Bone Osteosarcoma Research Articles

Clinical and imaging features of 112 patients with irregular and flat bone osteosarcoma

This study evaluated the clinical characteristics and imaging findings of 112 patients with irregular and flat bone osteosarcoma (IFBO). The age, gender, location, tumor size, density and signal intensity, osteoid matrix, periosteal reaction, and histological subtypes were analyzed for 112 patients with IFBO. A total of 112 patients with IFBO, including 64 males and 48 females, with a mean age of 34.8 years were enrolled in this study. Over half of the tumors (54.5%) were detected in the craniofacial region and the skull (24 in the maxilla bone, 17 in the mandible bone, 11 in the sphenoid bone, 7 in the temporal bone, 1 in the frontal bone, and 1 in the occipital bone). Other tumor locations included the pelvic region (20.5%; 20 in the ilium and 3 in the pubis), the chest (18.8%; 11 in the scapula, 7 in the ribs, and 3 in the clavicle), and the vertebrae (6.3%; 3 in the thoracic spine, 2 in the lumbar spine, 1 in the sacrum, and 1 in the cervical spine). Transarticular extension occurred in 11 of the 23 pelvic cases (47.8%), primarily involving the sacroiliac joint (90.9%; 10 of 11). Six cases (6/7; 85.7%) of vertebral osteosarcoma arose from the transverse process and the pedicle, and 1 (1/7; 14.3%) arose from the sacral tuberosity and the ala, with partial vertebral body involvement. Additionally, 27 patients (24.1%) presented with secondary osteosarcoma related to prior radiotherapy, and 2 (1.8%) were associated with osteoblastoma and fibrous dysplasia. Histological examination revealed high-grade tumors in 88 (78.6%) cases. The tumors presented as soft-tissue masses with a diameter of 7.5±3.2 cm. A total of 91 patients underwent X-ray examination and/or computed tomography (CT) examinations. The osteoid matrix was detected in 84 patients (84/91;92.3%). A periosteal reaction was detected in 56 cases (56/91; 61.5%), including a lamellar periosteal reaction in 10 patients (11.0%) and a spiculated periosteal reaction in 46 cases (50.5%). All 74 cases who underwent magnetic resonance imaging (MRI) examinations presented with heterogeneous masses in the surrounding soft tissue. Enhancement was homogenous in 12 cases (18.5%) and heterogeneous in 53 cases (81.5%). Peripheral rim enhancement was observed in 10 cases (13.5%). IFBO should be considered when diagnosing patients over 30 years of age who exhibit osteoid matrix in bone lesions. Maxillofacial osteosarcoma is commonly associated with a history of radiation exposure. Pelvic osteosarcoma is more likely to invade the sacroiliac joint. Vertebral osteosarcoma frequently arises in the transverse process and pedicle, with partial body involvement.

A predictive model with a risk-classification system for cancer-specific survival in patients with primary osteosarcoma of long bone

BackgroundOsteosarcoma (OS), most commonly occurring in long bone, is a group of malignant tumors with high incidence in adolescents. No individualized model has been developed to predict the prognosis of primary long bone osteosarcoma (PLBOS) and the current AJCC TNM staging system lacks accuracy in prognosis prediction. We aimed to develop a nomogram based on the clinicopathological factors affecting the prognosis of PLBOS patients to help clinicians predict the cancer-specific survival (CSS) of PLBOS patients. MethodWe studied 1199 PLBOS patients from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015 and randomly divided the dataset into training and validation cohorts at a proportion of 7:3. Independent prognostic factors determined by stepwise multivariate Cox analysis were included in the nomogram and risk-stratification system. C-index, calibration curve, and decision curve analysis (DCA) were used to verify the performance of the nomogram. ResultsAge, Histological type, Surgery of primary site, Tumor size, Local extension, Regional lymph node (LN) invasion, and Distant metastasis were identified as independent prognostic factors. C-indexes, calibration curves and DCAs of the nomogram indicating that the nomogram had good discrimination and validity. The risk-stratification system based on the nomogram showed significant differences (P < 0.05) in CSS among different risk groups. ConclusionWe established a nomogram with risk-stratification system to predict CSS in PLBOS patients and demonstrated that the nomogram had good performance. This model can help clinicians evaluate prognoses, identify high-risk individuals, and give individualized treatment recommendation of PLBOS patients.

