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Sinonasal Schwannoma with New Bone Formation Expressing Bone Morphogenic Protein
Kodama, Satoru
Okamoto, Tomoyo
Suzuki, Masashi
International Journal of Otolaryngology
Schwannoma is a benign tumor that arises from the sheath of myelinated nerve fibers and may occur in any part of the body. Osteogenesis in schwannoma is extremely rare and, to date, new bone formation in sinonasal schwannoma has not yet been reported. Here, we describe the first reported case of sinonasal schwannoma with new bone formation. The tumor was successfully treated by endoscopic sinus surgery, and the patient showed no evidence of recurrence 24 months postoperatively. Immunohistochemically, the tumor expressed bone morphogenic protein 4, indicating a possible role of this protein in the new bone formation in schwannomas.
Related Articles
The use of injectable sonication-induced silk hydrogel for VEGF165 and BMP-2 delivery for elevation of the maxillary sinus floor
Zhang, Wenjie
Wang, Xiuli
Wang, Shaoyi
Zhao, Jun
Xu, Lianyi
Zhu, Chao
Zeng, Deliang
Chen, Jake
Zhang, Zhiyuan
Kaplan, David L.
Jiang, Xinquan
Sonication-induced silk hydrogels were previously prepared as an injectable bone replacement biomaterial, with a need to improve osteogenic features. Vascular endothelial growth factor (VEGF165) and bone morphogenic protein-2 (BMP-2) are key regulators of angiogenesis and osteogenesis, respectively, during bone regeneration. Therefore, the present study aimed at evaluating in situ forming silk hydrogels as a vehicle to encapsulate dual factors for rabbit maxillary sinus floor augmentation. Sonication-induced silk hydrogels were prepared in vitro and the slow release of VEGF165 and BMP-2 from these silk gels was evaluated by ELISA. For in vivo studies for each time point (4 and 12 weeks), 24 sinus floors elevation surgeries were made bilaterally in 12 rabbits for the following four treatment groups: silk gel (group Silk gel), silk gel/VEGF165 (group VEGF), silk gel/BMP-2 (group BMP-2), silk gel/VEGF165/BMP-2 (group V+B) (n=6 per group). Sequential florescent labeling and radiographic observations were used to record new bone formation and mineralization, along with histological and histomorphometric analysis. At week 4, VEGF165 promoted more tissue infiltration into the gel and accelerated the degradation of the gel material. At this time point, the bone area in group V+B was significantly larger than those in the other three groups. At week 12, elevated sinus floor heights of groups BMP-2 and V+B were larger than those of the Silk gel and VEGF groups, and the V+B group had the largest new bone area among all groups. In addition, a larger blood vessel area formed in the remaining gel areas in groups VEGF and V+B. In conclusion, VEGF165 and BMP-2 released from injectable and biodegradable silk gels promoted angiogenesis and new bone formation, with the two factors demonstrating an additive effect on bone regeneration. These results indicate that silk hydrogels can be used as an injectable vehicle to deliver multiple growth factors in a minimally invasive approach to regenerate irregular bony cavities.
Related Articles
Genetic Analysis of the Roles of BMP2, BMP4, and BMP7 in Limb Patterning and Skeletogenesis
Bandyopadhyay, Amitabha
Tsuji, Kunikazu
Cox, Karen
Harfe, Brian D
Rosen, Vicki
Tabin, Clifford J
PLoS Genetics
Bone morphogenetic protein (BMP) family members, including BMP2, BMP4, and BMP7, are expressed throughout limb development. BMPs have been implicated in early limb patterning as well as in the process of skeletogenesis. However, due to complications associated with early embryonic lethality, particularly for Bmp2 and Bmp4, and with functional redundancy among BMP molecules, it has been difficult to decipher the specific roles of these BMP molecules during different stages of limb development. To circumvent these issues, we have constructed a series of mouse strains lacking one or more of these BMPs, using conditional alleles in the case of Bmp2 and Bmp4 to remove them specifically from the limb bud mesenchyme. Contrary to earlier suggestions, our results indicate that BMPs neither act as secondary signals downstream of Sonic Hedghog (SHH) in patterning the anteroposterior axis nor as signals from the interdigital mesenchyme in specifying digit identity. We do find that a threshold level of BMP signaling is required for the onset of chondrogenesis, and hence some chondrogenic condensations fail to form in limbs deficient in both BMP2 and BMP4. However, in the condensations that do form, subsequent chondrogenic differentiation proceeds normally even in the absence of BMP2 and BMP7 or BMP2 and BMP4. In contrast, we find that the loss of both BMP2 and BMP4 results in a severe impairment of osteogenesis.
A group of related signaling molecules called bone morphogenetic proteins (BMPs) are known to play important roles in the formation of the structures such as the limbs. However, because different members of this group often have similar effects on target cells and are produced in overlapping regions of the embryo and hence can be redundant with one another, removal of any single member of the BMP family may not reveal the full extent of the roles they play during development. We have therefore improved on this type of analysis by removing pairs of these factors (BMP2 and BMP4 or BMP2 and BMP7) specifically from the developing limb. Although some have speculated that these signals play an early role in organizing or "patterning" the different tissues of the limb, we find no evidence for such a role. We do find, however, that a minimal amount of BMP signal is required to form cartilage, and hence some cartilaginous elements fail to form in limbs deficient in both BMP2 and BMP4. Moreover, in the absence of these two BMP family members, there is a severe impairment in the development of bone tissue, resulting in severely deformed limbs. This study gives important new insight into the roles of these BMP signals in making skeletal tissues in the embryo.
Related Articles
Osteogenic Protein-1 for Long Bone Nonunion
Ontario Health Technology Assessment Series
Executive Summary
To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion.
Clinical Need
Although most fractures heal within a normal period, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life.
Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of calcium, vitamin D, or vitamin C, and side effects of medications such as anticoagulants, steroids, some anti-inflammatory drugs, and radiation. It has been shown that smoking interferes with bone repair in several ways.
Incidence of Nonunion and Delayed Union Cases
An estimated 5% to 10% of fractures do not heal properly and go on to delayed union or nonunion. If this overall estimate of incidence were applied to the Ontario population1, the estimated number of delayed union or nonunion in the province would be between 3,863 and 7,725.
Treatment of Nonunion Cases
The treatment of nonunion cases is a challenge to orthopedic surgeons. However, the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site.
Fracture stabilization and immobilization is frequently used with the other treatment modalities that provide biological support to the fractured bone. Biological support includes materials that could be served as a source of osteogenic cells (osteogenesis), a stimulator of mesenchymal cells (osteoinduction), or a scaffold-like structure (osteoconduction).
The capacity to heal a fracture is a latent potential of the stromal stem cells, which synthesize new bone. This process has been defined as osteogenesis. Activation of the stem cells to initiate osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction. These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process. Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells, the perivascular tissue, and capillaries into these structures.
Bone Grafts and Bone Graft Substitutes
Bone graft and bone graft substitutes have one or more of the following components:
Undifferentiated stem cells
Growth factors
Structural lattice
Undifferentiated stem cells are unspecialized, multipotential cells that can differentiate into a variety of specialized cells. They can also replicate themselves. The role of stem cells is to maintain and repair the tissue in which they are residing. A single stem cell can generate all cell types of that tissue. Bone marrow is a source of at least 2 kinds of stem cells. Hematopoietic stem cells that form all types of blood cells, and bone marrow stromal stem cells that have osteogenic properties and can generate bone, cartilage, and fibrous tissue.
Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures. Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the site of the nonunion fracture. The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow. It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen.
Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair. Of the many bone growth factors studied, bone morphogenetics (BMPs) have generated the greatest attention because of their osteoinductive potential. The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 (osteogenic protein). Human osteogenic protein-1 (OP-1) has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction.
The structural lattice is osteoconductive; it supports the ingrowth of developing capillaries and perivascular tissues. Three distinct groups of structural lattice have been identified: collagen, calcium sulphate, and calcium phosphate. These materials can be used to replace a lost segment of bone.
Grafts Used for Nonunion
Autologous bone graft is generally considered the gold standard and the best material for grafting because it contains several elements that are critical in promoting bone formation, including osteoprogenitor cells, the matrix, and bone morphogenetic proteins. The osteoconductive property of cancellous autograft is related to the porosity of bone. The highly porous, scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone. Sources of cancellous bone are the iliac crest, the distal femur, the greater trochanter, and the proximal tibia. However, harvesting the autologous bone graft is associated with postoperative pain at the donor site, potential injury to the surrounding arteries, nerves, and tissues, and the risk of infection. Thus the development of synthetic materials with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research.
Allograft is the graft of tissue between individuals who are of the same species but are of a disparate genotype. Allograft has osteoconductive and limited osteoinductive properties. Demineralized bone matrix (DBM) is human cortical and cancellous allograft. These products are prepared by acid extraction of allograft bone, resulting in the loss of most of the mineralized component while collagen and noncollagenous proteins, including growth factors, are retained. Figures 1 to 5 demonstrate the osteogenic, osteoinduction, and osteoconduction properties of autologous bone graft, allograft, OP-1, bone graft substitutes, and bone marrow.
Autologous Bone Graft
Osteogenic Protein-1
Allograft bone and Demineralized Bone Matrix
Bone Graft Substitutes
Autologous Bone Marrow Graft
New Technology Being Reviewed: Osteogenic Protein-1
Health Canada issued a Class IV licence for OP-1 in June 2004 (licence number 36320). The manufacturer of OP-1 is Stryker Biotech (Hapkinton, MA).
The United States Food and Drug Administration (FDA) issued a humanitarian device exemption for the application of the OP-1 implant as an "alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed." Regulatory agencies in Europe, Australia, and New Zealand have permitted the use of this implant in specific cases, such as in tibial nonunions, or in more general cases, such as in long bone nonunions.
