Nanoceria provides antioxidant and osteogenic properties to mesoporous silica nanoparticles for osteoporosis treatment.

Osteoporosis, a chronic metabolic bone disease, is the most common cause of fractures. Drugs for treating osteoporosis generally inhibit osteoclast (OC) activity, but are rarely aimed at encouraging new bone growth and often cause severe systemic side effects. Reactive oxygen species (ROS) are one of the key triggers of osteoporosis, by inducing osteoblast (OB) and osteocyte apoptosis and promoting osteoclastogenesis. Here we tested the capability of the ROS-scavenger nanoceria encapsulated within mesoporous silica nanoparticles (Ce@MSNs) to treat osteoporosis using a pre-osteoblast MC3T3-E1 cell monoculture in stressed and normal conditions. Ce@MSNs (diameter of 80 ± 10 nm) were synthesised following a scalable two-step process involving sol-gel and wet impregnation methods. The Ce@MSNs at concentration of 100 µg mL-1 induced a significant reduction in oxidative stress produced by t-butyl hydroperoxide and did not alter cell viability significantly. Confocal microscopy showed that MSNs and Ce@MsNs were internalised into the cytoplasm of the pre-osteoblasts after 24 h but were not in the nucleus, avoiding any DNA and RNA modifications. Ce@MSNs provoked mineralisation of the pre-osteoablasts without osteogenic supplements, which did not occur when the cells were exposed to MSN without nanoceria. In a co-culture system of MC3T3-E1 and RAW264.7 macrophages, the Ce@MSNs exhibited antioxidant capability and stimulated cell proliferation and osteogenic responses without adding osteogenic supplements to the culture. The work brings forward an effective platform based for facile synthesis of Ce@MSNs to interact with both OBs and OCs for treatment of osteoporosis.

All Benign and Malignant Apocrine Breast Lesions Over-Express Claudin 1 and 3 and Are Negative for Claudin 4.

Invasive apocrine carcinoma of the breast is an uncommon triple negative tumour that lacks a specific therapeutic target. Apocrine metaplasia of the breast shares common morphological features with apocrine carcinoma, and was previously found to consistently over-express claudin 1 and to lack claudin 4. This study was aimed at finding whether apocrine carcinoma, and other related apocrine breast lesions, have similar claudin profile. The immunohistochemical expression of claudin 1, 3 and 4 was studied in 11 cases of in situ and invasive apocrine breast carcinoma, 7 benign apocrine lesions and 45 consecutive morphologically non-apocrine triple negative breast carcinomas. All cases were also immunostained for Gross Cystic Disease Fluid Protein-15 (GCDFP-15), a marker for apocrine differentiation. Apocrine breast lesions maintained their expression pattern from benign through DCIS to invasive carcinoma; all showing strong expression of claudin 1 and 3 and absence of claudin 4. The same pattern of expression was seen in 2 out of the 45 morphologically non-apocrine tumours, but both showed strong positive staining for GCDFP-15. It is concluded that all benign and malignant apocrine lesions of the breast have a consistent pattern of claudin 1, 3 and 4 expression, suggesting the presence of a specific pathway for the development of invasive apocrine carcinoma. The over-expression of claudin 1 and 3 may have therapeutic implications as targets for managing apocrine cancers.

Analysis of clonal expansions through the normal and premalignant human breast epithelium reveals the presence of luminal stem cells.

It is widely accepted that the cell of origin of breast cancer is the adult mammary epithelial stem cell; however, demonstrating the presence and location of tissue stem cells in the human breast has proved difficult. Furthermore, we do not know the clonal architecture of the normal and premalignant mammary epithelium or its cellular hierarchy. Here, we use deficiency in the mitochondrial enzyme cytochrome c oxidase (CCO), typically caused by somatic mutations in the mitochondrial genome, as a means to perform lineage tracing in the human mammary epithelium. PCR sequencing of laser-capture microdissected cells in combination with immunohistochemistry for markers of lineage differentiation was performed to determine the clonal nature of the mammary epithelium. We have shown that in the normal human breast, clonal expansions (defined here by areas of CCO deficiency) are typically uncommon and of limited size, but can occur at any site within the adult mammary epithelium. The presence of a stem cell population was shown by demonstrating multi-lineage differentiation within CCO-deficient areas. Interestingly, we observed infrequent CCO deficiency that was restricted to luminal cells, suggesting that niche succession, and by inference stem cell location, is located within the luminal layer. CCO-deficient areas appeared large within areas of ductal carcinoma in situ, suggesting that the rate of clonal expansion was altered in the premalignant lesion. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The expression of CD44 in archival paraffin embedded interface tissues of failed orthopaedic implants.

CD44 hyaluronan receptor is present on large number of different cell type. It acts as one of the adhesion proteins, binding to hyaluronan and is known to play a part in cell migration from vessels in inflammation. The aim of this study was to examine the presence and distribution of CD44 in interface membrane in aseptic loosening. Immunohistochemistry (IHC) using human anti-mouse CD44 antibody studied 20 aseptically loosened interface samples. Extracted protein from all cases was examined by Western blot and RT-PCR. CD44 was detected in 85% of interfaces by IHC and the presence of protein confirmed by blotting and RT-PCR, which showed the mRNA level for CD44. CD44 was expressed by macrophage, multinucleated giant cells, mast cells and lymphocytes. Further studies are needed to characterise the role of this molecule in the inflammatory response to wear debris in aseptic loosening.