Systematic Transcriptome Profiling of hPSC-derived Osteoblasts Unveils CORIN's Mastery in Governing Osteogenesis Through CEBPD Modulation.

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect hPSC-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide ChIP enrichment and mechanistic studies show that p38 MAPK-mediated CEBPD upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in MSCs exerts a negative regulatory effect on osteogenesis through a similar mechanism. ChIP-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment.

Unveiling the prognostic implications of RPLP1 upregulation in osteosarcoma.

Osteosarcoma, a malignant bone tumor characterized by a high rate of metastasis and poor survival, presents a critical need for identifying novel biomarkers associated with metastasis. In this study, we conducted an extensive analysis utilizing transcriptional and clinical data sourced from databases such as GEO, TCGA, CCLE, R2, and Xena. And we discovered that Ribosomal protein LP1 (RPLP1) ranked among the top upregulated genes in relation to osteosarcoma metastasis. Notably, RPLP1 exhibited significant expression in both osteosarcoma cell lines and patient samples. Moreover, multiple osteosarcoma studies revealed a strong correlation between RPLP1 overexpression and worse metastasis-free survival as well as overall survival. Additionally, we observed a consistent association between dysregulation of RPLP1 and reduced overall survival across various tumor types. Knocking down of RPLP1 led to the down-regulation of MYL5 and functional enrichment toward cell cycle and cellular interaction. Based on these findings, we propose that RPLP1 has the potential to serve as a prognostic biomarker, indicating increased metastasis and worse survival outcomes in osteosarcoma. These insights contribute to a better understanding of the disease and may pave the way for future research and therapeutic approaches.

DLX2 promotes osteosarcoma epithelial-mesenchymal transition and doxorubicin resistance by enhancing HOXC8-CDH2 axis.

Metastasis and doxorubicin resistance are challenges in the clinical diagnosis and treatment of osteosarcoma, the mechanisms underlying these phenomena remain unclear. In this study, we found that DLX2 is highly expressed in metastatic osteosarcoma and is closely related to clinical prognosis. Knockdown of DLX2 inhibited tumor proliferation and migration in vitro and inhibited tumor growth in vivo. Mechanistically, we found that DLX2 enhanced the repression of CDH2 transcription by binding to HOXC8, thereby promoting the epithelial-mesenchymal transition in osteosarcoma cells. Through subsequent exploration, we found that targeting DLX2/HOXC8 signaling significantly restores the sensitivity of osteosarcoma cells to doxorubicin. In conclusion, our findings demonstrate that DLX2 may enhance the transcriptional regulation of CDH2 through interacting with HOXC8, which in turn promotes epithelial-mesenchymal transition and doxorubicin resistance in osteosarcoma. These findings hold great potential for clinical application and may guide the development of novel targeted therapies for osteosarcoma.

Child traumatic physical abuse rates and comparisons during the COVID-19 pandemic: Retrospective paediatric single institution review in Texas.

AIM: The COVID-19 pandemic drastically altered human behaviour and socialisation and may have created an environment that could lead to increased incidence of domestic abuse and non-accidental trauma, or child physical abuse (CPA). Initial reports about the effect of the COVID-19 pandemic on the rates of CPA have been mixed. The purpose of this study is to describe the effects of COVID-19 on rates of CPA in a large metropolitan paediatric hospital and level I paediatric trauma centre. METHODS: We identified and compared all CPA admissions under 18 years from May 2019 to February 2020 and considered that to be the pre-COVID time frame. The ensuing 12-month period of March 2020 to February 2021 was considered to be the intra-COVID time frame. RESULTS: There were 49 (0.32%) unique CPA patients pre-COVID and 83 (0.85%) unique CPA patients intra-COVID (P < 0.001) with lower total admissions for any reason during the intra-COVID time frame. Monthly CPA cases were increased (P < 0.03) during the intra-COVID time period (mean 6.9, 95% confidence interval: 5.8-12.7) compared to the pre-COVID time period (mean 4.9, 95% confidence interval: 3.3-8.2). CONCLUSION: During the COVID-19 pandemic, there were decreased overall hospital admissions in the period of mandated shutdowns and isolation. However, we saw an increased rate of CPA admissions compared to the time period prior to the pandemic. Knowledge of such data, trends and circumstances will help keep health-care providers alert and vigilant in identifying children at risk for maltreatment, and may impact child abuse protocols and guidelines.

Molecular mechanisms of osteosarcoma metastasis and possible treatment opportunities.