Short Latency Radiation Induced Osteosarcoma Detected on 18F-FDG PET/CT Scan in Solitary Plasmacytoma.

18Fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) plays a pivotal role in the staging, restaging, and surveillance of various bone tumors, including plasmacytomas and osteosarcomas. Solitary plasmacytomas most frequently occur in the bones and are primarily treated with either surgery or radiotherapy. Radiation-induced osteosarcomas (RIOS) usually develop after a median interval of 11 years between radiation and sarcoma presentation. However, these can rarely present with a short latent period of 4 years or even lesser. In such cases, whole-body imaging plays a vital role in the early detection and management of RIOS. Herein, we present the case of a 29-year-old female patient with solitary plasmacytoma undergoing a follow-up whole-body 18F-FDG PET/CT, which revealed metastatic RIOS after a short latent period.

Sphingosine Kinase-1 Is Overexpressed and Correlates with Hypoxia in Osteosarcoma: Relationship with Clinicopathological Parameters.

Simple SummaryHypoxia has been recognized as a hallmark of solid tumors and a negative prognostic factor for response to therapeutics and survival of patients. Studies have demonstrated that the Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway regulates the expression of the HIF-1 transcription factor in a number of solid tumor models, but no data are available in osteosarcoma characterized by hypoxia. The objectives of the present study were (i) to assess the contribution of SphK1/S1P signaling in regulating HIF-1α expression under hypoxia in various osteosarcoma cell models, (ii) quantify SphK1 enzymatic activity in biopsies of osteosarcoma, and (iii) examine the relationship between SphK1, S1P receptor 1 (S1P1) and hypoxia (GLUT-1) in 130 cases of osteosarcoma by immunohistochemistry. Our data suggest that the SphK1/S1P signaling might represent a potential target to investigate in osteosarcoma patients, considering that fingolimod, which inhibits SphK1 and the S1P1 receptor, is now reconsidered for repurposing in cancer.The Sphingosine kinase-1/Sphingosine 1-Phosphate (SphK1/S1P) signaling pathway is overexpressed in various cancers, and is instrumental for the adaptation to hypoxia in a number of solid tumor models, but no data are available in osteosarcoma. Here we report that SphK1 and the S1P1 receptor are involved in HIF-1α accumulation in hypoxic osteosarcoma cells. FTY720 (Fingolimod), which targets SphK1 and S1P1, prevented HIF-1α accumulation, and also inhibited cell proliferation in both normoxia and hypoxia unlike conventional chemotherapy. In human biopsies, a significant increase of SphK1 activity was observed in cancer compared with normal bones. In all sets of TMA samples (130 cases of osteosarcoma), immunohistochemical analysis showed the hypoxic marker GLUT-1, SphK1 and S1P1 were expressed in tumors. SphK1 correlated with the GLUT-1 suggesting that SphK1 is overexpressed and correlates with intratumoral hypoxia. No correlation was found between GLUT-1 or SphK1 and response to chemotherapy, but a statistical difference was found with increased S1P1 expression in patients with poor response in long bone osteosarcomas. Importantly, multivariate analyses showed that GLUT-1 was associated with an increased risk of death in flat bone, whereas SphK1 and S1P1 were associated with an increased risk of death in long bones.

