The receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by preventing macrophage phagocytosis.

The development of a vaccine specific to severe acute respiratory syndrome coronavirus 2 Omicron has been hampered due to its low immunogenicity. Here, using reverse mutagenesis, we found that a phenylalanine-to-serine mutation at position 375 (F375S) in the spike protein of Omicron to revert it to the sequence found in Delta and other ancestral strains significantly enhanced the immunogenicity of Omicron vaccines. Sequence FAPFFAF at position 371-377 in Omicron spike had a potent inhibitory effect on macrophage uptake of receptor-binding domain (RBD) nanoparticles or spike-pseudovirus particles containing this sequence. Omicron RBD enhanced binding to Siglec-9 on macrophages to impair phagocytosis and antigen presentation and promote immune evasion, which could be abrogated by the F375S mutation. A bivalent F375S Omicron RBD and Delta-RBD nanoparticle vaccine elicited potent and broad nAbs in mice, rabbits and rhesus macaques. Our research suggested that manipulation of the Siglec-9 pathway could be a promising approach to enhance vaccine response.

Design and Implementation of Machine Tool Life Inspection System Based on Sound Sensing.

The main causes of damage to industrial machinery are aging, corrosion, and the wear of parts, which affect the accuracy of machinery and product precision. Identifying problems early and predicting the life cycle of a machine for early maintenance can avoid costly plant failures. Compared with other sensing and monitoring instruments, sound sensors are inexpensive, portable, and have less computational data. This paper proposed a machine tool life cycle model with noise reduction. The life cycle model uses Mel-Frequency Cepstral Coefficients (MFCC) to extract audio features. A Deep Neural Network (DNN) is used to understand the relationship between audio features and life cycle, and then determine the audio signal corresponding to the aging degree. The noise reduction model simulates the actual environment by adding noise and extracts features by Power Normalized Cepstral Coefficients (PNCC), and designs Mask as the DNN's learning target to eliminate the effect of noise. The effect of the denoising model is improved by 6.8% under Short-Time Objective Intelligibility (STOI). There is a 3.9% improvement under Perceptual Evaluation of Speech Quality (PESQ). The life cycle model accuracy before denoising is 76%. After adding the noise reduction system, the accuracy of the life cycle model is increased to 80%.

Structure of LINC00511-siRNA-conjugated nanobubbles and improvement of cisplatin sensitivity on triple negative breast cancer.

The drug resistance of triple negative breast cancer (TNBC) is considered as a major obstacle for the curative effect of chemotherapy. Long intergenic noncoding RNA 00511 (LINC00511) has been considered as a target gene of drug resistance. A novel theranostic agent loaded with LINC00511-siRNA to deliver siRNA was structured, and the responses of drug sensitivity in TNBC were detected. Next-generation high-throughput RNA sequencing (RNA-Seq) was performed to accurately analyze the differential expression of mRNAs and lncRNA targets after LINC00511-siRNA transfection with low-frequency ultrasound (LFUS). The LINC00511-siRNA conjugated nanobubble complexes showed appropriate characterization, with a mean diameter of 516.1 ± 24.7 nm and a zeta potential of -38.05 ± 0.24 mV. The transfection efficiency of nanobubble complexes was approximately 50% with LFUS. By RNA-Seq, the differential expressions of lncRNA transcripts and mRNA transcripts were identified, and then analyzed. The GO and KEGG enrichment analyses revealed the TNBC drug resistance related target genes and pathways. The combination of LFUS irradiation and nanobubble complexes is regarded as an efficient and safe method for siRNA transfection. The TNBC drug resistance occurs as a result of synergistic reactions between a variety of genes and a variety of pathways.

Highly penetrating nanobubble polymer enhances LINC00511-siRNA delivery for improving the chemosensitivity of triple-negative breast cancer.

