1.1 were found to be comparable to those using the reference protocol (all P values >0.05). Conclusions: The 3D-printed phantom can simulate the radiological properties of tumors in the pelvis and was successfully used in imaging studies of pelvic bone tumors. According to our preliminary findings, a low-dose pelvic CT protocol with acceptable image quality is achievable using reduced tube current or increased pitch.

Hyaluronic Acid Hydrogels Hybridized With Au-Triptolide Nanoparticles for Intraarticular Targeted Multi-Therapy of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by synovial inflammation in multiple joints. Triptolide (TP) is a disease-modifying anti-rheumatic drug (DMARD) highly effective in patients with RA and has anti-inflammatory properties. However, its clinical application has been limited owing to practical disadvantages. In the present study, hyaluronic acid (HA) hydrogel-loaded RGD-attached gold nanoparticles (AuNPs) containing TP were synthesized to alleviate the toxicity and increase therapeutic specificity. The hydrogels can be applied for targeted photothermal-chemo treatment and in vivo imaging of RA. Hydrogel systems with tyramine-modified HA (TA-HA) conjugates have been applied to artificial tissue models as surrogates of cartilage to investigate drug transport and release properties. After degradation of HA chains, heat was locally generated at the inflammation region site due to near-infrared resonance (NIR) irradiation of AuNPs, and TP was released from nanoparticles, delivering heat and drug to the inflamed joints simultaneously. RA can be penetrated with NIR light. Intraarticular administration of the hydrogels containing low dosage of TP with NIR irradiation improved the inflamed conditions in mice with collagen-induced arthritis (CIA). Additionally, in vitro experiments were applied to deeply verify the antirheumatic mechanisms of TP-PLGA-Au@RGD/HA hydrogels. TP-PLGA-Au@RGD/HA hydrogel treatment significantly reduced the migratory and invasive capacities of RA fibroblast-like synoviocytes (RA-FLS) in vitro, through the decrease of phosphorylation of mTOR and its substrates, p70S6K1, thus inhibiting the mTOR pathway.

The naturally occurring flavonoid nobiletin reverses methotrexate resistance via inhibition of P-glycoprotein synthesis.

Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA). However, after long-term treatment, some patients develop resistance. P-glycoprotein (P-gp), as an indispensable drug transporter, is essential for mediating this MTX resistance. In addition, nobiletin (NOB), a naturally occurring polymethoxylated flavonoid, has also been shown to reverse P-gp-mediated MTX resistance in RA groups; however, the precise role of NOB in this process is still unclear. Here, we administered MTX and NOB alone or in combination to collagen II-induced arthritic (CIA) mice and evaluated disease severity using the arthritis index, synovial histopathological changes, immunohistochemistry, and P-gp expression. In addition, we used conventional RNA-seq to identify targets and possible pathways through which NOB reverses MTX-induced drug resistance. We found that NOB in combination with MTX could enhance its performance in synovial tissue and decrease P-gp expression in CIA mice compared to MTX treatment alone. In vitro, in MTX-resistant fibroblast-like synoviocytes from CIA cells (CIA-FLS/MTX), we show that NOB treatment downregulated the PI3K/AKT/HIF-1α pathway, thereby reducing the synthesis of the P-gp protein. In addition, NOB significantly inhibited glycolysis and metabolic activity of CIA-FLS/MTX cells, which could reduce the production of ATP and block P-gp, ultimately decreasing the efflux of MTX and maintaining its anti-RA effects. In conclusion, this study shows that NOB overcomes MTX resistance in CIA-FLS/MTX cells through the PI3K/AKT/HIF-1α pathway, simultaneously influencing metabolic processes and inhibiting P-gp-induced drug efflux.

The endoplasmic reticulum participated in drug metabolic toxicity.

Covalent binding of reactive metabolites formed by drug metabolic activation with biological macromolecules is considered to be an important mechanism of drug metabolic toxicity. Recent studies indicate that the endoplasmic reticulum (ER) could play an important role in drug toxicity by participating in the metabolic activation of drugs and could be a primarily attacked target by reactive metabolites. In this article, we summarize the generation and mechanism of reactive metabolites in ER stress and their associated cell death and inflammatory cascade, as well as the systematic modulation of unfolded protein response (UPR)-mediated adaptive pathways.

Recent advances of nanotechnology-based tumor vessel-targeting strategies.

Tumor vessels can provide oxygen and nutrition for solid tumor tissue, create abnormal tumor microenvironment (TME), and play a vital role in the development, immune escape, metastasis and drug resistance of tumor. Tumor vessel-targeting therapy has become an important and promising direction in anti-tumor therapy, with the development of five anti-tumor therapeutic strategies, including vascular disruption, anti-angiogenesis, vascular blockade, vascular normalization and breaking immunosuppressive TME. However, the insufficient drug accumulation and severe side effects of vessel-targeting drugs limit their development in clinical application. Nanotechnology offers an excellent platform with flexible modified surface that can precisely deliver diverse cargoes, optimize efficacy, reduce side effects, and realize the combined therapy. Various nanomedicines (NMs) have been developed to target abnormal tumor vessels and specific TME to achieve more efficient vessel-targeting therapy. The article reviews tumor vascular abnormalities and the resulting abnormal microenvironment, the application of NMs in the tumor vessel-targeting strategies, and how NMs can improve these strategies and achieve multi-strategies combination to maximize anti-tumor effects.

