Extracellular Matrix Viscosity Reprogramming by In Situ Au Bioreactor-Boosted Microwavegenetics Disables Tumor Escape in CAR-T Immunotherapy.

Incomplete microwave ablation (iMWA) caused by uncontrollable heat diffusion enhances the immunosuppressive tumor microenvironment (ITM), consequently disabling the prevalent immune checkpoint blockade-combined immunotherapy against tumor recurrence. Herein, we successfully constructed an intratumorally synthesized Au bioreactor to disperse heat in thermally sensitive hydrogel-filled tumors and improve the energy utilization efficiency, which magnified the effective ablation zone (EAZ), counteracted iMWA, and simultaneously established and enhanced multiple biological process-regulated microwavegenetics. More significantly, we identified the extracellular matrix (ECM) viscosity as a general immune escape "target". After remodeling ECM, including ECM ingredients and cell adhesion molecules, this physical target was blocked by viscosity reprogramming, furnishing an effective tool to regulate the viscosity target. Thereby, such in situ Au bioreactor-enlarged EAZ and enhanced microwavegenetics reversed the immune-desert tumor microenvironment, mitigated ITM, secreted immune cell-attracting chemokines, recruited and polarized various immune cells, and activated or reactivated them like dendritic cells, natural killing cells, M1-type macrophages, and effector CD8+ or CAR-T cells. Contributed by these multiple actions, the in situ oncolytic Au bioreactors evoked CAR-T immunotherapy to acquire a considerably increased inhibition effect against tumor progression and recurrence after iMWA, thus providing a general method to enhance iMWA and CAR-T immunotherapy.

Combined Photodynamic and Photothermal Therapy and Immunotherapy for Cancer Treatment: A Review.

Photoactivation therapy based on photodynamic therapy (PDT) and photothermal therapy (PTT) has been identified as a tumour ablation modality for numerous cancer indications, with photosensitisers and photothermal conversion agents playing important roles in the phototherapy process, especially in recent decades. In addition, the iteration of nanotechnology has strongly promoted the development of phototherapy in tumour treatment. PDT can increase the sensitivity of tumour cells to PTT by interfering with the tumour microenvironment, whereas the heat generated by PTT can increase blood flow, improve oxygen supply and enhance the PDT therapeutic effect. In addition, tumour cell debris generated by phototherapy can serve as tumour-associated antigens, evoking antitumor immune responses. In this review, the research progress of phototherapy, and its research effects in combination with immunotherapy on the treatment of tumours are mainly outlined, and issues that may need continued attention in the future are raised.

Multifunctional Nanoparticles-Mediated PTT/PDT Synergistic Immune Activation and Antitumor Activity Combined with Anti-PD-L1 Immunotherapy for Breast Cancer Treatment.

Introduction: Photoimmunotherapy is a breakthrough treatment for malignant tumors. Its uniqueness is that it uses antibody mediated targeted delivery to achieve high tumor specificity and uses laser-activated biophysical mechanism to accurately induce the rapid death of cancer cells and avoid damaging the surrounding normal tissues. Methods: In this paper, an iron-based micelle was designed to encapsulate the photothermal agent indocyanine green (ICG) and a cyclic tripeptide of arginine-glycine-aspartic acid (cRGD) as targeted multifunctional ICG@SANPs-cRGD nanoparticles for combined photothermal/photodynamic/immune therapy of breast cancer. Results: The experimental results show that ICG@SANPs-cRGD nanoparticles have good biocompatibility and photothermal conversion ability. Photothermal therapy (PTT) and photodynamic therapy (PDT) based on ICG@SANPs-cRGD can not only inhibit the proliferation, invasion and migration of tumor cells, but also directly kill tumor cells by inducing apoptosis or necrosis. Dual-mode fluorescence light (FL) and magnetic resonance imaging (MRI) imaging in mice confirmed the selective accumulation at tumor sites and imaging ability of ICG@SANPs-cRGD. PTT/PDT combined with Anti-PD-L1 immunotherapy based on ICG@SANPs-cRGD mediated the immunogenic cell death (ICD) of tumor cells by regulating the expression of immune-related indicators and activated the body's immune response mechanism, which enhanced the immunotherapy effect of immune checkpoint block (ICB). PTT/PDT combined with Anti-PD-L1 therapy not only prevented the progression of the primary tumor but also inhibited the distant metastasis of the tumor. Discussion: This study explores the biomedical application of PTT/PDT combined with Anti-PD-L1 based on ICG@SANPs-cRGD nanomaterials for breast cancer treatment and demonstrates the potential of ICG@SANPs-cRGD as a multifunctional therapeutic platform for future cancer therapy.