Ultrasound-mediated nanobubble destruction (UMND), which can utilize the physical energy of ultrasound irradiation to improve the transfer efficiency to target cells is becoming one of the most promising carriers for gene delivery. The purpose of this study was to establish cell-penetrating peptide (CPP)-loaded nanobubbles (CNBs) connected with long intergenic nonprotein coding RNA 00511-small interfering RNA (LINC00511-siRNA) and evaluate its feasibility for improving the chemosensitivity of triple-negative breast cancer in vitro. First, fluorescence imaging confirmed the loading of siLINC00511 on CNBs, and the CNBs-siLINC00511 were characterized by the Zetasizer Nano ZS90 analyzer and transmission electron microscopy. Next, cell counting kit 8 assay was used to detect the inhibitory activity of cisplatin on the proliferation of MDA-MB-231 cells, and the 50% inhibition concentration value before and after transfer was calculated. Finally, the silencing effect of siLINC00511 was evaluated in vitro using an apoptosis assay, transwell assay, real time-PCR and western blotting. UMND combined with CNBs could effectively transfer the siRNA to MDA-MB-231 cells, thus evidently reducing the expression of LINC00511. Furthermore, inhibitory activity of cisplatin on MDA-MB-231 cells was enhanced after downregulation of LINC00511 expression. Downregulation of LINC00511 alters expression of cell cycle-related (CDK 6) and apoptosis-related (Bcl-2 and Bax) proteins in MDA-MB-231 cells. These results suggested that siRNA-CNBs may be an ideal vector for the treatment of tumors, with high efficiency RNA interference under the combined action of UMND. It may provide a new therapeutic method for triple negative breast cancer.

Single-cell RNA sequencing reveals the mechanism of sonodynamic therapy combined with a RAS inhibitor in the setting of hepatocellular carcinoma.

BACKGROUND: Ras activation is a frequent event in hepatocellular carcinoma (HCC). Combining a RAS inhibitor with traditional clinical therapeutics might be hampered by a variety of side effects, thus hindering further clinical translation. Herein, we report on integrating an IR820 nanocapsule-augmented sonodynamic therapy (SDT) with the RAS inhibitor farnesyl-thiosalicylic acid (FTS). Using cellular and tumor models, we demonstrate that combined nanocapsule-augmented SDT with FTS induces an anti-tumor effect, which not only inhibits tumor progression, and enables fluorescence imaging. To dissect the mechanism of a combined tumoricidal therapeutic strategy, we investigated the scRNA-seq transcriptional profiles of an HCC xenograft following treatment. RESULTS: Integrative single-cell analysis identified several clusters that defined many corresponding differentially expressed genes, which provided a global view of cellular heterogeneity in HCC after combined SDT/FTS treatment. We conclude that the combination treatment suppressed HCC, and did so by inhibiting endothelial cells and a modulated immunity. Moreover, hepatic stellate secretes hepatocyte growth factor, which plays a key role in treating SDT combined FTS. By contrast, enrichment analysis estimated the functional roles of differentially expressed genes. The Gene Ontology terms "cadherin binding" and "cell adhesion molecule binding" and KEGG pathway "pathway in cancer" were significantly enriched by differentially expressed genes after combined SDT/FTS therapy. CONCLUSIONS: Thus, some undefined mechanisms were revealed by scRNA-seq analysis. This report provides a novel proof-of-concept for combinatorial HCC-targeted therapeutics that is based on a non-invasive anti-tumor therapeutic strategy and a RAS inhibitor.

Long noncoding RNA DUXAP10 promotes the stemness of glioma cells by recruiting HuR to enhance Sox12 mRNA stability.

Long noncoding RNA (lncRNA) DUXAP10 has been shown to act as an oncogene in various tumors; however, its roles in glioma progression have never been established. Here, we show that DUXAP10 is overexpressed in glioma tissues and cells. Loss of function experiments reveal that DUXAP10 knockdown has little effects on glioma cell viability, but significantly reduces the stemness of glioma cells, which is characterized as the decrease of stemness marker expression, tumor sphere-forming ability, and ALDH activity. RNA immunoprecipitation and immunofluorescence assays indicate that DUXAP10 can directly interact with HuR protein and suppress the cytoplasm-nuclear translocation of HuR, which subsequently enhances Sox12 mRNA stability in cytoplasm and thus increases Sox12 expression. Further rescuing experiments show that the HuR/Sox12 axis is responsible for DUXAP10-mediated effects on glioma cell stemness.

