A spatiotemporal drug release scaffold with antibiosis and bone regeneration for osteomyelitis.

INTRODUCTION: Scaffolds loaded with antibacterial agents and osteogenic drugs are considered essential tools for repairing bone defects caused by osteomyelitis. However, the simultaneous release of two drugs leads to premature osteogenesis and subsequent sequestrum formation in the pathological situation of unthorough antibiosis. OBJECTIVES: In this study, a spatiotemporal drug-release polydopamine-functionalized mesoporous silicon nanoparticle (MSN) core/shell drug delivery system loaded with antibacterial silver (Ag) nanoparticles and osteogenic dexamethasone (Dex) was constructed and introduced into a poly-l-lactic acid (PLLA) scaffold for osteomyelitis therapy. METHODS: MSNs formed the inner core and were loaded with Dex through electrostatic adsorption (MSNs@Dex), and then polydopamine was used to seal the core through the self-assembly of dopamine as the outer shell (pMSNs@Dex). Ag nanoparticles were embedded in the polydopamine shell via an in situ growth technique. Finally, the Ag-pMSNs@Dex nanoparticles were introduced into PLLA scaffolds (Ag-pMSNs@Dex/PLLA) constructed by selective laser sintering (SLS). RESULTS: The Ag-pMSNs@Dex/PLLA scaffold released Ag+ at the 12th hour, followed by the release of Dex starting on the fifth day. The experiments verified that the scaffold had excellent antibacterial performance against Escherichia coli and Staphylococcus aureus. Moreover, the scaffold significantly enhanced the osteogenic differentiation of mouse bone marrow mesenchymal stem cells. CONCLUSION: The findings suggested that this spatiotemporal drug release scaffold had promising potential for osteomyelitis therapy.

Stem Cell-Based Therapeutic Strategies for Premature Ovarian Insufficiency and Infertility: A Focus on Aging.

Reproductive aging is on the rise globally and inseparable from the entire aging process. An extreme form of reproductive aging is premature ovarian insufficiency (POI), which to date has mostly been of idiopathic etiology, thus hampering further clinical applications and associated with enormous socioeconomic and personal costs. In the field of reproduction, the important functional role of inflammation-induced ovarian deterioration and therapeutic strategies to prevent ovarian aging and increase its function are current research hotspots. This review discusses the general pathophysiology and relative causes of POI and comprehensively describes the association between the aging features of POI and infertility. Next, various preclinical studies of stem cell therapies with potential for POI treatment and their molecular mechanisms are described, with particular emphasis on the use of human induced pluripotent stem cell (hiPSC) technology in the current scenario. Finally, the progress made in the development of hiPSC technology as a POI research tool for engineering more mature and functional organoids suitable as an alternative therapy to restore infertility provides new insights into therapeutic vulnerability, and perspectives on this exciting research on stem cells and the derived exosomes towards more effective POI diagnosis and treatment are also discussed.

Meiosis resumption in human primordial germ cells from induced pluripotent stem cells by in vitro activation and reconstruction of ovarian nests.

BACKGROUND: The differentiation of human induced pluripotent stem cells (iPSCs) into oocytes, which involves the transformation from mitosis to meiosis, has been a hotspot of biological research for many years and represents a desirable experimental model and potential strategy for treating infertility. At present, studies have shown that most cells stagnate in the oogonium stage after differentiation into primordial germ cells (PGCs) from human iPSCs. METHODS: iPSCs carrying a SYCP3-mkate2 knock-in reporter were generated by the CRISPR/Cas9 strategy to monitor meiosis status during induced differentiation from iPSCs into oocytes. These induced PGCs/oogonia were activated by small molecules from the Wnt signaling pathway and then cocultured with reconstructed human ovarian nests in vivo for further development. RESULTS: First, human PGCs and oogonia were efficiently induced from iPSCs. Second, induced dormant PGCs resumed meiosis and then differentiated into primary oocytes through the in vitro activation of the Wnt signaling pathway. Finally, a new coculture system involving the reconstruction of ovarian nests in vitro could facilitate the differentiation of oocytes. CONCLUSIONS: Human PGCs/oogonia induced from iPSCs can be activated and used to resume meiosis by molecules of the Wnt signaling pathway. The coculture of activated PGCs and reconstruction of ovarian nests facilitated differentiation into primary oocytes and the generation of haploid human oocytes in vivo. These findings established a new strategy for germline competence in primary oocytes and provided a keystone for human gametogenesis in vitro and in vivo.

A retrospective study of spine injuries in electric bicycles related collisions.