According to the manufacturer, OP-1 is indicated for the treatment of long bone nonunions. It is contraindicated in the patient has a hypersensitivity to the active substance or collagen, and it should not be applied at the site of a resected tumour that is at or near the defect or fracture. Finally, it should not be used in patients who are skeletally immature (< 18 years of age), or if there is no radiological evidence of closure of epiphysis.
Review Strategy
To summarize the safety profile and effectiveness of OP-1 in the treatment of cases of long bone nonunion and bone defects
To compare the effectiveness and cost effectiveness of OP-1 in the treatment of long bone nonunions and bone defects with the alternative technologies, particularly the gold standard autologous bone graft.
Literature Search
International Network of Agencies for Health Technology Assessments (INAHTA), the Cochrane Database of Systematic Reviews and the CCTR (formerly Cochrane Controlled Trials Register) were searched for health technology assessments. MEDLINE, EMBASE, Medline In Process and Other Non-Indexed Citations were searched from January 1, 1996 to January 27, 2004 for studies on OP-1. The search was limited to English-language articles and human studies. The search yielded 47 citations. Three studies met inclusion criteria (2 RCTs and 1 Ontario-based study presented at an international conference.
Summary of Findings
Friedlaender et al. conducted a prospective, randomized, partially blinded clinical trial on the treatment tibial nonunions with OP-1. Tibial nonunions were chosen for this study because of their high frequency, challenging treatment requirements, and substantial morbidity. All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months. The patients were randomized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier. Both groups received reduction and fixation with an intramedullary rod. Table 1 summarizes the clinical outcomes of this study.
Outcomes in a Randomized Clinical Trial on Tibial Nonunions: Osteogenic Protein-1 versus Autologous Bone Grafting
Clinical success was defined as full weight-bearing, loss of severe pain at the fracture site on weight-bearing, and no further surgical treatment to enhance fracture repair.
The results of this study demonstrated that recombinant OP-1 is associated with substantial clinical and radiographic success for the treatment of tibial nonunions when used with intramedullary rod fixation. No adverse event related to sensitization was reported. Five per cent of the patients in the OP-1 group had circulating antibodies against type 1 collagen. Only 10% of the patients had a low level of anti-OP-1 antibodies, and all effects were transient. Furthermore, the success rate with the OP-1 implant was comparable with those achieved with autograft at 9 and 24 months follow-up. Eighty-two per cent of patients were successful at 24 months follow-up in both groups.
Statistically significant increased blood loss in the group treated with the autograft was observed (P = .049). Patients treated with autograft had longer operation and hospitalization times. All patients in the autograft group had pain at the donor site after surgery, and more than 80% judged their postoperative pain as moderate or severe. At their 6-month visit, 20% of the patients in the autograft group had persistent pain, mild or moderate in nature, at the donor site. This number fell to 13% at 12 months.
All patients in each of the groups had at least 1 adverse event that wasn't serious, such as fever, nausea and vomiting, leg edema, discomfort, and bruising at the operative site. The incidence of these events was similar in both groups. Serious adverse events were observed in 44% of both groups, none of which were considered related to the OP-1 implant or autograft.
On the basis of this data, the FDA issued a humanitarian device exemption for the application of OP-1 implant as an alternative to autograft in recalcitrant long bone nonunions when the use of autograft is unfeasible and alternative treatments have failed.
Study on Fibular Defects
Geesink et al. investigated the osteogenic activity of OP-1 by assessing its value in bridging fibular defects made at the time of tibial osteotomy for varus or valgus deformity of the knee. This study had 2 phases and included 12 patients in each phase. Each phase included 12 patients (6 in each group). Patients in the first phase received either DBM or were left untreated. Patients in the second phase received either OP-1 on collagen type-1 or collagen type-1 alone.
Radiological and Dual Energy X-ray Absorptiometry (DEXA) evaluation showed that in patients in whom the defect was left untreated, no formation of bone occurred. At 12 months follow-up, new bone formation with bridging occurred in 4 of the 6 patients in DMB group, and 5 of the 6 patients in OP-1 group. One patient in OP-1 group did not show any evidence of new bone formation at any point during the study.
Ontario Pilot Study
A prospective pilot study was conducted in Ontario, Canada to investigate the safety and efficacy of OP-1 for the treatment of recalcitrant long bone nonunions. The study looked at 15 patients with complex, recalcitrant, long bone nonunions whose previous treatment had failed. The investigators concluded that this bone graft substitute appears to be safe and effective in providing sufficient biological stimulation in difficult to treat nonunions. Results of a more complete study on 70 patients are ready for publication. According to the principal investigator, OP-1 was 90% effective in inducing bone formation and bone healing in this sample.
Alternative Technologies
The Medical Advisory Secretariat conducted a literature search from January 1, 2000 to February 28, 2005 to identify studies on nonunions/bone defects that had been treated with alternative technologies. A review of these studies showed that, in addition to the gold standard autologous bone marrow grafting, bone allografts, demineralized bone matrices, bone graft substitutes, and autologous bone marrow have been used for treatment of nonunions and bone defects. These studies were categorized according to the osteoinductive, osteoconductive, and osteogenesis properties of the technologies studied.
A review of these studies showed that bone allografts have been used mostly in various reconstruction procedures to restore the defect after excavating a bone lesion. Two studies investigated the effectiveness of DBM in healing fracture nonunions. Calcium phosphate and calcium sulphate have been used mostly for repair of bone defects.
Several investigators have looked at the use of autologous bone marrow for treatment of long bone nonunions. The results of these studies show that method of percutaneous bone marrow grafting is highly effective in the treatment of long bone nonunions. In a total of 301 fractures across all studies, 268 (89%) healed with a mean healing time of 2.5 to 8 months. This healing time as derived from these case series is less than the timing of the primary end point in Friedlaender's study (9 months). Table 2 summarizes the results of these studies. Table 2 summarizes the results of these studies.
Studies that used Percutaneous Bone Marrow Grafting for Treatment of Nonunions
Economic Analysis
Based on annual estimated incidence of long-bone nonunion of 3,863 - 7,725, the annual hospitalization costs associated with this condition is between $21.2 and $42.3 million based on a unit cost of $5,477 per hospital separation. When utilized, the device, a single vial of OP-1, is approximately $5,000 and if adopted universally in Ontario, the total device costs would be in the range of $19.3 - $38.6 million annually. The physician fee for harvest, insertion of bone, or OP-1 is $193 and is $193 for autologous bone marrow transplantation. Total annual physician costs are expected to be in the range of from $0.7 million to $1.3 million per year. Expenditures associated with long-bone nonunion are unlikely to increase since incidence of long-bone nonunion is unlikely to change in the future. However, the rate of uptake of OP-1 could have a significant impact on costs if the uptake were large.
The use of OP-1 and autologous bone marrow transplantation may offset pain medication costs compared with those associated with autologous bone harvest given that the former procedures do not involve the pain associated with the bone harvest site. However, given that this pain is normally not permanent, the overall offset is likely to be small. There are likely to be smaller OHIP costs associated with OP-1 than bone-harvest procedures given that only 1, rather than 2, incisions are needed when comparing the former with the latter procedure. This offset could amount to between $0.3 million to $0.7 million annually.
No data on the cost-effectiveness of OP-1 is available.
Related Articles
Patterning of the Dorsal-Ventral Axis in Echinoderms: Insights into the Evolution of the BMP-Chordin Signaling Network
Lapraz, François
Besnardeau, Lydia
Lepage, Thierry
PLoS Biology
Deciphering the process of dorsal-ventral patterning in the sea urchin reveals an extreme case of BMP translocation and an unusual configuration of the BMP-Chordin axis in echinoderms.
Formation of the dorsal-ventral axis of the sea urchin embryo relies on cell interactions initiated by the TGFβ Nodal. Intriguingly, although nodal expression is restricted to the ventral side of the embryo, Nodal function is required for specification of both the ventral and the dorsal territories and is able to restore both ventral and dorsal regions in nodal morpholino injected embryos. The molecular basis for the long-range organizing activity of Nodal is not understood. In this paper, we provide evidence that the long-range organizing activity of Nodal is assured by a relay molecule synthesized in the ventral ectoderm, then translocated to the opposite side of the embryo. We identified this relay molecule as BMP2/4 based on the following arguments. First, blocking BMP2/4 function eliminated the long-range organizing activity of an activated Nodal receptor in an axis rescue assay. Second, we demonstrate that BMP2/4 and the corresponding type I receptor Alk3/6 functions are both essential for specification of the dorsal region of the embryo. Third, using anti-phospho-Smad1/5/8 immunostaining, we show that, despite its ventral transcription, the BMP2/4 ligand triggers receptor mediated signaling exclusively on the dorsal side of the embryo, one of the most extreme cases of BMP translocation described so far. We further report that the pattern of pSmad1/5/8 is graded along the dorsal-ventral axis and that two BMP2/4 target genes are expressed in nested patterns centered on the region with highest levels of pSmad1/5/8, strongly suggesting that BMP2/4 is acting as a morphogen. We also describe the very unusual ventral co-expression of chordin and bmp2/4 downstream of Nodal and demonstrate that Chordin is largely responsible for the spatial restriction of BMP2/4 signaling to the dorsal side. Thus, unlike in most organisms, in the sea urchin, a single ventral signaling centre is responsible for induction of ventral and dorsal cell fates. Finally, we show that Chordin may not be required for long-range diffusion of BMP2/4, describe a striking dorsal-ventral asymmetry in the expression of Glypican 5, a heparin sulphated proteoglycan that regulates BMP mobility, and show that this asymmetry depends on BMP2/4 signaling. Our study provides new insights into the mechanisms by which positional information is established along the dorsal-ventral axis of the sea urchin embryo, and more generally on how a BMP morphogen gradient is established in a multicellular embryo. From an evolutionary point of view, it highlights that although the genes used for dorsal-ventral patterning are highly conserved in bilateria, there are considerable variations, even among deuterostomes, in the manner these genes are used to shape a BMP morphogen gradient.
