Pediatric Mandibular Defect Rehabilitation by Human Transforming Growth Factor-β3 with an Implant-Supported Prosthesis.

Large mandibular defects in children are an uncommon but challenging problem for surgeons to solve. The time-honored options of autologous bone grafts are seldom a viable option, as suitable donor sites are unavailable. Osteoinductive morphogens may yet provide a solution in these cases.

Osteogenic Competence and Potency of the Bone Induction Principle: Inductive Substrates That Initiate "Bone: Formation by Autoinduction".

The de novo induction of bone has always been a fascinating phenomenon, keeping skeletal reconstructionists and cellular developmental biologists continuously engaged to finally provide a molecular and cellular approach to the induction of bone formation. A significant advancement was made by the purification and cloning of the human recombinant bone morphogenetic proteins, members of the transforming growth factor-β supergene family. Human bone morphogenetic proteins are powerful inducers of bone in animal models including nonhuman primates.

Mortality after cardioverter-defibrillator replacement: Results of the DECODE survival score index.

Background: Device replacement is the ideal time to reassess health care goals regarding continuing implantable cardioverter-defibrillator (ICD) therapy. Only few data are available on the decision making at this time.

Objectives: The goals of this study were to identify factors associated with poor prognosis at the time of ICD replacement and to develop a prognostic index able to stratify those patients at risk of dying early.

Long Term Follow-Up of Pediatric Mandibular Reconstruction With Human Transforming Growth Factor-β3.

Translating bone regeneration induced by recombinant human bone morphogenetic proteins from animal models to human patients has proven inexplicably inconsistent. This prompted us to test in 5 pediatric patients, an alternative osteoinductive morphogen, recombinant human transforming growth factor β3 (hTGF-β3), to reconstruct mandibular defects of such a size to preclude reconstruction with autologous bone. An osteoinductive implant of human demineralized bone matrix (DBM) loaded with 125 μg hTGF-β3 per gram of DBM was implanted into one defect, and 250 μg hTGF-β3 per gram of DBM in another.

Donor CYP3A5 genotype influences tacrolimus disposition on the first day after paediatric liver transplantation.

Aim: The aim of the present study was to investigate the influence of the cytochrome P450 (CYP) 3A4/5 genotype in paediatric liver transplant recipients and donors, and the contribution of age and gender to tacrolimus disposition on the first day after transplantation.

Methods: The contribution of the CYP3A4/5 genotype in paediatric liver transplant recipients and donors to the tacrolimus blood trough concentrations (C ) and the tacrolimus concentration/weight-adjusted dose ratio on day 1 was evaluated in 67 liver-transplanted children: 33 boys and 34 girls, mean age 4.5 years.

GSH-targeted nanosponges increase doxorubicin-induced toxicity "in vitro" and "in vivo" in cancer cells with high antioxidant defenses.

Several reports indicate that chemo-resistant cancer cells become highly adapted to intrinsic oxidative stress by up-regulating their antioxidant systems, which causes an increase of intracellular GSH content. Doxorubicin is one of the most widely used drugs for tumor treatment, able to kill cancer cells through several mechanisms. However, doxorubicin use is limited by its toxicity and cancer resistance.

Mitochondrial Dysfunction in Cancer and Neurodegenerative Diseases: Spotlight on Fatty Acid Oxidation and Lipoperoxidation Products.

In several human diseases, such as cancer and neurodegenerative diseases, the levels of reactive oxygen species (ROS), produced mainly by mitochondrial oxidative phosphorylation, is increased. In cancer cells, the increase of ROS production has been associated with mtDNA mutations that, in turn, seem to be functional in the alterations of the bioenergetics and the biosynthetic state of cancer cells. Moreover, ROS overproduction can enhance the peroxidation of fatty acids in mitochondrial membranes.

Reconstruction of 56 mandibular defects with autologous compressed particulate corticocancellous bone grafts.

We retrospectively evaluated the results of particulate corticocancellous bone grafting of mandibular defects. Patients with deficits of mandibular continuity as a result of injuries or resection of disease had the affected segment debrided or resected, followed by placement of a patient-specific reconstruction plate. Eight weeks after resection, it was reconstructed with an autotransplant from the posterior iliac crest.

Improved Anti-Tumoral Therapeutic Efficacy of 4-Hydroxynonenal Incorporated in Novel Lipid Nanocapsules in 2D and 3D Models.

4-hydroxynonenal (HNE), a lipid peroxidation product, is a promising anti-neoplastic drug due to its remarkable anti-cancer activities. However, this possibility has not been explored, because the delivery of HNE is very challenging as a result of its low solubility and its poor stability. This study intentionally designed a new type of lipid nanocapsules specifically for HNE delivery.

Role of 4-hydroxynonenal-protein adducts in human diseases.

Significance: Oxidative stress provokes the peroxidation of polyunsaturated fatty acids in cellular membranes, leading to the formation of aldheydes that, due to their high chemical reactivity, are considered to act as second messengers of oxidative stress. Among the aldehydes formed during lipid peroxidation (LPO), 4-hydroxy-2-nonenal (HNE) is produced at a high level and easily reacts with both low-molecular-weight compounds and macromolecules, such as proteins and DNA. In particular, HNE-protein adducts have been extensively investigated in diseases characterized by the pathogenic contribution of oxidative stress, such as cancer, neurodegenerative, chronic inflammatory, and autoimmune diseases.