BACKGROUND: Electric bicycles related collisions could lead to severe consequences in spine injuries, while no study had comprehensively investigated the epidemiology and demography of spine injuries in electric bicycles related collisions. QUESTIONS/PURPOSES: The aim of this study is to (1) describe the epidemiological characteristics of spine injuries in electric bicycles related collisions, (2) develop clinical guideline of spine injuries in electric bicycles related collisions and (3) support the new road safety policy for electric bicycle riders. METHODS: A retrospective review of spine injuries in electric bicycle related collisions was performed from 86 patients in an urban trauma center between 2018 and 2020. The variables including gender, age, radiographic findings, associated injuries, neurologic injuries, treatment, average length of stay were fully collected. Chi-square test and paired sample mean t-test were used to test for statistically significant differences. All statistical analyses were performed using Statistical Product and Service Solutions 20.0.0 software. A P<0.001 was considered as significant. RESULTS: A total of 86 cases were involved in electric bicycles related collisions lead to spine injuries. The spine injuries victims were predominantly male (79.07%) and middle-aged (41-60years, 44.19%). The most common spine injuries were L1 fractures (10.48%). The most common fracture type was AO Fracture Classification type A (71.40%). Age and multivertebral fractures had significant difference between patients who suffered from an ASOI and from those who did not (P-value: 0.005, 0.005). There was significant difference between patients who suffered from neurologic injuries and from those who did not in AO Classification, multivertebral fractures and ASOI (P-value: 0.0001, 0.001, 0.032). Age, AO Classification, multivertebral fractures, ASOI and neurologic injuries had significant difference to influence patients' ISS and ALOS. CONCLUSIONS: Spine injuries in electric bicycles related collisions may make patients suffer from severe consequences including their potential permanent disability, economic cost, or even life safety. Patients with spine injuries in electric bicycles related collisions should be paid close attention to avoid missed diagnosis and misdiagnosis. Helmet, protective clothing or other safety gear should be required to use to provide greater protection for electric bicycle riders.

Silver-doped bioglass modified scaffolds: A sustained antibacterial efficacy.

Implant-related bacterial infection is a serious complication, which even causes implant failure. Silver (Ag) nanoparticles are broadly used antibacterial agents due to their excellent antibacterial ability and broad-spectrum bactericidal property. However, the significance of burst release cannot be entirely ignored. In this study, Ag doped mesoporous bioactive glasses (Ag-MBG) nanospheres were synthesized using modified Stöber method, then incorporated into poly L-lactic acid (PLLA) matrix to prepare the composite scaffolds via selective laser sintering (SLS) technology. Herein, Mesoporous bioactive glasses (MBG) sol had many negatively-charged silicon hydroxyl groups, which could adsorb positively-charged Ag ions by electrostatic interaction and eventually form Si-O-Ag bonds into MBG. Moreover, MBG promoted osteoblast colonization due to its continuous release of Si ions. The results showed the Ag-MBG/PLLA scaffold could sustainedly release Ag ions for 28 days, and exhibited significantly antibacterial ability against Escherichia coli, its bacterial inhibition rate was over 80%. In addition, the composite scaffold also showed good cytocompatibility. It may be concluded that the prepared Ag-MBG/PLLA scaffold has great potential to repair implant-associated bone infection.

Therapeutic Effect of Large Channel Endoscopic Decompression in Lumbar Spinal Stenosis.

Background: Percutaneous endoscopic decompression (PED) is a minimally invasive surgical technique that is now used for not only disc herniation but also lumbar spinal stenosis (LSS). However, few studies have reported endoscopic surgery for LSS. Therefore, we conducted this study to evaluate the outcomes and safety of large channel endoscopic decompression. Methods: Forty-one patients diagnosed with LSS who underwent PED surgery were included in the study. The estimated blood loss, operative time, length of hospital stay, hospital costs, reoperations, complications, visual analogue scale (VAS) score, Oswestry Disability Index (ODI) score, Japanese Orthopaedic Association (JOA) score and SF-36 physical-component summary scores were assessed. Preoperative and postoperative continuous data were compared through paired-samples t-tests. The significance level for all analyses was defined as p < 0.05. Results: A total of 41 consecutive patients underwent PED, including 21 (51.2%) males and 20 (48.8%) females. The VAS and ODI scores decreased from preoperatively to postoperatively, but the JOA and SF-36 physical component summary scores significantly increased. The VAS (lumbar) score decreased from 5.05 ± 2.33 to 0.45 ± 0.71 (P = 0.000); the VAS (leg) score decreased from 5.51 ± 2.82 to 0.53 ± 0.72 (P = 0.000); the ODI score decreased from 52.80 ± 20.41 to 4.84 ± 3.98 (P = 0.000), and the JOA score increased from 11.73 ± 4.99 to 25.32 ± 2.12 (P = 0.000). Only 1 patient experienced an intraoperative complication (2.4%; dural tear), and 1 patient required reoperation (2.4%). Conclusions: Surgical treatment for LSS is to sufficiently decompress and minimize the trauma and complications caused by surgery. This study did not reveal any obvious shortcomings of PED and suggested PED is a safe and effective treatment for LSS.

