Tspan8 is expressed in breast cancer and regulates E-cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles

Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8⁺ tumours formed multiple liver and spleen metastases, while Tspan8⁻ tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up-regulation of E-cadherin and down-regulation of Twist, p120-catenin, and β-catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal–epithelial transition. Furthermore, Tspan8⁺ cells exhibited enhanced cell–cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several-fold increase in EV number in cell culture and the circulation of tumour-bearing animals. We observed increased protein levels of E-cadherin and p120-catenin in these EVs; furthermore, Tspan8 and p120-catenin were co-immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

A morphometric and biomechanic comparison of titanium implants inserted in rabbit cortical and cancellous bone.

The removal torques for screw-shaped pure titanium implants inserted in rabbit tibia and the femoral part of the knee joint and the tissue response to these implants, as quantitated with light microscopic morphometry on ground sections, were compared after 6 weeks, 3 months, and 6 months. The bone surrounding the femoral intra-articular implants was mostly cancellous, while cortical bone was formed around the tibial implants. The torque needed to remove the intra-articular implants increased with time, but there was no such increase for the tibial implants. At 6 weeks, significantly less torque was needed to remove the intra-articular implants in spite of the fact that significantly more bone was found in the threads of these implants as compared with the tibial implants. When calculating the amount of bone in threads situated in the cortical and subchondral passage, more was found in the threads of the tibial implants, which corresponded to the higher removal torque. Additional light microscopic observations on implants unscrewed after 12 months in rabbit tibia indicated that rupture occurred between the implant surface and calcified bone. Findings indicate that the resistance to unscrewing is dependent on the amount of compact bone surrounding a titanium implant.     

Resorbable and nonresorbable hydroxyapatite granules as bone graft substitutes in rabbit cortical defects

Background: The use of various synthetic calcium phosphate compositions for the promotion of bone in bone defects is of potential interest because such materials may be tailor made and may bond to bone. There is yet an inadequate knowledge of the role of calcium phosphate composition and resorbability for the bone response. Purpose: The aim of the present study was to compare the ability of resorbable versus nonresorbable hydroxyapatite (HA) granules to promote new bone formation in cortical bone defects. Resorbable and nonresorbable HA granules, used as bone graft substitutes, were evaluated after 6 weeks and 3 months in the rabbit tibia. Circular defects (diameter 5.0 mm) were made in both tibias of 18 New Zealand white rabbits. The 36 defects were divided into three groups (six observations per group and time, respectively). The first group was augmented with resorbable HA granules, the second group was augmented with ceramic nonresorbable HA granules, and the third group was left without augmentation (control). The animals were killed after 6 weeks and 3 months, and the tissue was evaluated with light microscopic (LM) morphology and morphometry, scanning electron microscopy (SEM), and energy dispersive x‐ray analysis (EDX). Results: After 3 months LM morphometry revealed significantly more newly formed bone in the two HA augmented groups compared with that in the control. A close contact was found between both kinds of HA granules and new bone as viewed with light microscopy and SEM. A relatively slow degradation process was indicated by the small reduction of the total granule area in the cortical defects. However, LM observations showed a change of granule form. Pilot experiments using SEM‐EDX indicate that Ca and P contents had decreased in the resorbable HA granules between 6 weeks and 3 months. Further, a higher content of Ca and P was found in the newly formed bone close to granules, in comparison with more distant newly formed bone. Conclusions: Our results suggest that both resorbable and nonresorbable HA granules promote new bone formation in rabbit cortical defects, which does not occur in control defects.     

Differential diagnosis and treatment strategies for biologic complications and failing oral implants: a review of the literature.

The aim of this article was to review the literature on differential diagnosis and treatment of biologic complications and failing implants. All types of publications, with the exception of abstracts, published in English up to December 1998, were included. A multi-layered search strategy was used. Controlled clinical trials (CCTs) were searched in the Cochrane Oral Health Group's Specialized Register of Trials. This database contains all CCTs identified in MEDLINE and EMBASE. PubMed was searched using various key words and the "related articles" feature. All identified publications were obtained and none were excluded. Infection, impaired healing, and overload are considered the major etiologic factors for the loss of oral implants. Only a few clinical and animal investigations were found that tested the validity of the proposed therapeutic approaches. The treatment of failing implants is still based mainly on empirical considerations, often derived from periodontal research, from data extrapolated from in vitro findings, or from anecdotal case reports performed on a trial-and-error basis.     

Short-term bone response to titanium implants coated with thin radiofrequent magnetron-sputtered hydroxyapatite in rabbits

Background: It has been suggested that calcium phosphate (CaP) coatings initiate faster bone growth around implants. A major concern about the viable use of these coatings has been their biologic performance related to the coating characteristics. Purpose: The purpose of this study was to investigate the early bone response to micron‐ and submicron‐thick hydroxya‐patite (HA) coatings in cortical and trabecular bone. Materials and Methods: CaP coatings were manufactured by magnetron sputtering. Heat treatment was subsequently used to increase the crystallinity of the coatings. Coatings were characterized by x‐ray diffraction, Fourier transform infrared spectroscopy, inductively coupled plasma optical emission spectroscopy (ICP‐OES), and stylus profilometry. Four types of CaP‐coated implants were used (0.1 urn and 2.0 μm amorphous; 0.1 um and 2.0 μn crystalline); uncoated machined commercially pure titanium implants served as controls. Four hundred eighty implants were randomly placed in 60 rabbits. Ten animals were followed up for 1 week, 10 for 3 weeks, and 40 for 6 weeks. The bone response was histomorphometrically evaluated. Results: Coatings with a CaP ratio very close to that of HA were produced. Crystalline coatings significantly improved the early bone‐implant contact whereas the amorphous‐coated implants behaved similarly to uncoated titanium. Conclusions: Crystalline CaP coatings 100 nm thick on titanium implants elicited an improved early bone response compared with that of uncoated titanium implants. No further improvement in the bone response was observed with 2 μm coatings.     

Protection from EAE in DOCK8 mutant mice occurs despite increased Th17 cell frequencies in the periphery

Mutation of Dedicator of cytokinesis 8 (DOCK8) has previously been reported to provide resistance to the Th17 cell dependent EAE in mice. Contrary to expectation, we observed an elevation of Th17 cells in two different DOCK8 mutant mouse strains in the steady state. This was specific for Th17 cells with no change in Th1 or Th2 cell populations. In vitro Th cell differentiation assays revealed that the elevated Th17 cell population was not due to a T cell intrinsic differentiation bias. Challenging these mutant mice in the EAE model, we confirmed a resistance to this autoimmune disease with Th17 cells remaining elevated systemically while cellular infiltration in the CNS was reduced. Infiltrating T cells lost the bias toward Th17 cells indicating a relative reduction of Th17 cells in the CNS and a Th17 cell specific migration disadvantage. Adoptive transfers of Th1 and Th17 cells in EAE‐affected mice further supported the Th17 cell‐specific migration defect, however, DOCK8‐deficient Th17 cells expressed normal Th17 cell‐specific CCR6 levels and migrated toward chemokine gradients in transwell assays. This study shows that resistance to EAE in DOCK8 mutant mice is achieved despite a systemic Th17 bias.