Re-evaluating the induction of bone formation in primates.

The molecular cloning of the osteogenic proteins of the transforming growth factor-β (TGF-β) supergene family and the results of numerous pre-clinical studies in several mammalian species including non-human primates, have prematurely convinced molecular biologists, tissue engineers and skeletal reconstructionists alike to believe that single recombinant human bone morphogenetic/osteogenic proteins (hBMPs/OPs) would result in tissue induction when translated in clinical contexts. This theoretical potential has not been translated to acceptable clinical results. Clinical trials in craniofacial and orthopedic applications such as mandibular reconstruction and sinus-lift operations have indicated that supra physiological doses of a single recombinant human protein are needed to induce unacceptable tissue regeneration whilst incurring significant costs without achieving equivalence to autogenous bone grafts.

Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral-derived macroporous constructs.

Coral-derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre-loaded with either 500 μg of the calcium channel blocker, verapamil hydrochloride, or 240 μg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT-PCR.

Interim reconstruction and space maintenance of mandibular continuity defects preceding definitive osseous reconstruction.

The use of space maintenance in mandibular defects as an interim measure before definitive osseous reconstruction may prevent problems associated with delayed reconstruction including increased technical difficulty, contracture of soft tissues that limits the volume of the final reconstruction, and the potential for iatrogenic injury to adjacent anatomical structures. The use of a condyle/ramus spacer made of medical grade, ultrahigh-molecular-weight polyethylene, and a flexible body spacer made of high quality, inert, non-toxic medical and food grade silicone rubber, was tested in 38 patients with mandibular defects after the resection of benign but locally aggressive disease, advanced osteomyelitis, and injuries. The spacer was retained for a maximum of 8 weeks, and was then removed through an extraoral approach before definitive reconstruction with a particulate corticocancellous bone graft.

Rosiglitazone and AS601245 decrease cell adhesion and migration through modulation of specific gene expression in human colon cancer cells.

PPARs are nuclear receptors activated by ligands. Activation of PPARγ leads to a reduction of adhesion and motility in some cancer models. PPARγ transcriptional activity can be negatively regulated by JNK-mediated phosphorylation.

A Macroporous Bioreactor Super Activated by the Recombinant Human Transforming Growth Factor-β(3).

Macroporous single phase hydroxyapatite (HA) and biphasic HA/β-tricalcium phosphate with 33% post-sinter hydroxyapatite (HA/β-TCP) were combined with 25 or 125 μg recombinant human transforming growth factor-β3 (hTGF-β(3)) to engineer a super activated bioreactor implanted in orthotopic calvarial and heterotopic rectus abdominis muscle sites and harvested on day 30 and 90. Coral-derived calcium carbonate fully converted (100%) and partially converted to 5 and 13% hydroxyapatite/calcium carbonate (5 and 13% HA/CC) pre-loaded with 125 and 250 μg hTGF-β(3), and 1:5 and 5:1 binary applications of hTGF-β(3): hOP-1 by weight, were implanted in the rectus abdominis and harvested on day 20 and 30, respectively, to monitor spatial/temporal morphogenesis by high doses of hTGF-β(3). Bone formation was assessed on decalcified paraffin-embedded sections by measuring the fractional volume of newly formed bone.

AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells.

PPARαs are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc.) used to treat hyperlipidemia.

Biomimetic matrices self-initiating the induction of bone formation.

The new strategy of tissue engineering, and regenerative medicine at large, is to construct biomimetic matrices to mimic nature's hierarchical structural assemblages and mechanisms of simplicity and elegance that are conserved throughout genera and species. There is a direct spatial and temporal relationship of morphologic and molecular events that emphasize the biomimetism of the remodeling cycles of the osteonic corticocancellous bone versus the "geometric induction of bone formation," that is, the induction of bone by "smart" concavities assembled in biomimetic matrices of macroporous calcium phosphate-based constructs. The basic multicellular unit of the corticocancellous bone excavates a trench across the bone surface, leaving in its wake a hemiosteon rather than an osteon, that is, a trench with cross-sectional geometric cues of concavities after cyclic episodes of osteoclastogenesis, eventually leading to osteogenesis.

Perspectives in regenerative medicine and tissue engineering of bone.

This final review in a series of three focuses on how the advances made in the realm of molecular and cellular bone biology have been translated into experimental animal and human surgery.

Synergistic induction of bone formation by hOP-1, hTGF-beta3 and inhibition by zoledronate in macroporous coral-derived hydroxyapatites.

Thirty coral-derived calcium carbonate-based macroporous constructs with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) were implanted in the rectus abdominis of three adult non-human primate Papio ursinus to investigate the intrinsic induction of bone formation. Macroporous constructs with 125 microg human recombinant osteogenic protein-1 (hOP-1) or 125 microg human recombinant transforming growth factor-beta(3) (hTGF-beta(3)) were also implanted. The potential synergistic interaction between morphogens was tested by implanting binary applications of hOP-1 and hTGF-beta(3) 5:1 by weight, respectively.

Osteoinduction: translating preclinical promise into clinical reality.

This review, the second in a series of three editorials, focuses on the problems of translating basic scientific research on induction of bone into reliable clinical applications.