Author Summary
During early development of many organisms, patterning along the dorsal-ventral axis is regulated by the activities of two signaling centers located on the ventral and dorsal sides of the embryo. One of these centers produces growth factors of the BMP family that act as morphogens, whereas the other center secretes BMP antagonists such as Chordin that regulate the flow of BMPs along the dorsal-ventral axis. Expression from these two signaling centers results in roughly complementary distributions of BMP and BMP antagonist. We have analyzed BMP-mediated dorsal-ventral axis patterning in embryos of sea urchins, which are phylogenetically close to vertebrates and extensively rely on cell-cell interactions for their development. We found that in sea urchins, unlike in most organisms, the activity of a single signaling center located on the ventral side is responsible for generating both the ventral and the dorsal sides of the embryo. In addition, we discovered that the BMP2/4 gene is co-expressed with Chordin in this ventral center but that the BMP2/4 protein is translocated to the opposite side of the embryo where it activates the genetic program responsible for dorsal differentiation. Our study reveals an unusual example of signaling at a distance by a BMP growth factor. It also highlights that although the proteins used for dorsal-ventral patterning are evolutionarily conserved, there are considerable variations in the manner in which these proteins can be used in different species to generate a gradient of BMP morphogen.
Related Articles
Altered expression of tissue remodeling genes in a mouse model of acute allergic rhinitis
Sautter, Nathan B.
Delaney, Katherine L.
Trune, Dennis R.
International forum of allergy & rhinology
Osteogenesis, fibrosis and scarring are prominent pathologic changes resulting from chronic sinonasal inflammation, and these tissue changes may increase the degree of disease symptomatology and the level of surgical difficulty. Members of the Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) families of cytokines and the Matrix Metalloproteinase (MMP) family of endopeptidases are known to regulate tissue remodeling in other disease processes, but their role in acute and chronic sinonasal inflammation remains undefined.
A previously described mouse model of acute allergic rhinitis secondary to Aspergillus fumigatis exposure in BALB/C mice was utilized. Intranasal challenge was performed one week following intraperitoneal sensitization with A. fumigatis extract and mice were sacrificed 6 hours (n=8) and 24 hours (n=8) later. Additional mice were intranasally challenged 3× per week and sacrificed at the end of 7 days (n=8) and 21 days (n=8). The snouts were processed for quantitative RT-PCR and compared to untreated controls for mRNA expression of BMP1, 2, 3, 4, 5, 6, 7, 8a, 8b, 9, 10, FGF1, 2, 3, 4, 5, 6, 7, 8, 10 and MMP1a, 2, 3, 7, 8, 9, 12 and 14. Additional 21 day mice were prepared for sinonasal histopathology. Control mice were treated with the same protocol, with intraperitoneal PBS and intranasal PBS substituted for A. fumigatis extract. Untreated mice were used for additional comparison.
Compared to both the PBS and untreated control groups, statistically significant (p<0.05) up-regulation of MMP8 was observed in the 6 hour time point. Significant down-regulation of MMP8 was observed at 1 week. Significant up-regulation of FGF3 was observed at one week (p<0.05. BMP3 and BMP5 were significantly down-regulated in the 1 week group (p<0.05). The mice exhibited histologic sinonasal changes consistent with allergic inflammation.
Intranasal exposure to A. fumigatis results in altered expression of several tissue remodeling cytokines at varying time points in the acute allergic rhinitis mouse model. These changes in cytokine regulation may subsequently contribute to sinonasal osteogenesis, scarring and fibrosis as seen in chronic rhinosinusitis.
Related Articles
Different Effects of BMP-2 on Marrow Stromal Cells from Human and Rat Bone
Osyczka, Anna M.
Diefenderfer, David L.
Bhargave, Geeta
Leboy, Phoebe S.
Cells, tissues, organs
Bone morphogenetic proteins (BMPs) promote the differentiation of osteoprogenitor cells, and also induce osteogenesis in bone marrow stromal cells (MSC) from rats and mice. However, compared to results with animal models, BMPs are relatively inefficient in inducing human MSC to undergo osteogenesis, and are much less effective in promoting bone formation in human clinical trials. Previous studies indicated that, while human MSC respond to dexamethasone with elevated levels of the osteoblast marker alkaline phosphatase, most isolates of human MSC fail to show alkaline phosphatase induction in response to BMP-2, BMP-4, or BMP-7. Several other genes known to be induced by BMPs are appropriately regulated; thus, human MSC are capable of some BMP-activated signaling. Analysis of the BMP receptors ALK-3 and ALK-6 indicated that, although ALK-6 mRNA was not expressed in human MSC, overexpressing a constitutively active ALK-6 receptor did not induce elevated alkaline phosphatase. Real-time RT-PCR was used to investigate expression of several osteoblast-related transcription factors in MSC after 6 days' exposure to BMP2 or dexamethasone. Msx-2, a transcription factor that has been reported to inhibit differentiation of osteoprogenitor cells, showed 10-fold elevation in BMP-2-treated human MSC, but not in BMP-2-treated rat MSC. Overexpression of Msx-2 in human and rat MSC, however, did not alter alkaline phosphatase levels, which suggests that absence of BMP-stimulated alkaline phosphatase was not caused by the BMP-2-induced increase in Msx-2. Although Runx2 isoforms have been implicated in control of osteoblast differentiation, levels of this transcription factor were unaffected by BMP treatment. Expression of the FKHR transcription factor, which has been reported to regulate alkaline phosphatase transcription in mouse cells, showed a modest increase in response to BMP-2, but a much greater increase in dexamethasonetreated cells. We propose that BMP regulation of the bone/liver/kidney alkaline phosphatase gene is indirect, requiring expression of new transcription factor(s) that behave differently in rodent and human MSC.
Osteogenesis; Bone morphogenetic proteins; Transcription factors; Alkaline phosphatase; Mesenchymal stem cells; Marrow stromal cells
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BMP4 Promotes Prostate Tumor Growth in Bone Through Osteogenesis
Lee, Yu-Chen
Cheng, Chien-Jui
Bilen, Mehmet A.
Lu, Jing-Fang
Satcher, Robert L.
Yu-Lee, Li-Yuan
Gallick, Gary E.
Maity, Sankar N.
Lin, Sue-Hwa
Cancer research
Induction of new bone formation is frequently seen in the bone lesions from prostate cancer (PCa). However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, two xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from PCa bone metastases. When implanted subcutaneously in SCID mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors ("secretome") from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of BMP-4 and several cytokines including IL-8, Gro, and CCL2. We demonstrated that BMP-4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treating with BMP-4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP-4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of PCa in bone.
PCa; bone metastasis; chemokines; cytokines; osteoblast
Related Articles
Dual Delivery of rhPDGF-BB and Bone Marrow Mesenchymal Stromal Cells Expressing the BMP2 Gene Enhance Bone Formation in a Critical-Sized Defect Model
Park, Shin-Young
Kim, Kyoung-Hwa
Shin, Seung-Yun
Koo, Ki-Tae
Lee, Yong-Moo
Seol, Yang-Jo
Tissue Engineering. Part A
Bone tissue healing is a dynamic, orchestrated process that relies on multiple growth factors and cell types. Platelet-derived growth factor-BB (PDGF-BB) is released from platelets at wound sites and induces cellular migration and proliferation necessary for bone regeneration in the early healing process. Bone morphogenetic protein-2 (BMP-2), the most potent osteogenic differentiation inducer, directs new bone formation at the sites of bone defects. This study evaluated a combinatorial treatment protocol of PDGF-BB and BMP-2 on bone healing in a critical-sized defect model. To mimic the bone tissue healing process, a dual delivery approach was designed to deliver the rhPDGF-BB protein transiently during the early healing phase, whereas BMP-2 was supplied by rat bone marrow stromal cells (BMSCs) transfected with an adenoviral vector containing the BMP2 gene (AdBMP2) for prolonged release throughout the healing process. In in vitro experiments, the dual delivery of rhPDGF-BB and BMP2 significantly enhanced cell proliferation. However, the osteogenic differentiation of BMSCs was significantly suppressed even though the amount of BMP-2 secreted by the AdBMP2-transfected BMSCs was not significantly affected by the rhPDGF-BB treatment. In addition, dual delivery inhibited the mRNA expression of BMP receptor type II and Noggin in BMSCs. In in vivo experiments, critical-sized calvarial defects in rats showed enhanced bone regeneration by dual delivery of autologous AdBMP2-transfected BMSCs and rhPDGF-BB in both the amount of new bone formed and the bone mineral density. These enhancements in bone regeneration were greater than those observed in the group treated with AdBMP2-transfected BMSCs alone. In conclusion, the dual delivery of rhPDGF-BB and AdBMP2-transfected BMSCs improved the quality of the regenerated bone, possibly due to the modulation of PDGF-BB on BMP-2-induced osteogenesis.
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SMARCB1(INI1)-deficient Sinonasal Basaloid Carcinoma
Agaimy, Abbas
Koch, Michael
Lell, Michael
Semrau, Sabine
Dudek, Wojciech
Wachter, David L.
