Effect of bisphosphonate on bone microstructure, mechanical strength in osteoporotic rats by ovariectomy.

BACKGROUND: Bisphosphonate (BP) can treat osteoporosis and prevent osteoporotic fractures in clinical. However, the effect of BP on microstructure and mechanical properties of cortical and trabecular bone has been taken little attention, separately. METHODS: In this study, BP was used to intervene in ovariectomized female SD rats. The femoral micro-CT images were used to measure the structural parameters and reconstruct the 3D models in volume of interest. The structural parameters of cortical and trabecular bone were measured, and the mechanical properties were predicted using micro-finite element analysis. RESULTS: There was almost no significant difference in the morphological structure parameters and mechanical properties of cortical bone between normal, ovariectomized (sham-OVX) and BP intervention groups. However, BP could significantly improve bone volume fraction (BV/TV) and trabecular separation (Tb.SP) in inter-femoral condyles (IT) (sham-OVX vs. BP, p < 0.001), and had no significant effect on BV/TV in medial and lateral femoral condyles (MT, LT). Similarly, BPs could significantly affect the effective modulus in IT (sham-OVX vs. BP, p < 0.001), and had no significant difference in MT and LT. In addition, the structural parameters and effective modulus showed a good linear correlation. CONCLUSION: In a short time, the effects of BP intervention and osteoporosis on cortical bone were not obvious. The effects of BP on trabecular bone in non-main weight-bearing area (IT) were valuable, while for osteoporosis, the main weight-bearing area (MT, LT) may improve the structural quality and mechanical strength of trabecular bone through exercise compensation.

The m6A modification of ACSL4 mRNA sensitized esophageal squamous cell carcinoma to irradiation via accelerating ferroptosis.

Radioresistance is a major obstacle for the therapy of esophageal squamous cell carcinoma (ESCC) and lead to a poor prognosis. Ferroptosis is supposed to be responsible for radioresistance. However, the ferroptosis-induced radioresistance in ESCC and its related regulatory mechanisms are not yet fully understood. In this study, human ESCC cell line and the corresponding radioresistance cells were irradiated with 6 megavolts (MV) X-ray. It was showed that irradiation led to less ferroptosis in radioresistant ESCC cells as compared to the parental cells, as depicted by transmission electron microscopy, intracellular Fe2+ iron contents, lipid peroxidation, and expression of COX2. The increase of ASCL4 expression levels in radioresistant cells after radiotherapy was smaller than that in the parental cells. ACSL4 overexpression significantly enhanced ferroptosis. The fold increase in ACSL4 m6A modification in the radioresistant cells was significantly smaller than that in the parental cells as detected by methylated RNA immunoprecipitation with qRT-PCR. METTL14 overexpression accelerated ferroptosis induced by irradiation via upregulating m6A modification of ACSL4 mRNA. In conclusions, ferroptosis ablation was responsible for the radioresistant of ESCC. The METTL14-mediated m6A modification of ACSL4 mRNA sensitized ESCC to irradiation via accelerating ferroptosis. This study sheds new light on our understanding of radioresistant in ESCC, and provides potential strategies for ESCC radiotherapy.

Exposure to endocrine disruptor DEHP promotes the progression and radiotherapy resistance of pancreatic cancer cells by increasing BMI1 expression and properties of cancer stem cells.

Most patients diagnosed with pancreatic cancer are initially at an advanced stage, and radiotherapy resistance impact the effectiveness of treatment. This study aims to investigate the effects of endocrine disruptor Di-(2-ethylhexyl) phthalate (DEHP) on various biological behaviors and the radiotherapy sensitivity of pancreatic cancer cells, as well as its potential mechanisms. Our findings indicate that exposure to DEHP promotes the proliferation of various cancer cells, including those from the lung, breast, pancreas, and liver, in a time- and concentration-dependent manner. Furthermore, DEHP exposure could influence several biological behaviors of pancreatic cancer cells in vivo and vitro. These effects include reducing cell apoptosis, causing G0/G1 phase arrest, increasing migration capacity, enhancing tumorigenicity, elevating the proportion of cancer stem cells (CSCs), and upregulating expression levels of CSCs markers such as CD133 and BMI1. DEHP exposure can also increase radiation resistance, which can be reversed by downregulating BMI1 expression. In summary our research suggests that DEHP exposure can lead to pancreatic cancer progression and radiotherapy resistance, and the mechanism may be related to the upregulation of BMI1 expression, which leads to the increase of CSCs properties.

METTL3 in cancer-associated fibroblasts-derived exosomes promotes the proliferation and metastasis and suppresses ferroptosis in colorectal cancer by eliciting ACSL3 m6A modification.