Expression of TRPS1 in phyllodes tumor and sarcoma of the breast

When a sarcomatous neoplasm is identified in the breast, distinguishing metaplastic carcinoma, malignant phyllodes tumor (MPT), and primary sarcoma is a diagnostic challenge, especially on small biopsies, as all these tumors may have overlapping morphological features, thoroughly grossing with histological examination and immunohistochemical staining being the standard approach to aid in classifying these lesions. Recently, we identified a highly sensitive and specific breast carcinoma marker TRPS1 with high expression in metaplastic breast carcinoma. In the current study, we tested TRPS1 in MPTs and primary sarcoma of the breast. We found TRPS1 was highly expressed (95%) within spindle cell, chondro-osseous, and/or liposarcomatous components of MPTs, in all breast primary chondrosarcomas and extraskeletal osteosarcomas, but not in other sarcomas of the breast. In extramammary sarcomas, TRPS1 was expressed in 28% of conventional chondrosarcomas and 56% of osteosarcomas of bone, but rarely in undifferentiated pleomorphic sarcomas (UPSs), liposarcomas, and angiosarcomas. In summary, MPTs may share similar genetic background with metaplastic carcinoma exhibiting TRPS1 expression, and TRPS1 may play a role in chondro-osseous differentiation because of its expression in chondro-osseous sarcomas from both breast and extramammary sites. Our findings suggest TRPS1 may be clinically useful in distinguishing MPT and metaplastic carcinoma from primary breast sarcoma except for tumors with chondro-osseous differentiation.

Conventional grade 1 chondrosarcoma: a challenging diagnosis with important implications on therapy and prognosis.

Chondrosarcoma (CHS) is a malignant tumor of soft tissue with cartilaginous differentiation that represent one tenth of all malignant proliferations developed from bone tissues. Even if CHS represents the third malignancy with bone localization, after myeloma and osteosarcoma, it is far less diagnosed in the head and neck region. The current paper presented two cases of conventional CHSs, which were diagnosed in Department of Thoracic Surgery and Department of Otorhinolaryngology of Emergency City Hospital, Timişoara, Romania, between February and June 2021. The malignant cases were of peripheral CHSs, one of scapula, and the other one had an extremely rare tracheal location with microscopic features of conventional low-grade tumors (grade 1). In all cases, conservative surgical curative treatment was performed, with a favorable postoperative evolution.

Evaluation of cytotoxic activity and anticancer potential of indigenous Rosemary (Rosmarinus officinalis L.) and Oregano (Origanum vulgare L.) dry extracts on MG-63 bone osteosarcoma human cell line.

We aimed to investigate the cytotoxic activity of indigenous Rosemary and Oregano freeze-dried extracts upon MG-63 osteosarcoma human cell line. We have determined the influence of analyzed dry extracts on cell morphology, cell survival and cell proliferation. The evaluation of dry extracts effect upon cell proliferation and viability was assessed by means of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) method. For cytotoxicity evaluation, Live & Dead and lactate dehydrogenase assays have been used. To further investigate the potential anticancer effect, we have studied the influence of dry extracts upon cells, by means of caspase-3/7 assay and proliferation cell nuclear antigen (PCNA) expression. Cells were incubated with extracts in the following concentration range (100–700 μg/mL) for 24 hours. According to our results, both dry extracts have shown cytotoxic effects by means of all used methods. Bone osteosarcoma cells viability significantly decreased with increasing concentration of analyzed extracts (beyond 300 μg/mL for Rosemary dry extract and only at 700 μg/mL for Oregano dry extract). According to our results, apoptosis is one of the main mechanisms involved in the cytotoxic properties of analyzed extracts. Moreover, Rosemary extract has also shown decreased expression of PCNA, when compared to control (untreated cells). Both extracts were standardized in phenolic compounds (being a rich source of flavones and phenolcarboxylic acids), so we assume that these are the main constituents involved in the cytotoxic effect. Still, further preclinical studies are needed to confirm the antitumor properties and to go deeply in the molecular mechanisms involved.

Radiation-induced osteosarcoma in the pubic bone after proton radiotherapy for prostate cancer: a case report