Knöll, Antje
Iro, Heinrich
Haller, Florian
Hartmann, Arndt
The American Journal of Surgical Pathology
Poorly differentiated sinonasal carcinomas are a heterogenous group of aggressive neoplasms that encompasses squamous cell carcinoma including basaloid variant, lymphoepithelial carcinoma, sinonasal undifferentiated carcinoma, and neuroendocrine-type small cell carcinoma. We herein describe 3 cases of a hitherto unreported variant combining features of basaloid carcinoma with variable intermingled rhabdoid cells. Patients were 2 women (aged 28 and 35) and a man (52 y) who presented with sinonasal masses. All had advanced local disease with bone involvement (pT4). None had a history of irradiation or a family history of rhabdoid tumors. Treatment was surgery and adjuvant chemoradiation. One patient developed liver, lung, pleural, and pericardial metastases (63 mo) and is currently (70 mo) alive under palliative treatment. Another developed recurrent cervical lymph node metastases and died of disease 8.5 years later. The youngest patient was disease-free at last follow-up 7 years later. Histologic features were very similar in all 3 cases and showed intimate admixture of compact basaloid cell nests with peripheral palisading, perivascular pseudorosettes, and a few scattered rhabdoid cells. Rhabdoid cells were more extensive in the metastasis in 1 case but formed a minor inconspicuous component in the primary tumors in all cases. Striking features common to all cases were (1) basaloid "blue" appearance at low power, (2) papilloma-like exophytic component, (3) extensive pagetoid surface growth with prominent denuding features, and (4) replacement of underlying mucous glands mimicking an inverted papilloma. Clear-cut origin from benign papilloma and overt squamous differentiation were lacking. Diffuse (2) or partial (1) p16 expression was noted, but all cases lacked human papillomavirus DNA by molecular tests. In situ hybridization was negative for Epstein-Barr virus. Immunohistochemistry showed diffuse expression of pancytokeratin. CK5 and vimentin showed intermingling of CK5+/vimentin− basaloid and CK5−/vimentin+ rhabdoid cells. Complete loss of nuclear SMARCB1 expression was seen in all cases including also the denuding carcinoma in situ–like surface lesions. To our knowledge, this variant of sinonasal carcinoma has not been reported before. The identical features in all 3 cases suggest a specific disease rather than a nonspecific dedifferentiated phenotype. Awareness of this rare variant and thus reporting of additional cases is necessary for defining its full morphologic and biological spectrum.
rhabdoid carcinoma; basaloid carcinoma; SMARCB1; INI1; sinonasal tract; hybrid neoplasm
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Enhanced in vivo osteogenesis by nanocarrier-fused bone morphogenetic protein-4
Shiozaki, Yasuyuki
Kitajima, Takashi
Mazaki, Tetsuro
Yoshida, Aki
Tanaka, Masato
Umezawa, Akihiro
Nakamura, Mariko
Yoshida, Yasuhiro
Ito, Yoshihiro
Ozaki, Toshifumi
Matsukawa, Akihiro
International Journal of Nanomedicine
Bone defects and nonunions are major clinical skeletal problems. Growth factors are commonly used to promote bone regeneration; however, the clinical impact is limited because the factors do not last long at a given site. The introduction of tissue engineering aimed to deter the diffusion of these factors is a promising therapeutic strategy. The purpose of the present study was to evaluate the in vivo osteogenic capability of an engineered bone morphogenetic protein-4 (BMP4) fusion protein.
BMP4 was fused with a nanosized carrier, collagen-binding domain (CBD), derived from fibronectin. The stability of the CBD-BMP4 fusion protein was examined in vitro and in vivo. Osteogenic effects of CBD-BMP4 were evaluated by computer tomography after intramedullary injection without a collagen–sponge scaffold. Recombinant BMP-4, CBD, or vehicle were used as controls. Expressions of bone-related genes and growth factors were compared among the groups. Osteogenesis induced by CBD-BMP4, BMP4, and CBD was also assessed in a bone-defect model.
In vitro, CBD-BMP4 was retained in a collagen gel for at least 7 days while BMP4 alone was released within 3 hours. In vivo, CBD-BMP4 remained at the given site for at least 2 weeks, both with or without a collagen–sponge scaffold, while BMP4 disappeared from the site within 3 days after injection. CBD-BMP4 induced better bone formation than BMP4 did alone, CBD alone, and vehicle after the intramedullary injection into the mouse femur. Bone-related genes and growth factors were expressed at higher levels in CBD-BMP4-treated mice than in all other groups, including BMP4-treated mice. Finally, CBD-BMP4 potentiated more bone formation than did controls, including BMP4 alone, when applied to cranial bone defects without a collagen scaffold.
Altogether, nanocarrier-CBD enhanced the retention of BMP4 in the bone, thereby promoting augmented osteogenic responses in the absence of a scaffold. These results suggest that CBD-BMP4 may be clinically useful in facilitating bone formation.
BMP4; bone repair; bone tissue engineering; osteogenesis
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Bone-Derived Growth Factors
Capanna, R.
Campanacci, D.A.
De Biase, P.
Cuomo, P.
Lorenzoni, A.
Clinical Cases in Mineral and Bone Metabolism
Bone regeneration is based on the synergy between osteconduction, osteoinduction and osteogenesis. In recent years, we have witnessed the birth and development of numerous osteoconductive substrates, created with the intention of replacing bone grafts, both autologous and homologous. Recently, attention has shifted to osteogenesis, in other words, to the study of mesenchymal cells and their differentiation into osteoblastic cell lines that can be cultured in vitro (as already seen with chondroblasts). Osteoinduction, too, has been shown to be equally important, ever since Urist's 1967 study which drew attention to the demineralised bone matrix and its properties. The following twenty years led to the definition of bone morphogenetic protein (BMP) and finally to the marketing of the first ostegenic protein (OP-1) obtained by means of the gene recombination technique. The BMPs produced using this technique that, so far, have been shown to be most active are BMP-2 (Infuse) and BMP-7 (Osigraft). The BMPs are not the only molecules with osteoinductive capacity. Other molecules capable of influencing bone regeneration are: platelet-derived growth factors (PDGFs), the transforming growth factor-beta (TGF-β) family, insulin-like growth factor (IGF-I) and the acidic and basic fibroblast growth factors (FGFs). All these growth factors act in synergy with the BMPs, modulating their action and exerting an inductive and proliferative action on the cell lines responsible for regenerating the bone matrix. The literature has been literally invaded by studies, both experimental and preclinical, on these proteins (Termaat, 2005), and they have provided ample demonstration that the BMPs are effective in improving healing of fractures, pseudoarthrosis and spinal fusions. Important advantages of BMPs are the complete absence of risk of transmissible disease, given that they are produced using recombination technology; their purity, and thus absence of an immune response (although such a response could be linked to the carrier used to administer them); their efficacy, which derives from the use of a pre-established dose and not from the individual variability that is a specific feature of demineralized bone matrix homologous bone grafts. In addition to their use in fractures, pseudoarthrosis and spinal fusions, very recent studies are opening up new possibilities which may represent the future field of application of these proteins: Cook et al. (Cook, 2001, Barrack, 2003) have presented the first results obtained using OP-1 in prosthetic revisions carried out in the presence of bone defects; other authors have published a case report on osteonecrosis of the femoral head treated with grafts in association with OP-1; an Italian group is currently experimenting the use of OP-1 in distraction osteogenesis with the aim of speeding up the results that can be obtained using this already well-established technique. However, the most interesting results on the use of recombinant morphogenetic proteins are those obtained by Warnke et al. (2004), maxillo-facial surgeons who, by mixing synthetic spongious bone grafts, bone marrow concentrate and morphogenetic proteins, prepared a new, replacement mandible for implantation in a patient who had lost his own due to cancer, thereby creating new vacularised bone, tailored to that specific patient. The experimental applications of these new drugs are countless and, with regard to their therapeutic potential, the general feeling is that what we are seeing is only the tip of the iceberg. However, it is necessary to ensure that experiments in this field are always geared towards sustainable clinical applications and, to this end, they should be concentrated in a smaller number of centres and conducted in accordance with approved and recognised guidelines.
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Benign Inverted Papilloma with Intracranial Extension: Prognostic Factors and Outcomes
Wright, Ernest J.
Chernichenko, Natalya
Ocal, Eylem
Moliterno, Jennifer
Bulsara, Ketan R.
Judson, Benjamin L.
Skull Base Reports
We describe a case of benign inverted papilloma with intracranial extension treated with endoscopic resection combined with craniotomy. Intracranial involvement of inverted papilloma, in the absence of malignancy, is uncommon. We present an analysis of the literature identifying the characteristics and outcomes of benign intracranial inverted papilloma. PubMed database was searched using keywords intracranial, inverted or inverting, and papilloma. There are 17 reports of benign inverted papilloma with intracranial extension reported with a mean age of 49.2 years (range, 23 to 92 years), a female predominance, 22% of cases with an associated mucocele, and 60% recurrent disease. The most common sites of invasion are the frontal sinus or cribriform plate. The prognosis for benign intracranial inverted papilloma is dependent on the presence of dural invasion and the achievement of total resection. There are no reported recurrences after craniofacial resection with a mean follow-up of 7.9 years. Adjuvant radiation therapy has demonstrated benefit in cases of residual disease after resection. We expect that endoscopic resection, the standard treatment for sinonasal inverted papilloma, will be increasingly used in the presence of intracranial extension.
