Adolescent Bone Research Articles

Impact of Consolidative Radiation on Overall and Progression-Free Survival in Pediatric, Adolescent, and Young Adult Metastatic Bone and Soft Tissue Sarcoma

To determine the association between consolidative radiation (RT) and survival in children, adolescents, and young adults with metastatic sarcoma. Eligibility criteria included patients aged ≤39 years with newly diagnosed metastatic bone or soft tissue sarcoma who completed local control of the primary tumor without disease progression. Consolidative RT was defined as RT to all known sites of metastatic disease. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). The least absolute shrinkage and selection operator Cox provided adjusted estimates. To account for immortal time bias, consolidative RT was used as a time-varying covariate in a time dependent Cox model. Distant failure was estimated using the Fine-Gray model. Patients (n=85) had a median age at diagnosis of 14.8 years. Most common histology was Ewing Sarcoma (45.9%) followed by rhabdomyosarcoma (40.0%). Receipt of consolidative RT was associated with Ewing Sarcoma (P < .001) and local control modality as those who underwent local control with surgery and RT compared with surgery alone were more likely to be treated with consolidative RT (P=.034). Consolidative RT was independently associated with improved OS (hazard ratio [HR], 0.41; 95% CI, 0.17-0.98; P=.045) and improved PFS (HR, 0.37; 95% CI, 0.16-0.88; P=.024) after adjusting for confounding variables and immortal time bias. Patients treated with consolidative RT also experienced a lower risk of distant failure (HR, 0.33; 95% CI, 0.17-0.64; P=.001). In an independent data set of patients with metachronous progression (n=36), consolidative RT remained independently associated with improved OS. Consolidative RT was independently associated with improved OS and PFS and decreased risk of distant failure in child, adolescent, and young adult patients with metastatic sarcoma. Future work should evaluate biomarkers to optimize patient selection, timing, and dose for consolidative RT.

Targeted Therapy for EWS-FLI1 in Ewing Sarcoma.

Ewing sarcoma (EwS) is a rare and predominantly pediatric malignancy of bone and soft tissue in children and adolescents. Although international collaborations have greatly improved the prognosis of most EwS, the occurrence of macrometastases or relapse remains challenging. The prototypic oncogene EWS-FLI1 acts as an aberrant transcription factor that drives the cellular transformation of EwS. In addition to its involvement in RNA splicing and the DNA damage response, this chimeric protein directly binds to GGAA repeats, thereby modifying the transcriptional profile of EwS. Direct pharmacological targeting of EWS-FLI1 is difficult because of its intrinsically disordered structure. However, targeting the EWS-FLI1 protein complex or downstream pathways provides additional therapeutic options. This review describes the EWS-FLI1 protein partners and downstream pathways, as well as the related target therapies for the treatment of EwS.

Evaluation of the effect of sickle cell disease on the mandibular bone of children and adolescents by image texture and radiomorphometric analysis.

Sickle cell disease (SCD) can cause osteoporotic changes in the jaw bones. In this study, it was aimed to evaluate possible bone changes using fractal analysis (FA) and morphometric analyses in dental panoramic radiographs of children andadolescents diagnosed with both homozygous and heterozygous forms of SCD. Sixty-five individuals (33 SCD, 32 controls) aged 6-17years were included in the study. Four separate areas of interest (ROI) were selected for the right and left sides of all panoramic radiographs, and the FA value of the ROIs was calculated. Mandibular cortical width (MCW), panoramic mandibular index (PMI) and mandibular cortical index (MCI) and were evaluated. Data were statistically analyzed and p < 0.05 was accepted for statistical significance. Fractal values of right and left ROI1 (the center of the mandibular angle.) and ROI4 (the cortical bone), and right ROI2 (the middle of the mandibular ramus) were statistically lower in the case group (p < 0.05). Right ROI2 and ROI4 fractal values of individuals in the case group were lower than those on the left side (p < 0.05). While MCI categories did not differ from the case-control group (p > 0.05), PMI and MCW values were lower in the case group (p < 0.05). All evaluated parameters did not differ according to age and gender (p > 0.05). The results of this study showed that SCD affects the mandible. FA, MCW and PMI parameters can be used to detect early osteoporotic changes in the disease.

