Effect of novel polyethylene insert configurations on bone-implant micromotion and contact stresses in total ankle replacement prostheses: a finite element analysis.

Purpose: This study investigates the impact of elastic improvements to the artificial ankle joint insert on prosthesis biomechanics to reduce the risk of prosthesis loosening in TAR patients. Methods: CT data of the right ankle was collected from one elderly female volunteer. An original TAR model (Model A) was developed from CT images and the INBONE II implant system. The development of the new inserts adopts an elastic improvement design approach, where different geometric configurations of flexible layers are inserted into the traditional insert. The structure can be divided into continuous flexible layers and intermittent flexible layers. The flexible layers aim to improve the elasticity of the component by absorbing and dispersing more kinetic energy. The newly designed inserts are used to replace the original insert in Model A, resulting in the development of Models B-D. A finite element model of gait analysis was based by gait parameters. Discrepancies in micromotion and contact behaviour were analysed during the gait cycle, along with interface fretting and articular surface stress at 50% of the gait cycle. Results: In terms of micromotion, the improved elastic models showed reduced micromotion at the tibial-implant interfaces compared to the original model. The peak average micromotion decreased by 12.1%, 13.1%, and 14.5% in Models B, C, and D, respectively. The micromotion distribution also improved in the improved models, especially in Model D. Regarding contact areas, all models showed increased contact areas of articular surfaces with axial load, with Models B, C, and D increasing by 26.8%, 23.9%, and 24.4%, respectively. Contact stress on articular surfaces increased with axial load, reaching peak stress during the late stance phase. Models with continuous flexible layer designs exhibited lower stress levels. The insert and the talar prosthetic articular surfaces showed more uniform stress distribution in the improved models. Conclusion: Improving the elasticity of the insert can enhance component flexibility, absorb impact forces, reduce micromotion, and improve contact behavior. The design scheme of continuous flexible layers is more advantageous in transmitting and dispersing stress, providing reference value for insert improvement.

Neoadjuvant Endocrine Therapy: A Potential Way to Make Cold Hormone Receptor-Rich Breast Cancer Hot.

BACKGROUND: Turning the "cold" tumor immune microenvironment into "hot" is a critical issue in cancer treatment today. Hormone receptor-rich breast cancer (HR+ BC) was previously considered immunologically quiescent. OBJECTIVE: This study aims to explore the immunomodulatory effects of endocrine therapy on HR+ BCs. METHODS: The infiltrations and alterations of the tumor immune microenvironment in HR+ BCs before, after 10-14 days, and after three months of neoadjuvant endocrine therapy were computationally analyzed according to MCP-counter, CIBERSORT, xCell algorithms, and gene-set enrichment analysis (GSEA). The primary microarray data were obtained from three HR+ BC gene expression datasets (GSE20181, GSE55374, and GSE59515). Single-sample GSEA of hallmark and immune response gene sets was performed to evaluate the correlation between suspected treatment response and activated immune pathways in tumors. RESULTS: Both immune and stromal cells were specifically recruited into the HR+ BCs who responded to the neoadjuvant endocrine therapy by letrozole. Besides the enhanced infiltrations of immunosurveillance-related cells such as CD8+ T cells, dendritic cells, and the activation of immune response-related signals, the immunosuppressive M2-like macrophages, as well as the expression of immune checkpoint genes like PDCD1, SIRPA, and some HLA genes, were also stimulated in responders. We identified four pretreatment indicators (the intrinsic luminal subtype, the estrogen response early/late pathway, and the epithelial-mesenchymal transition pathway) as potential predictors of both clinical response and the activation of the tumor immune microenvironment post letrozole. CONCLUSION: Neoadjuvant endocrine therapy showed a promising way to convert the immunologically "cold" HR+ BCs into "hot" tumors. This study provides new insights into the application of immunotherapy for HR+ BCs, especially those who respond to endocrine therapy.

The Transverse Bearing Characteristics of the Pile Foundation in a Calcareous Sand Area.