The Role of miRNA in Tumor Immune Escape and miRNA-Based Therapeutic Strategies.

Tumor immune escape is a critical step in the malignant progression of tumors and one of the major barriers to immunotherapy, making immunotherapy the most promising therapeutic approach against tumors today. Tumor cells evade immune surveillance by altering the structure of their own, or by causing abnormal gene and protein expression, allowing for unrestricted development and invasion. These genetic or epigenetic changes have been linked to microRNAs (miRNAs), which are important determinants of post-transcriptional regulation. Tumor cells perform tumor immune escape by abnormally expressing related miRNAs, which reduce the killing effect of immune cells, disrupt the immune response, and disrupt apoptotic pathways. Consequently, there is a strong trend toward thoroughly investigating the role of miRNAs in tumor immune escape and utilizing them in tumor treatment. However, because of the properties of miRNAs, there is an urgent need for a safe, targeted and easily crossed biofilm vehicle to protect and deliver them in vivo, and exosomes, with their excellent biological properties, have successfully beaten traditional vehicles to provide strong support for miRNA therapy. This review summarizes the multiple roles of miRNAs in tumor immune escape and discusses their potential applications as an anti-tumor therapy. Also, this work proposes exosomes as a new opportunity for miRNA therapy, to provide novel ideas for the development of more effective tumor-fighting therapeutic approaches based on miRNAs.

Small-Baseline Approach for Monitoring the Freezing and Thawing Deformation of Permafrost on the Beiluhe Basin, Tibetan Plateau Using TerraSAR-X and Sentinel-1 Data.

The dynamic changes of the thawing and freezing processes of the active layer cause seasonal subsidence and uplift over a large area on the Qinghai-Tibet Plateau due to ongoing climate warming. To analyze and investigate the seasonal freeze-thaw process of the active layer, we employ the new small baseline subset (NSBAS) technique based on a piecewise displacement model, including seasonal deformation, as well as linear and residual deformation trends, to retrieve the surface deformation of the Beiluhe basin. We collect 35 Sentinel-1 images with a 12 days revisit time and 9 TerraSAR-X images with less-than two month revisit time from 2018 to 2019 to analyze the type of the amplitude of seasonal oscillation of different ground targets on the Beiluhe basin in detail. The Sentinel-1 results show that the amplitude of seasonal deformation is between -62.50 mm and 11.50 mm, and the linear deformation rate ranges from -24.50 mm/yr to 5.00 mm/yr (2018-2019) in the study area. The deformation trends in the Qinghai-Tibet Railway (QTR) and Qinghai-Tibet Highway (QTH) regions are stable, ranging from -18.00 mm to 6 mm. The InSAR results of Sentinel-1 and TerraSAR-X data show that seasonal deformation trends are consistent, exhibiting good correlations 0.78 and 0.84, and the seasonal and linear deformation rates of different ground targets are clearly different on the Beiluhe basin. Additionally, there are different time lags between the maximum freezing uplift or thawing subsidence and the maximum or minimum temperature for the different ground target areas. The deformation values of the alpine meadow and floodplain areas are higher compared with the alpine desert and barren areas, and the time lags of the freezing and thawing periods based on the Sentinel-1 results are longest in the alpine desert area, that is, 86 days and 65 days, respectively. Our research has important reference significance for the seasonal dynamic monitoring of different types of seasonal deformation and the extensive investigations of permafrost in Qinghai Tibet Plateau.

Permafrost Deformation Monitoring Along the Qinghai-Tibet Plateau Engineering Corridor Using InSAR Observations with Multi-Sensor SAR Datasets from 1997-2018.

As the highest elevation permafrost region in the world, the Qinghai-Tibet Plateau (QTP) permafrost is quickly degrading due to global warming, climate change and human activities. The Qinghai-Tibet Engineering Corridor (QTEC), located in the QTP tundra, is of growing interest due to the increased infrastructure development in the remote QTP area. The ground, including the embankment of permafrost engineering, is prone to instability, primarily due to the seasonal freezing and thawing cycles and increase in human activities. In this study, we used ERS-1 (1997-1999), ENVISAT (2004-2010) and Sentinel-1A (2015-2018) images to assess the ground deformation along QTEC using time-series InSAR. We present a piecewise deformation model including periodic deformation related to seasonal components and interannual linear subsidence trends was presented. Analysis of the ERS-1 result show ground deformation along QTEC ranged from -5 to +5 mm/year during the 1997-1999 observation period. For the ENVISAT and Sentinel-1A results, the estimated deformation rate ranged from -20 to +10 mm/year. Throughout the whole observation period, most of the QTEC appeared to be stable. Significant ground deformation was detected in three sections of the corridor in the Sentinel-1A results. An analysis of the distribution of the thaw slumping region in the Tuotuohe area reveals that ground deformation was associated with the development of thaw slumps in one of the three sections. This research indicates that the InSAR technique could be crucial for monitoring the ground deformation along QTEC.