Facile synthesis of nitrogen-doped graphene quantum dots as nanocarbon emitters for sensitive detection of catechol.

Development of nanomaterial-based electrochemiluminescence (ECL) emitters is highly desirable for the fabrication and wide applications of ECL sensors. Herein, nitrogen-doped graphene quantum dots (NGQDs) were easily synthesized as nanocarbon emitters with anodic ECL for sensitive ECL determination of catechol (CC). Facile synthesis of NGQDs was easily achieved using molecular fusion of a carbon precursor in a one-step hydrothermal process. The synthesis has advantages of simple and convenient operation and high yield. The as-prepared NGQDs have uniform size, good crystallinity, single-layered graphene structure, and excitation-independent fluorescence. In the presence of hydrogen peroxide (H2O2), NGQDs exhibit high anodic ECL owing to the presence of functional hydrazide groups. As CC could significantly reduce the ECL intensity of NGQDs, sensitive determination of CC was realized with a linear range from 100 nM to 10 µM and 10 µM to 60 µM with a low limit of detection (LOD, 42 nM). The determination of CC in environmental water was also achieved with high reliability.

Intraparticle Double-Scattering-Decoded Sonogenetics for Augmenting Immune Checkpoint Blockade and CAR-T Therapy.

Genetically arming new chimeric antigen receptors (CARs) on T cells is a prevalent method to fulfill CAR-T immunotherapy. However, this approach fails to completely address the poor infiltration, complex immunosuppressive tumor microenvironment (ITM), and insufficient immune cells, which are recognized as the three dominant hurdles to discouraging the trafficking and persistence of CAR-T and immune checkpoint blockade (ICB) immunotherapies against solid tumors. To address the three hurdles, a sonoimmunity-engineered nanoplatform is designed in which a rattle-type-structured carrier enables intraparticle-double-scattering to generate massive reactive oxygen species (ROS) during the sonodynamic process. Abundant ROS accumulation can directly kill tumor cells, release antigens, and activate systematic immune responses for expanding effector T or CAR-T cells, while alleviating ITM via immunosuppressive macrophage polarization and reduction in pro-tumorigenic cytokine secretion. Furthermore, the co-loaded phosphodiesterase-5 inhibitors release nitric oxide (NO) to impel vascular normalization and open the infiltration barrier (IB) for allowing more T cells to enter into the tumor. Systematic experiments demonstrate the feasibility of such intraparticle-double-scattering-decoded sonogenetics in the sonoimmunity-engineered nanoplatforms for expanding effector T or CAR-T cells, thereby promoting their infiltration into tumors and alleviating ITM. These compelling actions lead to excellent CAR-T and ICB immunotherapies against solid tumors with repressed tumor metastasis.

Effects of miRNA-140 on the Growth and Clinical Prognosis of SMMC-7721 Hepatocellular Carcinoma Cell Line.

