Hyperostosis frontalis interna: a Nubian case

The aim of this article is to present evidence of hyperostosis frontalis interna in a 40-year-old female recovered from a Meroitic cemetery (ca. 300 A.D.) in Sudanese Nubia. A review of the literature concerning the Morgagni-Stewart-Morel (MSM) syndrome suggests that the changes in the skull fragment are consistent with this diagnosis. This case is the earliest example of the condition so far reported, and therefore, in archaeological time and space, this is a disease not only of modern civilization, but also of antiquity. Current endocrinological reports suggest that the hyperostosis is the hallmark of a generalized disorder of bone metabolism, with increased androgens, prolactin, and somatotropins. Hyperostosis frontalis interna is the central feature of a syndrome first described over 200 years ago by the early pathologist Giovanni Batistta Morgagni, professor of anatomy at Padua (1719). He found thickening of the internal tables of the frontal bones in association with virilism and obesity. Stewart (1928) and Morel (1929) independently added several neuropsychiatric problems to this complex and questioned the possibility of an endocrine basis for the syndrome.     

Innovative approaches for treatment of osteosarcoma

Osteosarcoma (OS) is the most common primary malignant bone tumor, which usually occurs in children and adolescents. It is generally a high-grade malignancy presenting with extreme metastases to the lungs or other bones. The etiology of the disease is multifaceted and still remains obscure. A combination of surgery and chemotherapy has played a major role in the treatment of OS over the past three decades, and consequently, the overall survival rates for the disease have remained unchanged. Therefore, there is an urgent need to employ new comprehensive analyses and technologies to develop significantly more informative classification systems, with the aim of developing more effective and less toxic therapies for OS patients. This review discusses the existing knowledge of OS therapy and potential methods to develop novel therapeutic agents for the disease.     

Commentary on: SMARCB1 as a novel diagnostic and prognostic biomarker for osteosarcoma

In the last couple of decades, biomarkers have been on the rise for diagnostic and predictive value. There has been a rush to identify new markers using new technologies and drug repurposing approaches. SMARCB1 acronym arises from the SWI/SNF (SWItch/Sucrose Non-Fermentable)-related Matrix-associated Actin-dependent Regulator of Chromatin subfamily B member 1 (SMARCB1). It is a molecule, whose role is associated with the sucrose metabolism. SMARCB1 is also called INI1 (Integrase Interactor 1). The molecule was discovered in the mid-1990s. Its role as a loss-of-function marker for malignant rhabdoid tumors (MRT) of renal and extrarenal origin has enormously expanded the spectrum of involved neoplasms since that time. Several tumors have been characterized by genetic aberrations in the SMARCB1 gene. They include reduction in expression, loss of expression, and mosaic expression. Most of the tumors are sarcomas, but a variegated group of tumors with mixed phenotypes has also been delineated. It is well known that the outcome of patients harboring genetic aberrations in the SMARCB1 gene has been poor. Guo et al. reported that reduced SMARCB1 expression occurred in 70% of osteosarcomas. Their data significantly correlated with poor neoadjuvant response. These authors emphasize a shorter progression-free and overall survival of the patients demonstrating an altered expression of this gene. Interestingly, mRNA in silico analysis established that SMARCB1 expression correlates with the response to chemotherapy of osteosarcoma patients, but there was no reliable correlation between SMARCB1 expression level and metastasis, response to neoadjuvant therapy, overall survival, and progression-free survival. The study involved a tissue microarray (TMA) on bone tumors that may limit the full evaluation of the gene expression. Nevertheless, Guo et al.’s study is remarkable. It expands the list of the tumors harboring an altered SMARCB1 gene expression and suggests that this marker should be investigated in every pathology workup for potential predictive value. On the other side, much work needs to be done if we hope that we strive to provide additional therapeutic strategies for osteosarcoma patients with altered SMARCB1 gene expression.     

Treponematosis: a possible case from the late prehistoric of North Carolina

The skeleton of an adult female exhibiting evidence of treponemal infection was recently recovered from the Hardin site in the piedmont region of North Carolina. Archaeological indicators suggest a late prehistoric affiliation. The skeleton is affected by a diffuse process resulting in surface changes, both destructive and appositional, node formation and shaft expansion, medullary encroachment and filling, cortical thickening, and fracture. There is both cranial and postcranial involvement. While treponemal infection is indicated, the atypical nature of the total pattern raises the possibility of multiple pathological processes operating simultaneously. The significance of this case is threefold. It provides information on the ability of prehistoric peoples to cope with disease. It reminds the paleopathologist of the dangers inherent in attempts at singular and specific diagnoses. It sheds new light on the epidemiology of the treponemal diseases.     

