Nanosystem Delivers Senescence Activators and Immunomodulators to Combat Liver Cancer.

CD47 blockade has emerged as a promising immunotherapy against liver cancer. However, the optimization of its antitumor effectiveness using efficient drug delivery systems or combinations of therapeutic agents remains largely incomplete. Here, patients with liver cancer co-expressing CD47 and CDC7 (cell division cycle 7, a negative senescence-related gene) are found to have the worst prognosis. Moreover, CD47 is highly expressed, and senescence is inhibited after the development of chemoresistance, suggesting that combination therapy targeting CD47 and CDC7 to inhibit CD47 and induce senescence may be a promising strategy for liver cancer. The efficacy of intravenously administered CDC7 and CD47 inhibitors is limited by low uptake and short circulation times. Here, inhibitors are coloaded into a dual-targeted nanosystem. The sequential release of the inhibitors from the nanosystem under acidic conditions first induces cellular senescence and then promotes immune responses. In an in situ liver cancer mouse model and a chemotherapy-resistant mouse model, the nanosystem effectively inhibited tumor growth by 90.33% and 85.15%, respectively. Overall, the nanosystem in this work achieved the sequential release of CDC7 and CD47 inhibitors in situ to trigger senescence and induce immunotherapy, effectively combating liver cancer and overcoming chemoresistance.

Influence of porosity on osteogenesis, bone growth and osteointegration in trabecular tantalum scaffolds fabricated by additive manufacturing.

Porous tantalum implants are a class of materials commonly used in clinical practice to repair bone defects. However, the cumbersome and problematic preparation procedure have limited their widespread application. Additive manufacturing has revolutionized the design and process of orthopedic implants, but the pore architecture feature of porous tantalum scaffolds prepared from additive materials for optimal osseointegration are unclear, particularly the influence of porosity. We prepared trabecular bone-mimicking tantalum scaffolds with three different porosities (60%, 70% and 80%) using the laser powder bed fusing technique to examine and compare the effects of adhesion, proliferation and osteogenic differentiation capacity of rat mesenchymal stem cells on the scaffolds in vitro. The in vivo bone ingrowth and osseointegration effects of each scaffold were analyzed in a rat femoral bone defect model. Three porous tantalum scaffolds were successfully prepared and characterized. In vitro studies showed that scaffolds with 70% and 80% porosity had a better ability to osteogenic proliferation and differentiation than scaffolds with 60% porosity. In vivo studies further confirmed that tantalum scaffolds with the 70% and 80% porosity had a better ability for bone ingrowh than the scaffold with 60% porosity. As for osseointegration, more bone was bound to the material in the scaffold with 70% porosity, suggesting that the 3D printed trabecular tantalum scaffold with 70% porosity could be the optimal choice for subsequent implant design, which we will further confirm in a large animal preclinical model for better clinical use.

Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms.

Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters.

3D Printing for Bone-Cartilage Interface Regeneration.

Due to the vasculature defects and/or the avascular nature of cartilage, as well as the complex gradients for bone-cartilage interface regeneration and the layered zonal architecture, self-repair of cartilage and subchondral bone is challenging. Currently, the primary osteochondral defect treatment strategies, including artificial joint replacement and autologous and allogeneic bone graft, are limited by their ability to simply repair, rather than induce regeneration of tissues. Meanwhile, over the past two decades, three-dimension (3D) printing technology has achieved admirable advancements in bone and cartilage reconstruction, providing a new strategy for restoring joint function. The advantages of 3D printing hybrid materials include rapid and accurate molding, as well as personalized therapy. However, certain challenges also exist. For instance, 3D printing technology for osteochondral reconstruction must simulate the histological structure of cartilage and subchondral bone, thus, it is necessary to determine the optimal bioink concentrations to maintain mechanical strength and cell viability, while also identifying biomaterials with dual bioactivities capable of simultaneously regenerating cartilage. The study showed that the regeneration of bone-cartilage interface is crucial for the repair of osteochondral defect. In this review, we focus on the significant progress and application of 3D printing technology for bone-cartilage interface regeneration, while also expounding the potential prospects for 3D printing technology and highlighting some of the most significant challenges currently facing this field.

Construction and Comparison of Predictive Models for Length of Stay after Total Knee Arthroplasty: Regression Model and Machine Learning Analysis Based on 1,826 Cases in a Single Singapore Center.

The purpose of this study was to develop a predictive model for length of stay (LOS) after total knee arthroplasty (TKA). Between 2013 and 2014, 1,826 patients who underwent TKA from a single Singapore center were enrolled in the study after qualification. Demographics of patients with normal and prolonged LOS were analyzed. The risk variables that could affect LOS were identified by univariate analysis. Predictive models for LOS after TKA by logistic regression or machine learning were constructed and compared. The univariate analysis showed that age, American Society of Anesthesiologist level, diabetes, ischemic heart disease, congestive heart failure, general anesthesia, and operation duration were risk factors that could affect LOS (p < 0.05). Comparing with logistic regression models, the machine learning model with all variables was the best model to predict LOS after TKA, of whose area of operator characteristic curve was 0.738. Machine learning algorithms improved the predictive performance of LOS prediction models for TKA patients.