Management for lumbar spinal stenosis: A network meta-analysis and systematic review.

BACKGROUND: Conventional paired meta-analyses have shown inconsistent results regarding the safety and efficacy of different interventions. OBJECTIVE: To perform a network meta-analysis (NMA) and systematic review based on randomized controlled trials (RCTs) evaluating the efficacies of different interventions for lumbar spinal stenosis (LSS). METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and major scientific websites from inception to October 10, 2019, for randomized controlled trials comparing the nine most commonly used interventions for LSS. The main outcomes were disability and pain intensity. The PROSPERO number was CRD42020154247. RESULTS: First, laminotomy was better in improving patients' short- and long-term dysfunction (probability 49% and 25%, respectively). Second, decompression, decompression plus fusion, endoscopic decompression, interspinous process spacer device implantation, laminectomy, laminotomy and minimally invasive decompression were significantly more efficacious in relieving pain than non-surgical interventions (mean difference in the short-term -21.82, -22.00, -16.68, -17.47, -17.75, -17.61 and -18.86; in the long-term -37.14, -34.04, -34.07, -39.79, -36.14, -32.75 and -39.14, respectively). Third, endoscopic decompression had a lower complication rate (probability 51%). In addition, laminotomy had a lower reoperation rate (probability 45%). Fourth, decompression plus fusion resulted in more blood loss than any other surgical intervention (probability 96%). Finally, endoscopic decompression had the shortest hospitalization time (probability 96%). CONCLUSIONS: There were no significant differences among the different interventions in improving patient function. Surgical interventions were associated with better pain relief but a higher incidence of complications. Decompression plus fusion is not necessary for patients. In addition, endoscopic decompression as a novel and less invasive surgical approach may be a good choice for LSS patients.

Management for lumbar spinal stenosis: Protocol for a network meta-analysis and systematic review.

INTRODUCTION: Lumbar spinal stenosis (LSS) is caused by structural changes of the spine, which lead to several severe symptoms, including back pain, leg pain, numbness and tingling in the legs, as well as reduced physical function. However, there is little evidence suggesting whether a patient with LSS should be treated with surgery. If surgery is recommended, which type of surgery benefits the patient most? To answer these questions, we will conduct a network meta-analysis and a systematic review to compare surgical and nonsurgical interventions in terms of efficacy as well as safety in adult patients with LSS. METHODS AND ANALYSIS: We will search the PubMed, Cochrane library, and EMBASE databases for articles published prior to October 10, 2019. We will search for randomized controlled trials assessing surgical and nonsurgical interventions for adult patients with degenerative LSS without any language restrictions. The primary outcome measures will be pain and disability. The secondary outcomes will include adverse events (number of events or number of people with each type of adverse event), reoperations, complications, blood loss and operation time. We will obtain the full texts of the potentially relevant studies and independently assess them. The quality of evidence will be evaluated according to the Grading of Recommendations Assessment, Development and Evaluation framework. A random-effects network meta-analysis will be performed to analyze all the evidence under the frequentist framework, and the ranking results will be presented. We will generate plots depicting the network geometry using Stata. The network meta-analysis will be performed according to the Bayesian framework. Ethics and dissemination Ethics approval is not required. The research will be published in a peer-reviewed journal.

Forkhead box K2 promotes human colorectal cancer metastasis by upregulating ZEB1 and EGFR.