Effect of interleukin-18 on metastasis of mouse osteosarcoma cells

The effect of interleukin-18 (IL-18) on metastasis of highly metastatic LM8 mouse osteosarcoma cells was investigated using nude mice treated with anti-asialo GM1 serum to exclude anti-tumor actions of IL-18 through activation of T and natural killer cells. Injection of LM8 cells which do not express IL-18 receptor β into a tail vain resulted in the formation of pulmonary and hepatic metastatic foci. Daily injection of mice with IL-18 starting the fifth day from the cell injection had no significant effect on the number of metastatic foci, while five daily injections of IL-18 before and after the cell injection resulted in marked decreases. Culture of LM8 cells with IL-18 for 5 days before the injection into mice produced no significant effect on the number of pulmonary and hepatic metastatic foci. In contrast, pretreatment of mice with IL-18 for 5 days before the cell injection markedly decreased metastatic foci. The retention of LM8 cells in the lung 24 h after their injection was also reduced by the pretreatment of mice with IL-18. Serum obtained from mice pretreated with IL-18 for 5 days suppressed mobility of LM8 cells but IL-18 itself did not. These results suggest that IL-18 inhibits metastasis of LM8 cells partly by inducing a factor(s) in the host which suppresses cell mobility.     

基于生物信息学筛选染料木素抗骨肉瘤靶基因

染料木素是一种天然的小分子物质,在多种肿瘤中显示出抗肿瘤作用,探究染料木素作用于骨肉瘤的靶基因.从DrugBank下载与染料木素有关的靶基因,分别导入string数据库中进行分析,用Cytoscape作出蛋白质相互作用(PPI)网络,同时用插件Cytohubb分析PPI,获得25个关键基因,再用WebGestalt分析...     

Dextran-g-PEI nanoparticles as a carrier for co-delivery of adriamycin and plasmid into osteosarcoma cells

Combination of chemotherapy and gene therapy of cancer has synergistic effects on overcoming drug resistance. Macromolecular materials such as dextran and PEI have been a potential module for chemotherapeutics and gene delivery. Herein, we hypothesize the combinational strategy of chemotherapy and gene therapy in a single dextran-PEI nanoplatform. The physicochemical properties, cytotoxicity, transfection efficiency were investigated in vitro. Ultra-violet spectrum and ¹H NMR revealed adriamycin and PEI were grafted to dextran chain. Agarose gel electrophoresis demonstrated that the migration of plasmid was completely retarded when the N/P ratio of complex was 4. The sizes of DEX-ADM-PEI/DNA nanoparticles decreased and the zeta potentials enhanced with the increasing N/P ratio. Transmission electron microscope indicated a round morphology of the nanoparticles. DEX-ADM-PEI conjugation has higher cytotoxicity, compared to free adriamycin, in MG-63 and Saos-2 osteosarcoma cells but DEX-PEI maintained over 65% cell viability at the concentration of 8 mg/mL. The transfection efficiency of DEX-ADM-PEI/pEGFP-N1 at N/P ratio of 4:1 both in MG-63 and Saos-2 cell were slightly low than that of PEI 25k. But our nanoplatform efficiently delivered both plasmid pEGFP-N1 and adriamycin into osteosarcoma cells. This study demonstrated that DEX-ADM-PEI efficiently and selectively delivered both plasmid pEGFP-N1 and adriamycin to osteosarcoma cells with low cytotoxicity.     

Disease and mortality in the Early Bronze Age people of Bab edh-Dhra, Jordan.

During the 1977 field season at the Early Bronze Age site of Bab edh-Dhra 92 individuals were recovered from underground shaft tomb chambers. Morbid conditions found in these skeletons include trauma, possibly two cases of tuberculosis, osteomyelitis, post-menopausal osteoporosis and congenital anomalies. Of the 92 skeletons recovered 56 (61%) were 18 years of age or older, 28 (30%) were between 1 and 18 years of age and 8 (9%) were less than one year of age.     