Preparation of novel targeting nanobubbles conjugated with small interfering RNA for concurrent molecular imaging and gene therapy in vivo.

The aim of this study was to establish a novel targeting nanobubble (TNB) conjugated with small interfering RNA (siRNA)-cyanine 5 (Cy5) and to validate its theranostic ability in vivo. The TNB conjugated with neuroepithelial transforming gene 1 (NET-1) siRNA-Cy5 was prepared by thin-film hydration and mechanical sonication method. A hepatocellular carcinoma (HCC) xenograft model was established by subcutaneously injecting SMMC-7721 cells in BALB/c nude mice. The NET-1 siRNA-conjugated TNB was utilized for accurate contrast-enhanced ultrasound in vivo imaging, which was enabled by the target ligand GPC-3 antibody and specific gene transfection with the aid of low-frequency ultrasound (LFUS) irradiation. BALB/c nude mice bearing tumors were randomized into 5 groups and irradiated with LFUS for 5 min after TNB administration; mice were treated twice a week for a total of 60 d. The mean particle size of TNB was <500 nm. Mice treated with NET-1 siRNA-conjugated TNB showed a significant decrease in tumor growth and the highest survival rate. Our findings offer an effective and safe gene vehicle and probe for molecular imaging in vivo. It may improve the early diagnosis and treatment effects of HCC.-Wu, B., Shang, H., Liang, X., Sun, Y., Jing, H., Han, X., Cheng, W. Preparation of novel targeting nanobubbles conjugated with small interfering RNA for concurrent molecular imaging and gene therapy in vivo.

Quantitative dynamic contrast-enhanced ultrasound to predict intrahepatic recurrence of hepatocellular carcinoma after radiofrequency ablation: a cohort study.

PURPOSE: Quantitative dynamic contrast-enhanced ultrasonography (CEUS) reflects tumor blood perfusion. There are very few studies on the relationship between intrahepatic recurrence of hepatocellular carcinoma (HCC) and tumor perfusion. We investigated the correlation of dynamic CEUS parameters with intrahepatic recurrence after radiofrequency ablation (RFA). METHODS: This retrospective study enrolled 125 native HCC patients who underwent RFA between September 2017 and January 2019 with curative intent. Pre-ablation quantitative dynamic CEUS was performed. CEUS parameters were extracted from time-intensity curves. The correlation of CEUS parameters with intrahepatic recurrence was investigated. RESULTS: The mean follow-up time was 21.6 ± 7.9 months. The recurrence rate was 33.6%. Univariate and multivariate analyses revealed that tumor peak intensity (PI) was a significant independent risk factor for intrahepatic recurrence after RFA (hazard ratio (HR), 0.3; 95% CI, 0.1-0.9). A PI of 58.8% (area under curve, 0.72; 95% CI, 0.63-0.81) was considered as the optimal cutoff level to predict the intrahepatic recurrence of HCC in patients after RFA. The recurrence-free survival rate in patients with a PI > 58.8% was 94.4% at 1 year and 77.8% at 2 years. Subgroup analysis showed that the HR of time to peak (TTP) in intrahepatic recurrence was 1.1417 (95% CI, 0.9748-1.1436; p = 0.1973) in the patient group with tumor diameter > 31 mm. CONCLUSION: CEUS is commonly used in HCC patients who undergo RFA. The CEUS parameters PI and TTP are associated with intrahepatic recurrence after RFA, and can thus be used to identify patients at risk for intrahepatic recurrence.

Evaluation of the thyroid characteristics of patients with growth hormone-secreting adenomas.