Intracranial; inverted; inverting; Schneiderian; papilloma
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Effect of sonic hedgehog/β-TCP composites on bone healing within the critical-sized rat femoral defect
Experimental and Therapeutic Medicine
The creation of entirely synthetically derived bone substitute materials which are as effective as autologous bone grafts is desirable. Osteogenesis involves the concerted action of several proteins within a signaling cascade. Hedgehog proteins act upstream of this cascade, inducing the expression of various bone morphogenetic proteins (BMPs) and promoting physiological bone healing. Therefore, the hypothesis that hedgehog signaling in bone defects improves bone healing more than BMP signaling alone was tested. Recombinant N-terminal sonic hedgehog protein (N-SHh), BMP-2 or a combination of the two was added to β-tricalcium phosphate (β-TCP) and 5-mm femoral midshaft defects in nude rats were filled with these composites. The defects were stabilized with mini-plates. After eight weeks, the animals were sacrificed and the femora were explanted. The radiological evaluation was followed by a three-point bending test and histological examination. BMP-2/β-TCP composites showed a trend of increased stiffness compared with the controls (β-TCP without protein). N-SHh/β-TCP composites had lower stiffness compared with the control group and the N-SHh/BMP-2/β-TCP composites also had lower average stiffness compared with the controls (all not significant). Histomorphometry, however, revealed abundant cartilage and bone core formation in the N-SHh-composite groups. The sum of the new cartilage and bone was highest in the combination group N-SHh/BMP-2 (not significant). The addition of N-SHh to bone substitute materials appears to delay bone healing at the applied concentration and observation time but also showed a trend for higher amounts of ossifying cartilage.
bone substitute material; tricalcium phosphate; sonic hedgehog; bone morphogenetic protein-2; rat femur defect; three point bending test
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The Osteogenic Study of Tissue Engineering Bone with BMP2 and BMP7 Gene-Modified Rat Adipose-Derived Stem Cell
Qing, Wang
Guang-Xing, Chen
Lin, Guo
Liu, Yang
Journal of Biomedicine and Biotechnology
To evaluate the feasibility and advantages of constructing a novel tissue engineering bone, using β-tricalcium phosphate (β-TCP) and rat adipose-derived stem cells (ADSCs), modified with BMP2 and BMP7 by lentivirus. In the present study, ADSCs transfected with Lv-BMP2 and Lv-BMP7, alone or together, were seeded on β-TCP scaffold and cultured in vitro. Based on the results of DNA assay, alkaline phosphatase (ALP) activity, alizarin red staining and osteogenic marker genes expression analysis, the BMP2 and BMP7 genes cotransfection group exhibited a higher degree of osteogenic differentiation in vitro. To investigate the in vivo osteogenesis of the tissue engineering bone, the ADSCs/β-TCP constructs were implanted in rat femurs defects for 6 weeks and studied histomorphology and radiography. The results showed that BMP2 and BMP7 genes cotransfection group dramatically enhanced the efficiency of new bone formation than BMP2 group and BMP7 group in vivo. These results demonstrated that it was advantageous to construct tissue engineering bone using ADSCs cotransfected with BMP2 and BMP7 on β-TCP, providing a potential way for treating bone defects.
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Exogenous heparin binds and inhibits bone morphogenetic protein 6 biological activity
Brkljacic, Jelena
Pauk, Martina
Erjavec, Igor
Cipcic, Antonio
Grgurevic, Lovorka
Zadro, Renata
Inman, Gareth J.
Vukicevic, Slobodan
International Orthopaedics
The purpose of this study was to explore the effect of heparin on bone morphogenetic protein 6 (BMP6) osteogenic activity.
Western blot analysis was used to confirm the binding of BMP6 to heparin and to observe its effect on BMP6 signaling in C2C12-BRE-Luc myoblasts. Real-time RT-PCR was performed for the expression analysis of alkaline phosphatase (ALP) and osteocalcin (OC) in C2C12 myoblasts treated with BMP6 and heparin for 72 hours. Rat ectopic bone formation assay was performed to explore the effect of heparin on BMP6 osteogenic activity. Two weeks following implantation the implants were analysed morphologically and histologically. A mouse osteoporotic model was used to test the ability of BMP6 to improve the bone quality in vivo in the presence of heparin, followed by DEXA and μCT analyses. Blood coagulation was tested in rats previously treated with BMP6.
BMP6 specifically bound to heparin and induced Smad1/5/8 phosphorylation which was inhibited by heparin. After 48 and 72 hours of treatment, heparin inhibited BMP6-induced ALP and OC expression in C2C12 cells. Heparin dose dependently inhibited BMP6-induced new bone and cartilage formation in the rat ectopic bone formation assay, while in osteoporotic mice heparin inhibited the BMP6 potential to improve the bone quality as evidenced by decreased bone mineral density and trabecular bone parameters. Interestingly, BMP6 prevented the effect of heparin on the blood coagulation parameters.
The interaction of BMP6 with heparin might contribute to the heparin-induced osteoporosis and blood coagulation.
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Schneiderian papillomas: Comparative review of exophytic, oncocytic, and inverted types
Vorasubin, Nopawan
Vira, Darshni
Suh, Jeffrey D.
Bhuta, Sunita
Wang, Marilene B.
American Journal of Rhinology & Allergy
Sinonasal papillomas are benign epithelial neoplasms arising from Schneiderian mucosa. The three subtypes, exophytic, oncocytic, and inverted (inverted papilloma [IP]), should be distinguished from one another histopathologically. This study (1) highlights the histopathological and clinical differences between the Schneiderian papilloma subtypes and (2) identifies clinical features that potentially predict papilloma subtypes.
A retrospective review was performed of patients with Schneiderian papillomas over an 11-year period.
Seventy patients with sinonasal papillomas who underwent sinus surgery were identified. There were 50 (71%) male and 20 (29%) female subjects diagnosed at an average age of 53 years (range, 13–80 years). Exophytic (n = 25), oncocytic (n = 9), and IP (n = 37) were identified. IP was associated with transformation into squamous cell carcinoma in three (8%) cases and dysplasia in three (8%) cases. Neither oncocytic nor exophytic subtypes were associated with dysplasia or malignancy. On multivariate analysis of potential predictors of papilloma subtype, history of chronic rhinosinusitis (CRS) and location of papilloma were significantly associated with papilloma subtype. Using classification and regression tree model, papilloma subtypes can be predicted based on presence or absence of CRS and papilloma location with nominal 82.4% accuracy.
The inverted and exophytic type are the most common sinonasal papillomas, with the inverted type having an 8% rate of malignant transformation in this study. In contrast, the oncocytic type was not associated with dysplasia or malignancy in our series despite reports in the literature indicating malignant potential. History of CRS and papilloma location can provide clues to the histological subtype, which is important for surgical planning and patient counseling.
Cylindrical cell; exophytic; inverted; oncocytic; Schneiderian papillomas; sinonasal papillomas
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Risk of Cancer After Lumbar Fusion Surgery With Recombinant Human Bone Morphogenic Protein-2 (rh-BMP-2)
Cooper, Gregory S.
Kou, Tzuyung Doug
Supplemental Digital Content is Available in the Text.
In a cohort of Medicare beneficiaries who underwent lumbar spinal fusion, we investigated the association of recombinant human bone morphogenic protein (rhBMP) and risk of subsequent cancer. After a mean follow-up of 4.7 years, rhBMP was not associated with overall cancer incidence or risk of individual tumor types.
Study Design.
Retrospective cohort study among Medicare beneficiaries with lumbar spinal fusion surgery.
To determine the risk of subsequent cancer among patients who received recombinant human bone morphogenic protein (rhBMP) at surgery compared with those who did not.
Summary of Background Data.
rhBMP is commonly used to promote bone union after spinal surgery. BMP receptors are present on multiple cancer types, but the risk of cancer after receiving rhBMP has not been well studied.
We identified 146,278 subjects aged 67 years and older who underwent surgery in 2003 to 2008 and were followed through 2010 for a new diagnosis of 1 of 26 cancers. Proportional hazards models were used to determine cancer risk associated with rhBMP use.
rhBMP was administered in 15.1% of the cohort. After an overall average follow-up of 4.7 years, 15.4% of rhBMP-treated and 17.0% of untreated patients had a new cancer diagnosis, with most commonly recorded types as prostate, breast, lung, and colorectal. In a multivariate proportional hazards model, there was no association of rhBMP with cancer risk (hazard ratio: 0.99, 95% confidence interval: 0.95–1.02). There was also no association of rhBMP with the risk of any individual cancer types. The results were consistent in analyses using 2 secondary definitions of incident cancer.
In this large population-based analysis of Medicare beneficiaries, we found no evidence that administration of rhBMP at the time of lumbar fusion surgery was associated with cancer risk.
Level of Evidence: 4
recombinant human bone morphogenic protein-2; spinal fusion; neoplasms; Medicare; aged; SEER Program
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BMPs in periprosthetic tissues around aseptically loosened total hip implants
Waris, Ville
Waris, Eero
Sillat, Tarvo
Konttinen, Yrjö T
Acta Orthopaedica
Background and purpose
Primary and dynamically maintained periprosthetic bone formation is essential for osseointegration of hip implants to host bone. Bone morphogenetic proteins (BMPs) play a role in osteoinductive bone formation. We hypothesized that there is an increased local synthesis of BMPs in the synovial membrane-like interface around aseptically loosened total hip replacement (THR) implants, as body attempts to generate or maintain implant fixation.
Patients and methods
We compared synovial membrane-like interface tissue from revised total hip replacements (rTHR, n = 9) to osteoarthritic control synovial membrane samples (OA, n = 11. Avidin-biotin-peroxidase complex staining and grading of BMP-2, BMP-4, BMP-6, and BMP-7 was done. Immunofluorescence staining was used to study BMP proteins produced by mesenchymal stromal/stem cells (MSCs) and osteoblasts.