Establishment and cytogenetic characterization of a cell line from a pulmonary metastasis of osteosarcoma

Osteosarcoma (OS) is the most frequent malignant bone tumour in children and adolescents. In metastatic patients, the most common site of metastasis is the lung. There are relatively few cell lines of metastatic OS reported in the literature and the cytogenetic aspects of OS metastases are still controversial and inconclusive. Here we describe the establishment of a new OS cell line, M-OS, from a pulmonary metastasis of a typical osteoblastic OS of an 11-year-old boy with metastatic OS at diagnosis. M-OS cells have been maintained in culture for over 50 passages for more than 1 year. M-OS was characterized by immunohistochemistry, conventional cytogenetics and fluorescence in situ hybridization (FISH). In order to evaluate in vitro cell modification, the immunohistochemical analysis was performed in three different moments of the cell line: 10th, 30th and 50th passages. The conventional cytogenetic analysis revealed the ploidy of M-OS cell line as near-diploid, with most metaphases hyperdiploid and tetraploid. We found a copy number gain of MDM2 gene as the most frequent alteration in the FISH analysis. The immunohistochemical analysis confirmed that M-OS cell line maintained the osteogenic nature even after all passages for the cell line establishment in vitro.     

Interferons and osteosarcoma

In 1970, we initiated studies at the Karolinska hospital to find out whether biologically meaningful doses of interferon (IFN) alpha preparations could be administered systemically to patients with viral and tumour diseases without causing unacceptable side effects. Antiviral and antitumour efficiency was demonstrated. Only a limited number of patients were injected due to shortage of high dose IFN preparations. Osteosarcoma patients participated in these early attempts. Due to clinical observations on one patient and due to lack of meaningful systemic standard treatment for osteosarcoma at the time, we decided to continue to give adjuvant IFN treatment to a consecutive series of osteosarcoma patients attending our hospital .We were encouraged by the preliminary follow up results of the series and continued to use this therapeutic principle up to 1990. The clinical results achieved are briefly summarized in this mini-review as are the results obtained in simultaneously ongoing model experiments in vitro and in vivo. A randomized large scale ongoing trial, involving the use of adjuvant IFN treatment of osteosarcoma patients, has been initiated by the European and American osteosarcoma study group 35 years after the first osteosarcoma patient received IFN. The trial is briefly outlined in this article.     

SMARCB1 expression is a novel diagnostic and prognostic biomarker for osteosarcoma

Background: Although weak SWI/SNF related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1) expression is a known diagnostic and prognostic biomarker in several malignancies, its expression and clinical significance in osteosarcoma remain unknown. The aim of the present study was to investigate SMARCB1 expression in osteosarcoma and its clinical significance with respect to chemosensitivity and prognosis.Methods: We obtained 114 specimens from 70 osteosarcoma patients to construct a tissue microarray (TMA) and assess SMARCB1 protein expression via immunohistochemistry (IHC). The mRNA expression of SMARCB1 was in-silico analyzed using open-access RNA sequencing (RNA-Seq) and clinicopathological data provided by the Therapeutically Applicable Research to Generate Effective Treatments on Osteosarcoma (TARGET-OS) project. The correlations between SMARCB1 expression and clinical features were statistically analyzed.Results: Weak SMARCB1 expression occurred in 70% of the osteosarcoma patient specimens in the TMA, and significantly correlated with poor neoadjuvant response as well as shorter overall and progression-free survival (PFS). In addition, mRNA in-silico analysis confirmed that SMARCB1 expression correlates with chemotherapeutic response and prognosis in osteosarcoma patients.Conclusion: To our knowledge, the present study is the first to analyze SMARCB1 expression in osteosarcoma. SMARCB1 may serve as a novel diagnostic and prognostic biomarker in osteosarcoma.     