Objective: Radiation-induced sarcoma (RIS), which develops after radiotherapy, occurs as a secondary sarcoma in the irradiated area after a long latency period following radiation exposure.Patient: A 59-year-old man underwent hormone therapy for prostate cancer, followed by proton therapy (74 GyE) four years ago. Positron emission tomography/computed tomography performed 2.5 years later revealed 18F-FDG accumulation in the left pubis. Three years after proton therapy, the patient developed gradually worsening left inguinal pain and visited our department. Imaging revealed bone destruction with a mixture of osteolysis and osteogenesis in the left pubis and the presence of an extraosseous tumor. Following biopsy, the patient was diagnosed with osteosarcoma.Results: A systemic investigation revealed lung metastasis, and chemotherapy was initiated. The lung metastases shrank, and carbon ion radiotherapy (CIRT, 70.4 GyE) was performed on the left pubic lesion after colostomy. Six months after carbon ion radiotherapy, recurrence was observed in the irradiated field, and CIRT was performed again. However, the patient died 22 months after the initial diagnosis because of cancerous pleurisy and pericarditis.Conclusions: Although RIS is rare, it should be actively identified using biopsy to confirm the diagnosis, keeping in mind that it is an important late complication of radiotherapy.

The Emerging Role of MicroRNAs in Bone Diseases and Their Therapeutic Potential.

MicroRNAs (miRNAs) are a class of small (20–24 nucleotides), highly conserved, non-coding RNA molecules whose main function is the post-transcriptional regulation of gene expression through sequence-specific manners, such as mRNA degradation or translational repression. Since these key regulatory molecules are implicated in several biological processes, their altered expression affects the preservation of cellular homeostasis and leads to the development of a wide range of pathologies. Over the last few years, relevant investigations have elucidated that miRNAs participate in different stages of bone growth and development. Moreover, the abnormal expression of these RNA molecules in bone cells and tissues has been significantly associated with the progression of numerous bone diseases, including osteoporosis, osteosarcoma, osteonecrosis and bone metastasis, among others. In fact, miRNAs regulate multiple pathological mechanisms, including altering either osteogenic or osteoblast differentiation, metastasis, osteosarcoma cell proliferation, and bone loss. Therefore, in this present review, aiming to impulse the research arena of the biological implications of miRNA transcriptome in bone diseases and to explore their potentiality as a theragnostic target, we summarize the recent findings associated with the clinical significance of miRNAs in these ailments.

A Retrospective Comparative Analysis of Outcomes and Prognostic Factors in Adult and Pediatric Patients with Osteosarcoma.

Osteosarcoma is the most common primary bone malignancy in both children and adults. Despite introduction of intensive multimodal treatment with chemotherapy and surgery, outcomes are still poor, especially for patients with metastatic disease and adults. Hence, there is an ongoing need for better prognostic markers and outcome data to inform management decisions in both the adult and pediatric setting. Here, we retrospectively analyzed 112 patients with bone osteosarcoma treated at two large adult and pediatric tertiary academic centers between 1989 and 2019. Patients were divided into an adult (≥18 years) and pediatric (<18 years) cohort for comparison. Our aim was to evaluate predictors of outcomes in pediatric and adult patients, with a specific focus on the role of methotrexate when added to a combination of doxorubicin-cisplatin; the prognostic value of tumor necrosis after neoadjuvant chemotherapy; and outlining any differences in outcomes between adults and pediatric patients that could inform clinical management. Adult patients treated with methotrexate-doxorubicin-cisplatin and those treated with doxorubicin-cisplatin had similar 5-year PFS (26%, 95%CI: 45.5%–10% vs. 50%, 95%CI: 69.6%–26.2%, p = 0.1) and 5-year OS (63%, 95%CI: 82%–34%, vs. 78%, 95%CI: 90.6%–52.6%, p = 0.5). In the adult cohort, there was no difference between patients with ≥90% necrosis and <90% necrosis in either 5-year PFS (42%, 95%CI: 71.1%–11.3% vs. 38%, 95%CI: 57.7%–18.2%, p = 0.4) or 5-year OS (85%, 95%CI: 97.8%–33.4% vs. 56%, 95%CI: 76.8%–27.6%, p = 0.4). In the pediatric cohort, compared to patients with <90% necrosis, those with ≥90% necrosis had significantly better 5-year PFS (30%, 95%CI: 49.3%–14.1% vs. 55%, 95%CI: 73.9%–38.5%, p = 0.003) and 5-year OS (64%, 95%CI: 80.8%–41.1% vs. 78%, 95%CI: 92%–60.9%, p = 0.04). Adult and pediatric patients had similar 5-year OS (69%, 95%CI: 83.2%–49.8% vs. 73%, 95%CI: 83.2%–59.3%, p = 0.8) and 5-year PFS (37%, 95%CI: 52.4%–22.9% vs. 43%, 95%CI: 56.2%–30.4% p = 0.3) even though the proportion of patients with ≥90% necrosis after neoadjuvant chemotherapy was higher for children compared to adults (60.3% vs. 30%, OR: 3.54, 95%CI: 1.38–8.46, p = 0.006). In conclusion, in adult patients, the addition of methotrexate to doxorubicin and cisplatin did not correlate with a significant survival benefit, questioning the therapeutic value of methotrexate overall. Our study confirms the prognostic utility of percent tumor necrosis after neoadjuvant chemotherapy in pediatric patients but not in adult patients. Lastly, this is one of the few reported studies where patients with osteosarcoma younger and older than 18 years had similar PFS and OS.

