TRAF2 is a component of TNF superfamily signalling complexes and plays an essential role in the regulation and homeostasis of immune cells. TRAF2 deficient mice die around birth, therefore its role in adult tissues is not well-explored. Furthermore, the role of the TRAF2 RING is controversial. It has been claimed that the atypical TRAF2 RING cannot function as a ubiquitin E3 ligase but counterclaimed that TRAF2 RING requires a co-factor, sphingosine-1-phosphate, that is generated by the enzyme sphingosine kinase 1, to function as an E3 ligase. Keratinocyte-specific deletion of Traf2, but not Sphk1 deficiency, disrupted TNF mediated NF-κB and MAP kinase signalling and caused epidermal hyperplasia and psoriatic skin inflammation. This inflammation was driven by TNF, cell death, non-canonical NF-κB and the adaptive immune system, and might therefore represent a clinically relevant model of psoriasis. TRAF2 therefore has essential tissue specific functions that do not overlap with those of Sphk1.

The breast cancer predisposition gene, BRCA2, has a large number of genetic variants of unknown effect. The variant rs11571833, an A > T transversion in the final exon of the gene that leads to the creation of a stop codon 93 amino acids early (K3326*), is reported as a neutral polymorphism but there is some evidence to suggest an association with an increased risk of breast cancer. We assessed whether this variant was enriched in a cohort of breast cancer cases ascertained through familial cancer clinics compared to population-based non-cancer controls using a targeted sequencing approach. We identified the variant in 66/2634 (2.5%) cases and 33/1996 (1.65%) controls, indicating an enrichment in the breast cancer cases (p = 0.047, OR 1.53, 95% CI 1.00-2.34). This data is consistent with recent iCOGs data suggesting that this variant is not neutral with respect to breast cancer risk. rs11571833 may need to be included in SNP panels for evaluating breast cancer risk.

BACKGROUND: APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear. METHODS: APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort. RESULTS: Wild-type APC microsatellite stable (APC-wt/MSS) tumours from the proximal colon showed poorer overall and recurrence-free survival (OS, RFS) than APC-mt/MSS proximal, APC-wt/MSS distal and APC-mt/MSS distal tumours (OS HR⩾1.79, P⩽0.015; RFS HR⩾1.88, P⩽0.026). APC was a stronger prognostic indicator than BRAF, KRAS, PIK3CA, TP53, CpG island methylator phenotype or chromosomal instability status (P⩽0.036). Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature (P=0.019). APC status did not affect outcomes in MSI tumours. In a validation on 206 patients with proximal colon cancer, APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases (OS HR⩾2.50, P⩽0.010; RFS HR⩾2.14, P⩽0.025). Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway (P⩽0.016). CONCLUSIONS: APC-wt status is a marker of poor prognosis in MSS proximal colon cancer.

The grainyhead-like (grhl) transcription factors play crucial roles in craniofacial development, epithelial morphogenesis, neural tube closure, and dorso-ventral patterning. By utilising the zebrafish to differentially regulate expression of family members grhl2b and grhl3, we show that both genes regulate epithelial migration, particularly convergence-extension (CE) type movements, during embryogenesis. Genetic deletion of grhl3 via CRISPR/Cas9 results in failure to complete epiboly and pre-gastrulation embryonic rupture, whereas morpholino (MO)-mediated knockdown of grhl3 signalling leads to aberrant neural tube morphogenesis at the midbrain-hindbrain boundary (MHB), a phenotype likely due to a compromised overlying enveloping layer (EVL). Further disruptions of grhl3-dependent pathways (through co-knockdown of grhl3 with target genes spec1 and arhgef19) confirm significant MHB morphogenesis and neural tube closure defects. Concomitant MO-mediated disruption of both grhl2b and grhl3 results in further extensive CE-like defects in body patterning, notochord and somite morphogenesis. Interestingly, over-expression of either grhl2b or grhl3 also leads to numerous phenotypes consistent with disrupted cellular migration during gastrulation, including embryo dorsalisation, axial duplication and impaired neural tube migration leading to cyclopia. Taken together, our study ascribes novel roles to the Grhl family in the context of embryonic development and morphogenesis.

Prostate cancer is a genetic disease. While next generation sequencing has allowed for the emergence of molecular taxonomy, classification is restricted to the nuclear genome. Mutations within the maternally inherited mitochondrial genome are known to impact cancer pathogenesis, as a result of disturbances in energy metabolism and apoptosis. With a higher mutation rate, limited repair and increased copy number compared to the nuclear genome, the clinical relevance of mitochondrial DNA (mtDNA) variation requires deeper exploration. Here we provide a systematic review of the landscape of prostate cancer associated mtDNA variation. While the jury is still out on the association between inherited mtDNA variation and prostate cancer risk, we collate a total of 749 uniquely reported prostate cancer associated somatic mutations. Support exists for number of somatic events, extent of heteroplasmy, and rate of recurrence of mtDNA mutations, increasing with disease aggression. While, the predicted pathogenic impact for recurrent prostate cancer associated mutations appears negligible, evidence exists for carcinogenic mutations impacting the cytochrome c oxidase complex and regulating metastasis through elevated reactive oxygen species production. Due to a lack of lethal cohort analyses, we provide additional unpublished data for metastatic disease. Discussing the advantages of mtDNA as a prostate cancer biomarker, we provide a review of current progress of including elevated mtDNA levels, of a large somatic deletion, acquired tRNAs mutations, heteroplasmy and total number of somatic events (mutational load). We confirm via meta-analysis a significant association between mtDNA mutational load and pathological staging at diagnosis or surgery (p < 0.0001).