BACKGROUND: Acromegaly is highly associated with thyroid disorders. However, the clinical characteristics of thyroid nodules in individuals with acromegaly who present with thyroid diseases have not been completely elucidated. METHODS: Overall, 134 consecutive participants with growth hormone (GH)-secreting adenoma (n = 67) and non-functioning (NF) pituitary adenoma (n = 67) were recruited from the outpatient and inpatient patient department of The First Affiliated Hospital, Jinan University from August 2015 to August 2017. Thyroid ultrasonography was performed using an ultrasound system. The cytopathological results of fine-needle aspiration biopsy were analyzed by a pathologist according to the Bethesda system. Twenty-one patients with GH-secreting adenoma and thyroid disease underwent transsphenoidal pituitary adenoma resection and were followed up for 1 year. RESULTS: The prevalence of thyroid disease increased in the GH-secreting adenoma group compared with that in the NF pituitary adenoma group. The number of hypoechoic, isoechogenic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenoma plus thyroid disease compared with that in patients with NF pituitary adenoma plus thyroid disease. Finally, we found significant decreases in the morphology of solid nodules and significant increases in the morphology of cystic nodules after surgery compared with those before surgery in the cured group. Moreover, the numbers of heterogeneous and vascular thyroid nodules decreased significantly after surgery compared with those before surgery in the cured group. However, the characteristics of the thyroid nodules did not change after surgery compared with those before surgery in the non-cured group. CONCLUSIONS: The numbers of hypoechoic, isoechoic, heterogeneous, and vascular thyroid nodules increased in patients with GH-secreting adenomas. In these patients, surgery resulted in significant changes from solid to cystic nodules and also reduced the numbers of heterogeneous and vascular thyroid nodules.

Targeted nanobubbles in low-frequency ultrasound-mediated gene transfection and growth inhibition of hepatocellular carcinoma cells.

The use of SonoVue combined with ultrasound exposure increases the transfection efficiency of short interfering RNA (siRNA). The objective of this study was to prepare targeted nanobubbles (TNB) conjugated with NET-1 siRNA and an antibody GPC3 to direct nanobubbles to hepatocellular carcinoma cells. SMMC-7721 human hepatocellular carcinoma cells were treated with six different groups. The transfection efficiency and cellular apoptosis were measured by flow cytometry. The protein and messenger RNA (mRNA) expression were measured by Western blot and quantitative real-time PCR, respectively. The migration and invasion potential of the cells were determined by Transwell analysis. The results show that US-guided siRNA-TNB transfection effectively enhanced gene silencing. In summary, siRNA-TNB may be an effective delivery vector to mediate highly effective RNA interference in tumor treatment.

Evaluation of a large adrenal carcinoma with 3D reconstruction of computed tomography images: A case report and literature review.

Adrenocortical carcinoma (ACC) is an extremely rare disease caused by a cancerous growth in the adrenal cortex. Although most of adrenal tumors are benign, the functional ACC is malignant resulting in endocrine dysfunction and necessitates surgical removal. Retroperitoneal laparoscope adrenalectomy is often used to perform adrenal gland surgery. Here, we reported a case of huge ACC with the size of 6.8 cm × 5.2 cm. To achieve better surgical outcome, we integrated 3D reconstructed CT images into a dynamic video for preoperative planning and intraoperative guiding to resect the diseased adrenal gland completely without neighbor organ's injury and surgery complications. Moreover, we reviewed associated applications using 3D reconstructed CT imaging in surgery field. Finally, the evaluation and effect of such technology were discussed to reveal that the 3D dynamic video can help surgeon to make better preoperative assessment so as to give patients better therapy.

A tetravalent nanoparticle vaccine elicits a balanced and potent immune response against dengue viruses without inducing antibody-dependent enhancement.

