The oncological relevance of fragile sites in cancer

Recent developments in sequencing the cancer genome have provided the first in-depth mapping of structural variants (SV) across 38 tumour types. Sixteen signatures of structural variants have been proposed which broadly characterise the variation seen across cancer types. One signature shows increased duplications and deletions at fragile sites, with little association with the typical DNA repair defects. We discuss how, for many of these fragile sites, the clinical impacts are yet to be explored. One example is NAALADL2, one of the most frequently altered fragile sites in the cancer genome. The copy-number variations (CNVs) which occur at fragile sites, such as NAALADL2, may span many genes without typical DNA repair defects and could have a large impact on cell signalling

Effects of Photobiomodulation Therapy on Regulation of Myogenic Regulatory Factor mRNA Expression In Vivo: A Systematic Review

Non-invasive promotion of myogenic regulatory factors (MRFs), through photobiomodulation therapy (PBMT), may be a viable method of facilitating skeletal muscle regeneration post-injury, given the importance of MRF in skeletal muscle regeneration. The aim of this systematic review was to collate current evidence, identifying key themes and changes in expression of MRF in in vivo models. Web of Science, PubMed, Scopus and Cochrane databases were systematically searched and identified 1459 studies, of which 10 met the inclusion criteria. Myogenic determination factor was most consistently regulated in response to PBMT treatment, and the expression of remaining MRFs was heterogenous. All studies exhibited a high risk of bias, primarily due to lack of blinding in PBMT application and MRF analysis. Our review suggests that the current evidence base for MRF expression from PBMT is highly variable. Future research should focus on developing a robust methodology for determining the effect of laser therapy on MRF expression, as well as long-term assessment of skeletal muscle regeneration

Prevalence of familial cluster headache: a systematic review and meta-analysis

INTRODUCTION: The population rate of familial cluster headache (CH) has been reported to be as high as 20% however this varies considerably across studies. To obtain a true estimate of family history in CH, we conducted a systematic review and meta-analysis of previously published data. METHODS: Our systematic review involved a search of electronic databases (Medline, EMBASE, PubMed, CINAHL) to identify and appraise studies of interest utilising the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. To further ameliorate the accuracy of our analysis we included an additional unpublished cohort of CH patients recruited at a tertiary referral centre for headache, who underwent detailed family history with diagnostic verification in relatives. Data was extracted and meta-analysis conducted to provide a true estimation of family history. RESULTS: In total, we identified 7 studies which fulfilled our inclusion criteria. The estimated true prevalence of CH patients with a positive family history was 6.27% (95% CI:4.65-8.40%) with an overall I2 of 73%. Fitted models for gender subgroups showed higher estimates 9.26% (95% CI: 6.29-13.43%) in females. However the I2 for the female model was 58.42% and significant (p = 0.047). CONCLUSION: Our findings estimate a rate of family history in CH to be approximately 6.27% (95% CI: 4.65-8.40%). While estimates were larger for female probands, we demonstrated high heterogeneity in this subgroup. These findings further support a genetic role in the aetiology of CH

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for co-targeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future

A Modified Newcastle-Ottawa Scale for Assessment of Study Quality in Genetic Urological Research

Our modification of the traditional Newcastle-Ottawa scale enables urological researchers to effectively appraise and communicate the quality of genetic-based research in urology

Genetic correlates of prostate cancer visibility (and invisibility) on mpMRI: It's time to take stock