Reviewing literature revealed that the studies on the bearing characteristics of pile foundations mainly focuses on clay, ordinary sand, loess, saline soil, and other areas. However, few studies on the bearing characteristics of the pile foundation in calcareous sand were conducted. Besides, existing traditional studies ignored the variation of soil compression modulus with depth, and the effect of void ratio on the transverse bearing characteristics of the pile foundation in a calcareous sand area were not well understood. In response of these problems, this study conducted a theoretical investigation on the transverse bearing characteristics of the pile foundation in a calcareous sand area. The transverse bearing characteristics of the pile foundation were derived based on the Pasternak foundation model and the Winkler foundation model, incorporating the heterogeneous distribution of compressive modulus with buried depth. The calculation results of the Pasternak foundation model are closer to the observed results than the Winkler foundation model. Therefore, the following research on the transverse bearing characteristics of the pile foundation in the calcareous sand area adopts the Pasternak foundation model. Then, the effects of the pile length, pile diameter, pile elastic modulus, horizontal load, bending moment, and void ratio on the transverse bearing characteristics of the pile foundation in a calcareous sand area were thoroughly analyzed. Furthermore, the difference between the transverse bearing characteristics of the pile foundation in a calcareous sand area and a quartz sand area was discussed. Results show that the horizontal displacement of the pile top in a calcareous sand area is greater than the quartz sand area under the same conditions.

Network-based approach to identify prognosis-related genes in tamoxifen-treated patients with estrogen receptor-positive breast cancer.

Tamoxifen is an estrogen receptor (ER) antagonist that is most commonly used for the treatment of ER-positive breast cancer. However, tamoxifen resistance remains a major cause of cancer recurrence and progression. Here, we aimed to identify hub genes implicated in the progression and prognosis of ER-positive breast cancer following tamoxifen treatment. Microarray data (GSE9893) for 155 tamoxifen-treated primary ER-positive breast cancer samples were obtained from the Gene Expression Omnibus database. In total, 1706 differentially expressed genes (DEGs), including 859 up-regulated and 847 down-regulated genes, were identified between relapse and relapse-free samples. Weighted correlation network analysis clustered genes into 13 modules, among which the tan and blue modules were the most significantly related to prognosis. From these two modules, we further identified and validated two prognosis-related hub genes (G-rich RNA sequence binding factor 1 (GRSF1) and microtubule-associated protein τ (MAPT)) via survival analysis based on several publicly available datasets. High expression of GRSF1 predicted poor prognosis, whereas MAPT indicated favorable outcomes in ER-positive breast cancer. Using breast cancer cell lines and tissue samples, we confirmed that GRSF1 was significantly up-regulated and MAPT was down-regulated in the tamoxifen-resistant group compared with the tamoxifen-sensitive group. The prognostic value of GRSF1 and MAPT was also verified in 48 tamoxifen-treated ER-positive breast cancer patients in our hospital. Gene set enrichment analysis (GSEA) suggested that GRSF1 was potentially involved in RNA degradation and cell cycle pathways, while MAPT was strongly linked to immune-related signaling pathways. Taken together, our findings established novel prognostic biomarkers to predict tamoxifen sensitivity, which may facilitate individualized management of breast cancer.

Deformation Prediction of Unstable Slopes Based on Real-Time Monitoring and DeepAR Model.

With increased urbanization, accidents related to slope instability are frequently encountered in construction sites. The deformation and failure mechanism of a landslide is a complex dynamic process, which seriously threatens people's lives and property. Currently, prediction and early warning of a landslide can be effectively performed by using Internet of Things (IoT) technology to monitor the landslide deformation in real time and an artificial intelligence algorithm to predict the deformation trend. However, if a slope failure occurs during the construction period, the builders and decision-makers find it challenging to effectively apply IoT technology to monitor the emergency and assist in proposing treatment measures. Moreover, for projects during operation (e.g., a motorway in a mountainous area), no recognized artificial intelligence algorithm exists that can forecast the deformation of steep slopes using the huge data obtained from monitoring devices. In this context, this paper introduces a real-time wireless monitoring system with multiple sensors for retrieving high-frequency overall data that can describe the deformation feature of steep slopes. The system was installed in the Qili connecting line of a motorway in Zhejiang Province, China, to provide a technical support for the design and implementation of safety solutions for the steep slopes. Most of the devices were retained to monitor the slopes even after construction. The machine learning Probabilistic Forecasting with Autoregressive Recurrent Networks (DeepAR) model based on time series and probabilistic forecasting was introduced into the project to predict the slope displacement. The predictive accuracy of the DeepAR model was verified by the mean absolute error, the root mean square error and the goodness of fit. This study demonstrates that the presented monitoring system and the introduced predictive model had good safety control ability during construction and good prediction accuracy during operation. The proposed approach will be helpful to assess the safety of excavated slopes before constructing new infrastructures.