Formulation of a novel anti-human bone tumor supplement by silver nanoparticles green-synthesized using Nigella sativa leaf aqueous extract

IntroductionIn the present research, we formulated a modern chemotherapeutic drug by silver nanoparticles (AgNPs) containing Nigella sativa aqueous extract for the treatment of bone tumor.Material and methodsCharacterization of AgNPs was done by UV–Visible Spectroscopy (UV-Vis), Fourier Transformed Infrared Spectroscopy (FT‐IR), Transmission Electron Microscopy (TEM), and Field Emission Scanning Electron Microscopy (FE‐SEM). For investigating the antioxidant properties of AgNO3, N. sativa, and AgNPs, the DPPH test was used in the presence of butylated hydroxytoluene as the positive control. To survey the cytotoxicity and anti-bone tumor effects of AgNO3, N. sativa, and AgNPs, MTT assay was used on the human bone Ewing’s sarcoma (CADO-ES1 and MHH-ES1), human bone osteosarcoma (HOS and MG-63), and human bone chondrosarcoma (SW-1353 and CH-3573) cell lines.ResultsDPPH test revealed similar antioxidant potentials for N. sativa, AgNPs, and butylated hydroxytoluene. Silver nanoparticles had very low cell viability and anti-bone tumor properties dose-dependently against CADO-ES1, MHH-ES1, HOS, MG-63, SW-1353, and CH-3573 cell lines without any cytotoxicity on the normal cell line. The best result of anti-bone tumor properties of AgNPs against the above cell lines was seen in the case of the MG-63 cell line.ConclusionsAccording to the above findings, the silver nanoparticles containing N. sativa aqueous extract can be administrated in humans for the treatment of several types of bone tumors.

Pervasive cytoquakes in the actomyosin cortex across cell types and substrate stiffness.

The actomyosin cytoskeleton enables cells to resist deformation, crawl, change their shape and sense their surroundings. Despite decades of study, how its molecular constituents can assemble together to form a network with the observed mechanics of cells remains poorly understood. Recently, it has been shown that the actomyosin cortex of quiescent cells can undergo frequent, abrupt reconfigurations and displacements, called cytoquakes. Notably, such fluctuations are not predicted by current physical models of actomyosin networks, and their prevalence across cell types and mechanical environments has not previously been studied. Using micropost array detectors, we have performed high-resolution measurements of the dynamic mechanical fluctuations of cells' actomyosin cortex and stress fiber networks. This reveals cortical dynamics dominated by cytoquakes-intermittent events with a fat-tailed distribution of displacements, sometimes spanning microposts separated by 4μm, in all cell types studied. These included 3T3 fibroblasts, where cytoquakes persisted over substrate stiffnesses spanning the tissue-relevant range of 4.3kPa-17kPa, and primary neonatal rat cardiac fibroblasts and myofibroblasts, human embryonic kidney cells and human bone osteosarcoma epithelial (U2OS) cells, where cytoquakes were observed on substrates in the same stiffness range. Overall, these findings suggest that the cortex self-organizes into a marginally stable mechanical state whose physics may contribute to cell mechanical properties, active behavior and mechanosensing.

MVP Expression Facilitates Tumor Cell Proliferation and Migration Supporting the Metastasis of Colorectal Cancer Cells.