Results and interpretation
All BMPs studied were present in the synovial lining or lining-like layer, fibroblast-like stromal cells, interstitial macrophage-like cells, and endothelial cells. In OA and rTHR samples, BMP-6 positivity in cells, inducible by the proinflammatory cytokines tumor necrosis factor−α and interleukin-1β, predominated over expression of other BMPs. Macrophage-like cells positive for BMP-4, inducible in macrophages by stimulation with particles, were more frequent around loosened implants than in control OA samples, but apparently not enough to prevent loosening. MSCs contained BMP-2, BMP-4, BMP-6, and BMP-7, but this staining diminished during osteogenesis, suggesting that BMPs are produced by progenitor cells in particular, probably for storage in the bone matrix.
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Clinico-pathological profile of sinonasal masses: a study from a tertiary care hospital of India
Acta Otorhinolaryngologica Italica
The present study examined the clinico-pathological profile of sinonasal masses in patients attending an Ear Nose Throat clinic of a rural tertiary care hospital of western Maharashtra in India, between May 2007 to June 2009. During the study period, 112 patients presented with sinonasal masses (male 68, female 44; age group 8-70 years). Nasal polyploid masses were non-neoplastic in 80 (71.4%) subjects, and neoplastic in 32 (28.6%) cases. Nasal obstruction was the most common (97.3%) presenting complaint, followed by rhinorrhoea (49.1%), hyposmia (31.25%), intermittent epistaxis (17.9%), headache (16.9%), facial swelling (11.6%) and eye-related symptoms (10.7%). The most common site of origin of polyploid masses was the middle meatus (54.4%) followed by the lateral wall of the nasal cavity (16.1%) and superior meatus (10.7%). Unilateral nasal masses was present in 47.7% patients, while the remaining patients had bilateral nasal masses. Allergic (62.5%) and inflammatory (25%) polyps were the most common non-neoplastic mass. Haemangioma (47.3%) and inverted papilloma (36.8%) were most common benign neoplastic mass; 92.3% of all malignant masses were squamous cell carcinoma. Surgery was the major mode of treatment. It included Caldwell-Luc operation (7.1%), polypectomy (17.8%), excision of mass (25.0%) and functional endoscopic sinus surgery (44.6%). Malignancies were treated with radiotherapy.
Sino nasal mass; Polyp; Nasal obstruction; Squamous cell carcinoma; FESS
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Bone Morphogenetic Protein Type I Receptor Antagonists Decrease Growth and Induce Cell Death of Lung Cancer Cell Lines
Langenfeld, Elaine
Hong, Charles C.
Lanke, Gandhi
Langenfeld, John
PLoS ONE
Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.
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Improvement of osteogenic potential of biphasic calcium phosphate bone substitute coated with two concentrations of expressed recombinant human bone morphogenetic protein 2
Choi, Hyunmin
Park, No-Je
Jamiyandorj, Otgonbold
Choi, Kyung-Hee
Hong, Min-Ho
Oh, Seunghan
Park, Young-Bum
Kim, Sungtae
Journal of Periodontal & Implant Science
The aim of this study was to determine whether biphasic calcium phosphate (BCP) bone substitute with two different concentrations of Escherichia coli-expressed recombinant human bone morphogenetic protein 2 (ErhBMP-2) enhances new bone formation in a standardized rabbit sinus model and to evaluate the concentration-dependent effect of ErhBMP-2.
Standardized, 6-mm diameter defects were made bilaterally on the maxillary sinus of 20 male New Zealand white rabbits. Following removal of the circular bony windows and reflection of the sinus membrane, BCP bone substitute without coating (control group) was applied into one defect and BCP bone substitute coated with ErhBMP-2 (experimental group) was applied into the other defect for each rabbit. The experimental group was divided into 2 subgroups according to the concentration of ErhBMP-2 (0.05 and 0.5 mg/mL). The animals were allowed to heal for either 4 or 8 weeks and sections of the augmented sinus and surrounding bone were analyzed by microcomputed tomography and histologically.
Histologic analysis revealed signs of new bone formation in both the control and experimental groups with a statistically significant increase in bone formation in experimental group 1 (0.05 mg/mL ErhBMP-2 coating) after a 4-week healing period. However, no statistically significant difference was found between experimental group 1 and experimental group 2 (0.5 mg/mL ErhBMP-2 coating) in osteoinductive potential (P<0.05).
ErhBMP-2 administered using a BCP matrix significantly enhanced osteoinductive potential in a standardized rabbit sinus model. A concentration-dependent response was not found in the present study.
Bone morphogenetic protein 2; Bone regeneration; Bone substitute; Maxillary sinus; Rabbits
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Addition of bone morphogenetic protein type 2 to ascorbate and β-glycerophosphate supplementation did not enhance osteogenic differentiation of human adipose-derived stem cells
CRUZ, Ariadne Cristiane Cabral
SILVA, Mariana Lúcia
CAON, Thiago
SIMÕES, Cláudia Maria Oliveira
Journal of Applied Oral Science
Bone morphogenetic protein type 2 (BMP-2) is a potent local factor, which promotes bone formation and has been used as an osteogenic supplement for mesenchymal stem cells.
This study evaluated the effect of a recombinant BMP-2 as well as the endogenous BMP-4 and BMP-7 in the osteogenic differentiation of adipose-derived stem cells (ASCs) in medium supplemented with ascorbate and β-glycerophosphate.
Material and Methods
Human ASCs were treated with osteogenic medium in the presence (ASCs+OM+BMP-2) or absence (ASCs+OM) of BMP-2. The alkaline phosphatase (ALP) activity was determined and the extracellular matrix mineralization was evaluated by Von Kossa staining and calcium quantification. The expressions of BMP-4, BMP-7, Smad1, Smad4, and phosphorylated Smad1/5/8 were analyzed by western blotting. Relative mRNA expressions of Smad1, BMP receptor type II (BMPR-II), osteonectin, and osteocalcin were evaluated by qPCR. Results: ASCs+OM demonstrated the highest expression of BMP-4 and BMP-7 at days 21 and 7, respectively, the highest levels of BMPR-II mRNA expression at day 28, and the highest levels of Smad1 mRNA at days 14 and 28. ASCs+OM+BMP-2 demonstrated the highest levels of Smad1 mRNA expression at days 1, 7, and 21, the highest expression of Smad1 at day 7, the highest expression of Smad4 at day 14, the highest ALP activity at days 14 and 21, and expression of phosphorylated Smad1/5/8 at day 7. ASCs+OM and ASCs+OM+BMP2 showed similar ALP activity at days 7 and 28, similar osteonectin and osteocalcin mRNA expression at all time periods, and similar calcium depositions at all time periods.
We concluded that human ASCs expressed endogenous BMP-4 and BMP-7. Moreover, the supplementation of ASCs with BMP-2 did not increase the level of osteogenic markers in the initial (ALP activity), intermediate (osteonectin and osteocalcin), or final (calcium deposition) phases, suggesting that the exogenous addition of BMP-2 did not improve the in vitro osteogenesis process of human ASCs.
Stem cells; Cell differentiation; Osteogenesis; Bone morphogenetic protein 2; Bone morphogenetic protein 4; Bone morphogenetic protein 7
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Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities
Berasi, Stephen P
Varadarajan, Usha
Archambault, Joanne
Cain, Michael
Souza, Tatyana A
Abouzeid, Abe
Li, Jian
Brown, Christopher T
Dorner, Andrew J
Seeherman, Howard J
Jelinsky, Scott A
Growth Factors (Chur, Switzerland)
Ectopic expression of recombinant human bone morphogenetic protein 2 (rhBMP2) induces osteogenesis, while ectopic expression of rhBMP12 and rhBMP13 induces the formation of tendon-like tissue. Despite their different in vivo activities, all three ligands bound to the type I bone morphogenic protein receptors (BMPRs), activin receptor-like kinase (ALK)-3 and ALK6, and to the type II BMPRs, activin receptor type-2A, activin receptor type-2B, and BMPR2, with similar affinities. Treatment of C3H10T1/2 cells with rhBMP2 activated SMAD signaling and induced expression of osteoblast markers including osteocalcin mRNA (Ocn). In contrast, treatment with rhBMP12 or rhBMP13 resulted in a dose-dependent induction of a tendon-specific gene (Thbs4) expression with no detectable activation of SMAD 1, 5, and 8. Differential regulation of Thbs4 and Ocn has potential utility as an in vitro biomarker for induction of tenogenic signaling. Such an assay also permits the ability to distinguish between the activities of different BMPs and may prove useful in studies on the molecular mechanisms of BMP tenogenic activity.
Bone morphogenetic proteins; thrombospondin 4; tendon markers
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Fascin Over Expression is Associated with Dysplastic Changes in Sinonasal Inverted Papillomas: A Study of 47 Cases
Wu, Hope H.
Zafar, Samiah
Huan, Youming
Yee, Herman
Chiriboga, Luis
Wang, Beverly Y.
Head and Neck Pathology
Sinonasal inverted papilloma (IP) is a primary benign lesion with a tendency for local recurrence. Malignant transformation may develop in up to 15% of cases. Fascin (Fascin 1) is an actin cross-link binding protein required for the formation of actin-based cell-surface protrusions and cell motility. Fascin up-regulation in lung, gastric, breast and hepatobiliary carcinomas correlates with aggressiveness and decreased survival. Here we evaluate immunohistochemical expression of fascin in 47 sinonasal IPs from 34 patients. Fascin over-expression is significantly more common in sinonasal IP with high-grade dysplasia than in those with no dysplastic or low-grade dysplastic epithelium (P = 0.0001). No significant change in fascin expression is seen with recurrence. Over expression of fascin in high-grade dysplastic epithelium in IP may be associated with tumor progression and malignant transformation.
Fascin; Sinonasal inverted papilloma; Dysplasia; Malignant transformation; Immunohistochemistry
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Diva Frame Wallet Sewing Pattern
The perfect accessory for any occasion.