BACKGROUND AND PURPOSE: Recent years have seen a rapid increase in the use of resurfacing hip arthroplasty despite the lack of literature on the long-term outcome. In particular, there is little evidence regarding the outcome of revisions of primary resurfacing. The purpose of this analysis was to examine the survivorship of primary resurfacing hip arthroplasties that have been revised. PATIENTS AND METHODS: Over 12,000 primary resurfacing hip arthroplasties were recorded by the Australian Orthopaedic Association National Joint Replacement Registry between September 1, 1999 and December 31, 2008. During this time, 397 revisions for reasons other than infection were reported for these primary resurfacings and classified as acetabular, femoral, or both acetabular and femoral revisions. The survivorship of the different types of revisions was estimated using the Kaplan-Meier method and compared using proportional hazard models. Additionally, the outcome of a femoral-only revision was compared to that of primary conventional total hip arthroplasty. RESULTS: Acetabular-only revision had a high risk of re-revision compared to femoral-only and both acetabular and femoral revision (5-year cumulative per cent revision of 20%, 7%, and 5% respectively). Femoral-only revision had a risk of re-revision similar to that of revision of both the acetabular and femoral components. Femoral-only revision had over twice the risk of revision of primary conventional total hip arthroplasty. INTERPRETATION: Revision of a primary resurfacing arthroplasty is associated with a major risk of re-revision. The best outcome is achieved when either the femoral-only or both the acetabular and femoral components are revised. Technically straightforward femoral-only revisions generally have a worse outcome than a primary conventional total hip arthroplasty.

BACKGROUND AND PURPOSE: Joint Replacement Registries play a significant role in monitoring arthroplasty outcomes by publishing data on survivorship of individual prostheses or combinations of prostheses. The difference in outcomes can be device- or non-device-related, and these factors can be analyzed separately. Although registry data indicate that most prostheses have similar outcomes, some have a higher than anticipated rate of revision when compared to all other prostheses in their class. This report outlines how the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) has developed a method to report prostheses with a higher than expected rate of revision. These are referred to as "outlier" prostheses. MATERIAL AND METHODS: Since 2004, the AOANJRR has developed a standardized process for identifying outliers. This is based on a 3-stage process consisting of an automated algorithm, an extensive analysis of individual prostheses or combinations by registry staff, and finally a meeting involving a panel from the Australian Orthopaedic Association Arthroplasty Society. Outlier prostheses are listed in the Annual Report as (1) identified but no longer used in Australia, (2) those that have been re-identified and that are still used, and (3) those that are being identified for the first time. RESULTS: 78 prostheses or prosthesis combinations have been identified as being outliers using this approach (AOANJRR 2011 Annual Report). In addition, 5 conventional hip prostheses were initially identified, but after further analysis no longer met the defined criteria. 1 resurfacing hip prosthesis was initially identified, subsequently removed from the list, and then re-identified the following year when further data were available. All unicompartmental and primary total knee prostheses identified as having a higher than expected rate of revision have continued to be re-identified. INTERPRETATION: It is important that registries use a transparent and accountable process to identify an outlier prosthesis. This paper describes the development, implementation, assessment, and impact of the approach used by the Australian Registry.

BACKGROUND AND PURPOSE: While highly crosslinked polyethylene has shown reduced in vivo wear and lower rates of revision for total hip arthroplasty, there have been few long-term studies on its use in total knee arthroplasty (TKA). We compared the rate of revision of non-crosslinked polyethylene to that of crosslinked polyethylene in patients who underwent TKA for osteoarthritis. PATIENTS AND METHODS: We examined data from the Australian Orthopaedic Association National Joint Replacement Registry on 302,214 primary TKA procedures with non-crosslinked polyethylene and 83,890 procedures with crosslinked polyethylene, all of which were performed for osteoarthritis. The survivorship of the different polyethylenes was estimated using the Kaplan-Meier method and was compared using proportional hazard models. RESULTS: The 10-year cumulative revision rate for non-crosslinked polyethylene was 5.8% (95% CI: 5.7-6.0) and for crosslinked polyethylene it was 3.5% (95% CI: 3.2-3.8) (> 6.5-year HR = 2.2 (1.5-3.1); p < 0.001). There was no effect of surgical volume or method of prosthesis fixation on outcome. There were 4 different TKA designs that had a minimum of 2,500 procedures in at least 1 of the polyethylene groups and a follow-up of ≥ 5 years. 2 of these, the NexGen and the Natural Knee II, had a lower rate of revision for crosslinked polyethylene. The Scorpio NRG/Series 7000 and the Triathlon Knee did not show a lower rate of revision for crosslinked polyethylene. INTERPRETATION: There is a lower rate of revision for crosslinked polyethylene in TKA, and this appears to be prosthesis-specific and when it occurs is most evident in patients < 65 years of age. The difference in revision rates was mainly due to revisions because of lysis and loosening.

