A personal reflection upon navigating into a senior academic role.

There are 22,795 University professors in the UK, where 6,340 are women and only 40 are Black women, whilst Asian women are a few more in number. This clearly demonstrates the uncommon narrative of the under-representation of Black minority ethnic (BME) academics in higher education (HE) which has been written about in detail. In contrast, it is rare to read reports on initiatives to successfully navigate senior academic posts. In this article, I will describe two initiatives that I have developed and organized to successfully navigate senior BME academic posts, which have impacted my journey. The first initiative was to understand why postdoctoral researchers were "post-docing" for years, having not been successful in making the transition to lecturers. What was hindering the transition? I was one of them, and some of my female peers as well, who incidentally left HE. I was determined not to leave. I again thought about how to tackle it. It is a known fact that hearing successful BME people experiences and journeys and also understanding how they navigated HE can be powerful. In addition, empowering oneself with additional skills including mentoring, networking, applying for positions, not excluding ourselves due to the lack of confidence, and finally, the importance of having a work-life balance is important as health is wealth. I used this to put together the BME Early Career Researcher (ECR) conference-How to Stay in Academia. After 6 years, it is still going strong. In this article, I will share the impact made over the years which will include testimonies and promotions, including my recent promotion to an associate professor. The second initiative was to understand the barriers and challenges of senior lecturers being promoted to readers and professors. Having successfully transitioned to a lecturer, being overlooked for promotion was now an issue. The project was conducted in 2016/17 at KCL as part of the action plans that needed to be delivered having been a recipient of the Bronze Race Equality Charter Mark. I was provided with a cohort of 51 names of BME staff from different disciplines and was directed to see how I would engage them to hear their experiences. My first concern was that the staff would have engaged in previous initiatives with little or no benefits to them; however, this did not deter me. I thought of the best approach which commenced with a phone interview and then followed up with a focus group, ending with an informal conversation with the Principal of the University. Within 6 months, a BME male was promoted to professor. After a year, both genders were promoted to associate professors (readers) and professors, and to date, I am aware of at least 10 promotions. In both examples, I will demonstrate the support from our allies, some of whom are senior leaders that have openly supported us in our journey. This article will demonstrate a slight shift in the narrative, but a lot more needs to be done, and I am convinced the time is right to start pushing for more. This special issue is an example.

P16/p53 expression and telomerase activity in immortalized human dental pulp cells.

INTRODUCTION: Residing within human dental pulp are cells of an ectomesenchymal origin which have the potential to differentiate into odontoblast-like cells. These cells have a limited growth potential owing to the effects of cell senescence. This study examines the effects of immortalizing odontoblast-like cells on cell proliferation and mineralization by comparing transformed dental pulp stem cells (tDPSCs) and non-transformed dental pulp stem cells (nDPSCs). RESULTS: With the exogenous expression of hTERT, tDPSCs maintained a continued expression of odontogenic markers for cell proliferation and mineralization (ALP, COL-1, DMP-1, DSPP, OCN amd OPN)as did nDPScs. Oncoprotein expression was seen in both groups except for a noted absence of p16 in the tDPSCs. nDPSCs also showed lower levels of total ALP and DNA activity in comparison to tDPSCs when assayed as well as low telomerase activity readings. METHODS: Using a retroviral vector, exogenous human telomerase reverse transcriptase (hTERT) was expressed in tDPSCs. Both cell groups were cultured and their telomerase activities is determined using a telomerase quantification assay. Also examined were the expression of genes involved in proliferation and mineralization such as human alkaline phosphatase (ALP), ß-actin, collagen 1 (col-1), core binding factor (cbfa-1), dentin matrix protein (DMP-1), dentin sialophosphoprotein (DSPP), GAPDH, hTERT, osteocalcin (OCN), osteopontin (OPN) as well as oncoproteins involved in senescence (p16, p21 and p53) using RT-PCR. DNA and alkaline phosphatase activity was assayed in both cell groups. CONCLUSIONS: These results indicate maintainance of odontoblast-like differentiation characteristics after retroviral transformation with hTERT and suggest a possible link with a reduced p16 expression.

Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3.

OBJECTIVE: To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic. MATERIALS AND METHODS: The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin. RESULTS: Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations. CONCLUSION: The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations.