This framed wallet is sure to turn some heads! It's so easy to make, you can make 1 to go with each of your bags so you'll be super trendy! Inside is a zippered coin pocket, 2 open pockets for cash and receipts, and 6 individual card pockets. Great for sticking all your essentials for a night out on the town, or just for your average everyday fun! It's even fat quarter friendly! Finished closed size is 8"W x 4 1/2"L, and open size is 8"W x 9"L using 2 fat quarters, plus additional yardage.
Electronic download is available as a PDF and in formats compatible with your e-reader.
Electronic download is available as a PDF and in formats compatible with your e-reader.
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Diva Frame Wallet Sewing Pattern
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August 2, 2014
August 2, 2014
Where do we get metal frames for these wallets?
Annie's Customer ServiceBonnie - You can find the frames at American Purse Supplies
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text:
I have a problem with the menu.
I have a mantra theme version 22.214.171.124.
When ever i publish something, it always appear in the menu.
For example, the legal information page, i dont want it to appear in the menu.
How can i do so that one page that is publish will not appear in the menu?
And other question is how can i disable or remove the link of one tab of the menu?I tried with url=# but is not working
Thanks you very much


text:
Quantifying Personal Boundaries
Kaley Cuoco Shows Off Her Tennis Skills
The James Bond Movies Ranked
Sorry, Lamar: Khloe Kardashian, James Harden Seen Together At Hollywood Club
6 TV Finales That Failed Spectacularly
The 10 Most Promising TV Shows of Fall 2015
The Long, Troubled Future History of 'Back to The Future Part IV'
Will Christian Bale Ever Play Batman Again?
Movies You Didn't Know Were Blatant Rip-Offs
First Look At Leaked Warcraft Movie Trailer
Game Of Thrones Season 6 Delayed!
Quentin Tarantino Got Offered The Biggest Movies After His Biggest Flop
The 10 Fall TV Shows We Can't Wait To Watch
Back to the Future Predicted 9/11
Teen Titans Live Action is Headed to TNT
Star Trek: New Series Could Run Many Seasons
Real-Life Couples Who Starred in Movies Together
First Look At Tom Green's "Monsters: Dark Continent"
10 Celebrities Who Almost Died While Filming
15 Original Netflix Series That You Should Be Watching
Sam Wilson is the New Captain America
Ridley Scott on Why Prometheus 2 is Now Alien: Paradise Lost
Exclusive: Rinko Kikuchi Talks Pacific Rim 2 and Star Wars: Episode VIII
This Japanese Star Wars: The Force Awakens Trailer May Have Dropped a Huge Spoiler
The 15 Biggest Oscar Snubs Of The Past 20 Years
10 Truly Scary Horror Movies
10 Movie Characters You Can't Root for Anymore
See the First Appearance of Marvel's Female Thor!
The Walking Dead Executive Producer: What Actually Died in Sunday's Shocking Episode
Mark Wahlberg's The Six Billion Dollar Man Gets a Release Date


text: On Friday, October 19, 2012, Jesse Gumm wrote: > I'm running into a bit of an issue in trying to compile the mimetypes > package. . . . > I've tested this with R15B - R15B02 on both Windows 7, Windows XP, and > Linux. Linux (as expected) works reliably. I had issues with the mimetypes application on Windows because it expected Unix line-endings in one of the files. I submitted a patch for it, and if my deciphering of GitHub is correct, I think it got merged into the main branch. (I'm not a GitHub guru, though, so maybe I did it wrong.) Check to make sure you've got the most recent version. Once I made that change, it did work for me, so I can confirm that it can work on Windows. Otherwise, I can't help you. Cheers, DBM


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Google Chrome Canary is the cutting-edge version of the Google Browser. At the moment, you can download Google Chrome Stable, Google Chrome Beta, Google Chrome Developer versions and now, Google Chrome Canary which is the Alpha/pre-Alpha version of the browser.
This means that anything that appears in Google Canary, will eventually probably appear in both the developer and stable versions, so if you want to stay at the very cutting edge of Google Chrome, Canary is what you need. The good news is, when you install Google Canary, it won't install itself over any other version you've got installed, so you can test it to your heart's content.
However, since its completely untested and designed for those that want to help Google develop the next version of Chrome, you'll find it very unstable and unreliable at times and be warned that it will send anonymous usage stats back to Google.
If you want to see the cutting edge latest in the development of Chrome, Google Chrome Canary is your answer.
For reasons that do not depend on Softonic, you will be redirected to download Google Chrome Canary on the author's website.
- Lets you see the latest upcoming features of Chrome
- Doesn't install over Stable or Developer version
- Very unstable
- Not much extension support
"Google Chrome Canary is the best browser for Windows 8.1"
Google Chrome Canary is NOW my favorite browser. It is the most stable and works with all the web sites I love. For example live.com work better in Canary than it does in Firefox. I had upgraded to Windows 8.1 and found that Firefox became unstable in certain circumstances. Google Chrome Canary is perfect for use with Windows 8.1
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text:
Police report - May 5-7, 2006
Published: Monday, May 8, 2006 at 6:01 a.m.
Last Modified: Monday, May 8, 2006 at 12:35 p.m.
Portions of the following information are based on facts provided by the arrested individuals. Those individuals have been booked with, not convicted of, the offenses shown. All accused should be presumed innocent until proven guilty.
- May 6, 2006
Michael Andrea Lee, 20, 113 Paul Fredrick Road, Luling, theft of goods more than $500.
- May 7, 2006
Chris Joseph Edwards, 39, 1816 Coteau Road, Houma, theft of animals, criminal trespass.
- May 5, 2006
Beau Edward Eschete, 19, 3557 Bayou Black Drive, Houma, simple battery, aggravated battery, resisting arrest by flight.
Tamara Lynn McClanahan, 37, 708 Angela Drive, Houma, contempt of court.
Michael Lagarde, 38, 2622 Daniel Turner Trailer Park, Houma, theft of goods, unlawful possession drug paraphernalia.
Nakia Lashawn Cheavis, 21, 330 Bayou Dularge Road, Houma, theft of goods more than $500.
- May 6, 2006
Calvalet Noel Calloway, 25, 309 East St., Houma, theft of goods, resisting an officer.
- May 7, 2006
Cleveland Jones, 49, 121 Odelia St., Houma, DWI, improper lane usage, hit-and-run.
Gerald Douglas, 49, 608 High St., Houma, aggravated battery, resisting arrest by violence.
Michael Amacker, 42, 111 Academy St., Houma, unlawful possession drug paraphernalia, contempt of court, aggravated battery, resisting arrest by violence.
- May 6, 2006
Rydelle Rodricker Rounds, 22, 200 Johnson Ridge Lane, Thibodaux, simple obstruction of highway, resisting a officer, disturbing the peace by offensive language, throwing stone or other instrument, obstruction of justice, two counts failure to appear.
- May 7, 2006
Horace Monroe Rounds, 37, 200 Johnson Ridge Lane, Thibodaux, throwing stone or other instrument, simple obstruction of highway, resisting an officer, obstruction of justice, disturbing the peace by offensive language, misrepresentation during booking, ignoring a command to disperse.
Rashawd James Ramsey, 20, 157 Als Trailer Park, Gray, possession with intent to distribute schedule II controlled dangerous substance, illegal transaction involving drug proceeds, failure to possess drug-tax stamp, illegal use of a controlled dangerous substance in the presence of a juvenile, two counts failure to appear, failure to complete community-service work, probation violation, battery (domestic abuse), speeding (reduced zone), reckless operation, violating traffic control signal, no drivers license.
- May 5, 2006
Derrick Paul Joseph, 37, 121 Johnson Ridge, Thibodaux, possession of drugs and drug paraphernalia.
Jermaine Joseph Netters, 22, 330 American Blvd., Houma, probation revocation.
Kimberly Anne Pellegrin, 34, 105 Harding Drive, Houma, DWI, careless operation.
Audie John Lafont, 34, 203 Leblanc Drive, Lockport, DWI, improper lane usage.
Clint Steven Lawson, 26, 1498 Capital Drive, Houma, violating traffic-control signal, second-offense DWI, driving under suspension.
- May 6, 2006
Trent Armond Triche, 34, 702 Natalie Drive, Houma, fourth-offense DWI, improper lane usage, two counts driving under suspension, simple battery, resisting an officer, violating loud noise ordinance, improper left turn, issuing worthless checks less than $100.
- May 7, 2006
Delores Calva Flores, 26, 249 Richmond Ave., Houma, DWI, improper lane usage, no drivers license.
Navor Aleman, 29, 164 Gouaux Ave., Houma, DWI, improper lane usage, no drivers license.
- May 5, 2006
Brain Matunzi, 31, 323 Ash St., Houma, speeding.
- May 5, 2006
Jermain James Cortez, 26, 22847 High Ridge Drive, Vacherie, writ of habeas corpus, theft of goods.
Kenneth Michel Rushing 52, 203 Leona St., Houma, DWI.
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text:
Jamba Juice challenges Starbucks with oatmeal launch
[caption id="attachment_11430" align="alignright" width="201" caption="Jamba Juice will debut oatmeal in most U.S. smoothie shops. (CLICK PHOTO TO ENLARGE)"][/caption]
Instead of giving customers a refreshing cool lift, Jamba Juice (JMBA) wants to warm you up.
Starting today, Jamba Juice plans to sell oatmeal in a majority of its 700 shops. The national roll out of the hot morning grub is a milestone for the company -- marking the first significant debut of a non-smoothie item on its menu, said newly appointed Chief executive James D. White.
"It's our foray into food," said White, a former brand executive at California supermarket chain Safeway (SWY).
