Micro-CT-Based Bone Microarchitecture Analysis of the Murine Skull.

X-ray micro-computed tomography (micro-CT) imaging has important applications in microarchitecture analysis of cortical and trabecular bone structure. While standardized protocols exist for micro-CT-based microarchitecture assessment of long bones, specific protocols need to be developed for different types of skull bones taking into account differences in embryogenesis, organization, development, and growth compared to the rest of the body. This chapter describes the general principles of bone microarchitecture analysis of murine craniofacial skeleton to accommodate for morphological variations in different regions of interest.

Craniofacial Phenomics: Three-Dimensional Assessment of the Size and Shape of Cranial and Dentofacial Structures.

Craniofacial phenomics has opened up numerous opportunities to correlate genetic and epigenetic factors to craniofacial phenotypes in order to improve our understanding of growth and development in health and disease. Three-dimensional (3D) imaging has played a key role in advancing craniofacial phenomics by facilitating highly sensitive and specific characterizations of craniofacial and dental morphology. Here we describe the use of micro-computed tomography (micro-CT) to image the murine craniofacial complex, followed by surface reconstruction for traditional morphometric analyses.

Effect of Selenium and Iodine on Oxidative Stress in the First Trimester Human Placenta Explants.

Imbalanced maternal micronutrient status, poor placentation, and oxidative stress are associated with greater risk of pregnancy complications, which impact mother and offspring health. As selenium, iodine, and copper are essential micronutrients with key roles in antioxidant systems, this study investigated their potential protective effects on placenta against oxidative stress. First trimester human placenta explants were treated with different concentrations of selenium (sodium selenite), iodine (potassium iodide), their combination or copper (copper (II) sulfate).

Optimal Lateral Row Anchor Positioning in Posterior-Superior Transosseous Equivalent Rotator Cuff Repair: A Micro-Computed Tomography Study.

Background: The optimal placement of suture anchors in transosseous-equivalent (TOE) double-row rotator cuff repair remains controversial.

Purpose: A 3-dimensional (3D) high-resolution micro-computed tomography (micro-CT) histomorphometric analysis of cadaveric proximal humeral greater tuberosities (GTs) was performed to guide optimal positioning of lateral row anchors in posterior-superior (infraspinatus and supraspinatus) TOE rotator cuff repair.

Study Design: Descriptive laboratory study.

Bone marrow lesions detected by specific combination of MRI sequences are associated with severity of osteochondral degeneration.

Background: Bone marrow lesions (BMLs) are useful diagnostic and prognostic markers in knee osteoarthritis (OA), but what they represent at the tissue level remains unclear. The aim of this study was to provide comprehensive tissue characterization of BMLs detected using two specific MRI sequences.

Methods: Tibial plateaus were obtained from 60 patients (29 females, 31 males), undergoing knee arthroplasty for OA.

Anticancer efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in osteolytic breast cancer murine models.

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, hypoxia offers treatment opportunities, exemplified by the development of compounds that target hypoxic regions within tumors. Evofosfamide (TH-302) is a prodrug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide mustard (Br-IPM).

Doxorubicin overcomes resistance to drozitumab by antagonizing Inhibitor of Apoptosis Proteins (IAPs).

Background/aim: Drozitumab is a fully human agonistic monoclonal antibody that binds to death receptor DR5 and induces apoptosis. However, drozitumab resistance is a major obstacle limiting anticancer efficacy.

Materials And Methods: We examined the potential for the chemotherapeutic agent doxorubicin to overcome resistance against drozitumab-resistant breast cancer cells both in vitro and in vivo.

Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma.

Tumor hypoxia is a major cause of treatment failure for a variety of malignancies. However, tumor hypoxia also offers treatment opportunities, exemplified by the development compounds that target hypoxic regions within tumors. TH-302 is a pro-drug created by the conjugation of 2-nitroimidazole to bromo-isophosphoramide (Br-IPM).

Pharmacologic inhibition of bone resorption prevents cancer-induced osteolysis but enhances soft tissue metastasis in a mouse model of osteolytic breast cancer.

Osteoprotegerin (OPG) is a secreted member of the TNF receptor superfamily, which binds to the receptor activator of nuclear factor κB ligand (RANKL) and inhibits osteoclast activity and bone resorption. Systemic administration of recombinant OPG was previously shown to inhibit tumor growth in bone and to prevent cancer-induced osteolysis. In this study, we examined the effect of OPG, when produced locally by breast cancer cells located within bone, using a mouse model of osteolytic breast cancer.

RECK in osteosarcoma: a novel role in tumour vasculature and inhibition of tumorigenesis in an orthotopic model.

