Senolytics ameliorate the failure of bone regeneration through the cell senescence-related inflammatory signalling pathway.

Stress-induced premature senescent (SIPS) cells induced by various stresses deteriorate cell functions. Dasatinib and quercetin senolytics (DQ) can alleviate several diseases by eliminating senescent cells. α-tricalcium phosphate (α-TCP) is a widely used therapeutic approach for bone restoration but induces bone formation for a comparatively long time. Furthermore, bone infection exacerbates the detrimental prognosis of bone formation during material implant surgery due to oral cavity bacteria and unintentional contamination. It is essential to mitigate the inhibitory effects on bone formation during surgical procedures. Little is known that DQ improves bone formation in Lipopolysaccharide (LPS)-contaminated implants and its intrinsic mechanisms in the study of maxillofacial bone defects. This study aims to investigate whether the administration of DQ ameliorates the impairments on bone repair inflammation and contamination by eliminating SIPS cells. α-TCP and LPS-contaminated α-TCP were implanted into Sprague-Dawley rat calvaria bone defects. Simultaneously, bone formation in the bone defects was investigated with or without the oral administration of DQ. Micro-computed tomography and hematoxylin-eosin staining showed that senolytics significantly enhanced bone formation at the defect site. Histology and immunofluorescence staining revealed that the levels of p21- and p16-positive senescent cells, inflammation, macrophages, reactive oxygen species, and tartrate-resistant acid phosphatase-positive cells declined after administering DQ. DQ could partially alleviate the production of senescent markers and senescence-associated secretory phenotypes in vitro. This study indicates that LPS-contaminated α-TCP-based biomaterials can induce cellular senescence and hamper bone regeneration. Senolytics have significant therapeutic potential in reducing the adverse osteogenic effects of biomaterial-related infections and improving bone formation capacity.

Identification of Prognostic and Immune Characteristics of Two Lung Adenocarcinoma Subtypes Based on TRPV Channel Family Genes.

Lung adenocarcinoma (LUAD) is one of the deadliest malignant tumors worldwide. Transient receptor potential vanilloid (TRPV) channels take pivotal parts in many cancers, but their impact on LUAD remains unexplored. In this study, LUAD samples were classified into two subtypes according to the expression characteristics of TRPV1-6 genes, with LUAD subtype cluster2 exhibiting significantly higher survival rates than cluster1. Subsequently, analysis of differentially expressed genes (DEGs) was performed between cluster1 and cluster2, revealing enrichment of DEGs in channel activity and Ca2+ signaling pathways. We established a protein-protein interaction network based on DEGs and constructed a LUAD prognostic model by using Cox regression analysis based on genes corresponding to 170 protein nodes. The prognostic model demonstrated good predictive ability for patient prognosis, with higher survival rates observed in the low-risk (LR) group. The risk score was validated as an independent prognostic indicator, according to Cox regression analysis. A clinically applicable nomogram was plotted. Immunological analysis indicated that the LR and high-risk (HR) groups had varied proportions of immune cell infiltration. The immunotherapy prediction indicated that LUAD patients in LR group had a greater likelihood to benefit from immune checkpoint blockade therapy. Furthermore, we hypothesized that the expression patterns of feature genes in the LUAD model were related to the sensitivity to lung cancer therapeutic drugs TAS-6417 and Erlotinib. To sum up, our LUAD prognostic model possessed clinical applicability for prognosis and immunotherapy response prediction.

Artifacts in two-dimensional shear wave elastography of liver.

