Physical training attenuates systemic cytokine response and tissue damage triggered by apical periodontitis.

Apical periodontitis (AP) is a condition characterized by inflammatory and infectious components in the tooth canal. AP affects periradicular tissues and has systemic repercussions. Physical exercise is a structured activity that requires cardiorespiratory function, and can modulate the inflammatory profile in pathological conditions. As a result, this study aimed to determine the effects of aerobic physical training (PT) on the alveolar bone with and without AP, and its systemic inflammatory repercussions. AP was induced in the mandibular first molars, and PT was performed on a treadmill for five consecutive days over four weeks, with progressive increases in speed and activity time. Blood samples were collected to determine serum cytokine levels using immunoassays, and alveolar bone samples were collected for histopathological evaluation, lesion volume and microarchitecture assessment using computed microtomography. Animals with AP had increased pro-inflammatory cytokines levels compared to those without AP; however, these levels were attenuated or restored by PT. Compared to the AP group, the AP + PT group had a smaller lesion volume and greater preservation of the bone trabeculae in the remaining alveolar bone surrounding the lesion. In overall, PT minimized the severity of AP proving to be a valid strategy for individuals undergoing endodontic treatment.

Atypical parathyroid adenoma with severe bone manifestations in early adolescence.

This is a case of primary hyperparathyroidism in a female teenager with multiple fractures and severe bone manifestations. The histopathology revealed atypical parathyroid adenoma, an exceedingly rare form of hyperparathyroidism; its main differential diagnosis is parathyroid carcinoma, as it shares both clinical and histological characteristics with it, in addition to its still uncertain malignant potential.

Smart osteoclasts targeted nanomedicine based on amorphous CaCO3 for effective osteoporosis reversal.

BACKGROUND: Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. RESULTS: Osteoclasts' microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. CONCLUSION: The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.

A Representative Clinical Course of Progression, with Molecular Insights, of Hormone Receptor-Positive, HER2-Negative Bone Metastatic Breast Cancer.

Despite treatment advances, breast cancer remains a leading cause of death of women in the United States, mostly due to metastatic disease. Bone is a preferential site for breast cancer metastasis, and most metastatic breast cancer patients experience bone involvement at the time of death. The majority of patients with bone metastatic breast cancer are first diagnosed with and treated for early-stage disease, and from development of early-stage breast cancer to the recurrence of cancer in the bones, up to 30 years may elapse. Throughout this timeframe, a typical patient undergoes many treatments that have effects on the bone microenvironment. Therefore, this review explores the clinical course of a representative patient with hormone receptor-positive bone metastatic breast cancer, examining key treatment options at each stage and their effects on preventing and treating bone metastases.

Congenital solitary osseous choristoma of the left lateral canthus: a case report.

BACKGROUND: An ocular osseous choristoma is a growth of mature, compact bone in the ocular or periocular soft tissue, and it is the rarest form of ocular choristoma, accounting for only 1.7% of all epibulbar choristomas. CASE PRESENTATION: Herein we present the case of a 20-month-old girl who was referred to the oculoplasty clinic with a progressively growing mass in the left lateral canthus. It had been present since birth without ocular involvement. Upon examination the mass was firm with a smooth surface, measured 9 × 6 × 3 mm, and exhibited no episcleral attachment or ocular involvement. An excisional biopsy was performed, and the histopathological findings were consistent with osseous choristoma of the left lateral canthus. CONCLUSIONS: This report highlights the importance of considering osseous choristoma in the differential diagnosis of eyelid lesions, particularly those that have been present since birth. It also emphasizes the need for further studies investigating associations between osseous choristomas and ocular canthi.

Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors.

Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells, dendritic cells, and megakaryocytes, evaluating their interaction with cytotoxic T lymphocytes and contribution to bone metastasis. As important components of skeletal tissue, osteoclasts and osteoblasts derived from bone marrow stromal cells, engaging in 'vicious cycle' accelerate osteolytic bone metastasis. We also explain the concept tumor dormancy and investigate underlying role of immune microenvironment on it. Additionally, a thorough review of emerging treatments for bone metastatic malignancy in clinical research, especially immunotherapy, is presented, indicating current challenges and opportunities in research and development of bone metastasis therapies.

A statistical symptomatic evaluation on SAPHO syndrome from 56 cases of confirmed diagnosis and 352 cases of non-SAPHO involvement.