Cancer cells show significant dysregulation of genes expression, which may favor their survival in the tumor environment. In this study, the cellular vault’s components MVP (major vault protein), TEP1 (telomerase-associated protein 1) and vPARP (vault poly(ADP-ribose) polymerase) were transiently or completely inhibited in U2OS cells (human bone osteosarcoma epithelial cells) to evaluate their impact on the cell proliferative and migratory capacity as well as on the development of their resistance to the drug vinorelbine. Comparative analysis of MVP protein expression level in normal colon tissue, primary colorectal tumor, and metastasis showed that the expression of this protein does not increase significantly in the primary tumor, but its expression increases in metastatic cells. Further comparative molecular analysis using the whole transcriptome microarrays for MVP-positive and MVP-negative cells showed that MVP is involved in regulating proliferation and migration of cancer cells. MVP may facilitate metastasis of colon cancer due to its impact on cell migration. Moreover, two vault proteins, MVP and TEP1, contribute the resistance to vinorelbine, while vPARP does not.

Exosomal miR-21-5p derived from bone marrow mesenchymal stem cells promote osteosarcoma cell proliferation and invasion by targeting PIK3R1.

Mesenchymal stem cells (MSCs) are a class of pluripotent cells that can release a large number of exosomes which act as paracrine mediators in tumour‐associated microenvironment. However, the role of MSC‐derived exosomes in pathogenesis and progression of cancer cells especially osteosarcoma has not been thoroughly clarified until now. In this study, we established a co‐culture model for human bone marrow‐derived MSCs with osteosarcoma cells, then extraction of exosomes from induced MSCs and study the role of MSC‐derived exosomes in the progression of osteosarcoma cell. The aim of this study was to address potential cell biological effects between MSCs and osteosarcoma cells. The results showed that MSC‐derived exosomes can significantly promote osteosarcoma cells’ proliferation and invasion. We also found that miR‐21‐5p was significantly over‐expressed in MSCs and MSC‐derived exosomes by quantitative real‐time polymerase chain reaction (qRT‐PCR), compared with human foetal osteoblastic cells hFOB1.19. MSC‐derived exosomes transfected with miR‐21‐5p could significantly enhance the proliferation and invasion of osteosarcoma cells in vitro and in vivo. Bioinformatics analysis and dual‐luciferase reporter gene assays validated the targeted relationship between exosomal miR‐21‐5p and PIK3R1; we further demonstrated that miR‐21‐5p‐abundant exosomes derived human bone marrow MSCs could activate PI3K/Akt/mTOR pathway by suppressing PIK3R1 expression in osteosarcoma cells. In summary, our study provides new insights into the interaction between human bone marrow MSCs and osteosarcoma cells in tumour‐associated microenvironment.

Beyond immunosuppressive effects: dual roles of myeloid-derived suppressor cells in bone-related diseases.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells (IMCs) with immunosuppressive functions, whereas IMCs originally differentiate into granulocytes, macrophages, and dendritic cells (DCs) to participate in innate immunity under steady-state conditions. At present, difficulties remain in identifying MDSCs due to lacking of specific biomarkers. To make identification of MDSCs accurately, it also needs to be determined whether having immunosuppressive functions. MDSCs play crucial roles in anti-tumor, angiogenesis, and metastasis.Meanwhile, MDSCs could make close interaction with osteoclasts, osteoblasts, chondrocytes, and other stromal cells within microenvironment of bone and joint, and thereby contributing to poor prognosis of bone-related diseases such as cancer-related bone metastasis, osteosarcoma (OS), rheumatoid arthritis (RA), osteoarthritis (OA), and orthopedic trauma. In addition, MDSCs have been shown to participate in the procedure of bone repair. In this review, we have summarized the function of MDSCs in cancer-related bone metastasis, the interaction with stromal cells within the bone microenvironment as well as joint microenvironment, and the critical role of MDSCs in bone repair. Besides, the promising value of MDSCs in the treatment for bone-related diseases is also well discussed.

