Increased expression of long non-coding RNA FIRRE promotes hepatocellular carcinoma by HuR-CyclinD1 axis signaling.

There is a critical need to understand the disease processes and identify improved therapeutic strategies for hepatocellular carcinoma (HCC). The long noncoding RNAs (lncRNAs) display diverse effects on biological regulations. The aim of this study was to identify a lncRNA as a potential biomarker of HCC and investigate the mechanisms by which the lncRNA promotes HCC progression using human cell lines and in vivo. Using RNA-Seq analysis, we found that lncRNA FIRRE was significantly upregulated in hepatitis C virus (HCV) associated liver tissue and identified that lncRNA FIRRE is significantly upregulated in HCV-associated HCC compared to adjacent non-tumor liver tissue. Further, we observed that FIRRE is significantly upregulated in HCC specimens with other etiologies, suggesting this lncRNA has the potential to serve as an additional biomarker for HCC. Overexpression of FIRRE in hepatocytes induced cell proliferation, colony formation, and xenograft tumor formation as compared to vector-transfected control cells. Using RNA pull-down proteomics, we identified HuR as an interacting partner of FIRRE. We further showed that the FIRRE-HuR axis regulates cyclin D1 expression. Our mechanistic investigation uncovered that FIRRE is associated with an RNA-binding protein HuR for enhancing hepatocyte growth. Together, these findings provide molecular insights into the role of FIRRE in HCC progression.

The Hippo pathway regulates axis formation and morphogenesis in Hydra.

How did cells of early metazoan organisms first organize themselves to form a body axis? The canonical Wnt pathway has been shown to be sufficient for induction of axis in Cnidaria, a sister group to Bilateria, and is important in bilaterian axis formation. Here, we provide experimental evidence that in cnidarian Hydra the Hippo pathway regulates the formation of a new axis during budding upstream of the Wnt pathway. The transcriptional target of the Hippo pathway, the transcriptional coactivator YAP, inhibits the initiation of budding in Hydra and is regulated by Hydra LATS. In addition, we show functions of the Hippo pathway in regulation of actin organization and cell proliferation in Hydra. We hypothesize that the Hippo pathway served as a link between continuous cell division, cell density, and axis formation early in metazoan evolution.

Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.

Colonoscopy findings after increasing two-stool faecal immunochemical test (FIT) cut-off: Cross-sectional analysis of the SCREESCO randomized trial.

BACKGROUND: We determined the impact of an increased two-stool faecal immunochemical test (FIT) cut-off on colonoscopy positivity and relative sensitivity and specificity in the randomized controlled screening trial screening of Swedish colons conducted in Sweden. METHODS: We performed a cross-sectional analysis of participants in the FIT arm that performed FIT between March 2014 and 2020 within the study registered with ClinicalTrials.gov, NCT02078804, who had a faecal haemoglobin concentration of at least 10 µg/g in at least one of two stool samples and who underwent a colonoscopy (n = 3841). For each increase in cut-off, we computed the positive predictive value (PPV), numbers needed to scope (NNS), sensitivity and specificity for finding colorectal cancer (CRC) and advanced neoplasia (AN; advanced adenoma or CRC) relative to cut-off 10 µg/g. RESULTS: The PPV for AN increased from 23.0% (95% confidence intervals [CI]: 22.3%-23.6%) at cut-off 10 µg/g to 28.8% (95% CI: 27.8%-29.7%) and 33.1% (95% CI: 31.9%-34.4%) at cut-offs 20 and 40 µg/g, respectively, whereas the NNS to find a CRC correspondingly decreased from 41 to 27 and 19. The PPV for AN was higher in men than women at each cut-off, for example 31.5% (95% CI: 30.1%-32.8%) in men and 25.6% (95% CI: 24.3%-27.0%) in women at 20 µg/g. The relative sensitivity and relative specificity were similar in men and women at each cut-off. CONCLUSION: A low cut-off of around 20-40 µg/g allows detection and removal of many AN compared to 10 µg/g while reducing the number of colonoscopies in both men and women.

The role of endoscopist adenoma detection rate in in sex differences in colonoscopy findings: cross-sectional analysis of the SCREESCO randomized controlled trial.