BACKGROUND: Artifacts are common when using two-dimensional shear wave elastography (2-D SWE) to measure liver stiffness (LS), but they are poorly recognized. AIM: To investigate the presence and influence of artifacts in 2-D SWE of liver. METHODS: We included 158 patients with chronic liver disease, who underwent 2-D SWE examination by a novice and an expert. A cross line at the center of the elastogram was drawn and was divided it into four locations: top-left, top-right, bottom-left, and bottom-right. The occurrence frequency of artifacts in different locations was compared. The influence of artifacts on the LS measurements was evaluated by comparing the elastogram with the most artifacts (EMA) and the elastogram with the least artifacts (ELA). RESULTS: The percentage of elastograms with artifacts in the novice (51.7%) was significantly higher than that of the expert (19.6%) (P < 0.001). It was found that both operators had the highest frequency of artifacts at bottom-left, followed by top-left and bottom-right, and top-right had the lowest frequency. The LS values (LSVs) and standard deviation values of EMAs were significantly higher than those of ELAs for both operators. An intraclass correlation coefficient value of 0.96 was found in the LSVs of EMAs of the two operators, and it increased to 0.98 when the LSVs of the ELAs were used. Both operators had lower stability index values for EMAs than ELAs, but the difference was only statistically significant for the novice. CONCLUSION: Artifacts are common when using 2-D SWE to measure LS, especially for the novice. Artifacts may lead to the overestimation of LS and reduce the repeatability and reliability of LS measurements.

Activation of NLRP3 signaling contributes to cadmium-induced bone defects, associated with autophagic flux obstruction.

Cadmium (Cd) is a widespread environmental and industrial pollutant to cause various bone metabolic diseases. Our former study reported that Cd promoted adipogenesis and inhibited osteogenic differentiation of primary bone marrow-derived mesenchymal stem cells (BMSCs) by NF-κB inflammation signaling and oxidative stress, and Cd-induced osteoporosis of long bone and compromised repair of cranial bone defect in vivo. However, the underlying mechanisms of Cd-induced bone damage remain elusive. In this study, we used Sprague Dawley (SD) rat and NLRP3-knockout mouse models to elucidate the exact effects and molecular mechanisms of Cd-induced bone damage and aging. Herein we found that the exposure of Cd preferentially targeted a few specific tissues such as bone and kidney. Cd triggered NLRP3 inflammasome pathways and the accumulation of autophagosomes of primary BMSCs, and also Cd stimulated the differentiation and bone resorption function of primary osteoclasts. Moreover, Cd not only activated ROS/NLRP3/caspase-1/p20/IL-1ß pathways, but also influenced Keap1/Nrf2/ARE signaling. The data revealed that autophagy dysfunction and NLRP3 pathways synergistically mediated the impairments of Cd in bone tissues. Loss of NLRP3 function partially alleviated Cd-induced osteoporosis and craniofacial bone defect in the NLRP3-knockout mouse model. Furthermore, we characterized the protective effects and potential therapeutic targets of the combined treatment of anti-aging agents (rapamycin+melatonin+NLRP3 selective inhibitor MCC950) on Cd-induced bone damage and inflammatory aging. These results illuminate that ROS/NLRP3 pathways and autophagic flux obstruction are involved in the Cd-induced toxic actions of bone tissues. Collectively, our study unveils some therapeutic targets and the regulatory mechanism to prevent Cd-caused bone rarefaction. The findings improve the mechanistic understanding of environmental Cd exposure-caused bone metabolism disorders and tissue damage.

Circ_SATB2 knockdown inhibits the tumorigenesis of non-small cell lung cancer via miR-760/KIF2A axis.