Background: Metastasis is the major reason for high recurrence rates and poor survival among patients with colorectal cancer (CRC). However, the underlying molecular mechanism of CRC metastasis is unclear. This study aimed to investigate the role of forkhead box K2 (FOXK2), one of the most markedly increased FOX genes in CRC, and the mechanism by which it is deregulated in CRC metastasis. Methods: FOXK2 levels were analyzed in two independent human CRC cohorts (cohort I, n = 363; cohort II, n = 390). In vitro Transwell assays and in vivo lung and liver metastasis models were used to examine CRC cell migration, invasion and metastasis. Chromatin immunoprecipitation and luciferase reporter assays were used to measure the binding of transcription factors to the promoters of FOXK2, zinc finger E-box binding homeobox 1 (ZEB1) and epidermal growth factor receptor (EGFR). Cetuximab was utilized to treat FOXK2-mediated metastatic CRC. Results: FOXK2 was significantly upregulated in human CRC tissues, was correlated with more aggressive features and indicated a poor prognosis. FOXK2 overexpression promoted CRC migration, invasion and metastasis, while FOXK2 downregulation had the opposite effects. ZEB1 and EGFR were determined to be direct transcriptional targets of FOXK2 and were essential for FOXK2-mediated CRC metastasis. Moreover, activation of EGFR signaling by EGF enhanced FOXK2 expression via the extracellular regulated protein kinase (ERK) and nuclear factor (NF)-κB pathways. The EGFR monoclonal antibody cetuximab significantly inhibited FOXK2-promoted CRC metastasis. In clinical CRC tissues, FOXK2 expression was positively correlated with the expression of p65, ZEB1 and EGFR. CRC patients who coexpressed p65/FOXK2, FOXK2/ZEB1 and FOXK2/EGFR had poorer prognosis. Conclusions: FOXK2 serves as a prognostic biomarker in CRC. Cetuximab can block the EGF-NF-κB-FOXK2-EGFR feedback loop and suppress CRC metastasis.

Sex determining region Y-box 12 (SOX12) promotes gastric cancer metastasis by upregulating MMP7 and IGF1.

Metastasis is the major cause of poor survival and therapeutic failure in gastric cancer (GC). However, the molecular mechanisms underlying GC metastasis remain unclear. Here, we analyzed the expression patterns of sex determining region Y-box 12 (SOX12) in two independent cohorts of paired GC tissues and adjacent nontumor tissues and conducted in vitro and in vivo functional studies to determine the role of SOX12 in GC cells. High SOX12 expression in GC tissues was associated with increased frequency of recurrence and poorer patient survival. SOX12 overexpression increased GC cell migration, invasion and metastasis, whereas SOX12 downregulation decreased these behaviors. Reporter assays revealed that matrix metallopeptidase 7 (MMP7) and insulin-like growth factor 1 (IGF1) are transcriptional targets of SOX12 and indicated their requirement for SOX12-mediated GC metastasis. IGF1 induced SOX12 expression via the PI3K/AKT/CREB pathway, forming an IGF1/CREB/SOX12 feedback loop that contributed to GC metastasis. SOX12 expression correlated with MMP7 and IGF1 expression in GC tissues, and patients expressing SOX12 and either MMP7 or IGF1 had higher metastasis and recurrence rates and shorter survival than patients without that expression pattern. In conclusion, SOX12 is a novel prognostic biomarker and regulator of GC metastasis.

Basigin-2 upregulated by receptor activator of NF-κB ligand enhances lung cancer-induced osteolytic lesions.

BACKGROUND: Lung cancer bone metastasis causes poor prognosis. Basigin-2, a novel cancer-associated biomarker, is upregulated in lung cancer and has been linked with tumor progression. But little is known about the role of basigin-2 in lung cancer bone metastasis and osteolytic lesion. METHODS: Basigin-2 expression was evaluated in biopsy tissue specimens of 20 lung cancer patients with bone metastases via immunohistochemistry. Invasion assay and MTT proliferation assay were performed to test the invasion and proliferation of lung cancer cell after modulated basigin-2 expression. The osteoclastic activity of basigin-2 was detected in tibia cancer model by injected of lung cancer cells. The regulation role of receptor activator of NF-κB ligand (RANKL) on basigin-2 and its downstream molecules were measured by real-time quantitative RT-PCR, gelatin zymography and western blot analysis. RESULTS: We found that basigin-2 was highly expressed in lung cancer bone metastases. Then, we demonstrated that basigin-2 could promote lung cancer cells invasion, metastasis and proliferation through upregulating metalloproteinases-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF) expression. The lung cancer cells overexpressing basigin-2 strongly induced the osteolytic lesions in immunodeficient mice, which were reduced by treatment with basigin-2 blocking antibody. Furthermore, we explored the enhanced basigin-2 molecular mechanism in lung cancer bone metastasis. Our results indicated the RANKL, pivotal for the control of bone resorption, could increase basigin-2 and its downstream molecules MMP-2, MMP-9 and VEGF expression in vitro. CONCLUSIONS: Basigin-2 upregulated by RANKL induces MMPs and VEGF, which may increase lung cancer cell metastasis ability and support osteoclastic activity. Thus, our data suggest important roles for basigin-2 in lung cancer-induced osteolytic lesion and implicate this protein potential application as a target for lung cancer bone metastasis therapy.