BACKGROUND: Fewer adenomas are detected at colonoscopy in women compared to men and failure to detect adenomas and sessile serrated polyps is associated with an increased risk of post-colonoscopy colorectal cancer. The aim of this study was to investigate whether this was in part due to the greater difficulty of conducting colonoscopy in women, with the difference being more apparent in colonoscopies conducted by less skilled endoscopists. MATERIAL AND METHODS: Cross-sectional exploratory analysis of data on 16,551 individuals undergoing a primary colonoscopy (PCOL group) or colonoscopy after positive faecal immunochemical test (FIT group) within the randomized controlled trial SCREESCO. Endoscopist adenoma detection rate (ADR; low or high) was determined based on each endoscopist's colonoscopies performed in SCREESCO. In each study group, the relationship between the sex difference in colonoscopy outcome and endoscopist ADR was assessed using multiplicative interaction tests. RESULTS: Endoscopists performed equally many colonoscopies in men and women (median 52% men). There were no signs of effect modification of the risk ratio of any finding (men vs women) by endoscopist ADR in the PCOL group (p = 0.33) or the FIT group (p = 0.30). The proportion of incomplete index colonoscopies was lower in men than in women in both groups and there was no effect modification by endoscopist ADR in either the PCOL group (p = 0.41) or the FIT group (p = 0.96). CONCLUSIONS: This study provides no evidence that endoscopist skill measured by ADR underlies the sex difference in adenoma detection at colonoscopy. This study has trial number NCT02078804 and is registered with ClinicalTrials.gov.

Do risk scores improve use of faecal immunochemical testing for haemoglobin in symptomatic patients in primary care?

AIM: Faecal immunochemical testing (FIT) is used in the detection of colorectal cancer (CRC). FIT is invariably used at a single faecal haemoglobin (f-Hb) concentration threshold. The aim of this observational study was to explore risk scoring models (RSMs) with f-Hb and other risk factors for CRC in symptomatic patients attending primary care, potentially speeding diagnosis and saving endoscopy resources. METHOD: Records of patients completing FIT were linked with The Scottish Cancer Registry and with other databases with symptoms, full blood count and demographic variables, and randomized into derivation and validation cohorts. Stepwise multivariable logistic regression created RSMs assessed in the validation cohort. RESULTS: Of 18 805 unique patients, 9374 and 9431 were in the derivation and validation cohorts, respectively: f-Hb, male sex, increasing age, iron deficiency anaemia and raised systemic immune inflammation index created the final RSM. A risk score threshold of ≥2.363, generating the same number of colonoscopies as a f-Hb threshold of ≥10 µg Hb/g gave improved sensitivity for CRC in both cohorts. A RSM which excluded f-Hb was used to investigate the effect of raising the f-Hb threshold from ≥10 to ≥20 µg Hb/g in those with a low risk score. This approach would have generated 234 fewer colonoscopies but missed four CRCs. CONCLUSION: The RSM conferred no significant benefit to patients with very low f-Hb and CRC. Alternative strategies combining FIT with other variables may be more appropriate for safety-netting of symptomatic patients. Further work to develop and investigate the value of RSM for significant bowel disease other than CRC may also be beneficial.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Traffic light Hydra allows for simultaneous in vivo imaging of all three cell lineages.

We present a new transgenic Hydra vulgaris line expressing a distinct fluorescent protein in each of the three cell lineages of the adult polyp. Plasmid microinjection was used to generate a novel transgenic Hydra line expressing the yellow fluorescent protein YPet in the ectodermal epithelial cell lineage. Tissue grafting was then used to combine a YPet animal with a line that expresses DsRed2 in the endodermal epithelial lineage and eGFP in the interstitial cell (i-cell) lineage. The resulting triple-labeled ("tricolored") transgenic line provides, for the first time, a Hydra in which all three cell lineages can be imaged simultaneously in vivo. We show example confocal images of whole animals and individual cells to illustrate the imaging capabilities that this new line makes possible. We also used this line to carry out new studies of cell fate in the tentacles. Specifically, we evaluated the well-accepted notion that all tentacle cells are terminally differentiated and are displaced or migrate exclusively towards the distal end of the tentacle. We found that ectodermal and endodermal epithelial cells are displaced distally, as expected. In contrast, members of the i-cell lineage, which resembled neuronal precursors, could migrate out of a tentacle into the body column. This example illustrates how this tricolored transgenic line enables new in vivo studies of cell behaviors in Hydra.

Long noncoding RNA ELDR promotes cell cycle progression in normal oral keratinocytes through induction of a CTCF-FOXM1-AURKA signaling axis.