PURPOSE: This study was aimed at exploring the function and underlying mechanism of circ_SATB2 in non-small cell lung cancer (NSCLC). METHODS: The levels of circ_SATB2, microRNA-760 (miR-760) and Kinesin family member 2a (KIF2A) were determined using quantitative real-time polymerase chain reaction or western blot assay. The proliferation was detected using MTT and colony formation assays. Cell cycle and apoptosis were evaluated by flow cytometry. Transwell assay for migration and invasion and western blot for metastasis-associated proteins were conducted. Dual-luciferase reporter assay was used to analyze the interaction between miR-760 and circ_SATB2 or KIF2A. The effect of circ_SATB2 on NSCLC tumor growth in vivo was studied by xenograft mice model. RESULTS: Circ_SATB2 was upregulated in NSCLC tissues and cells. Circ_SATB2 knockdown caused inhibitory effects on NSCLC cell proliferation and metastasis but accelerated apoptosis. Circ_SATB2 served as a sponge of miR-760 to act in the development of NSCLC. Moreover, miR-760 could target KIF2A, and KIF2A expression was positively regulated by circ_SATB2. Furthermore, KIF2A overexpression neutralized miR-760-mediated inhibition effects on NSCLC cell progression. Besides, circ_SATB2 enhanced NSCLC tumorigenesis by targeting miR-760/KIF2A axis in vivo. CONCLUSION: Circ_SATB2 was highly expressed and participated in the progression of NSCLC through the modulation of the miR-760/KIF2A axis, suggesting that circ_SATB2 might be a potential biomarker for the diagnosis of NSCLC.

Efficacy and Safety of Thermal Ablation for Treating Lymph Node Metastasis From Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

Objective: To evaluate the efficacy and safety of thermal ablation, including radiofrequency ablation (RFA), microwave ablation (MVA), and laser ablation (LA), for treating lymph node metastasis (LNM) from papillary thyroid carcinoma (PTC). Design and Methods: PubMed and EMBASE were searched for studies reporting the efficacy and safety of thermal ablation for treating LNM in PTC. After selecting the relevant literature (including 11 papers, 208 patients, 412 lymph nodes), the QUADAS-2 tool was used to evaluate its quality. Then, both the fixed-effects and random-effects models combined with subgroup analysis were used to calculate data on volume changes in metastatic lymph nodes and changes in serum thyroglobulin (Tg) levels. We pooled the proportion of major and overall complication rates and complete disappearance rates and used subgroup forest plots and funnel plots for visual representation. Because of publication bias, we also performed a trim-and-filled model for correction. The rate of recurrence and distant metastasis with ablated details were pooled. Results: In the 11 articles (208 patients and 412 diseased lymph nodes), all thermal ablation methods showed effectiveness in reducing lymph node volume (P = 0.02) and serum Tg levels (P < 0.01) which showed no between-group difference. The pooled proportion of major complications was 0%(95% CI: -0.14; 0.15, P = 1) and the overall complication rate was 5% (95% CI: -0.09; 0.20, P = 1), which revealed no significant difference among modalities. The pooled proportion of the complete disappearance rate was 82% (95% CI: 0.43; 0.96, P < 0.01) and the data with statistical significance which contains RFA and LA showed complete disappearance rate was 59% and 81% respectively. Conclusion: All thermal ablation methods, including RFA, MWA, and LA, were effective and safe for treating LNM in PTC and were especially suitable for nonsurgical patients. Besides, subgroup analysis showed no significant difference, except for LA is better than RFA in complete disappearance rate.

Effect of Q-Box size on liver stiffness measurement by two-dimensional shear wave elastography.

PURPOSE: To investigate the effect of the Q-Box size on liver stiffness (LS) measurement by two-dimensional shear wave elastography (2D SWE). METHODS: Ninety-eight patients with chronic liver disease were enrolled. Each patient was continuously measured five times. The Q-Box diameter was adjusted to 10, 20, and 30 mm each time. The liver stiffness values (LSVs) at different diameters were compared in the following groups: LSVs ≤6.2 kPa, 6.2 kPa < LSVs ≤11 kPa, LSVs >11 kPa. The reliability and repeatability of LS measurement at different diameters were evaluated. RESULTS: The differences in LSVs at different Q-Box diameters were statistically significant only when LSV ≤6.2 kPa (p = 0.004). There were no statistically significant differences in standard deviation (SD), SD/median, coefficient of variation (CV), and interquartile range (IQR)/median at different Q-Box diameters (p > 0.05). There were statistical differences in minimum LSVs and percentage of minimum LSVs ≤0.2 kPa as well as in stability index (SI) and percentage of SI <90% at different Q-Box diameters (p < 0.05). The intraclass correlation coefficients (ICCs) were up to 0.98 at Q-Box diameters of 10, 20, and 30 mm. CONCLUSIONS: Our study showed that Q-Box size may lead to significant differences in LSVs, especially when LSVs ≤6.2 kPa. The Q-Box size had a large effect on the reliability of a single LS measurement but did not affect the repeatability of multiple measurements.