Jamba Juice's oatmeal takes 40 minutes to prepare, but is available to customers instantly, the chain said. It is made with organic, steel-cut oats and comes with a choice of three real fruit toppings: blueberry-blackberry, apple cinnamon or fresh bananas. (Cost: $2.95)
But, is Jamba Juice too late? The the arrival of oatmeal comes after Starbucks (SBUX) beat Jamba Juice to the breakfast table. Starbucks introduced a $2.45 oatmeal last fall (2008), a move that gave the struggling coffee chain a much-needed financial boost.
Is Jamba Juice copying Starbucks? Will coffee be next on the smoothie chain's menu? White, reached by phone Wednesday to discuss the oatmeal launch, addressed those questions and more during a phone interview.
Here's what he had to say:
Q: How many units will get oatmeal?
A: It will be more than 600 stores. Southern California is definitely a core market.
Q: Jamba Juice began a breakfast program in spring. How well are those breakfast drinks and yogurts doing?
A: They are doing well enough. They were at first breakfast-only items, but we've made them available all day (due to demand.)
Q: How much revenue will this new day part add to your overall sales?
A: That's not something we want to share at this point.
Q: Coming from Safeway (SWY), your background is in brand strategy. How do smoothies and oatmeal go together? Do you really expect someone to order a Strawberries Wild with a side of oatmeal?
A: Jamba Juice, as a brand, is bigger than just smoothies. It's a lifestyle brand. It's a better for you, high quality brand. That's why we are serving slow-cooked, organic oatmeal with real fruit toppings. We want new people to come and look at us, and grab a fresh juice and oatmeal.
[caption id="attachment_11490" align="alignright" width="186" caption="Starbucks oatmeal"][/caption]
Q:Coincidence that you added oatmeal to your menu months after Starbucks saw success with its new oatmeal?
A: We've been working on this a year and we think we deliver a higher quality offering. One is instant, and one is slow cooked. [For the record: White is right. Starbucks confirms that its oatmeal is instant.]
Q: Can Jamba Juice customers expect more food on the menu in the future? What about coffee?
A: We're considering lots of options. We're getting very serious about food offerings that complement the core smoothie business. We've announced tests of wraps. We are very focused on foods (for) all the day parts.
To learn if your local Jamba Juice is selling oatmeal, call Jamba Juice's customer service line at 1-866-4R-FRUIT.
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text:
July 14, 2014
Comedian Tracy Morgan has filed a lawsuit against Walmart following a crash last month on the New Jersey Turnpike in which he was severely injured, while James McNair, a comedian known as Jimmy Mack was killed and two others were hurt.
July 11, 2014
UPDATED -- The complaint alleges that Navistar actively concealed that its 2008-2013 model trucks, equipped with the MaxxForce Advanced exhaust gas recirculation diesel engines, contained a defective emission system that caused the trucks to suddenly break down.
July 10, 2014
Truck drivers in California are entitled to paid rest breaks and meal breaks, according to a Wednesday ruling from a federal court in San Francisco.
July 8, 2014
Lawyers for trucking companies have filed lawsuits in three states against the parent company of International Trucks, claiming Navistar failed to disclose known defects and problems with its EPA 2010 MaxxForce engines.
June 26, 2014
Auditors have signed off on truckstop chain Pilot Flying J's math in determining whether it correctly calculated what it owed trucking company customers in a fuel rebate program that has been the focal point of a federal investigation.
The U.S. Fourth Circuit Court of Appeals has upheld a earlier ruling in the U.S. Equal Employment Opportunity Commission's favor in obtaining a jury verdict and more than $243,000, along with injunctive relief, for victims of racial harassment and retaliation perpetrated by A.C. Widenhouse, a Concord, N.C.-based trucking company.
June 25, 2014
The U.S. Supreme Court has denied a petition by the trucking company Swift Transportation to review a lower court ruling against the company involving independent contractor driver leases.
June 23, 2014
Truck component makers Meritor and Eaton have reached a settlement agreement relating to an antitrust lawsuit filed in 2006.
June 19, 2014
A group of small carriers and brokers lost their legal challenge of the Federal Motor Carrier Safety Administration's CSA safety enforcement program. In a ruling handed down Wednesday the U.S. Court of Appeals for the District of Columbia Circuit dismissed the suit by the Alliance for Safe, Efficient and Competitive Truck Transportation
A Florida attorney is warning truck driver commercial licenses have been placed at further risk due to a change in Florida law.
June 10, 2014
Winebrenner Transfer, a Hagerstown, Md.-based trucking company, will pay $42,000 to a female truck driver to resolve a lawsuit for retaliation filed by the U.S. Equal Employment Opportunity Commission.
June 9, 2014
The Owner-Operator Independent Drivers Association and the trucking company C.R. England have reached a settlement in a case regarding compliance with federal regulations governing the leasing relationship between motor carriers and truck owner-operators.
The trucking company New England Motor Freight has agreed to pay $870,500 to settle a federal class action lawsuit that it failed to get proper authorization from truck drivers before checking their credit reports and then later denying them employment.
May 20, 2014
The family of a Los Angeles student killed last month when the charter bus he was in was hit by a FedEx Freight truck in Orland, Calif., is filing a wrongful death lawsuit, according to the Los Angeles Times.
May 16, 2014
The logistics operation of trucking industry giant Schneider has agreed to pay $21 million to settle a class action lawsuit filed that includes as many 1,800 employees over alleged wage and hour violations.
May 9, 2014
Plaintiffs in the latest class-action lawsuit allege Caterpillar hid details of defects and performance issues from customers that the engine maker knew about.
May 2, 2014
A tough critic of the California Air Resources Board and its policies over its regulation of diesel emissions, who was fired from his job at a California university, is finally getting his day in court this coming November.
April 28, 2014
A 41-year-old Mississippi woman, seriously injured when her pick-up truck rolled over, after it was rear-ended by an 18-wheel tractor-trailer driver on a Texas interstate highway in 2011, was awarded $4.1 million by a Dallas, Texas jury.
April 23, 2014
The first known lawsuit stemming from a crash between a FedEx Freight truck and a bus that killed 10 people earlier this month has been filed.
April 18, 2014
The tanker trucking company Kenan Transport will pay $27,000 to settle a pregnancy discrimination and retaliation lawsuit brought by the Equal Employment Opportunity Commission, the agency announced Thursday.
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Fresenius Kabi Product Partnering leads the way in contract development and manufacture of sterile pharmaceuticals and medical devices. As Fresenius Kabi's business-to-business platform we offer also oncology products, beta-lactam antibiotics and special APIs like Lactulose and Hydroxyethyl-Starch.
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Billy Fontenots Professional
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text:
Pakistan's President Declares State of Emergency
President Gen. Pervez Musharraf declared a state of emergency in Pakistan on Saturday ahead of a crucial Supreme Court decision on whether to overturn his recent election win and amid rising Islamic militant violence.
Related NPR Stories
Pakistanis Fear Violent Election Season Oct. 26, 2007
Play Connects Pakistan's Past and Present Oct. 20, 2007
Suicide Attack in Pakistan kills 8, Wounds Scores Nov. 1, 2007
Bhutto Travels Outside Pakistan Nov. 1, 2007
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I've been streaming Netflix Watch Instantly videos to my Xbox 360 for months now using Windows Media Center and a free program called vmcNetflix , but now that the New Xbox Experience released this morning also supports Netflix streaming, users have two different options for streaming movies to their Xbox. The question is, which option is better? The obvious answer is that the official offering is the hands-down winner, but having used the alternative for the past few months, Netflix on the New Xbox Experience left me cold. Here's why.
What's Great About Netflix Streaming on the Xbox 360Netflix streaming on the Xbox 360 has a few major pros over vmcNetflix .
- For one, the video quality is better. In fact, you can even stream the video in HD—which I don't believe is an option (yet) in vmcNetflix.
- Also, as opposed to vmcNetflix, you don't need a Vista PC to use it.
- And last but certainly not least, it's less buggy and subject to breaking, since Microsoft and Netflix are actually working together on it.
- Aside from that, the official Netflix offering has an attractive interface, which is always a draw.
How Could vmcNetflix Possibly Be Better?Okay, so at this point choosing the official Netflix channel seems like a no-brainer. To a large extent it is, but vmcNetflix is actually way better than the official Netflix-on-Xbox streaming in a few very important ways.
- vmcNetflix can browse the entire Netflix Watch Instantly library, and when you find something you want, you can play it. The app organizes movies by genre, popularity, and new releases, so it's not only a destination when you want to watch a movie you've added to your Netflix Watch Instantly queue—it's also a destination when you're just looking for a movie to watch. The New Xbox Experience currently only lets you stream movies you've already added to your Watch Instantly queue.
- vmcNetflix can do way more, including search the Netflix library and add to or remove movies from your Instant Queue or your DVD queue.
- vmcNetflix allows you to save movies to your hard drive. It's not necessarily copacetic with the Netflix ToS, but it can come in handy if you have a slower connection.


text:
I'd usually preorder ASAP, but I want to see if Xseed is doing an LE for this one ad they did with their psp Ys releases.
I thought all launch copies of those PSP Ys games were LEs with stand alone game-only copies not coming until subsequent production runs (if at all). If that remains the case, a pre-order now would essentially be a pre-order of the LE.


text:
Kyle Parker's two-run single in the eighth
inning lifted Clemson to a 6-5 comeback victory over Oklahoma State
in the deciding game of the Clemson Regional on Monday night.
Parker drove in Ben Paulsen and John Nester with a liner to left
field off Cowboys closer Randy McCurry, who came in for starter
Tyler Lyons (7-6). Chris Epps' two-out, two-run homer after an
error by the Cowboys, who led 5-1 through six innings, sparked the
Matt Vaughn (4-1) pitched the final 3 2-3 innings for the Tigers
(44-20), who advanced to play at Arizona State in the super
regionals next weekend.