Composite grafts in the treatment of osteosarcoma of the proximal humerus

Treatment of osteosarcoma (OSA) of the proximal humerus poses many difficulties and challenges to the treating team. Between 1993 and 2000, we treated 11 patients (three women, eight men; age range, 17–74 years) suffering from OSA of the proximal humerus by composite: massive allografts and long humeral prosthesis. At presentation, 10 patients were at stage 2-B and one at stage 3-B of OSA. One patient presented with a pathologic fracture. All patients except patient No. 6, received preoperative chemotherapy followed by limb salvage surgery and postoperative chemotherapy.Surgical margins were graded as wide in all patients. Postoperative complications included non-union at the allograft/host junction (which united after auto grafting) and superficial wound infections that resolved after antibiotic therapy. All surgical procedures were performed by a team headed by an orthopedic oncologist and shoulder surgeon. At latest follow-up (December 2001) all patients, with the exception of one (who was at stage 3-B at presentation) were alive, and had good function of the upper limb. It is our opinion that the team approach comprising an orthopedic oncologist and shoulder surgeon greatly contributed to the good surgical outcome, and hence the good survival and functional results of the patients. Bone allograft offers a modular malleable durable solution to the resected bone segment.     

Identification of a plasma proteomic signature to distinguish pediatric osteosarcoma from benign osteochondroma

Osteosarcoma (OS) is the most common malignant bone tumor in children. To identify a plasma proteomic signature that can detect OS, we used SELDI MS to perform proteomic profiling on plasma specimens from 29 OS and 20 age-matched osteochondroma (OC) patients. Nineteen statistically significant ion peaks that were differentially expressed in OS when compared with OC patients were identified (p < 0.001 and false discovery rate < 10%). Using the proteomic profiles, we constructed a multivariate 3-nearest neighbors classifier to distinguish OS from OC patients with a sensitivity of 97% and a specificity of 80% based on external leave-one-out crossvalidation. Permutation test showed that the classification result was statistically significant (p < 0.00005). One of the proteins (m/z 11 704) in the proteomic signature was identified as serum amyloid protein A (SAA) by PMF. The higher plasma level of SAA in OS patients was further validated by Western blotting when compared to that of osteochrondroma patients and normal subjects as reference. The classifier based on this plasma proteomic signature may be useful to differentiate malignant bone cancer from benign bone tumors and for early detection of OS in high-risk individuals.     

Gankyrin promotes osteosarcoma tumorigenesis by forming a positive feedback loop with YAP

BackgroundAlthough gankyrin has been identified as a vital regulator of tumorigenesis, its role and regulatory mechanism in osteosarcoma (OS) remain unclear.MethodsQRT-PCR, western blot and IHC staining were conducted to detect the expression of gankyrin in OS. Pearson’s χ² test was adopted to examine the associations between gankyrin expression and clinicopathologic characteristics. Kaplan-Meier method was used to investigate the relationship between gankyrin expression and overall survival of patients with OS. Next, a series of in vitro and in vivo assays were performed to determine the positive feedback loop between gankyrin and YAP in OS.ResultsWe first reported that gankyrin is upregulated in human OS specimens and cell lines and predicts OS progression and poor prognosis. Furthermore, we demonstrated that gankyrin protects miR-200a-mediated yes-associated protein (YAP) downregulation through p53 and establishes a positive feedback loop to regulate YAP signaling in U2OS and MG63 cells. Intriguingly, gankyrin interacts with YAP to promote OS cell growth in vitro. In addition, our results showed that gankyrin promotes OS tumor growth and regulates YAP levels in vivo. Notably, we also observed a positive correlation between gankyrin and YAP expression in human OS tissues, and co-upregulation of gankyrin and YAP indicated a poor prognosis.ConclusionsOur results identify that gankyrin acts as an oncogene in OS by forming a positive feedback loop with YAP, and disrupting the gankyrin-YAP regulation may be beneficial for controlling OS tumorigenesis.     

miR-30 inhibits the progression of osteosarcoma by targeting MTA1

Objectives:MicroRNAs (miRNAs) have been considered as a new class of novel diagnostic and predictive biomarker in many diseases. However, there are few studies on miRNA in osteosarcoma (OS). This study aimed to investigate the roles of miR-30 on OS occurrence and development.Methods:PCR was used to detect mRNA levels of miR-30 and MTA1 in cancer tissues, adjacent non-cancerous tissues from OS patients. Western blot was used to detect MTA1 protein expression in all tissues and cell lines (hFOb1.19,Saos-2, MG63, and U2OS). The correlation between miR-30 and MTA1 was predicted through bioinformatics software, and identified by a luciferase reporting experiment. In vitro, functional test detected the specific effects of miR-30 and MTA1 on the development of OS.Results:miR-30 expression was significantly reduced, while the expression of MTA1 was increased in OS tissues and cells. Luciferase reporting experiment showed that miR-30 sponged MTA1 which was negatively correlated with miR-30 expression. Furthermore, rescue tests revealed that MTA1 restrained the functions of miR-30 on cell proliferation and migration of OS.Conclusion:Our finding showed that miR-30 modulated the proliferation and migration by targeting MTA1 in OS.     