Long noncoding RNAs (lncRNAs) have gained widespread attention as a new layer of regulation in biological processes during development and disease. The lncRNA ELDR (EGFR long noncoding downstream RNA) was recently shown to be highly expressed in oral cancers as compared to adjacent nontumor tissue, and we previously reported that ELDR may be an oncogene as inhibition of ELDR reduces tumor growth in oral cancer models. Furthermore, overexpression of ELDR induces proliferation and colony formation in normal oral keratinocytes (NOKs). In this study, we examined in further detail how ELDR drives the neoplastic transformation of normal keratinocytes. We performed RNA-seq analysis on NOKs stably expressing ELDR (NOK-ELDR), which revealed that ELDR enhances the expression of cell cycle-related genes. Expression of Aurora kinase A and its downstream targets Polo-like kinase 1, cell division cycle 25C, cyclin-dependent kinase 1, and cyclin B1 (CCNB1) are significantly increased in NOK-ELDR cells, suggesting induction of G2/M progression. We further identified CCCTC-binding factor (CTCF) as a binding partner of ELDR in NOK-ELDR cells. We show that ELDR stabilizes CTCF and increases its expression. Finally, we demonstrate the ELDR-CTCF axis upregulates transcription factor Forkhead box M1, which induces Aurora kinase A expression and downstream G2/M transition. These findings provide mechanistic insights into the role of the lncRNA ELDR as a potential driver of oral cancer during neoplastic transformation of normal keratinocytes.

Faecal haemoglobin concentrations are associated with all-cause mortality and cause of death in colorectal cancer screening.

BACKGROUND: Colorectal cancer (CRC) screening reduces all-cause and CRC-related mortality. New research demonstrates that the faecal haemoglobin concentration (f-Hb) may indicate the presence of other serious diseases not related to CRC. We investigated the association between f-Hb, measured by a faecal immunochemical test (FIT), and both all-cause mortality and cause of death in a population-wide cohort of screening participants. METHODS: Between 2014 and 2018, 1,262,165 participants submitted a FIT for the Danish CRC screening programme. We followed these participants, using the Danish CRC Screening Database and several other national registers on health and population, until December 31, 2018. We stratified participants by f-Hb and compared them using a Cox proportional hazards regression on all-cause mortality and cause of death reported as adjusted hazard ratios (aHRs). We adjusted for several covariates, including comorbidity, socioeconomic factors, demography and prescription medication. RESULTS: We observed 21,847 deaths in the study period. Our multivariate analyses indicated an association relationship between increasing f-Hb and the risk of dying in the study period. This risk increased steadily from aHR 1.38 (95% CI: 1.32, 1.44) in those with a f-Hb of 7.1-11.9 µg Hb/g faeces to 2.20 (95% CI: 2.10, 2.30) in those with a f-Hb ≥60.0 µg Hb/g faeces, when compared to those with a f-Hb ≤7.0 µg Hb/g faeces. The pattern remained when excluding CRC from the analysis. Similar patterns were observed between incrementally increasing f-Hb and the risk of dying from respiratory disease, cardiovascular disease and cancers other than CRC. Furthermore, we observed an increased risk of dying from CRC with increasing f-Hb. CONCLUSIONS: Our findings support the hypothesis that f-Hb may indicate an elevated risk of having chronic conditions if causes for the bleeding have not been identified. The mechanisms still need to be established, but f-Hb may be a potential biomarker for several non-CRC diseases.

Trigeminocardiac Reflex: A Review and Key Implications to Dermatologic Surgery.

BACKGROUND: The trigeminocardiac reflex is a common but underreported occurrence that can vary from benign to life threatening. This reflex can be elicited by placing direct pressure on the globe of the eye or from traction of the extraocular muscles, stimulating the trigeminal nerve. OBJECTIVE: To provide a review of potential stimuli for the trigeminocardiac reflex within dermatologic surgery and to discuss management options for the treatment of the trigeminocardiac reflex. METHODS: PubMed and Cochrane were used to identify articles and case reports that established scenarios in which the trigeminocardiac reflex was provoked and subsequently how the reflex was managed. RESULTS: Within the field of dermatologic surgery, the trigeminocardiac reflex can be stimulated during biopsies, cryoablations, injections, laser treatments, Mohs micrographic surgery, and oculoplastic interventions, most often occurring in an office setting. The most common presentations include significant bradycardia, hypotension, gastric hypermobility, and lightheadedness. The most definitive treatment is cessation of the inciting stimulus, monitoring, and symptomatic management. Glycopyrrolate and atropine are common treatments for severe, intractable cases of the trigeminocardiac reflex. CONCLUSION: The trigeminocardiac reflex, while underreported and underrepresented in dermatologic literature and dermatologic surgery settings, should be considered in the setting of bradycardia and hypotension during dermatologic procedures.