OBJECTIVE: To report a statistical evaluation of symptomatology based on 56 cases of SAPHO syndrome and 352 non-SAPHO involvement cases, to propose a symptomatic scoring system in consideration of early warning for SAPHO syndrome. METHODS: A cohort comprising 56 subjects diagnosed with SAPHO syndrome was reported, as well as 352 non-SAPHO involvement cases, including their chief complaints, skin manifestations, radiological findings, and laboratory tests. We systematically reviewed previous published five representative huge cohorts from different countries to conclude several specific features of SAPHO by comparing with our case series. The score of each specific index is based on respective incidence and comparison of two cohorts was performed. RESULT: In terms of complaint rates, all subjects of two cohorts suffered from osseous pain, which appeared in the anterior chest wall, spine, and limb which were calculated. In respect to dermatological lesions, SAPHO patients suffered from severe acne, and other patients (82.14%) accompanied with palmoplantar pustulosis. Having received radiological examinations, most SAPHO subjects rather than non-SAPHO involvement cases showed abnormal osteoarticular lesions under CT scanning and more detailed information under whole-body bone scintigraphy. Differences also emerged in elevation of inflammation values and rheumatic markers like HLA-B27. Based on our cases and huge cohorts documented, the early warning standard is set to be 5 scores. CONCLUSIONS: SAPHO syndrome case series with 56 subjects were reported and an accumulative scoring system for the early reminder on SAPHO syndrome was proposed. The threshold of this system is set to be 5 points. Key Points • Fifty-six patients diagnosed by SAPHO syndrome with detailed symptoms and radiological findings were reported. • Comparison was made between the 56 SAPHO patients and 352 non-SAPHO involvement cases. • An accumulative scoring system for the early reminder on SAPHO syndrome was proposed and the threshold of this system is set to be five points.

The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease.

Multiple myeloma (MM) is an osteolytic malignancy that is incurable due to the emergence of treatment resistant disease. Defining how, when and where myeloma cell intrinsic and extrinsic bone microenvironmental mechanisms cause relapse is challenging with current biological approaches. Here, we report a biology-driven spatiotemporal hybrid agent-based model of the MM-bone microenvironment. Results indicate MM intrinsic mechanisms drive the evolution of treatment resistant disease but that the protective effects of bone microenvironment mediated drug resistance (EMDR) significantly enhances the probability and heterogeneity of resistant clones arising under treatment. Further, the model predicts that targeting of EMDR deepens therapy response by eliminating sensitive clones proximal to stroma and bone, a finding supported by in vivo studies. Altogether, our model allows for the study of MM clonal evolution over time in the bone microenvironment and will be beneficial for optimizing treatment efficacy so as to significantly delay disease relapse.

Role of epidural fat in the local milieu: what we know and what we don't.

PURPOSE: Traditionally, the epidural fat (EF) is known as a physical buffer for the dural sac against the force and a lubricant facilitating the relative motion of the latter on the osseous spine. Along with the development of the studies on EF, controversies still exist on vital questions, such as the underlying mechanism of the spinal epidural lipomatosis. Meanwhile, the scattered and fragmented researches hinder the global insight into the seemingly dispensable tissue. METHODS: Herein, we reviewed literature on the EF and its derivatives to elucidate the dynamic change and complex function of EF in the local milieu, especially at the pathophysiological conditions. We start with an introduction to EF and the current pathogenic landscape, emphasizing the interlink between the EF and adjacent structures. We generally categorize the major pathological changes of the EF into hypertrophy, atrophy, and inflammation. RESULTS AND CONCLUSIONS: It is acknowledged that not only the EF (or its cellular components) may be influenced by various endogenic/exogenic and focal/systematic stimuli, but the adjacent structures can also in turn be affected by the EF, which may be a hidden pathogenic clue for specific spinal disease. Meanwhile, the unrevealed sections, which are also the directions the future research, are proposed according to the objective result and rational inference. Further effort should be taken to reveal the underlying mechanism and develop novel therapeutic pathways for the relevant diseases.

Bone mimetic environments support engineering, propagation, and analysis of therapeutic response of patient-derived cells, ex vivo and in vivo.

Bone metastases are the most common milestone in the lethal progression of prostate cancer and prominent in a substantial portion of renal malignancies. Interactions between cancer and bone host cells have emerged as drivers of both disease progression and therapeutic resistance. To best understand these central host-epithelial cell interactions, biologically relevant preclinical models are required. To achieve this goal, we here established and characterized tissue-engineered bone mimetic environments (BME) capable of supporting the growth of patient-derived xenograft (PDX) cells, ex vivo and in vivo. The BME consisted of a polycaprolactone (PCL) scaffold colonized by human mesenchymal stem cells (hMSCs) differentiated into osteoblasts. PDX-derived cells were isolated from bone metastatic prostate or renal tumors, engineered to express GFP or luciferase and seeded onto the BMEs. BMEs supported the growth and therapy response of PDX-derived cells, ex vivo. Additionally, BMEs survived after in vivo implantation and further sustained the growth of PDX-derived cells, their serial transplant, and their application to study the response to treatment. Taken together, this demonstrates the utility of BMEs in combination with patient-derived cells, both ex vivo and in vivo. STATEMENT OF SIGNIFICANCE: Our tissue-engineered BME supported the growth of patient-derived cells and proved useful to monitor the therapy response, both ex vivo and in vivo. This approach has the potential to enable co-clinical strategies to monitor bone metastatic tumor progression and therapy response, including identification and prioritization of new targets for patient treatment.