In osteosarcoma patients, metastasis of the primary cancer is the leading cause of death. At present, management options to prevent metastasis are limited and non-curative. In this study, we review the current state of knowledge on the molecular mechanisms of metastasis and discuss promising new therapies to combat osteosarcoma metastasis. Genomic and epigenomic changes, metabolic reprogramming, transcription factors, dysregulation of physiologic pathways, and alterations to the tumor microenvironment are some of the changes reportedly involved in the regulation of osteosarcoma metastasis. Key factors within the tumor microenvironment include infiltrating lymphocytes, macrophages, cancer-associated fibroblasts, platelets, and extracellular components such as vesicles, proteins, and other secreted molecules. We conclude by discussing potential osteosarcoma-limiting agents and their clinical studies.

Infection and Nonunion Following Operative Treatment of Lateral Humeral Condyle Fractures.

BACKGROUND: Lateral humeral condyle fractures (LHCF) are the second most frequent type of pediatric elbow fracture. The purpose of this study is to characterize infections and nonunions of LHCF treated at a single institution. This is the largest series on infections and nonunions of LHCF to date. METHODS: Pediatric patients undergoing surgical treatment for a LHCF from 2012 to 2022 at a single children's hospital were identified for a retrospective review. Patients who were diagnosed with an active infection or nonunion after surgery were included. Data collected included demographics, original treatment course, presentation, effective treatments, outcomes, and timing of events. RESULTS: Out of 863 surgical patients, 12 (1.4%) patients developed 13 infections: 8 were diagnosed with superficial cellulitis, 3 with soft tissue infections, and 2 with osteomyelitis. Eleven fractures were stabilized with percutaneous pins and 1 with buried pins. The average time to infection diagnosis was 29 days and the most common presenting symptom was increased or new onset of pain. All 12 patients received antibiotics for an average 18 days, 6 required hospital admission, 3 required surgical incision and drainage, and 2 required intravenous antibiotics without admission. One patient that developed osteomyelitis developed a nonunion. Ten (1.2%) surgical patients developed nonunion. There were 3 Weiss type II fractures and 7 type III fractures. On average, nonunions were diagnosed 12 weeks after initial treatment. Nine patients underwent nonunion surgery, and all went on to union. Patient's elbows were immobilized for an average 16 weeks and at least 5 patients required an average of 10 physical therapy sessions to regain their range of motion. CONCLUSION: Infection and nonunion are rare complications of LHCF, but greatly change the timeline and number of healthcare interactions required for healing. Infectious complications typically require admission, additional surgery, or emergency department visits. Nonunions require extensive cast time, additional surgery, and rehabilitation. LEVEL OF EVIDENCE: Level IV - case series.

Cardiotoxicity of Antineoplastic Therapies and Applications of Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

The therapeutic landscape for the treatment of cancer has evolved significantly in recent decades, aided by the development of effective oncology drugs. However, many cancer drugs are often poorly tolerated by the body and in particular the cardiovascular system, causing adverse and sometimes fatal side effects that negate the chemotherapeutic benefits. The prevalence and severity of chemotherapy-induced cardiotoxicity warrants a deeper investigation of the mechanisms and implicating factors in this phenomenon, and a consolidation of scientific efforts to develop mitigating strategies. Aiding these efforts is the emergence of induced pluripotent stem cells (iPSCs) in recent years, which has allowed for the generation of iPSC-derived cardiomyocytes (iPSC-CMs): a human-based, patient-derived, and genetically variable platform that can be applied to the study of chemotherapy-induced cardiotoxicity and beyond. After surveying chemotherapy-induced cardiotoxicity and the associated chemotherapeutic agents, we discuss the use of iPSC-CMs in cardiotoxicity modeling, drug screening, and other potential applications. Improvements to the iPSC-CM platform, such as the development of more adult-like cardiomyocytes and ongoing advances in biotechnology, will only enhance the utility of iPSC-CMs in both basic science and clinical applications.

Modeling of osteosarcoma with induced pluripotent stem cells.

Osteosarcoma is the most common type of bone cancer. Osteosarcoma is commonly associated with TP53 inactivation (around 95% of cases) and RB1 inactivation (around 28% of cases). With the discovery of reprogramming factors to induce pluripotency even in terminally differentiated cells, induced pluripotent stem cells (iPSCs) have emerged as a promising disease model. iPSC-based disease modeling uniquely recapitulates disease phenotypes and can support discoveries into disease etiology and is used extensively today to study a variety of diseases, including cancers. This paper focuses on iPSC-based modeling of Li-Fraumeni syndrome (LFS), an autosomal dominant disorder commonly associated with TP53 mutation and high osteosarcoma incidence. As iPSCs are increasingly utilized as a platform for cancer modeling, the experimental approaches that we discuss here may serve as a guide for future studies.