BACKGROUND: Cancer-associated fibroblasts (CAFs) have been reported that can affect cancer cell proliferation, metastasis, ferroptosis, and immune escape. METTL3-mediated N6-methyladenine (m6A) modification is involved in the tumorigenesis of colorectal cancer (CRC). Herein, we investigated whether METTL3-dependent m6A in CAFs-derived exosomes (exo) affected CRC progression. METHODS: qRT-PCR and western blotting analyses detected levels of mRNAs and proteins. Cell proliferation and metastasis were evaluated using MTT, colony formation, transwell, and wound healing assays, respectively. Cell ferroptosis was assessed by detecting cell viability and the levels of Fe+, reactive oxygen species, and glutathione after erastin treatment. Exosomes were isolated from CAFs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction between METTL3 and ACSL3 (acyl-CoA synthetase 3) was verified using dual-luciferase reporter assay. Animal models were established for in vivo analysis. RESULTS: CAFs promoted CRC cell proliferation and metastasis, and suppressed cell ferroptosis. METTL3 was enriched in CAFs and was packaged into exosomes. The m6A modification and METTL3 expression were increased in CRC samples. Knockdown of METTL3 in CAFs-exo suppressed CRC cell proliferation and metastasis, and induced cell ferroptosis. Mechanistically, METTL3 induced ACSL3 m6A modification and stabilized its expression. The anticancer effects mediated by METTL3-silenced CAFs-exo could be rescued by ACSL3 overexpression. Moreover, in vivo assay also showed that CAFs-exo with decreased METTL3 could hinder CRC growth and metastasis in mice models. CONCLUSION: CAFs promoted the proliferation and metastasis, and restrained the ferroptosis in CRC by exosomal METTL3-elicited ACSL3 m6A modification.

Effects of bone marrow sparing radiotherapy on acute hematologic toxicity for patients with locoregionally advanced cervical cancer: a prospective phase II randomized controlled study.

OBJECTIVE: To evaluate effects of bone marrow sparing (BMS) radiotherapy on decreasing the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients treated by pelvic irradiation. MATERIALS AND METHODS: LACC patients were recruited prospectively from May 2021 to May 2022 at a single center and were evenly randomized into the BMS group and the control group. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy and BM V40 < 25% in the BMS group was additionally prescribed. Acute HT was assessed weekly. Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. The trial was registered with Chinese clinical trial registry (ChiCTR2200066485). RESULTS: A total of 242 patients were included in the analysis. Baseline demographic, disease and treatment characteristics were balanced between the two groups. In the intention-to-treat population, BMS was associated with a lower incidence of grade ≥ 2 and grade ≥ 3 acute HT, leukopenia and neutropenia s(72.70% v 90.90%, P < 0.001*; 16.50% vs. 65.30%, P < 0.001*; 66.10% vs. 85.10%, P = 0.001*; 13.20% vs. 54.50%, P < 0.001*; 37.20% vs. 66.10%, P < 0.001*; 10.70% vs. 43.80%, P < 0.001*). BMS also resulted in decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femoral head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥ 3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959-3.815, P < 0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance. CONCLUSIONS: Receiving BMS pelvic irradiation could reduce the incidence of acute HT in LACC patients, and BM V40 < 25% may be a significant factor in reducing the risks of acute HT.

Functionally graded stem optimizes the fixed and sliding surface coupling mechanism.

Whether the optimization of fixed surface and sliding surface coupling mechanism is related to the hierarchical level of functionally graded porous stem is unknown. The functionally graded porous finite element stem models were constructed using tetrahedral microstructure with the porosities of 47-95%. The stress distribution for femoral bone gradually strengthened, the stress shielding was decreased along the increase of hierarchical levels of the stem after implantation. The coupling mechanism of fixed and sliding surfaces can be optimized by the functional gradient porous stem, the performance advantages become more prominent with the increase of hierarchical levels of the structure.

Efficacy of post­mastectomy radiotherapy in patients with T1­2N1 breast cancer aged ≤35 years or with a positive HER­2 status.

Post-mastectomy radiotherapy (PMRT) is highly recommended for patients with breast cancer with one to three positive nodes; however, there remains some controversy regarding its use. The present retrospective study aimed to explore which patients may be able to avoid PMRT and its associated side effects. A total of 728 patients with T1-2N1 breast cancer who were treated with or without PMRT were included in the present study. The results suggested that PMRT significantly decreased the locoregional recurrence rate (LRR) [hazard ratio (HR)=5.602, 95% confidence interval (CI)=3.139-9.998, P<0.01; 3-year LRR: 4 vs. 17%] and improved overall survival (OS) (HR=0.651, 95% CI=0.437-0.971, P=0.03; 3-year OS: 91 vs. 87%) for patients with T1-2N1 breast cancer. By contrast, PMRT had no significant effect on the distant metastasis (DM) rate (HR=0.691, 95% CI=0.468-1.019, P=0.06; 3-year DM: 10 vs. 15%). Further stratified analysis revealed that PMRT did not reduce the LRR and DM, or improve OS in patients aged ≤35 years or in those with a positive human epidermal growth factor receptor-2 (HER-2) status. The analysis of 438 patients treated with PMRT revealed that patients aged ≤35 years or those with a positive HER-2 status were more likely to experience local recurrence even following PMRT. Thus, the benefits of using PMRT in patients with T1-2N1 breast cancer who are aged ≤35 years or in those with a positive HER-2 status need to be carefully considered. Further studies are required to confirm whether this patient group may be exempted from PMRT.