MFNG is an independent prognostic marker for osteosarcoma

BackgroundOsteosarcoma (OS) has been the most common malignancy of the bone in children and adolescents, and the unsatisfactory prognosis of OS sufferers has long been a hard nut. Here, we delved into the markers with a prognostic value for predicting the prognosis of OS patients.MethodsThe messenger RNA (mRNA) sequencing data and clinical data of OS were retrieved from a Gene Expression Omnibus (GEO) dataset (GSE39058). Next, prognosis-related genes (PRGs) were filtered with the aid of Kaplan–Meier (K-M) curves and Cox regression analysis (CRA). Later, Gene Ontology (GO) biological process analysis was used in verifying the function of different genes. CCK-8 and cell apoptosis assay were performed to evaluate the function of MFNG in U2OS cells.ResultsAmong the obtained genes, Manic Fringe (MFNG) had the closest relevance to prognosis and clinical traits, thus becoming the research object herein. In light of the expression level of MFNG, patients fell into high- and low-MFNG groups. Patients with elevated MFNG expression had a worse prognosis, according to the survival analysis. It was unveiled by the univariate and multivariate analyses that MFNG expression was an independent adverse prognostic factor for disease-free survival in OS patients (p = 0.006). Meanwhile, MFNG expression was linked to gender and tumor recurrence, and it was higher in patients with OS recurrence. Moreover, overexpression of MFNG promoted the cell proliferation and inhibited the cell apoptosis of U2OS cells.ConclusionsThe expression level of MFNG negatively correlated with OS progression, and as an independent adverse prognostic factor for disease-free survival in OS patients. Moreover, MFNG regulated the cell proliferation and apoptosis of OS cells.

A Comprehensive Review of Minerals and Vitamins Synergy: Impacts on Childhood and Adolescent Bone Development

Bone development during childhood and adolescence is a critical period that lays the foundation for lifelong skeletal health. Adequate nutrition, particularly the intake of minerals and vitamins, is pivotal in ensuring optimal bone growth and development. This comprehensive review examines the synergy between minerals and vitamins and its impact on childhood and adolescent bone development. The review begins with exploring the significance of bone health during the formative years, emphasizing the long-term implications of suboptimal bone development. The topic then turns to the precise roles essential vitamins, particularly vitamin D, and crucial minerals, such as calcium and phosphorus, play in maintaining healthy bones. It highlights their interdependent roles and the interconnected biochemical pathways facilitating bone growth. Moreover, this review sheds light on the factors influencing these nutrients' absorption, utilization, and bioavailability in children and adolescents. Genetic factors, dietary habits, lifestyle choices, and other variables are examined for their potential effects on bone health outcomes. Through a meticulous analysis of existing clinical studies and observations, the review evaluates the impact of minerals and vitamin synergy on bone density, mineral content, and overall bone strength in the pediatric population. Furthermore, it elucidates the potential benefits of optimizing these nutrients during crucial growth stages. Evidence-based recommendations are provided to guide parents, caregivers, and healthcare professionals in promoting healthy bone development in children and adolescents. The importance of tailored dietary strategies, supplementation when necessary, and lifestyle modifications is emphasized for maximizing bone health outcomes. In conclusion, this comprehensive review underscores the vital role of minerals and vitamin synergy in childhood and adolescent bone development. It consolidates existing knowledge, identifies research gaps, and sets the stage for future investigations in pediatric skeletal health. Ultimately, this work aims to raise awareness about the significance of adequate nutrition in shaping resilient and robust bones, contributing to the overall well-being of the younger generation. Here we will discuss the necessary bone nutrients, such as Phosphorus, Calcium, Vit D, Vit A, Vit K2, Zinc, Magnesium, and Branched Chain Amino Acid.&#x0D;

Stress injuries of bone in children and adolescents

Stress injuries of bone in childhood and adolescence are the result of an imbalance between physical stress on the growing musculoskeletal system and its intrinsic resilience. Children who are very active in sports are particularly affected. The classical stress injuries mainly occur in the area of the lower leg, the metatarsus and the lower lumbar spine due to the disproportionate load on healthy bone; however, overuse syndromes can also occur in the area of the growth plates and possibly lead to growth plate disorders. The anamnesis usually shows stress-related pain that has existed for along time without trauma. As part of the differential diagnosis, a stress injury must first be included in the considerations due to it being a rare entity. An X‑ray examination can show the first signs of astress reaction. In the event of aconspicuous periosteal reaction, amalignant event must also be considered. As arule, the MRI examination is then groundbreaking and in some rare cases biopsies have to be considered. The treatment of stress injuries is usually conservative. Recurrences should be counteracted by exercise control.

