Experimental and clinical validation of an artificial intelligence metal artifact correction algorithm for low-dose following up CT of percutaneous vertebroplasty.

Background: Low-dose following up computed tomography (CT) of percutaneous vertebroplasty (PVP) that involves the use of bone cement usually suffers from lightweight metal artifacts, where conventional techniques for CT metal artifact reduction are often not sufficiently effective. This study aimed to validate an artificial intelligence (AI)-based metal artifact correction (MAC) algorithm for use in low-dose following up CT for PVP. Methods: In experimental validation, an ovine vertebra phantom was designed to simulate the clinical scenario of PVP. With routine-dose images acquired prior to the cement introduction as the reference, low-dose CT scans were taken on the cemented phantom and processed with conventional MAC and AI-MAC. The resulting image quality was compared in CT attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR), followed by a quantitative evaluation of the artifact correction accuracy based on adaptive segmentation of the paraspinal muscle. In clinical validation, ten cases of low-dose following up CT after PVP were enrolled to test the performance of diagnosing sarcopenia with measured CT attenuation per cemented vertebral segment, via receiver operating characteristic (ROC) analysis. Results: With respect to the reference image, no significant difference was found for AI-MAC in CT attenuation, image noise, SNRs, and CNR (all P>0.05). The paraspinal muscle segmented on the AI-MAC image was 18.6% and 8.3% more complete to uncorrected and MAC images. Higher area under the curve (AUC) of the ROC analysis was found for AI-MAC (AUC =0.92) compared to the uncorrected (AUC =0.61) and MAC images (AUC =0.70). Conclusions: In low-dose following up CT for PVP, the AI-MAC has been fully validated for its superior ability compared to conventional MAC in suppressing artifacts and may be a reliable alternative for diagnosing sarcopenia.

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.

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.

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.

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.