Bisphosphonate-functionalized poly(amido amine) crosslinked 2-hydroxyethyl methacrylate hydrogel as tissue engineering scaffold

• Bisphosphonate-functionalized poly(amido amine) macromer (PAA-BP) was synthesized. • Crosslinking with PAA-BP adds excellent mineralization ability to 2-hydroxyethyl methacrylate (HEMA) hydrogel. • This hydrogel is biocompatible and facilitates cell adhesion after mineralization. • PAA-BP improves swelling and degradation properties of the hydrogel. • This hydrogel can be used for tissue engineering scaffolds. The first water soluble, bisphosphonate (BP, not bisphosphonic acid)-functionalized poly(amido amine) macromer (PAA-BP) is synthesized and used as a crosslinker for synthesis of a biodegradable and biocompatible hydrogel for tissue engineering scaffolds. The synthesis of PAA-BP is performed in three steps, the first two giving the control macromers (PAA-NHBoc and PAA-NH 2 ): i) Michael addition reaction of N,N’ -methylene bisacrylamide and N -Boc-1,6-hexanediamine (acrylamide/amine ratios of 1.2), ii) deprotection of Boc-protected amine groups, iii) Michael addition reaction of the amine groups with tetraethyl vinylidene bisphosphonate. The degree of BP substitution is 50% and molecular weight of the PAA-BP macromer is found to be 4800 g/mol. These macromers are incorporated into hydrogels by copolymerization with 2-hydroxyethyl methacrylate and the influence of bisphosphonate functionality on hydrogel properties; degradation, swelling, mechanical and mineralization, is investigated. The mineralization abilities, hence the mechanical properties of the hydrogels are strongly influenced by the BP functionality; PAA-BP forming strong (E = 83 ± 1 kPa) hydrogel-apatite composites, PAA-NH 2 also working to a lesser degree (E = 54 ± 3 kPa). Cytocompatibility of the hydrogels is observed on Saos-2 human osteosarcoma, U-2 OS human bone osteosarcoma epithelial, C2C12 mouse myoblast muscle and NIH mouse embryonic fibroblast 3T3 cells. PAA-BP crosslinked hydrogels facilitate adhesion of C2C12 cells after mineralization. In summary, BP-functionalized hydrogel may have a potential impact on bone tissue engineering.

Thallium Use, Toxicity, and Detoxification Therapy: An Overview

Thallium (Tl) is released into the environment, where is present at very low levels, from both natural and anthropogenic sources. Tl is considered as one of the most toxic heavy metals; it is a non-essential metal, present in low concentrations in humans. Tl toxicity causes dermatological and gastrointestinal diseases and disorders of the nervous system, and may even result in death. Many isotopes of Tl exist, with different uses. One of the isotopes of this metal (201Tl) is used in cardiovascular scintigraphy and for the diagnosis of malignant tumors such as breast or lung cancer and osteosarcoma bone cancer. Many Tl compounds are tasteless, colorless, and odorless. Due to these characteristics and their high toxicity, they have been used as poisons in suicides and murders for criminal purposes, as well as instances of accidental poisoning. Impaired glutathione metabolism, oxidative stress, and disruption of potassium-regulated homeostasis may play a role in the mechanism of Tl toxicity. Solanum nigrum L. and Callitriche cophocarpa have been suggested as promising agents for the phytoremediation of Tl. In addition, macrocyclic compounds such as crown ethers (18-crown-6) are good candidates to absorb Tl from wastewater. Through this review, we present an update to general information about the uses and toxicity of Tl. Furthermore, the attention is focused on detoxification therapies.

Innovative Biomaterials for the Treatment of Bone Cancer.

Bone cancer is a demanding challenge for contemporary medicine due to its high frequency of presentation and significant heterogeneity of malignant lesions developing within the bone. To date, available treatments are rarely curative and are primarily aimed at prolonging patients’ survival and ameliorating their quality of life. Furthermore, both pharmacological and surgical therapies are aggravated by a consistent burden of adverse events and subsequent disability due to the loss of healthy bone structural and functional properties. Therefore, great research efforts are being made to develop innovative biomaterials able to selectively inhibit bone cancer progression while reducing the loss of bone structural properties secondary to local tissue invasion. In this review, we describe the state of the art of innovative biomaterials for the treatment of bone cancer. Along with physiological bone remodeling, the development of bone metastasis and osteosarcoma will be depicted. Subsequently, recent advances on nanocarrier-based drug delivery systems, as well as the application of novel, multifunctional biomaterials for the treatment of bone cancer will be discussed. Eventually, actual limitations and promising future perspectives regarding the employment of such approaches in the clinical scenario will be debated.