Differences in bone accrual over one year in young girls with obesity compared to Normal weight controls.

Despite higher bone mineral density (BMD), women with obesity are at an increased risk of fracture compared to normal-weight women. Optimal adolescent bone accrual is critical for normal peak bone mass acquisition and future bone health. Whereas several studies have examined the impact of low body weight on bone accrual in youth, data are lacking regarding the impact of obesity on bone accrual. We examined bone accrual over one year in young women with moderate to severe obesity (OB) (n=21) versus normal-weight controls (NWC) (n=50). Participants were 13-25years old. We used dual-energy X-ray absorptiometry to assess areal BMD (aBMD) and high resolution peripheral quantitative computed tomography (distal radius and tibia) to assess volumetric BMD (vBMD), bone geometry, and microarchitecture. Analyses were controlled for age and race. The mean age was 18.7±2.7years. OB and NWC were similar for age, race, height, and physical activity. OB had a higher BMI (p<0.0001) and younger menarchal age (p=0.022) than NWC. Over one year, OB did not demonstrate the increase in total hip BMD observed in NWC (p=0.03). Increases in percent cortical area and cortical thickness, and cortical and total vBMD at the radius were lower in OB than in NWC (p≤0.037). Groups did not differ for tibial bone accrual. We demonstrate that longitudinal bone accrual is impaired at the total hip and radial cortex in young women with obesity, raising concerns regarding their future bone health.

Molecular profile &amp; clinical outcome in 121 cases - experience from a tertiary referral centre in South India

Ewing sarcoma is the second most common sarcoma involving the bones in children and adolescents. Published data on the clinical features, morphology, translocation and follow-up of patients with Ewing sarcoma from India, is sparse. Objectives of this study were to analyse the clinico-pathologic features of Ewing sarcoma and compare with translocation status, BCoR immunohistochemistry, treatment and survival. 406 cases of Ewing sarcoma were diagnosed in the Department of Pathology, Christian Medical College, Vellore during the period 2008-2015. 135 patients underwent molecular testing for common translocations by RT-PCR and were included in this study.Mean age of patients at diagnosis was 22 years. Most common location of tumour was appendicular skeleton (31.4%) and 19% had solid organ involvement. Distant metastasis was present in 21.5% patients. Translocation was seen in 63 (46.7%) cases, EWS-FLI1 type I (87%), EWS-FLI1 type II(11%) and one patient had EWS-ERG translocation. Seven out of 30 patients were classified as “Sarcoma with BCOR genetic alteration”. Patients who underwent 6 cycles of chemotherapy had a better mean survival. Mean follow-up was 13.72 months and 3 year event free survival of patients was 93.8%.Percentage of viable tumour &amp;#60;10% was the only significant histologic parameter predicting survival. Age at diagnosis ≤15yrs, female sex, size ≤12cm, extra-osseous site, chemotherapy and translocation positivity predicted an improved survival. This study has analysed the type of mutations/translocations seen in a subset of Indian patients with Ewing sarcoma and correlated the clinical and pathological factors affecting survival.

A Conceptual Approach for Examining Effects of the Adolescent Bone Marrow Milieu on MSC Phenotype.