Dengue fever is a global health threat caused by the dengue virus (DENV), a vector-borne and single-stranded RNA virus. Development of a safe and efficacious vaccine against DENV is a demanding challenge. The greatest pitfall in the development of vaccines is antibody-dependent enhancement (ADE), which is closely associated with disease exacerbation. We displayed the modified envelope proteins from the four serotypes of the DENV on a 24-mer ferritin nanoparticle, respectively. This tetravalent nanoparticle vaccine induced potent humoral and cellular immunity in mice without ADE and conferred efficient protection against the lethal challenge of DENV-2 and DENV-3 in AG6 mice. Further exploration of immunization strategies showed that even single-dose vaccination could reduce pathologic damage in BALB/c mice infected with high doses of DENV-2. Treatment with cyclic-di-guanosine monophosphate facilitated a higher titer of neutralizing antibodies and a stronger type-1 T-helper cell-biased immune response, thereby revealing it to be an effective adjuvant for dengue nanoparticle vaccines. These data suggest that a promising tetravalent nanoparticle vaccine could be produced to prevent DENV infection.

IR-820@NBs Combined with MG-132 Enhances the Anti-Hepatocellular Carcinoma Effect of Sonodynamic Therapy.

Purpose: Sonodynamic therapy (SDT) is a promising and significant measure for the treatment of tumors. However, the internal situation of hepatocellular carcinoma (HCC) is complex, separate SDT treatment is difficult to play a good therapeutic effect. Here, we used SDT combined with MG-132 to mediate apoptosis and autophagy of HCC cells to achieve the purpose of treatment of cancer. Methods: To determine the generated reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm), HepG2 cells were stained by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide (JC-1) staining to determine the IR-820@NBs-mediated SDT to achieve HCC therapy through the mitochondrial pathway. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to detect cell viability and apoptosis rate of HepG2 cells. Autophagy was detected by mCherry-GFP-LC3B fluorescence labeling. Chloroquine (Cq) pretreatment was used to explore the relationship between autophagy and apoptosis. To detect the ability of HepG2 cells migration and invasion, cell scratch assay and transwell assay were used. Results: The successfully prepared IR-820@NBs could effectively overcome the shortcomings of IR-820 and induce lethal levels of ROS by ultrasound irradiation. As a dual agonist of apoptosis and autophagy, MG-132 could effectively enhance the efficacy of SDT in the process of treating HCC. After pre-treatment with Cq, the cell activity increased and the level of apoptosis decreased, which proved that apoptosis and autophagy were induced by combined therapy, autophagy, and apoptosis have the synergistic anti-tumor effect, and part of apoptosis was autophagy-dependent. After combined therapy, the activity and invasive ability of HCC cells decreased significantly. Conclusion: SDT combined with MG-132 in the process of treating liver cancer could effectively induce apoptosis and autophagy anti-tumor therapy, which is helpful to the research of new methods to treat liver cancer.

Clinical value of combined preoperative-postoperative neutrophil-to-lymphocyte ratio in predicting hepatocellular carcinoma prognosis after radiofrequency ablation.

OBJECTIVE: Previous studies focused on the prognostic significance of the pre- or post-operative neutrophil-lymphocyte ratio (NLR); the significance of combined pre- and post-operative NLR (PP-NLR) remains unknown. Therefore, we investigated the value of PP-NLR for predicting prognosis after radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) to improve treatment and prolong survival. METHODS: We investigated pre- and post-operative NLR and PP-NLR in predicting prognosis after RFA in patients with HCC. Optimal thresholds for leukocytes, lymphocytes, neutrophils, and NLR before and after RFA were retrospectively assessed in patients with HCC who had undergone RFA between January 2018 and June 2019 in Harbin Medical University Cancer Hospital. Risk factors for early HCC recurrence and those affecting recurrence-free survival (RFS) were analyzed. RESULTS: The respective pre- and post-operative optimal thresholds were as follows: neutrophils, 3.431 and 4.975; leukocytes, 5.575 and 6.61; lymphocytes, 1.455 and 1.025; and NLR, 1.53 and 4.36. Univariate analysis revealed tumor number; alpha-fetoprotein level; post-operative leukocytes, lymphocytes, NLR, and neutrophils; pre-operative neutrophils and NLR; and PP-NLR as factors influencing early recurrence and RFS. Multivariate analysis indicated PP-NLR as an independent risk factor for poor RFS and early recurrence. CONCLUSION: PP-NLR was more effective for predicting prognosis than pre- or post-operative NLR alone for patients with HCC. ADVANCES IN KNOWLEDGE: The novelty of this study lies in the combination of pre- and post-operative NLR, namely PP-NLR, to study its prognostic value for HCC patients after RFA, which has not been found in previous studies. The contribution of our study is that PP-NLR can provide clinicians with a new reference index to judge the prognosis of patients and make timely treatment to help patients improve their prognosis.