Matrine impedes colorectal cancer proliferation and migration by downregulating endoplasmic reticulum lipid raft associated protein 1 expression.

Matrine exhibits anti-tumor effect on the proliferation and invasion of colorectal cancer (CRC) cells by reducing the activity of the p38 signaling pathway. However, these studies were limited because the underlying mechanism by which matrine inhibited CRC progression remained unclear. In this study, we provided for the first time that endoplasmic reticulum lipid raft associated protein 1 (Erlin1) is a novel target of matrine. Erlin1 was significantly upregulated in tumors and its knockdown suppressed the proliferation and migration of CRC cells, while its overexpression promoted CRC cell growth and migration. Furthermore, Erlin1 overexpression promoted inhibited apoptosis. Importantly, matrine treatment could reverse the oncogenic function of Erlin1 on CRC cell proliferation and migration. When Erlin1 was knocked down, matrine exhibited a more obvious anti-tumor effect in CRC cells. Partly due to this, matrine functions as an important anti-tumor drug and the results discovered here may clarify the mechanisms of matrine application for CRC treatment. CRC patients with low expression of Erlin1 might be more suitable for the treatment of matrine. This study could promote the application of matrine to be a promising therapeutic strategy for CRC patients.

Biomechanical effect of metal augment and bone graft on cup stability for acetabular reconstruction of total hip arthroplasty in hip dysplasia: a finite element analysis.

BACKGROUND: Different methods of acetabular reconstruction with total hip arthroplasty (THA) for Crowe II and III of adult developmental dysplasia of the hip (DDH) acetabular bone defect have been implemented clinically. However, the biomechanical effect of different augmented materials for acetabular reconstruction in THA on shell stability has never been discussed. METHODS: In the present study, autologous bone graft (BG)and metal (Ti6Al4V) augment (MA) were simulated with several acetabular bone defect models of DDH in THA. The contact pressure and micromotion between the shell and host bone were measured for evaluating the shell stability using a finite element method. RESULTS: The peak contact stress between shell and host bone was higher in the MA situation (12.45 vs 8.71 MPa). And the load transfer path was different, for BG models, the high local contact stresses were found at the junction of bone graft and host bone while for MA models the concentrated contact stresses were at the surface of MA. The peak relative micromotion between shell and host bone was higher in the MA situation (12.61 vs 11.13 µm). However, the peak micromotion decreased in the contact interface of MA and cup compared to the BG models. CONCLUSIONS: The higher micromotion was found in MA models, however, enough for bone ingrowth, and direct stronger fixation was achieved in the MA-cup interface. Thus, we recommended the MA can be used as an option, even for Crowe III, however, the decision should be made from clinical follow-up results.

Green Synthesized Gold Nanoparticles Using Viola betonicifolia Leaves Extract: Characterization, Antimicrobial, Antioxidant, and Cytobiocompatible Activities.

INTRODUCTION: Viola betonicifolia is a rich source of numerous secondary metabolites, such as alkaloids, flavonoids, tannins, phenolic compounds, saponins, triterpenoids, and so on, that are biologically active towards different potential biomedical applications. To broaden the potential use of Viola betonicifolia in the realm of bionanotechnology, we investigated the plant's ability to synthesize gold nanoparticles (Au NPs) in a green and efficient manner for the very first time. METHODS: The gold nanoparticles (VB-Au NPs) were synthesized using the leaves extract of Viola betonicifolia, in which plant's secondary metabolites function as both reducing and capping agents. The VB-Au NPs were successfully characterized with spectroscopic techniques. The antimicrobial properties of the VB-Au NPs were further explored against bacterial and mycological species. Additionally, their antioxidant, cytotoxic, and cytobiocompatibility properties were examined in vitro against linoleic acid peroxidation, MCF-7 cancer cells, and human mesenchymal stem cells (hMSCs), respectively. RESULTS: Results demonstrated that VB-Au NPs presented excellent antibacterial, antifungal, and biofilm inhibition performance against all the tested microbial species compared to plant leaves extract and commercially purchased chemically synthesized gold NPs (CH-Au NPs). Moreover, they also exhibited significant antioxidant potential, comparable to the external standard. The VB-Au NPs displayed good cytobiocompatibility with hMSCs and demonstrated excellent cytotoxic potential against MCF-7 cancer cells compared to CH-Au NPs. The current work presents a green method for synthesizing VB-Au NPs with enhanced antioxidant, antimicrobial, cytotoxic and biofilm inhibition efficacy compared to CH-Au NPs might be attributed to the synergistic effect of the nanoparticle's physical properties and the adsorbed biologically active phytomolecules from the plant leaves extract on their surface. CONCLUSION: Thus, our study establishes a novel ecologically acceptable route for nanomaterials' fabrication with increased and/or extra medicinal functions derived from their herbal origins.