Children with bone fragility often exhibit elevated bone marrow lipid levels, which may affect mesenchymal stem cell (MSC) differentiation potential and ultimately bone strength via cell-autonomous and/or non-cell-autonomous factors. Here, we use standard co-culture techniques to study biological effects of bone marrow cell-derived secretome on MSC. Bone marrow was collected during routine orthopedic surgery, and the entire marrow cell preparation, with or without red blood cell (RBC) reduction, was plated at three different densities. Conditioned medium (secretome) was collected after 1, 3, and 7 days. ST2 cells, a murine MSC line, were then cultured in the secretomes. Exposure to the secretomes was associated with reductions of up to 62% in MSC MTT outcomes that depended on the duration of secretome development, as well as marrow cell plating density. Reduced MTT values were not associated with diminished cell number and viability assessed using Trypan Blue exclusion. Expression of pyruvate dehydrogenase kinase 4 was modestly elevated, and β-actin levels were transiently reduced in ST2 cells exposed to secretome formulations that had elicited maximal reductions in MTT outcomes. The findings from this study can inform the design of future experimental studies to examine contributions of cell-autonomous and non-cell-autonomous factors in the bone marrow to MSC differentiation potential, bone formation, and skeletal growth. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Malignant transformation of a recurrent giant cell tumor of bone with lung metastasis: a case report

Giant cell tumors (GCT) are benign tumors with potential for aggressive behaviour and capacity to metastasize. It is a locally destructive tumor that occurs predominantly in long bones of adolescents and young adults in the epiphysis. Although rarely lethal, benign bone tumors may be associated with a substantial disturbance of the local bony architecture that can be particularly troublesome in peri-articular locations. It is characterized by a proliferation of mononuclear stromal cells and the presence of many multi-nucleated giant cells with homogenous distribution. There are varying surgical techniques ranging from intra-lesional curettage to wide resection. As most giant cell tumors are benign and are located near a joint in young adults, several authors favour an intralesional approach that preserves anatomy of bone. Although GCT is classified as a benign lesion, few patients develop progressive lung metastases with poor outcomes. Malignant transformation without radiotherapy exposure, is an uncommon event, occurring in less than 1% of giant cell tumors of bone. Here we reported a case of recurrent GCT of tibia that at the time of final recurrence was found to have undergone malignant transformation over a period of 6 years following several limb salvaging procedures. Concurrent metastases were found in the lung, but these were non-transformed GCT following which the patient has undergone above knee amputation.

Development and Evaluation of an e-Book for Bone Health and Osteoporosis Education in Adolescents.

Achieving optimum peak bone mass during adolescence is crucial for lifetime bone health. This study is aimed at developing and assessing an e-book designed for adolescent bone health knowledge and osteoporosis education. A needs assessment was conducted among 43 adolescents, aged 13-16 years, living in urban areas in Malaysia to determine their needs and preference for health educational material. The researchers also searched for relevant guidelines and articles regarding adolescent bone health. Subsequently, an e-book was developed based on the needs assessment and literature search. Five expert panelists (mean work experience = 11.3 years) validated the e-book contents and assessed its understandability and actionability using the Patient Educational Materials Assessment Tool for Audio-Visual Material (PEMAT-A/V). The internet (72.1%), parents (44.2%), television (41.9%), and teachers (39.5%) were the top four sources of health information among the respondents. Magazines (4.6%) and newspapers (11.6%) were the least preferred resources. Most adolescents were interested in cartoon-themed educational materials, and they perceived that including a short video, quiz, and infographic in the educational material would make it much more interactive for users. The developed e-book includes seven infographic chapters, a link to a quiz, and a summary video. The topics cover basic information on bones and the formation and resorption processes, osteoporosis and its risk factors, key nutrients for bone health (calcium and vitamin D), along with their sources and recommended amounts, physical activity and exercise for bone health, and tips for healthy lifestyle practices for bone health. All chapters and the video were rated with a median score of 100% for understandability and actionability, respectively. Some of the comments received from evaluators included that the e-book made good use of infographics, was easy to understand and interesting, and contained well-organized content. Some suggestions for improvement included adding take-home messages relevant to the topic, using colors to highlight keywords, and narrating all points presented in the video. Overall, the newly developed e-book on adolescent bone health was highly rated by expert panelists. However, the acceptance and effectiveness of the e-book in increasing bone health and osteoporosis knowledge among adolescents are yet to be evaluated. The e-book could be used as one of the educational tools to promote bone health in adolescents.