Sex variation in colorectal cancer mortality: trends and implications for screening.

BACKGROUND: Colorectal cancer (CRC) screening using faecal tests reduces disease-specific mortality. To investigate mortality and its association with sex, rates in women and men, and in different age ranges, were examined, before and after screening began in Scotland. METHODS: From 1990-99, no structured screening existed. Three pilots ran from 2000 to 2007 and subsequent full roll-out completed in 2009. Crude mortality rates for 1990-2020 were calculated relative to Scottish population estimates, and age-sex standardized rates calculated for all, pre-screening (<50 years), screening (5-74 years) and post-screening (>74 years) age ranges. RESULTS: CRC mortality declined from 1990 to 2020, but not linearly, and differed between sexes. In women, 1990-99 showed a steady decline [average annual percentage change (AAPC): -2.1%, 95% confidence interval (CI): -2.8% to -1.4%], but a less marked decline after 2000 (AAPC: -0.7%, 95% CI: -0.9% to -0.4%). In men, no clear decline was seen from 1990 to 1999 (AAPC: -0.4%, 95% CI: -1.1% to 0.4%), but mortality declined from 2000 to 2020 (AAPC: -1.7%, 95% CI: -1.9% to -1.5%). This pattern was exaggerated in the screening age ranges. For 2000-20, the overall reduction in mortality was less in women and in the screening age range. In the post-screening age range, reductions were smaller, but an increase was seen in the pre-screening age range, greater in women. CONCLUSIONS: CRC mortality fell during 1990-2020, but the decline differed markedly between sexes, indicating a larger beneficial effect of screening on CRC mortality in men compared to women: use of different thresholds for the sexes might lead to equality.

An evaluation of the feasibility of implementing the BeWEL lifestyle intervention programme for people at increased risk of colorectal cancer - from research to real life.

BACKGROUND: The BeWEL randomised controlled trial (RCT) of weight loss in people with colorectal adenomas demonstrated that a significant proportion of people are interested in lifestyle interventions (49%) and clinically relevant changes in body weight were achieved at 12-month follow-up. The current work aimed to assess the feasibility of the BeWEL programme invitation and delivery in a nonresearch setting to assess whether the original results could be replicated. METHODS: The original BeWel programme was modified through the provision of verbal introductions (vs. letter), requirement for people to contact BeWEL team (vs. BeWEL team contacting them), community delivery (vs. home), duration (12 weeks vs. 12 months) and two intervention visits (vs. 3) and inclusion of people with predisposition to colorectal cancer. Eligible people were informed about the BeWel programme from National Health Service (NHS) staff after colonoscopy procedures and invited to contact a dedicated Bowel Cancer UK lifestyle team. RESULTS: Findings demonstrated that programme uptake (10.6% vs. 33%) and retention (71% vs. 93%) was significantly lower than that obtained from the BeWEL RCT. For people who participated in the 3-month programme (n = 21), self-reported weight loss (mean: -7% body weight) was successful, and the programme was well received. CONCLUSIONS: The current approach to engaging clients with the BeWEL programme is unsustainable. Reliance on busy NHS staff to deliver invitations and the need for people to contact the delivery team (due to data protection) may have impacted on uptake. Alternative approaches to supporting weight management in this population should be explored further.

Ancestral roles of atypical cadherins in planar cell polarity.