Co-Axial Gyro-Spinning of PCL/PVA/HA Core-Sheath Fibrous Scaffolds for Bone Tissue Engineering.

The present study aspires towards fabricating core-sheath fibrous scaffolds by state-of-the-art pressurized gyration for bone tissue engineering applications. The core-sheath fibers comprising dual-phase poly-ε-caprolactone (PCL) core and polyvinyl alcohol (PVA) sheath are fabricated using a novel "co-axial" pressurized gyration method. Hydroxyapatite (HA) nanocrystals are embedded in the sheath of the fabricated scaffolds to improve the performance for application as a bone tissue regeneration material. The diameter of the fabricated fiber is 3.97 ± 1.31 µm for PCL-PVA/3%HA while pure PCL-PVA with no HA loading gives 3.03 ± 0.45 µm. Bead-free fiber morphology is ascertained for all sample groups. The chemistry, water contact angle and swelling behavior measurements of the fabricated core-sheath fibrous scaffolds indicate the suitability of the structures in cellular activities. Saos-2 bone osteosarcoma cells are employed to determine the biocompatibility of the scaffolds, wherein none of the scaffolds possess any cytotoxicity effect, while cell proliferation of 94% is obtained for PCL-PVA/5%HA fibers. The alkaline phosphatase activity results suggest the osteogenic activities on the scaffolds begin earlier than day 7. Overall, adaptations of co-axial pressurized gyration provides the flexibility to embed or encapsulate bioactive substances in core-sheath fiber assemblies and is a promising strategy for bone healing.

Construction and Validation of a Macrophage-Associated Risk Model for Predicting the Prognosis of Osteosarcoma.

Background Osteosarcoma is one of the most common bone tumors among children. Tumor-associated macrophages have been found to interact with tumor cells, secreting a variety of cytokines about tumor growth, metastasis, and prognosis. This study aimed to identify macrophage-associated genes (MAGs) signatures to predict the prognosis of osteosarcoma. Methods Totally 384 MAGs were collected from GSEA software C7: immunologic signature gene sets. Differential gene expression (DGE) analysis was performed between normal bone samples and osteosarcoma samples in GSE99671. Kaplan–Meier survival analysis was performed to identify prognostic MAGs in TARGET-OS. Decision curve analysis (DCA), nomogram, receiver operating characteristic (ROC), and survival curve analysis were further used to assess our risk model. All genes from TARGET-OS were used for gene set enrichment analysis (GSEA). Immune infiltration of osteosarcoma sample was calculated using CIBERSORT and ESTIMATE packages. The independent test data set GSE21257 from gene expression omnibus (GEO) was used to validate our risk model. Results 5 MAGs (MAP3K5, PML, WDR1, BAMBI, and GNPDA2) were screened based on protein-protein interaction (PPI), DGE, and survival analysis. A novel macrophage-associated risk model was constructed to predict a risk score based on multivariate Cox regression analysis. The high-risk group showed a worse prognosis of osteosarcoma (p < 0.001) while the low-risk group had higher immune and stromal scores. The risk score was identified as an independent prognostic factor for osteosarcoma. MAGs model for diagnosis of osteosarcoma had a better net clinical benefit based on DCA. The nomogram and ROC curve also effectively predicted the prognosis of osteosarcoma. Besides, the validation result was consistent with the result of TARGET-OS. Conclusions A novel macrophage-associated risk score to differentiate low- and high-risk groups of osteosarcoma was constructed based on integrative bioinformatics analysis. Macrophages might affect the prognosis of osteosarcoma through macrophage differentiation pathways and bring novel sights for the progression and prognosis of osteosarcoma.