Outcomes of Surgical Treatment of Diaphyseal Fractures of Long Bones in Children and Adolescents through Open Reduction and Intramedullary K-Wire Fixation at Yopougon Teaching Hospital, Abidjan (Côte d’Ivoire)

Outcomes of Surgical Treatment of Diaphyseal Fractures of Long Bones in Children and Adolescents through Open Reduction and Intramedullary K-Wire Fixation at Yopougon Teaching Hospital, Abidjan (Côte d’Ivoire)

Chondroblastoma of foot bones; a clinicopathological study of 29 cases confirming the diagnostic utility of H3K36M and H3G34W antibodies at an uncommon site

ObjectiveChondroblastoma (CB) is a benign cartilaginous bone neoplasm which commonly occurs in long bones of adolescents. CB can uncommonly involve foot. Its mimics include both benign and malignant lesions. H3K36M immunohistochemical (IHC) stain is a helpful tool for establishing the diagnosis of CB in such challenging situations. In addition, H3G34W IHC stain helps to rule out giant cell tumor which is the closest differential of CB. Our objective was to describe the clinicopathological features and frequencies of H3K36M, H3G34W and SATB2 IHC stains in CB of foot. Materials and methodsWe reviewed H&E slides and blocks of 29 cases diagnosed as “chondroblastoma” of foot at our institutions. ResultsPatient's age ranged from 6 to 69 (mean: 23.3 and median: 23) years. Males were almost 5 times more commonly affected than females. Talus and calcaneum were involved in 13 (44.8 %) cases each. Microscopically, tumors were composed of polygonal mononuclear cells and multinucleated giant cells and chondroid matrix. Other histological features included aneurysmal bone cyst-like (ABC-like) change (44.8 %), osteoid matrix (31 %), chicken-wire calcification (20.7 %), and necrosis (10.3 %). H3K36M was expressed in 100 % and SATB2 in 91.7 % cases. H3G34W was negative in all cases, where performed. One out of 11 patients with follow up information developed local recurrence after 48 months. ConclusionCB in foot occur at an elder age and show more frequent ABC-like changes as compared to long bones. Males are affected ~5:1 as compared to 2:1 in long bones. H3K36M are H3G34W are extremely useful diagnostic markers for CB, especially elderly (aged or higher) patients and we report the largest series of foot CB cases confirmed by immunohistochemistry.

Abstract 5984: CDK9 inhibition as a potential therapeutic strategy in Ewing sarcoma

Abstract Ewing sarcoma (EWS) is the second most common bone and soft tissue sarcoma in children and adolescents and accounts for approximately 2% of all childhood cancer diagnoses. EWS is a highly aggressive cancer: the overall 5-year survival rate for localized and metastatic EWS are 67 and 38%, respectively. Each year, approximately 200 children and adolescents in the United States are diagnosed with EWS. Genetically, nearly all EWS have chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with 85% of cases being EWSR1-FLI1. Cyclin-dependent kinase 9 (CDK9) is a serine/threonine protein kinase involved in transcription elongation through phosphorylation and activation of RNA polymerase II (RPB1) and increases the levels of key oncogenic genes like myeloid cell leukemia-1 (MCL-1) and c-Myc, which are reported to be involved in chemoresistance. CDK9 may be a viable target in transcriptionally addicted cancers including EWS driven by oncogenic fusion genes like EWSR1-FLI1. TP-1287 is an investigational orally delivered phosphate pro-drug of alvocidib, a potent CDK9 inhibitor. We hypothesized that alvocidib, the pharmaceutically active form of TP-1287, may show activity in EWS cells as a single agent and in combination with standard of care agents. Alvocidib demonstrated the suppression of downstream targets of CDK9 including c-Myc in EWS cell lines after 6-hr treatment. In cell viability assays using CellTiter-Glo, alvocidib resulted in IC50 values of 68 - 125 nM in EWS cell lines after 3-day treatment and 27 - 160 nM in EWS cells from patient derived xenograft (PDX) models, after 6-day treatment. MCL-1 amplified EWS cells were observed significantly more sensitive to alvocidib than MCL-1 diploid EWS cells in the EWS cells from PDX models (p=0.004). Further bioinformatic analysis to predict alvocidib sensitivity is currently underway. Alvocidib demonstrated an additive inhibitory response in combination with topotecan, phosphoramide mustard, a biologically active metabolite of cyclophosphamide, and palifosfamide, a biologically active metabolite of ifosfamide, in EWS cell lines after 3-day treatment. Alvocidib treatment showed reduction of RAD51 which is involved in DNA damage response (DDR), suggesting the activity of alvocidib on DDR may contribute to this additive response. In an in vivo preclinical study using the A-673 model, TP-1287 (2.5 mg/kg, QD) showed tumor growth inhibition (TGI). In vivo combination studies with standard of care agents using EWS xenograft models are currently ongoing. In summary, alvocidib has shown activity inhibiting the growth of EWS cells as a single agent and an additive response in combination with EWS standard of care agents in EWS cell lines. TP-1287 may be a potential therapeutic option for the current regimen in EWS. TP-1287 is being investigated for solid tumors including EWS (clinicaltrials.gov, NCT03604783). Citation Format: Yuta Matsumura, Richard E. Heinz, Curtis A. Allred, Adam Siddiqui, Jason M. Foulks, Steven L. Warner. CDK9 inhibition as a potential therapeutic strategy in Ewing sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5984.