Fat, Fat-like, and Dachsous family cadherins are giant proteins that regulate planar cell polarity (PCP) and cell adhesion in bilaterians. Their evolutionary origin can be traced back to prebilaterian species, but their ancestral function(s) are unknown. We identified Fat-like and Dachsous cadherins in Hydra, a member of phylum Cnidaria a sister group of bilaterian. We found Hydra does not possess a true Fat homolog, but has homologs of Fat-like (HyFatl) and Dachsous (HyDs) that localize at the apical membrane of ectodermal epithelial cells and are planar polarized perpendicular to the oral-aboral axis of the animal. Using a knockdown approach we found that HyFatl is involved in local cell alignment and cell-cell adhesion, and that reduction of HyFatl leads to defects in tissue organization in the body column. Overexpression and knockdown experiments indicate that the intracellular domain (ICD) of HyFatl affects actin organization through proline-rich repeats. Thus, planar polarization of Fat-like and Dachsous cadherins has ancient, prebilaterian origins, and Fat-like cadherins have ancient roles in cell adhesion, spindle orientation, and tissue organization.

Faecal immunochemical testing (FIT) in patients with signs or symptoms of suspected colorectal cancer (CRC): a joint guideline from the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Society of Gastroenterology (BSG).

Faecal immunochemical testing (FIT) has a high sensitivity for the detection of colorectal cancer (CRC). In a symptomatic population FIT may identify those patients who require colorectal investigation with the highest priority. FIT offers considerable advantages over the use of symptoms alone, as an objective measure of risk with a vastly superior positive predictive value for CRC, while conversely identifying a truly low risk cohort of patients. The aim of this guideline was to provide a clear strategy for the use of FIT in the diagnostic pathway of people with signs or symptoms of a suspected diagnosis of CRC. The guideline was jointly developed by the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology, specifically by a 21-member multidisciplinary guideline development group (GDG). A systematic review of 13 535 publications was undertaken to develop 23 evidence and expert opinion-based recommendations for the triage of people with symptoms of a suspected CRC diagnosis in primary care. In order to achieve consensus among a broad group of key stakeholders, we completed an extended Delphi of the GDG, and also 61 other individuals across the UK and Ireland, including by members of the public, charities and primary and secondary care. Seventeen research recommendations were also prioritised to inform clinical management.

Inhibition of Long Noncoding RNA Linc-Pint by Hepatitis C Virus in Infected Hepatocytes Enhances Lipogenesis.

BACKGROUND AND AIMS: HCV often causes chronic infection in liver, cirrhosis, and, in some instances, HCC. HCV encodes several factors' those impair host genes for establishment of chronic infection. The long noncoding RNAs (lncRNAs) display diverse effects on biological regulations. However, their role in virus replication and underlying diseases is poorly understood. In this study, we have shown that HCV exploits lncRNA long intergenic nonprotein-coding RNA, p53 induced transcript (Linc-Pint) in hepatocytes for enhancement of lipogenesis. APPROACH AND RESULTS: We identified a lncRNA, Linc-Pint, which is significantly down-regulated in HCV-replicating hepatocytes and liver specimens from HCV infected patients. Using RNA pull-down proteomics, we identified serine/arginine protein specific kinase 2 (SRPK2) as an interacting partner of Linc-Pint. A subsequent study demonstrated that overexpression of Linc-Pint inhibits the expression of lipogenesis-related genes, such as fatty acid synthase and ATP-citrate lyase. We also observed that Linc-Pint significantly inhibits HCV replication. Furthermore, HCV-mediated enhanced lipogenesis can be controlled by exogenous Linc-Pint expression. Together, our results suggested that HCV-mediated down-regulation of Linc-Pint enhances lipogenesis favoring virus replication and liver disease progression. CONCLUSIONS: We have shown that SRPK2 is a direct target of Linc-Pint and that depletion of SRPK2 inhibits lipogenesis. Our study contributes to the mechanistic understanding of the role of Linc-Pint in HCV-associated liver pathogenesis.

Understanding patient barriers and facilitators to uptake of lung screening using low dose computed tomography: a mixed methods scoping review of the current literature.

BACKGROUND: Targeted lung cancer screening is effective in reducing mortality by upwards of twenty percent. However, screening is not universally available and uptake is variable and socially patterned. Understanding screening behaviour is integral to designing a service that serves its population and promotes equitable uptake. We sought to review the literature to identify barriers and facilitators to screening to inform the development of a pilot lung screening study in Scotland. METHODS: We used Arksey and O'Malley's scoping review methodology and PRISMA-ScR framework to identify relevant literature to meet the study aims. Qualitative, quantitative and mixed methods primary studies published between January 2000 and May 2021 were identified and reviewed by two reviewers for inclusion, using a list of search terms developed by the study team and adapted for chosen databases. RESULTS: Twenty-one articles met the final inclusion criteria. Articles were published between 2003 and 2021 and came from high income countries. Following data extraction and synthesis, findings were organised into four categories: Awareness of lung screening, Enthusiasm for lung screening, Barriers to lung screening, and Facilitators or ways of promoting uptake of lung screening. Awareness of lung screening was low while enthusiasm was high. Barriers to screening included fear of a cancer diagnosis, low perceived risk of lung cancer as well as practical barriers of cost, travel and time off work. Being health conscious, provider endorsement and seeking reassurance were all identified as facilitators of screening participation. CONCLUSIONS: Understanding patient reported barriers and facilitators to lung screening can help inform the implementation of future lung screening pilots and national lung screening programmes.