BACKGROUND: A growing number of studies have suggested that microRNAs exert an essential role in the development and occurrence of multiple tumours and act as crucial regulators in various biological processes. However, the expression and function of miRNA-140 in hepatocellular carcinoma (HCC) cells are not yet adequately identified and manifested. METHODS: The expression of miRNA-140 was determined in HCC tissues and adjacent nontumour tissues by quantitative real-time polymerase chain reaction (qRT-PCR). Kaplan-Meier survival analysis and Cox regression analysis were performed to explore the correlation between miRNA-140 expression level and the survival rate of patients with HCC. Additionally, overexpression experiments were conducted to investigate the biological role of miRNA-140 in HCC cells. Bioinformatics was used to predict the related target genes and pathways of miRNA-140. RESULTS: QRT-PCR results signified that the expression level of miRNA-140 in HCC was lower than that of adjacent normal tissues (P < 0.0001). Compared with the control group, the SMMC-7721 HCC cells in the miRNA-140 mimic group had a decrease in proliferation, migration, and invasion (P < 0.05), whereas those in the miRNA-140 inhibitor group had an increase in proliferation, migration, and invasion (P < 0.05). Cell cycle arrest occurred in the G0/1 phase. Prognosis analysis showed that the expression level of miRNA-140 was not related to the prognosis of HCC. Furthermore, the Kaplan-Meier test revealed that patients with lower miRNA-140 expression levels in liver cancer tissue had significantly shorter disease-free survival (DFS, P = 0.004) and overall survival (OS) times (P = 0.010) after hepatectomy. Cox regression analysis further indicated that miRNA-140 was an independent risk factor that may affect the DFS (P = 0.004) and OS times (P = 0.014) of patients after hepatectomy. Our results suggested that miRNA-140 might be a crucial regulator involved in the HCC progression and is thus considered a potential prognostic biomarker and therapeutic target for HCC.

Associations between hepatocellular carcinoma risk and rs3212227 and rs568408 polymorphisms: a systematic review and meta-analysis.

BACKGROUND: Interleukin-12 (IL-12) is considered to be a risk factor for cancer; however, its role in hepatocellular carcinoma (HCC) remains unknown. This study aimed to explore the impacts of the IL-12 rs3212227 and rs568408 gene polymorphisms on HCC. METHODS: We searched PubMed, Embase, Web of Science, and Chinese Knowledge Infrastructure databases for studies on the associations between HCC and IL-12 rs568408 and rs3212227 polymorphisms published prior to 1 May 2020. The effects of the polymorphisms on HCC susceptibility were presented as odds ratios (ORs) and associated 95% confidence intervals. RESULTS: Seven studies were ultimately included, including 2375 cases and 3445 controls. The rs3212227 polymorphism was significantly associated with the risk of HCC in both the dominant model (CC+AC vs. AA, OR=1.22) and the allele model (C vs. A, OR=1.12). Combined analysis of rs568408 yielded a significant relative risk for HCC in the dominant (AA+AG vs. GG, OR=1.13), recessive (AA vs. AG+GG, OR=1.72), allele (A vs. G, OR=1.29), heterozygote (AG vs. GG, OR=1.27), and homozygote models (AA vs. GG, OR 1.17). CONCLUSION: The IL-12 rs3212227 and rs568408 gene polymorphisms are associated with an increased risk of HCC.

Upregulation of Long Non-Coding RNA ENST00000429227.1 Is Correlated with Poor Prognosis in Human Hepatocellular Carcinoma.

BACKGROUND Long non-coding RNAs (lncRNAs) have been shown to play an important regulatory role in many tumors. This study was designed to investigate the expression of lncRNA ENST00000429227.1 in hepatocellular carcinoma (HCC) and to determine whether the expression of lncRNA ENST00000429227.1 affects the prognosis of HCC. MATERIAL AND METHODS lncRNA ENST00000429227.1 showing differences in expression between M1 and M2 was screened by microarray expression measurements. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of lncRNA ENST00000429227.1 in 161 HCC patients. The chi-square test was used to evaluate the relationship between the expression of ENST00000429227.1 and clinicopathological parameters. A survival curve was drawn and analyzed by Kaplan-Meier method. Cox regression was used for univariate and multivariate analysis to determine whether lncRNA ENST00000429227.1 is an independent factor of the occurrence and prognosis of HCC. RESULTS A total of 3703 differentially expressed lncRNAs were obtained, of which 1777 were upregulated and 1926 were downregulated, with multiple change >1.5. The expression of lncRNA ENST00000429227.1 was upregulated in M2 cells. The expression of lncRNA ENST00000429227.1 in HCC tissues was higher than that in adjacent normal tissues (p<0.05), which was correlated with pathological parameters such as surgical margin (p=0.042), AFP (p=0.022) and Barcelona Clinic Liver Cancer (BCLC) stage (p=0.008). Survival analysis showed that high expression of lncRNA ENST00000429227.1 was associated with a decrease in overall survival (OS) rate of HCC patients. Cox regression analysis showed that high expression of ENST00000429227.1 may be an independent risk factor affecting the prognosis of HCC patients. CONCLUSIONS The results suggest that upregulation of ENST00000429227.1 is associated with poor prognosis of HCC patients, and may be a new biomarker for the diagnosis of HCC.