Case report of an Afro-Caribbean adolescent with moderate hypodontia managed with a partial flexible denture

A 14-year-old male of Afro-Caribbean descent presented with moderate hypodontia, missing some of the permanent mandibular premolars and the lower central incisors, which was a rare finding. There were no apparent associated systemic or syndromic relationships. The main dental concerns were aesthetics, function and space maintenance until adolescent craniofacial bone growth had ceased. Thus, an initial intervention entailed provision of a unilateral removable partial flexible denture that was acceptable to the patient and provided a suitable aesthetic result for the young person. This approach was preferred to a ‘band and loop’ appliance proposed in the literature because the removable partial denture supported function and aesthetics. CPD/Clinical Relevance: Unilateral removable partial flexible dentures may be useful in mid-adolescent cases of hypodontia.

Long-term morphometric changes in the anterior alveolar bone in adolescents and adults after space closure: A retrospective study.

To analyse the morphometric changes in the anterior alveolar bone of both the maxilla and mandible after space closure and retention for 18-36 mo in adults and adolescents. Forty-two subjects with 4 first premolars extracted followed by retracting anterior teeth were included and divided into two age groups: adult group (4 males, 17 females, mean age: 23.67 ± 5.29 y, treatment duration: 27.95 mo, retention duration: 26.96 mo, ANB: 4.8 ± 2.1, U1-L1: 117.2 ± 9.2, U1-PP: 120.2 ± 7.2, L1-MP: 99.2 ± 5.3) and adolescent group (6 males, 15 females, mean age: 11.52 ± 1.21 y, treatment duration: 26.18 mo, retention duration: 25.79 mo, ANB: 5.2 ± 2.1, U1-L1: 116.0 ± 8.6, U1-PP: 119.8 ± 4.9, L1-MP: 99.7 ± 4.9). Alveolar bone height and thickness of anterior teeth in both groups were measured using cone beam computed tomography (CBCT) imaging performed at the pretreatment (T1), posttreatment (T2) and retention phases (T3). One-way repeated-measure ANOVAs were performed to evaluate the alveolar bone changes. Voxel-based superimpositions were performed to measure the amount of tooth movement. After orthodontic treatment, the lingual bone height and thickness of both arches and the labial bone height of the mandible decreased significantly in both age groups (P < .05). Most of the labial bone height and thickness of the maxilla in both groups remained unchanged (P > .05). After retention, the lingual bone height and thickness increased significantly in both age groups (P < .05). The amounts of increased height ranged from 1.08 to 1.64 mm in adults and from 0.78 to 1.21 mm in adolescents, and the amounts of increased thickness ranged from 0.23 mm to 0.62 mm in adults and from 0.16 mm to 0.36 mm in adolescents. Obvious movements of the anterior teeth during retention were not found (P > .05). Although lingual alveolar bone loss occurred in adolescents and adults during orthodontic treatment, continuous remodelling occurred in the later retention phase, which provides a reference for clinical treatment planning of bimaxillary dentoalveolar protrusion.

Does adolescent pregnancy affect postmenopausal bone mineral density?