Prognostic value of albumin-bilirubin score in pancreatic cancer patients after pancreatoduodenectomy with liver metastasis following radiofrequency ablation.

Objective: The current study aimed to investigate the prognostic value of albumin-bilirubin (ALBI) score in predicting clinical outcomes of pancreatic cancer patients after pancreatoduodenectomy with liver metastasis following radiofrequency ablation. Methods: This retrospective study included 90 pancreatic cancer patients after pancreatoduodenectomy with liver metastasis from January 2012 to December 2018. In this study, the Chi-square or Fisher's exact tests, the receiver operating characteristic (ROC) curve, Kaplan-Meier method and Log-rank test, univariate and multivariate Cox proportional hazard regression analyses, nomogram, calibration curves and decision curve analysis were used for all statistical analysis. Results: We analyzed the optimal cut-off value of ALBI by ROC curve, and the optimal cut-off value was -2.60. According to ALBI score, these patients were divided into two groups: low ALBI group (n = 33) and high ALBI group (n = 57). Patients with low ALBI score was significantly related to longer progression free survival (PFS) (p = 0.0002, HR: 3.039, 95% CI: 1.772-5.210) and overall survival (OS) (p = 0.0005, HR: 2.697, 95% CI: 1.539-4.720). The 1-, 3-, and 5-year PFS and OS rates in low ALBI group were higher than those in high ALBI group. ALBI was a potential independent prognostic factor for pancreatic cancer patients after pancreatoduodenectomy with liver metastasis following radiofrequency ablation. Moreover, the nomogram was used to predict the 1-, 3-, and 5-year survival probabilities of PFS and OS. The calibration curve shown that the prediction line matched the reference line well for postoperative 3-year PFS and OS. The DCA shown that nomogram model was better than the only ALBI, and indicated the ability for clinical decision-making, especially in 1-year PFS, and 3-, 5-year OS. Conclusion: ALBI is a potential independent factor for PFS and OS, and can predict the prognosis of pancreatic cancer patients after pancreatoduodenectomy with liver metastasis following radiofrequency ablation.

Sonosensitizer Nanoplatforms Augmented Sonodynamic Therapy-Sensitizing Shikonin-Induced Necroptosis Against Hepatocellular Carcinoma.

Background: Apoptosis resistance of hepatocellular carcinoma (HCC) often leads to treatment failure. Nonetheless, overcoming the resistance of HCC to apoptosis by inducing necroptosis of tumor cells to bypass the apoptotic pathway may be a promising treatment strategy. Sonodynamic therapy (SDT) has broad prospects in disease treatment because of its noninvasive characteristic and spatiotemporal control. The combination of SDT and shikonin in the treatment of HCC is expected to be a new tumor treatment method that can overcome apoptosis resistance. Methods: In this study, the antitumor effect was evaluated using normal liver cell line WRL68, HCC cell line HepG2 and HepG2 xenograft mouse models. Indocyanine green (ICG) was loaded on nanobubbles (NBs) to construct ICG-loaded nanobubbles (ICG-NBs). Combined sonosensitizer nanoplatforms with ultrasound (US) to achieve efficient SDT, the combination of SDT and shikonin in treating HCC can activate shikonin-induced necroptosis. As a result, tumor cells that produced apoptosis resistance were destroyed by necroptosis. Results: The results indicated a successful preparation of ICG-NBs with a uniform particle size of 273.0 ± 118.9 nm spherical structures. ICG-NB-mediated SDT, in combination with shikonin treatment, inhibited the viability, invasion, and migration of tumor cells. SDT + shikonin treatment group caused a substantial increase in necroptotic cells. The increased degree of tumor necrosis and the upregulated expression of receptor-interacting protein 3 kinase were observed in vivo studies, which indicated that the antitumor effect was accompanied by enhanced necroptosis in the SDT + shikonin treatment group. Conclusion: ICG-NB-mediated SDT combined with shikonin inhibits the growth of HCC by increasing the necroptosis of tumor cells. Therefore, this combination therapy is a promising treatment strategy against the specific cancer.