FANCI Cooperates with IMPDH2 to Promote Lung Adenocarcinoma Tumor Growth via a MEK/ERK/MMPs Pathway.

PURPOSE: Fanconi anemia complementation group I (FANCI) is a key protein in ribosome biogenesis and DNA repair. Here, we aimed to determine the clinical significance, prognostic value and biology functions of FANCI in lung adenocarcinoma (LUAD). METHODS: The expression of FANCI in LUAD tissue and its relationship with patient outcomes were assessed using bioinformatics analysis, as well as quantitative reverse-transcription PCR (qRT-PCR) and Western blot analysis of LUAD tissue and adjacent normal lung tissue. The chi-squared test and Cox regression analysis were used to analyze the clinical significance of FANCI expression. The biological effects of FANCI knockdown in human LUAD cell lines were investigated by analysis of proliferation, colony formation, cell cycle distribution, migration, and invasion in vitro, and monitoring of tumor xenograft growth in vivo. FANCI interactions with IMPDH2 and involvement in MEK/ERK/MMPs signaling were analyzed using co-immunoprecipitation assays, immunofluorescence microscopy, and Western blotting. RESULTS: FANCI was identified as a hub gene for LUAD. FANCI expression was upregulated in LUAD tissues compared with normal lung tissues and was positively associated with lymphatic metastasis, distant metastasis, and poor outcome. FANCI was also an independent prognostic factor in LUAD patients. Knockdown of FANCI in LUAD cell lines decreased their proliferation, migration, invasion, and cell cycle progression in vitro, and decreased the growth of xenografts in mice. Direct binding of FANCI to IMPDH2 decreased IMPDH2 degradation, regulated activation of MEK/ERK/MMPs signaling. Overexpression of IMPDH2 reversed the inhibitory effects of FANCI knockdown. CONCLUSION: FANCI may act as an oncogene in LUAD by cooperating with IMPDH2 to promote cell proliferation via the MEK/ERK/MMPs pathway. These results identify FANCI as a potential prognostic biomarker and therapeutic target for LUAD.

Does Operator Experience and the Q-Box Diameter Affect the Repeatability of Liver Stiffness Measurements Obtained by 2-Dimensional Shear Wave Elastography?

OBJECTIVES: The purpose of this research was to evaluate whether operator experience and the quantitative analysis system (Q-Box; SuperSonic Imagine, Aix-en-Provence, France) diameter affect the repeatability of liver stiffness measurements. METHODS: We enrolled 417 outpatients. All measurements were performed by 2 operators, including an expert and a novice. Each patient was continuously measured 3 times by the 2 operators. The Q-Box diameter was adjusted to 10, 20, and 30 mm each time, and the mean elasticity values were recorded. Intraobserver repeatability was evaluated by the intraclass correlation coefficient (ICC). Interobserver repeatability was evaluated by the ICC, coefficient of variation (CV), and Bland-Altman plots. RESULTS: The study group included 241 male and 176 female patients. The expert operator had higher ICCs than the novice operator at each Q-Box diameter. The overall interobserver agreement was excellent, and the results showed that compared to other groups, the ICC was the lowest and the CV was the largest for the 30-mm-diameter group. The ICC and CV values were similar between the 10- and 20 mm-diameter groups. The Bland-Altman plots showed that the mean difference was -0.2 kPa for the 10-, 20-, and 30 mm-diameter groups. However, the limits of agreement were the largest in the 30-mm-diameter group and were similar between the 10- and 20-mm-diameter groups. CONCLUSIONS: The repeatability of liver stiffness measurements is affected not only by experience but also by the Q-Box diameter.