Aim: This study aims to investigate the effect of adolescent pregnancies on bone mineral density in the postmenopausal period and to contribute to this controversial issue.&#x0D; Material and Method: Our study included 70 women at postmenopausal ages. The participants were divided into two groups. Thirty-five women with a history of pregnancy in adolescence were considered group 1, and 35 women without a history of pregnancy were considered group 2. The BMD was measured in the total hip, femoral neck, and lumbar spine. The data were compared using SPSS version 26, and p

Fluoxetine Inhibits STAT3-mediated Survival and Invasion of Osteosarcoma Cells.

Osteosarcoma (OS) is a common primary malignancy of bone in adolescents. Its highly metastatic characteristics can lead to treatment failure and poor prognosis. Although standard treatments, including surgery, radiotherapy, and chemotherapy, have progressed in the past decade, treatment options to overcome metastatic progression remain sparse. Fluoxetine, an anti-depressant, has been widely used in patients with cancer for their mental issues and was reported to possess antitumor potential. However, the effect of fluoxetine on OS remains unclear. In this study, we used cell viability, invasion/migration transwell, wound-healing and aortic ring assays to identify the effects of fluoxetine on metastasis and progression in OS. Fluoxetine induced cytotoxicity in OS cells by activating both extrinsic/intrinsic apoptosis signaling pathways. Proliferation and anti-apoptosis-related factors such as cyclin D1 and X-linked inhibitor of apoptosis were suppressed by fluoxetine. Additionally, fluoxetine suppressed the invasive/migratory abilities of OS and inhibited the development of angiogenesis by reducing the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Metastasis-associated factors, vascular endothelial growth factors, matrix metallopeptidase 2 and -9, were all reduced in OS cells by fluoxetine treatment. Fluoxetine not only induces cytotoxicity and apoptosis of OS cells, but also suppresses metastasis and angiogenesis by targeting STAT3.

Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma.

Chromothripsis is a catastrophic event of chromosomal instability that involves intensive fragmentation and rearrangements within localized chromosomal regions. However, its cause remains unclear. Here, we show that reduction and inactivation of Ran GTPase-activating protein 1 (RanGAP1) commonly occur in human osteosarcoma, which is associated with a high rate of chromothripsis. In rapidly expanding mouse osteoprogenitors, RanGAP1 deficiency causes chromothripsis in chr1q, instant inactivation of Rb1 and degradation of p53, consequent failure in DNA damage repair, and ultrafast osteosarcoma tumorigenesis. During mitosis, RanGAP1 anchors to the kinetochore, where it recruits PP1-γ to counteract the activity of the spindle-assembly checkpoint (SAC) and prevents TOP2A degradation, thus safeguarding chromatid decatenation. Loss of RanGAP1 causes SAC hyperactivation and chromatid decatenation failure. These findings demonstrate that RanGAP1 maintains mitotic chromosome integrity and that RanGAP1 loss drives tumorigenesis through its direct effects on SAC and decatenation and secondary effects on DNA damage surveillance.

Morphologic Mandibular Bone Changes on Panoramic Radiographs of Children and Adolescents with Congenital Heart Disease

Congenital heart disease (CHD) has effects on growth and development. However, information on how the structure of the mandibular bone is affected is limited. In the present study, we aim to compare mandibular bone structures of children affected with CHD and healthy ones through the fractal analysis method and radiomorphometric indices based on panoramic radiographs. The study consisted of 80 children (20 with cyanotic CHD, 20 with acyanotic CHD, 40 control) who were diagnosed with CHD and were treated through interventional therapy or followed up through medical therapy. Fractal dimension (FD) was performed in three different areas (angulus, corpus, and interdental bone) on 80 panoramic radiographs. Additionally, we assessed various radiomorphometric indices: mandibular cortical width (MCW), panoramic mandibular index (PMI), mandibular cortical index (MCI), and simple visual estimation (SVE). p < 0.05 was accepted as statistically significant in the analysis. Values of mean MCW, PMI, MCI, SVE, and FD measurements in children affected with CHD were found to be similar to the control group, regardless of whether they were cyanotic or acyanotic (p > 0.05). In this study, fractal analysis and radiomorphometric indices revealed no trabecular structure and mineral density changes in mandibular bone of children and adolescents with CHD compared to healthy subjects.