Platelet-derived growth factor subunit B is required for tendon-bone healing using bone marrow-derived mesenchymal stem cells after rotator cuff repair in rats.

As a common cause of shoulder pain and disability, rotator cuff injury (RCI) represents a debilitating condition affecting an individual's quality of life. Although surgical repair has been shown to be somewhat effective, many patients may still suffer from reduced shoulder function. The aim of the current study was to identify a more effective mode of RCI treatment by investigating the effect of platelet-derived growth factor subunit B (PDGF-B) on tendon-bone healing after RCI repair by modifying bone marrow-derived mesenchymal stem cells (BMSCs). Surface markers of BMSCs were initially detected by means of flow cytometry, followed by establishment of the rat models and construction of the lentiviral vector. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide (MTT) assay, alizarin red staining, and oil red O staining were used to provide verification that PDGF-B was indeed capable of promoting BMSC viability, osteogenic and adipogenic differentiation capability. Furthermore, biomechanical assessment results indicated that PDGF-B could increase the ultimate load and stiffness of the tendon tissue. Real-time reverse-transcription quantitative polymerase chain reaction and Western blot analysis methods provided evidence suggesting that PDGF-B facilitated the expression of tendon-bone healing-related genes and proteins, while contrasting results were obtained after PDGF-B silencing. Taken together, the key findings of the current study provided evidence suggesting that overexpressed PDGF-B could act to enhance tendon-bone healing after RCI repair, thus highlighting the potential of the functional promotion of PDGF-B as a future RCI therapeutic approach.

Characterization and comparison of post-natal rat Achilles tendon-derived stem cells at different development stages.

Tendon stem/progenitor cells (TSPCs) are a potential cell source for tendon tissue engineering. The striking morphological and structural changes of tendon tissue during development indicate the complexity of TSPCs at different stages. This study aims to characterize and compare post-natal rat Achilles tendon tissue and TSPCs at different stages of development. The tendon tissue showed distinct differences during development: the tissue structure became denser and more regular, the nuclei became spindle-shaped and the cell number decreased with time. TSPCs derived from 7 day Achilles tendon tissue showed the highest self-renewal ability, cell proliferation, and differentiation potential towards mesenchymal lineage, compared to TSPCs derived from 1 day and 56 day tissue. Microarray data showed up-regulation of several groups of genes in TSPCs derived from 7 day Achilles tendon tissue, which may account for the unique cell characteristics during this specific stage of development. Our results indicate that TSPCs derived from 7 day Achilles tendon tissue is a superior cell source as compared to TSPCs derived from 1 day and 56 day tissue, demonstrating the importance of choosing a suitable stem cell source for effective tendon tissue engineering and regeneration.

Mohawk promotes the tenogenesis of mesenchymal stem cells through activation of the TGFß signaling pathway.

The transcription factor Mohawk (Mkx) is expressed in developing tendons and is an important regulator of tenogenic differentiation. However, the exact roles of Mkx in tendinopathy and tendon repair remain unclear. Using gene expression Omnibus datasets and immunofluorescence assays, we found that Mkx expression level was dramatically lower in human tendinopathy tissue and it is activated at specific stages of tendon development. In mesenchymal stem cells (MSCs), ectopic Mkx expression strikingly promoted tenogenesis more efficiently than Scleraxis (Scx), a well-known master transcription factor of tendon. Significantly higher levels of tenogenic gene expression and collagen fibril growth were observed with Mkx versus Scx. Interestingly, it was observed that Mkx dramatically upregulated Scx through binding to the Tgfb2 promoter. Additionally, the transplantation of Mkx-expressing-MSC sheets promoted tendon repair in a mouse model of Achilles-tendon defect. Taken together, these data shed light on previously unrecognized roles of Mkx in tendinopathy, tenogenesis, and tendon repair as well as in regulating the TGFß pathway.