Recent Advances in Research on Antibacterial Metals and Alloys as Implant Materials.

Implants are widely used in orthopedic surgery and are gaining attention of late. However, their use is restricted by implant-associated infections (IAI), which represent one of the most serious and dangerous complications of implant surgeries. Various strategies have been developed to prevent and treat IAI, among which the closest to clinical translation is designing metal materials with antibacterial functions by alloying methods based on existing materials, including titanium, cobalt, tantalum, and biodegradable metals. This review first discusses the complex interaction between bacteria, host cells, and materials in IAI and the mechanisms underlying the antibacterial effects of biomedical metals and alloys. Then, their applications for the prevention and treatment of IAI are highlighted. Finally, new insights into their clinical translation are provided. This review also provides suggestions for further development of antibacterial metals and alloys.

The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer.

BACKGROUND: Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed. RESULTS: We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and - 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis. CONCLUSIONS: Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.

Automatic Discoid Lateral Meniscus Diagnosis from Radiographs Based on Image Processing Tools and Machine Learning.

The aim of the present study is to build a software implementation of a previous study and to diagnose discoid lateral menisci on knee joint radiograph images. A total of 160 images from normal individuals and patients who were diagnosed with discoid lateral menisci were included. Our software implementation includes two parts: preprocessing and measurement. In the first phase, the whole radiograph image was analyzed to obtain basic information about the patient. Machine learning was used to segment the knee joint from the original radiograph image. Image enhancement and denoising tools were used to strengthen the image and remove noise. In the second phase, edge detection was used to quantify important features in the image. A specific algorithm was designed to build a model of the knee joint and measure the parameters. Of the test images, 99.65% were segmented correctly. Furthermore, 97.5% of the tested images were segmented correctly and their parameters were measured successfully. There was no significant difference between manual and automatic measurements in the discoid (P=0.28) and control groups (P=0.15). The mean and standard deviations of the ratio of lateral joint space distance to the height of the lateral tibial spine were compared with the results of manual measurement. The software performed well on raw radiographs, showing a satisfying success rate and robustness. Thus, it is possible to diagnose discoid lateral menisci on radiographs with the help of radiograph-image-analyzing software (BM3D, etc.) and artificial intelligence-related tools (YOLOv3). The results of this study can help build a joint database that contains data from patients and thus can play a role in the diagnosis of discoid lateral menisci and other knee joint diseases in the future.

The relationship between mental health/physical activity and pain/dysfunction in working-age patients with knee osteoarthritis being considered for total knee arthroplasty: a retrospective study.

BACKGROUND: Increasing total knee arthroplasty (TKA) surgeries are being performed on working-age patients with prominent manifestations of pain and dysfunction. But few studies have explored the risk factors for pain and dysfunction in working-age patients with knee osteoarthritis (KOA) being considered for TKA. Therefore, this study sought to explore the relationship between mental health/physical activity and pain/dysfunction in working-age patients with KOA being considered for TKA. METHODS: This study was a secondary analysis of data derived from a public database, the Work participation In Patients with Osteoarthritis cohort study, which included 152 working-age patients (65 men and 87 women) with KOA planning for TKA. We analyzed preoperative data comprising age, educational level, body mass index (BMI), mental factors (Patient Health Questionnaire-9 [PHQ-9] and the 36-Item Short Form Survey Instrument [SF-36 mental health]), physical activity level, and clinical outcomes (the Western Ontario and McMaster Universities Osteoarthritis Index and SF-36 sub-item score). Multivariate regression analysis was performed to determine risk factors for pain and dysfunction in working-age patients with KOA being considered for TKA. RESULTS: Women had lower pain, worse function, and higher PHQ-9 scores than men (p < 0.001). The depression scores were significantly linearly related to pain and function scores in women after adjusting for age, BMI, educational level, and physical activity (P < 0.05), whereas this relation was not observed in men. After adjusting for age, BMI, educational level, and mental factors, exercise time was found to be positively correlated with pain scores in women (P < 0.05). CONCLUSIONS: Depression scores and exercise time were significantly correlated with pain and dysfunction in working-age women with KOA being considered for TKA.

Case report: A rare case of focal myositis presenting as Sartorius muscle contracture: A case report and review of literature.

RATIONALE: Focal myositis (FM) is a very rare myopathy of unknown etiology characterized by focal enlargement within one single skeletal muscle. In particular, it occurs only involving the Sartorius muscle has never been reported. PATIENT CONCERNS: A 25-year-old man was admitted to the hospital with progressive restricted left hip joint extension, left thigh discomfort and gait disturbance for 6 years. DIAGNOSES: Combining clinical manifestations with results of radiological and pathological examinations, it was consistent with the diagnosis of FM INTERVENTIONS:: The patient received a surgery under general anesthesia to release the contracted Sartorius tendon. OUTCOMES: The range of motion of the patient's left hip and ipsilateral knee has significantly improved as well as the discomfort of his left thigh relieved obviously after the surgery. LESSONS: This case report is the first to report FM presenting as sartorius muscle contracture and the surgery is an alternative therapy for these patients.