Metastatic PSMA avid prostate tumour with penile uptake; a rare metastatic site on PET-CT.

Prostate carcinoma is the most common malignancy in males and the second most common cause of mortality. Initially, metastatic prostate cancers tend to involve bones, but these tumours can involve any system. Gallium-68 prostate specific membrane antigen (PSMA) positron emission computed tomography (PET-CT) scan is indicated in prostate cancer patients if PSA levels are raised, and CT and bone scans are inconclusive. Metastatic penile involvement is a rare phenomenon. We present a case of prostate cancer with foci of PSMA uptake in the penile region. .

Huge osteoma in the frontoparietal bone caused by trauma from 18 years ago: a case report.

BACKGROUND: Osteomas are asymptomatic, benign tumors and are diagnosed accidentally by radiological investigations conducted for other reasons. In some cases, they may cause aesthetic or functional symptoms by affecting nearby organs. The cause of osteoma is still dialectical. Many theories suggest that inflammation, trauma, or congenital causes are behind its formation. In our case, the patient presented with a symptomatic and huge osteoma in the frontoparietal bone caused by trauma from 18 years ago. CASE PRESENTATION: A 24-year-old Syrian woman came to our hospital complaining of headaches, syncope episodes, blurred vision, and tumor formation in the frontoparietal region. The medical and surgical histories of the patient revealed appendectomy and head trauma when she was 6 years old in a traffic accident. Radiological investigations showed thickness in the space between the two bone plates in the left frontoparietal region, which reached the orbital roof without cortical destruction or periosteum reaction; the tumor size was 5 cm × 5 cm. A surgical excision was indicated. Under general anesthesia, the surgery was done for the tumor excision. The histopathology examination emphasized the diagnosis of osteoma. The follow-up for 7 months was uneventful. CONCLUSION: This paper highlights the importance of focusing on the medical history of patients with osteoma in an attempt to explain the reasons for its occurrence. It stresses the need to put osteoma within the differential diagnoses of skull tumors.

Histologic Heterogeneity of Chondrosarcoma Reflected on Bone SPECT/CT.

ABSTRACT: Chondrosarcomas are a heterogeneous group of cartilage-forming tumors. The tumor is graded on areas demonstrating the highest grade. A 71-year-old man underwent bone SPECT/CT to investigate a tumorous lesion on his right femur. Correlating with the pathological findings, the high-grade area showed higher uptake in bone SPECT/CT. This case suggests that bone SPECT/CT could aid in selecting an optimal biopsy site for diagnosis, and determining the proper treatment of patients with suspected chondroid tumors.

The Role of Breast Cancer Cells in Bone Metastasis: Suitable Seeds for Nourishing Soil.

PURPOSE OF REVIEW: The purpose of this review was to describe the characteristics of breast cancer cells prone to developing bone metastasis and determine how they are regulated by the bone microenvironment. RECENT FINDINGS: The bone is a site of frequent breast cancer metastasis. Bone metastasis accounts for 70% of advanced breast cancer cases and remains incurable. It can lead to skeletal-related events, such as bone fracture and pain, and seriously affect the quality of life of patients. Breast cancer cells escape from the primary lesion and spread to the bone marrow in the early stages. They can then enter the dormant state and restore tumourigenicity after several years to develop overt metastasis. In the last few years, an increasing number of studies have reported on the factors promoting bone metastasis of breast cancer cells, both at the primary and metastatic sites. Identifying factors associated with bone metastasis aids in the early recognition of bone metastasis tendency. How to target these factors and minimize the side effects on the bone remains to be further explored.

Histological and immunohistochemical analyses of osteoclast maturation in giant cell tumor of bone.

INTRODUCTION: Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor characterized by the occurrence of multinucleated osteoclast-like giant cells that play a key role in GCTB pathogenesis. However, little is known about the molecular mechanisms underlying osteoclast differentiation in GCTB. Denosumab, a human monoclonal antibody against RANKL, is used for GCTB treatment. Here, we performed morphological and immunohistochemical examinations of pre- and post-denosumab treatment changes by analyzing each stage of osteoclast differentiation. METHODS: We retrieved 15 archival cases of GCTB with tumor samples from both pre- and post-denosumab treatment. We selected three immunohistochemical markers from the expression data from a previous single-cell RNA study: FOS, a progenitor osteoclast marker, and JDP2 and NFATc1, mature osteoclast markers. RESULTS: The mean positivity of the markers decreased after denosumab treatment from 11.1% to 8.9% for FOS, from 10.6% to 7.2% for JDP2, and from 10.0% to 0.2% for NFATc1. Only NFATc1 positivity decreased significantly (P < 0.001) after denosumab treatment. CONCLUSIONS: We identified a new differentiation stage of osteoclast maturation, intermediate cell, by comparing histological findings before and after denosumab treatment. We demonstrated that discrepancies exist between histological and molecular data and highlight the need for establishing an integrated definition of osteoclasts considering morphology and marker expression.