Sono-Immunotherapy Mediated Controllable Composite Nano Fluorescent Probes Reprogram the Immune Microenvironment of Hepatocellular Carcinoma.

Background: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy. Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety. Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an M1 phenotype. Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma.

Recent Progress Toward Imaging Application of Multifunction Sonosensitizers in Sonodynamic Therapy.

Sonodynamic therapy (SDT) is a rapidly developing non-surgical therapy that initiates sensitizers' catalytic reaction using ultrasound, showing great potential for cancer treatment due to its high safety and non-invasive nature. In addition, recent research has found that using different diagnostic and therapeutic methods in tandem can lead to better anticancer outcomes. Therefore, as essential components of SDT, sonosensitizers have been extensively explored to optimize their functions and integrate multiple medical fields. The review is based on five years of articles evaluating the combined use of SDT and imaging in treating cancer. By developing multifunctional sonosensitive particles that combine imaging and sonodynamic therapy, we have integrated diagnosis into the treatment of precision medicine applications, improving SDT cell uptake and antitumor efficacy utilizing different tumour models. This paper describes the imaging principle and the results of cellular and animal imaging of the multifunctional sonosensitizers. Efforts are made in this paper to provide data and design references for future SDT combined imaging research and clinical application development and to provide offer suggestions.

Prediction Model and Nomogram of Early Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation Based on Logistic Regression Analysis.

The purpose of this study was to screen for high-risk factors leading to the early recurrence of hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) and to construct a prediction model and nomogram. This retrospective study included 108 patients with primary HCC who underwent RFA treatment at the Harbin Medical University Cancer Hospital between January 2018 and June 2019. Four risk factors were screened for using univariate and multivariate logistic regression analyses: number of tumors (hazard ratio [HR] = 14.684, 95% confidence interval [CI]: 1.099-196.215, p = 0.042), neutrophil-to-lymphocyte ratio (NLR) (HR = 2.178, 95% CI: 1.003-4.730, p = 0.049), contrast-enhanced ultrasound (CEUS) performance (HR = 6.482, 95% CI: 1.161-36.184, p = 0.033) and α-fetoprotein (AFP) level (HR = 1.001, 95% CI: 1.000-1.003, p = 0.040). We established a prediction model: Logit(p) = -3.096 + 2.827 × (number of tumors >1 = 1) + 1.851 × (CEUS revealing rapid enhancement of blood flow signal in the arterial phase and clearance in the portal phase = 1) + 1.941 × (NLR >1.55 = 1) + 0.257 × (AFP >32.545 = 1). Through clinical decision curve analysis, the model's threshold was 0.043-0.873, indicating a high clinical value. Patients with a high AFP level, typical CEUS enhancement pattern, multiple tumors and elevated NLR are more likely to relapse early.

RNA-Seq Explores the Mechanism of Oxygen-Boosted Sonodynamic Therapy Based on All-in-One Nanobubbles to Enhance Ferroptosis for the Treatment of HCC.

BACKGROUND: The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) has failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention. METHODS: In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety. RESULTS: MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. We found that they were significantly enriched in the ferroptosis-related pathway MAPK cascade and cell proliferation. Then, we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes "SLC37A2" and "ITGB7" may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma. CONCLUSION: The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.