Multiparametric magnetic resonance imaging (mpMRI) has enhanced risk stratification for men at risk of prostate cancer, through accurate pre‐biopsy detection of high‐risk disease. However, it has become apparent that not all clinically significant prostate cancer is detected by mpMRI. Approximately 10‐20% of significant disease is invisible to mpMRI, depending on the threshold set for significance, and on the quality of mpMRI acquisition and interpretation. The threshold for significance has recently been challenged by the 29‐year follow‐up of the SPCG‐4 study, in which men with overall Gleason score 3 + 4 did not suffer prostate‐cancer‐related death, whilst those with overall Gleason score 4 + 3 did suffer prostate‐cancer related death (adjusted relative risk 5.73; 95% CI 1.59–20.67) potentially suggesting a new threshold for clinically significant disease. This finding is important, given that in PROMIS, no men with overall Gleason score 4 + 3 had negative pre‐biopsy mpMRI, indicating that actually mpMRI may identify all truly significant cancer (if SPCG‐4 is used to guide our threshold). Nonetheless, over the past two years, there has been increasing drive to better understand the nature of mpMRI‐inconspicuous disease, particularly at the molecular level

Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis

CONTEXT: Multiparametric magnetic resonance imaging (mpMRI) detects most, but not all, clinically significant prostate cancer. The genetic basis of prostate cancer visibility and invisibility on mpMRI remains uncertain. OBJECTIVE: To systematically review the literature on differential gene expression between mpMRI-visible and mpMRI-invisible prostate cancer, and to use bioinformatic analysis to identify enriched processes or cellular components in genes validated in more than one study. EVIDENCE ACQUISITION: We performed a systematic literature search of the Medline, EMBASE, PubMed, and Cochrane databases up to January 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The primary endpoint was differential genetic features between mpMRI-visible and mpMRI-invisible tumours. Secondary endpoints were explanatory links between gene function and mpMRI conspicuity, and the prognostic value of differential gene enrichment. EVIDENCE SYNTHESIS: We retrieved 445 articles, of which 32 met the criteria for inclusion. Thematic synthesis from the included studies showed that mpMRI-visible cancer tended towards enrichment of molecular features associated with increased disease aggressivity, including phosphatase and tensin homologue (PTEN) loss and higher genomic classifier scores, such as Oncotype and Decipher. Three of the included studies had accompanying publicly available data suitable for further bioinformatic analysis. An over-representation analysis of these datasets revealed increased expression of genes associated with extracellular matrix components in mpMRI-visible tumours. CONCLUSIONS: Prostate cancer that is visible on mpMRI is generally enriched with molecular features of tumour development and aggressivity, including activation of proliferative signalling, DNA damage, and inflammatory processes. Additionally, there appears to be concordant cellular components and biological processes associated with mpMRI conspicuity, as highlighted by bioinformatic analysis of large genetic datasets. PATIENT SUMMARY: Prostate cancer that is detected by magnetic resonance imaging (MRI) tends to have genetic features that are associated with more aggressive disease. This suggests that MRI can be used to assess the likelihood of aggressive prostate cancer, based on tumour visibility

An optimised saliva collection method to produce high-yield, high-quality RNA for translational research

Saliva represents an ideal matrix for diagnostic biomarker development as it is readily available and requires no invasive collection procedures. However, salivary RNA is labile and rapidly degrades. Previous attempts to isolate RNA from saliva have yielded poor quality and low concentrations. Here we compare collection and processing methods and propose an approach for future studies. The effects of RNA stabilisers, storage temperatures, length of storage and fasting windows were investigated on pooled saliva samples from healthy volunteers. Isolated RNA was assessed for concentration and quality. Bacterial growth was investigated through RT-PCR using bacterial and human primers. Optimal conditions were implemented and quality controlled in a clinical setting. The addition of RNAlater increased mean RNA yield from 4912 ng/μl to 15,473 ng and RNA Integrity Number (RIN) from 4.5 to 7.0. No significant changes to RNA yield were observed for storage at room temperature beyond 1 day or at -80 °C. Bacterial growth did not occur in samples stored at ambient temperature for up to a week. There was a trend towards higher RNA concentration when saliva was collected after overnight fasting but no effect on RIN. In the clinic, RNA yields of 6307 ng and RINs of 3.9 were achieved, improving on previous reports. The method we describe here is a robust, clinically feasible saliva collection method using preservative that gives high concentrations and improved RINs compared to saliva collected without preservative