External Mechanical Stability Regulates Hematoma Vascularization in Bone Healing Rather than Endothelial YAP/TAZ Mechanotransduction.

Bone fracture healing is regulated by mechanobiological cues. Both, extracellular matrix (ECM) deposition and microvascular assembly determine the dynamics of the regenerative processes. Mechanical instability as by inter-fragmentary shear or compression is known to influence early ECM formation and wound healing. However, it remains unclear how these external cues shape subsequent ECM and microvascular network assembly. As transcriptional coactivators, the mechanotransducers yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) translate physical cues into downstream signaling events, yet their role in sprouting angiogenesis into the hematoma after injury is unknown. Using bone healing as model system for scar-free regeneration, the role of endothelial YAP/TAZ in combination with tuning the extrinsic mechanical stability via fracture fixation is investigated. Extrinsically imposed shear across the gap delayed hematoma remodeling and shaped the morphology of early collagen fiber orientations and microvascular networks, suggesting that enhanced shear increased the nutrient exchange in the hematoma. In contrast, endothelial YAP/TAZ deletion has little impact on the overall vascularization of the fracture gap, yet slightly increases the collagen fiber deposition under semi-rigid fixation. Together, these data provide novel insights into the respective roles of endothelial YAP/TAZ and extrinsic mechanical cues in orchestrating the process of bone regeneration.

Optimized design of an enthesis-mimicking suture anchor-tendon hybrid graft for mechanically robust bone-tendon repair.

Repair of functionally graded biological interfaces requires joining dissimilar materials such as hard bone to soft tendon/ligament, with re-injuries/re-tears expected to be minimized by incorporating biomimicking, stress-reducing features within grafts. At bone-tendon interfaces (entheses), stress can be reduced via angled insertion, geometric flaring, mechanical gradation, and interdigitation of tissues. Here, we incorporated enthesis attributes into 3D in silico and physical models of a unique suture anchor-tendon hybrid graft (SATHG) and investigated their effects on stress reduction via finite element analyses (FEA) studies. Over 20 different simulations altering SATHG angulation, flaring, mechanical gradation, and interdigitation identified an optimal design, which included 90° angulation, 25° flaring, and a compliant (ascending then descending) mechanical gradient in SATHG's bone-to-tendon-like transitional region. This design reduced peak stress concentration factor (SCF) by 43.6 % relative to an ascending-only mechanical gradient typically used in hard-to-soft tissue engineering. To verify FEA results, SATHG models were fabricated using a photocrosslinkable bone-tendon-like polyurethane (QHM polymer) for ex vivo tensile assessment. Tensile testing showed that ultimate load (132.9 N), displacement-at-failure (1.78 mm), stiffness (135.4 N/mm), and total work-to-failure (422.1 × 10-3 J) were highest in the optimized design. Furthermore, to assess envisioned usage, SATHG pull-out testing and 6-week in vivo implantation into large, 0.5-cm segmental supraspinatus tendon defects was performed. SATHG pull-out testing showed secure bone attachment while histological assessment such as hematoxylin and eosin (H&E) together with Safranin-O staining showed biocompatibility including enthesis regeneration. This work demonstrates that engineering biomaterials with FEA-optimized, enthesis-like attributes shows potential for enhancing hard-to-soft tissue repair. STATEMENT OF SIGNIFICANCE: Successful repair of hard-to-soft tissue injuries is challenging due to high stress concentrations within bone-tendon/ligament grafts that mechanically compromise repair strength. While stress-reducing gradient biomaterials have been reported, little-to-no attention has focused on other bone-tendon/ligament interface (enthesis) features. To this end, a unique bone-tendon graft (SATHG) was developed by combining two common orthopaedic devices along with biomimetic incorporation of four enthesis-like features to reduce stress and encourage widespread clinician adoption. Notably, utilizing designs based on natural stress dissipation principles such as anchor insertion angle, geometric flaring, and mechanical gradation reduced stress by 43.6 % in silico, which was confirmed ex vivo, while in vivo studies showed SATHG's ability to support native enthesis regeneration. Thus, SATHG shows promise for hard-to-soft tissue repairs.