Background: Targeted therapy in osteosarcoma (OS) is needed to improve patient outcomes. Human RECK may have a role because it inhibits cancer invasion and regulates angiogenesis. This study aimed to characterize RECK expression in human OS, to examine in vitro effects of RECK on vascular endothelium and OS cell behavior, and to analyze the effect of RECK on OS grown orthotopically in nude mice.

Anticancer efficacy of Apo2L/TRAIL is retained in the presence of high and biologically active concentrations of osteoprotegerin in vivo.

Osteoprotegerin (OPG) is a secreted member of the tumor necrosis factor (TNF) receptor superfamily that binds to the ligand for receptor activator of nuclear factor κB (RANKL) and inhibits bone resorption. OPG can also bind and inhibit the activity of the TNF-related apoptosis-inducing ligand (Apo2L/TRAIL), raising the possibility that the anticancer efficacy of soluble Apo2L/TRAIL may be abrogated in the bone microenvironment where OPG expression is high. In this study we used a murine model of breast cancer growth in bone to evaluate the efficacy of recombinant soluble Apo2L/TRAIL against intratibial tumors that were engineered to overexpress native full-length human OPG.

Zoledronic acid protects against osteosarcoma-induced bone destruction but lacks efficacy against pulmonary metastases in a syngeneic rat model.

Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and adolescents. In spite of successful control of the primary tumor, death from lung metastasis occurs in more than a third of patients. To investigate the efficacy of zoledronic acid (ZOL) on the development, progression and metastatic spread of OS, we used a rat model of OS, with features of the disease similar to human patients, including spontaneous metastasis to lungs.

Apomab, a fully human agonistic antibody to DR5, exhibits potent antitumor activity against primary and metastatic breast cancer.

Apomab, a fully human agonistic DR5 monoclonal antibody, triggers apoptosis through activation of the extrinsic apoptotic signaling pathway. In this study, we assessed the cytotoxic effect of Apomab in vitro and evaluated its antitumor activity in murine models of breast cancer development and progression. MDA-MB-231-TXSA breast cancer cells were transplanted into the mammary fat pad or directly into the tibial marrow cavity of nude mice.

Zoledronic acid inhibits both the osteolytic and osteoblastic components of osteosarcoma lesions in a mouse model.

Purpose: To evaluate the efficacy of zoledronic acid (ZOL) against osteosarcoma (OS) growth, progression, and metastatic spread using an animal model of human OS that closely resembles the human disease.

Experimental Design: Human K-HOS or KRIB OS cells, tagged or untagged with a luciferase reporter construct, were transplanted directly into the tibial cavity of nude mice. ZOL was given as weekly, or a single dose of 100 microg/kg body weight, equivalent to the 4 mg i.

Targeted disruption of the CXCL12/CXCR4 axis inhibits osteolysis in a murine model of myeloma-associated bone loss.

The plasma cell (PC) malignancy, multiple myeloma (MM), is unique among hematological malignancies in its capacity to cause osteoclast (OC)-mediated skeletal destruction. We have previously shown that elevated plasma levels of PC-derived CXCL12 are associated with presence of X-ray detectable osteolytic lesions in MM patients. To further investigate this relationship, plasma levels of CXCL12 and betaCrossLaps, a marker of bone loss, were measured.

Apo2L/TRAIL inhibits tumor growth and bone destruction in a murine model of multiple myeloma.

Purpose: Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma.

Experimental Design: We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice.

Apo2l/Tumor necrosis factor-related apoptosis-inducing ligand prevents breast cancer-induced bone destruction in a mouse model.

Breast cancer is the most common carcinoma that metastasizes to bone. To examine the efficacy of recombinant soluble Apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against breast cancer growth in bone, we established a mouse model in which MDA-MB-231 human breast cancer cells were transplanted directly into the marrow cavity of the tibiae of athymic nude mice producing osteolytic lesions in the area of injection. All vehicle-treated control animals developed large lesions that established in the marrow cavity, eroded the cortical bone, and invaded the surrounding soft tissue, as assessed by radiography, micro-computed tomography, and histology.

The histone deacetylase inhibitor, suberoylanilide hydroxamic acid, overcomes resistance of human breast cancer cells to Apo2L/TRAIL.

While the apoptosis-inducing ligand Apo2L/TRAIL is a promising new agent for the treatment of cancer, the sensitivity of cancer cells for induction of apoptosis by Apo2L/TRAIL varies considerably. Identification of agents that can be used in combination with Apo2L/TRAIL to enhance apoptosis in breast cancer cells would increase the potential utility of this agent as a breast cancer therapeutic. Here, we show that the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can sensitize Apo2L/TRAIL-resistant breast cancer cells to Apo2L/TRAIL-induced apoptosis.