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas.

Chordomas are rare primary malignant bone tumours that derive from notochord precursor cells and express brachyury, a molecule involved in notochord development. Little is known about the genetic events responsible for driving the growth of this tumour, but it is well established that brachyury is regulated through fibroblastic growth factor receptors (FGFRs) through RAS/RAF/MEK/ERK and ETS2 in ascidian, Xenopus and zebrafish, although little is known about its regulation in mammals. The aim of this study was to attempt to identify the molecular genetic events that are responsible for the pathogenesis of chordomas with particular focus on the FGFR signalling pathway on the basis of the evidence in the ascidian and Xenopus models that the expression of brachyury requires the activation of this pathway. Immunohistochemistry showed that 47 of 50 chordomas (94%) expressed at least one of the FGFRs, and western blotting showed phosphorylation of fibroblast growth factor receptor substrate 2 alpha (FRS2alpha), an adaptor signalling protein, that links FGFR to the RAS/RAF/MEK/ERK pathway. Screening for mutations in brachyury (all coding exons and promoter), FGFRs 1-4 (previously reported mutations), KRAS (codons 12, 13, 51, 61) and BRAF (exons 11 and 15) failed to show any genetic alterations in 23 chordomas. Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification of these genes, although there was minor allelic gain in brachyury in three tumours, or translocation for ERG and ETS2 loci. The key genetic events responsible for the initiation and progression of chordomas remain to be discovered.

GNAS1 mutations occur more commonly than previously thought in intramuscular myxoma.

Mutation detection plays an important role in diagnostic pathology, not only in providing a tissue diagnosis, but also in predicting response to antitumourigenic agents. However, mutation detection strategies are often hampered by masking of mutant alleles by wild-type sequences. Coamplification at lower denaturation temperature PCR (COLD-PCR) reportedly increases the proportion of rare variant sequences in a wild-type background by using PCR cycles in which the denaturation temperature is reduced to favour product formation with lower melt temperatures and heteroduplexes arising from minor variants. Intramuscular myxoma is a rare benign soft tissue neoplasm that occurs sporadically and less commonly in association with fibrous dysplasia (Mazabraud's syndrome). Fibrous dysplasia results from activating GNAS1 mutations, and the same mutations have been identified in small numbers of intramuscular myxoma. The aim of the study was primarily to establish whether COLD-PCR is more sensitive than conventional PCR; this was achieved by testing for GNAS1 mutations in intramuscular myxomas using the two methodologies. Mutations were detected in 8 of 28 (29%) cases of intramuscular myxomas using conventional PCR followed by mutation-specific restriction enzyme digestion (PCR-MSRED) whereas 17 of 28 (61%) mutations were detected using COLD-PCR/MSRED. Mutations were detected in two cases where a diagnosis of low-grade myxofibrosarcoma had been favoured over intramuscular myxoma. No mutations were detected in an additional 9 low-grade and 19 high-grade myxofibrosarcomas, and another 40 control samples. This study shows the power of COLD-PCR compared with conventional PCR in mutation detection, and shows that GNAS1 mutation detection increases diagnostic accuracy when distinguishing between intramuscular myxoma and low-grade myxofibrosarcoma.

Mutations in SH3BP2, the cherubism gene, were not detected in central or peripheral giant cell tumours of the jaw.

Giant cell granulomas of the jaw (GCGJ) are non-familial, generally unilateral osteoclast-rich lesions that are histopathologically indistinguishable from cherubism. Cherubism is an autosomal dominant disease that is characterised by bilateral radiolucencies of the jaw, and caused by mutations that occur in SH3BP2 exon 10. The aim of the study was to screen lesional GCGJ tissue for SH3BP2 mutations. Lesional mononuclear stromal or spindle cells were microdissected from paraffin-embedded tissue from GCGJ, and DNA was then extracted and sequenced for SH3BP2 mutations associated with cherubism. No mutations were detected in 26 GCGJ (15 central, 11 peripheral), which indicated that people with GCGJ do not harbour cherubism-related germline SH3BP2 mutations, and that GCGJ do not harbour somatic SH3BP2 mutations. This suggests that cherubism and GCGJ arise on a different genetic background, and therefore detection of SH3BP2 mutations can be a useful means of distinguishing between them.