Heat shock protein expression in canine osteosarcoma

Abnormal levels of heat shock proteins have been observed in a number of human neoplasms and demonstrate prognostic, predictive and therapeutic implications. Since osteosarcoma (OSA) in dogs provides an important model for the same disease in humans, the aim of this study was to evaluate the immunohistochemical expression of Hsp27, Hsp72, Hsp73 and Hsp90 in 18 samples of canine appendicular OSA, in relation to histological grade and overall survival (OS), in order to investigate their potential prognostic, predictive and/or therapeutic value. A semiquantitative method was used for the analysis of the results. Hsp27, Hsp73 and Hsp90 showed a variably intense, cytoplasmic and nuclear immunoreactivity that was not associated with histological type or grade. On the other hand, a high percentage of Hsp72 immunostaining was significantly associated with grade III (P < 0.01) and a lack of immunolabelling was significantly correlated to a longer OS (P = 0.006). Neoplastic emboli were occasionally positive for Hsp27, faintly immunoreactive for Hsp72 and intensely immunolabelled by Hsp73 and Hsp90. In conclusion, absence of Hsp72 immunosignal appears to be associated with a favourable prognosis whilst the widespread Hsp90 immunoreactivity detected in all tumour cases as well as in neoplastic emboli, suggests this protein could be targeted in the therapy of canine OSA, and likewise in its human counterpart.     

Shanidar 1: a case of hyperostotic disease (DISH) in the middle Paleolithic.

The Shanidar 1 Neandertal partial skeleton presents osteophytic lesions on its vertebrae and appendicular skeleton which appear independent of the multiple traumatic and degenerative joint disease lesions on the individual. In particular, the large flowing osteophyte on the L3 body, a smaller one on the L5 body, and enthesopathic osteophytes on both calcaneal tuberosities, both patellae and the left ulnar olecranon, support a diagnosis of hyperostotic disease (DISH). The diagnosis is supported by small enthesopathic osteophytes on the preserved femoral greater trochanter and scapular corocoid process. This diagnosis would make it the oldest hominid specimen clearly presenting this systemic condition.     

Functional elucidation of MiR-34 in osteosarcoma cells and primary tumor samples

MiR-34s have been characterized as direct p53 targets, which induce apoptosis, cell cycle arrest, and senescence. MiR-34s were found to associate with tumorigenesis. Thus far, there is no study on the role of MiR-34s in osteosarcoma. In the current study, we intensively investigated the function of MiR-34s in two osteosarcoma cell lines: U2OS (p53^+/+) and SAOS-2 (p53^−/−). We found that MiR-34s affect the expression of its target genes partially in a p53-dependent manner. And p53 also partially contributes to the MiR-34s induced cell cycle arrest and apoptosis. Finally, we examined the expression, genetic and epigenetic alterations of MiR-34 gene in 117 primary osteosarcoma samples. Expression of MiR-34s was decreased in tumor samples, and MiR-34 genes underwent minimal deletions and epigenetic inactivation in osteosarcomas.     

Design,synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma

Respiratory failure due to pulmonary metastasis is the major cause of death for patients with osteosarcoma. However, the molecular basis for metastasis of osteosarcoma is poorly understood. Recently, ezrin, a member of the ERM family of proteins, has been associated with osteosarcoma metastasis to the lungs. The small molecule NSC 668394 was identified to bind to ezrin, inhibit in vitro and in vivo cell migration, invasion, and metastatic colony survival. Reported herein are the design and synthesis of analogues of NSC 668394, and subsequent functional ezrin inhibition studies. The binding affinity was characterized by surface plasmon resonance technique. Cell migration and invasion activity was determined by electrical cell impedance methodology. Optimization of a series of heterocyclic-dione analogues led to the discovery of compounds 21k and 21m as potential novel antimetastatic agents.