Association between osteosarcopenic obesity and hypertension among four minority populations in China: a cross-sectional study.

OBJECTIVE: Osteosarcopenic obesity (OSO) may be associated with an increased prevalence of hypertension. The aim of this study was to examine the difference in the prevalence of OSO and hypertension among four minority populations in China and explore the relationship between OSO and hypertension by sex. DESIGN: This study adopted a cross-sectional design. PARTICIPANTS: In total, 1939 participants aged ≥50 years, including 459 Jing, 514 Maonan, 535 Hmong and 431 Yao participants from Guangxi Province, China, were included using stratified cluster random sampling. MAIN OUTCOME MEASURES: The body composition, bone mineral density and blood pressure were measured by an MC-180 body composition analyser, Achilles Express ultrasound bone densitometer and OMRON HEM-1000 electronic sphygmomanometer, respectively. RESULTS: The results showed that 65.77% of Hmong men, 58.79% of Hmong women, 54.82% of Maonan men, 50.00% of Maonan women, 41.92% of Jing men, 45.21% of Jing women, 53.66% of Yao men and 42.32% of Yao women suffered from hypertension. Compared with those among the normal group, the adjusted OR and 95% CI of age among the women with OSO was 3.15 (1.13 to 8.78). After adjusting for age, ethnicity, smoking status, alcohol consumption, physical activity and menopausal status, the women with OSO also had a higher OR (OR=3.18, 95% CI 1.14 to 8.88) for hypertension than those in the normal group. However, the ORs (95% CI) for hypertension in men with one or more components were not significant after adjusting for age and ethnicity. CONCLUSION: These results suggest that OSO is a risk factor for hypertension, especially in women. Furthermore, the prevalence of OSO and hypertension in the present study displayed sex-specific and ethnic-specific differences among the four minority populations.

Effects of fat distribution on lung function in young adults.

AIMS: To study the associations between fat distribution and lung functions in healthy subjects of young adults and to explore potential gender difference in these correlations. METHODS: A total of 2101 adult participants were recruited. Height, weight, and vital capacity index (VCI) were measured and recorded according to the national physical fitness test standard. Body compositions, including body mass index (BMI), body fat percentage (BFP), waist-to-hip ratio (WHR), fat-free mass (FFM), trunk muscle mass (TMM), fat mass (FM), visceral fat area (VFA), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT), were conducted using body composition analyzer. Data were analyzed by SPSS 20.0 software. RESULTS: We found that male participants showed significantly higher BMI, WHR, FFM, TMM, VFA, and VCI, but lower FM, BFP, and SAT in comparison with women. However, there was no significant difference in VAT between the male and female. Lung functions represented by VCI were negatively correlated with FM, VAT, SAT, and VFA for both men and women (r < 0; P < 0.05). Among these negative correlations, VCI was more inversely correlated with VFA for men but with SAT for women, respectively. After dividing the whole populations by BMI, BFP, and WHR, further correlation analysis showed VCI was still more negatively correlated with VFA for all male subgroups (r < 0; P < 0.05). On the contrary, VCI was more negatively correlated with SAT in BMI-underweight, BMI-normal, BFP-low fat, BFP-normal fat, WHR-normal, and WHR-obese subgroups (r < 0; P < 0.05), while VFA and VAT was more inversely correlated with VCI in BMI- and BFP-overweight+obese subgroups (r < 0; P < 0.05). CONCLUSIONS: Fat accumulation is highly associated with the vital capacity index in young adults. In general, VCI was more negatively correlated with VFA for men but with SAT for women, respectively, in comparison with other tested indices.