MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer.

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

Efficacy of high-density versus semipermeable PTFE membranes in an elderly experimental model.

OBJECTIVE: The clinical effectiveness of expanded polytetrafluoroethylene (PTFE) membranes for guided bone regeneration has been reported in the literature on several occasions. However, one major drawback of this material is the need for a second surgical operation for removal of the membrane. In addition, most studies involving guided bone regeneration in animal models have used young animals or animals of unspecified age, but in some clinical situations guided bone regeneration may be indicated in elderly jaw bones. The objectives of this investigation were (1) to evaluate the effectiveness of a newly introduced high-density PTFE membrane (TefGen-FD)-a material that does not require second-stage surgery for its removal-for enhancement of bone ingrowth in elderly rabbits' calvaria and (2) to compare the findings with those obtained with the commonly used semipermeable expanded PTFE membrane (Gore-Tex). STUDY DESIGN: Eighteen elderly rabbits (each more than 30 months old) served as the experimental animals in this study. Two non-self-healing, full-thickness defects were created in each rabbit calvarium. One of the 2 defects was fully covered with macroprous expanded PTFE membrane (Gore-Tex); the other defect was covered with microporous PTFE membrane (TefGen-FD). Specimens were obtained at 4, 8, and 16 weeks and examined by means of light microscopy. RESULTS: Clinically, the high-density TefGen membrane was much easier to detach from the underlying bone than was the semipermeable Gore-Tex membrane, which showed strict adherence to bone surface on removal. Microscopically, the Gore-Tex membrane lamellae were infiltrated by fibro-osseous tissue at the membrane's lower surface. A relatively greater speed and quantity of bone regeneration were observed in the defective cavities covered with Gore-Tex membrane than in those covered with TefGen membrane. CONCLUSIONS: It appears that the semipermeable Gore-Tex membrane is more effective than the high-density TefGen-FD membrane with respect to guided bone regeneration in elderly bone. These findings have relevance for the clinical situation of using guided bone regeneration in conjunction with implant placement and ridge augmentation procedures in atrophic elderly jaws.

Enhancement of bone ingrowth into collagen/HA composite implants using e-PTFE membranes.

The objective of this investigation was to study the effectiveness of expanded polytetrafluoroethylene (e-PTFE) membranes for enhancement of bone ingrowth through subperiosteally implanted collagen/HA composite blocks. Twelve rabbits aged 12-15 months served as the experimental animals in this study. Two compressed Collagen/HA composite blocks in the shape of two attached cylinders of different diameters were inserted into two defects of each rabbit calvarium, the smaller cylinder being intrabony, the larger subperiosteal in location. One of the two implants was covered with non-resorbable e-PTFE membrane. The other implant was left uncovered. Specimens were obtained at 4, 8, and 12 weeks. While the implant specimens on the membrane side showed progressive bone formation between and around HA particles at the subperiosteal extrabony locations, the HA particles on the non-membrane side were surrounded and separated by dense fibrous tissue. At intraosseous sites, HA particles were surrounded by new bone throughout the defect on the membrane side, but new bone formation occurred only along the periphery on the non-membrane side. It appears that guided tissue regeneration may be used to enhance new bone formation around and between subperiosteally implanted HA particles.

Modified bovine type I collagen membrane as a wound graft material in oral surgery (an experimental study).

The use of collagen biomaterials in various types, structures and forms to aid in wound healing and in reconstructive surgery has been reported in several occasions in the literature. This paper evaluates the biocompatibility and effectiveness of a modified bovine type I collagen membrane as a graft material in experimental oral wounds in dogs. 2.5 x 2.5 cm wounds were prepared bilaterally in the labial mucosa of nine dogs. Bovine type I atelopeptide reconstituted collagen membrane was placed over the surgery site on one side of the labial mucosa. The contralateral sides served as controls. Clinical and histopathologic evaluation were done at 1, 2 and 3 weeks post-operatively, comparing the experimental side with the control side. Results demonstrated an improved rate of wound healing on the experimental side. The collagen membrane had a topical hemostatic effect at the time of its application and did not cause any adverse reaction post-operatively. It is concluded that the modified collagen membrane used in this study is biologically acceptable to the oral mucosa and is, from the clinical point of view, an excellent wound graft material. The clinical utilization of these collagen sheets offers exciting applications in the field of oral surgery.

Alveolar ridge augmentation using a new design of inflatable tissue expander: surgical technique and preliminary results.

Ridge augmentation with particulate hydroxyapatite (HA) is compromised by the propensity for the HA particles to disseminate throughout any surgically created space within the tissues. Several techniques designed to overcome this problem have been described, including the use of inflatable tissue expanders. Some of the residual problems related to this technique are attributable to aspects of expander design and surgical technique. This paper which describes a new design of tissue expander which is completely submerged in use, also describes in detail the surgical technique associated with it. Preliminary results are discussed.

In vitro and in vivo studies with collagen/hydroxyapatite implants.

There is limited literature describing the early events that follow subperiosteal suprabony implantation of particulate hydroxyapatite (HA)/collagen composite grafts. This paper investigates, both in vitro and in vivo, the influence of a water-based environment on compressed collagen fiber cylinders and compressed HA/collagen blocks. Following subperiosteal extrabony implantation of an HA/collagen block, the HA particles were not retained within the original dimensions of the preformed dry block. The separation of the particles was related to the expansion of collagen on hydration and to the amount, degree of cross-linking, and degree of compression of the collagen.