The AF-6/afadin protein, which contains a single PDZ domain, forms a peripheral component of cell membranes at specialized sites of cell-cell junctions. To identify potential receptor-binding targets of AF-6 we screened the PDZ domain of AF-6 against a range of COOH-terminal peptides selected from receptors having potential PDZ domain-binding termini. The PDZ domain of AF-6 interacts with a subset of members of the Eph subfamily of RTKs via its COOH terminus both in vitro and in vivo. Cotransfection of a green fluorescent protein-tagged AF-6 fusion protein with full-length Eph receptors into heterologous cells induces a clustering of the Eph receptors and AF-6 at sites of cell-cell contact. Immunohistochemical analysis in the adult rat brain reveals coclustering of AF-6 with Eph receptors at postsynaptic membrane sites of excitatory synapses in the hippocampus. Furthermore, AF-6 is a substrate for a subgroup of Eph receptors and phosphorylation of AF-6 is dependent on a functional kinase domain of the receptor. The physical interaction of endogenous AF-6 with Eph receptors is demonstrated by coimmunoprecipitation from whole rat brain lysates. AF-6 is a candidate for mediating the clustering of Eph receptors at postsynaptic specializations in the adult rat brain.

BACKGROUND AND PURPOSE: The Kaplan-Meier (KM) method is often used in the analysis of arthroplasty registry data to estimate the probability of revision after a primary procedure. In the presence of a competing risk such as death, KM is known to overestimate the probability of revision. We investigated the degree to which the risk of revision is overestimated in registry data. PATIENTS AND METHODS: We compared KM estimates of risk of revision with the cumulative incidence function (CIF), which takes account of death as a competing risk. We considered revision by (1) prosthesis type in subjects aged 75–84 years with fractured neck of femur (FNOF), (2) cement use in monoblock prostheses for FNOF, and (3) age group in patients undergoing total hip arthroplasty (THA) for osteoarthritis (OA). RESULTS: In 5,802 subjects aged 75–84 years with a monoblock prosthesis for FNOF, the estimated risk of revision at 5 years was 6.3% by KM and 4.3% by CIF, a relative difference (RD) of 46%. In 9,821 subjects of all ages receiving an Austin Moore (non-cemented) prosthesis for FNOF, the RD at 5 years was 52% and for 3,116 subjects with a Thompson (cemented) prosthesis, the RD was 79%. In 44,365 subjects with a THA for OA who were less than 70 years old, the RD was just 1.4%; for 47,430 subjects > 70 years of age, the RD was 4.6% at 5 years. INTERPRETATION: The Kaplan-Meier method substantially overestimated the risk of revision compared to estimates using competing risk methods when the risk of death was high. The bias increased with time as the incidence of the competing risk of death increased. Registries should adopt methods of analysis appropriate to the nature of their data.

BACKGROUND AND PURPOSE: The outcome of modern resurfacing remains to be determined. The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) started collection of data on hip resurfacing at a time when modern resurfacing was started in Australia. The rate of resurfacing has been higher in Australia than in many other countries. As a result, the AOANJRR has one of the largest series of resurfacing procedures. This study was undertaken to determine the results of this series and the risk factors associated with revision. PATIENTS AND METHODS: Data from the AOANJRR were used to analyze the survivorship of 12,093 primary resurfacing hip replacements reported to the Joint Replacement Registry between September 1999 and December 2008. This was compared to the results of primary conventional total hip replacement reported during the same period. The Kaplan-Meier method and proportional hazards models were used to determine risk factors such as age, sex, femoral component size, primary diagnosis, and implant design. RESULTS: Female patients had a higher revision rate than males; however, after adjusting for head size, the revision rates were similar. Prostheses with head sizes of less than 50 mm had a higher revision rate than those with head sizes of 50 mm or more. At 8 years, the cumulative per cent revision of hip resurfacing was 5.3 (4.6-6.2), as compared to 4.0 (3.8-4.2) for total hip replacement. However, in osteoarthritis patients aged less than 55 years with head sizes of 50 mm or more, the 7-year cumulative per cent revision for hip resurfacing was 3.0 (2.2-4.2). Also, hips with dysplasia and some implant designs had an increased risk of revision. INTERPRETATION: Risk factors for revision of resurfacing were older patients, smaller femoral head size, patients with developmental dysplasia, and certain implant designs. These results highlight the importance of patient and prosthesis selection in optimizing the outcome of hip resurfacing.