What can We Learn From High-Performing Screening Programs to Increase Bowel Cancer Screening Participation in Australia?

BACKGROUND: Colorectal cancer (CRC) is the second most diagnosed cancer in men and women and second most common cause of cancer death in Australia; Australia's CRC incidence and mortality are among the world's highest. The Australian National Bowel Cancer Screening Program began in 2006; however, only 33% of those approached for the first time by the Program between 2018 and 2019 returned the kit. Of the 5.7 million kits sent during this period, only 44% were returned. Our aim was to identify practices and features of national bowel cancer screening programs in countries with similar programs but higher screening participation, to identify potential interventions for optimising Australian CRC screening participation. METHODS: We searched published and grey literature for CRC screening programs reporting at least 50% screening participation using postal invitation and free return of iFOBT home kits. Interviews were conducted with cancer registry staff and academic researchers, focused on participant and practitioner engagement in screening. RESULTS: National programs in Netherlands, Scotland, Denmark, and Finland reported over 50% screening participation rates for all invitation rounds. Shared characteristics include small populations within small geographic areas relative to Australia; relatively high literacy; a one-sample iFOBT kit; national registration systems for population cancer screening research; and screening program research including randomised trials of program features. CONCLUSIONS: Apart from the one-sample kit, we identified no single solution to persistent Australian low uptake of screening. Research including randomised trials within the program promises to increase participation. IMPACT: This screening program comparison suggests that within-program intervention trials will lead to increased Australian screening participation.

Long non-coding RNA ELDR enhances oral cancer growth by promoting ILF3-cyclin E1 signaling.

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer with a 5-year overall survival rate of 50%. Thus, there is a critical need to understand the disease process, and to identify improved therapeutic strategies. Previously, we found the long non-coding RNA (lncRNA) EGFR long non-coding downstream RNA (ELDR) induced in a mouse tongue cancer model; however, its functional role in human oral cancer remained unknown. Here, we show that ELDR is highly expressed in OSCC patient samples and in cell lines. Overexpression of ELDR in normal non-tumorigenic oral keratinocytes induces cell proliferation, colony formation, and PCNA expression. We also show that ELDR depletion reduces OSCC cell proliferation and PCNA expression. Proteomics data identifies the RNA binding protein ILF3 as an interacting partner of ELDR. We further show that the ELDR-ILF3 axis regulates Cyclin E1 expression and phosphorylation of the retinoblastoma (RB) protein. Intratumoral injection of ELDR-specific siRNA reduces OSCC and PDX tumor growth in mice. These findings provide molecular insight into the role of ELDR in oral cancer and demonstrate that targeting ELDR has promising therapeutic potential.

Strategies to minimise the current disadvantages experienced by women in faecal immunochemical test-based colorectal cancer screening.

Currently, women are disadvantaged compared to men in colorectal cancer (CRC) screening, particularly in programmes that use faecal immunochemical tests for haemoglobin (FIT) followed by colonoscopy. Although there is no single cause for all the known disadvantages, many can be attributed to the ubiquitous finding that women have lower faecal haemoglobin concentrations (f-Hb) than men; there are many plausible reasons for this. Generally, a single f-Hb threshold is used in CRC screening programmes, leading to lower positivity for women than men, which causes poorer outcomes for women, including lower CRC detection rate, higher interval cancer (IC) proportion, and higher CRC mortality. Many of the now widely advocated risk scoring strategies do include factors taking account of sex, but these have not been extensively piloted or introduced. Using different f-Hb thresholds for the sexes seems advantageous, but there are difficulties, including deciding which characteristic should be selected to achieve equivalency, for example, positivity, IC proportions, or specificity. Moreover, additional colonoscopy resources, often constrained, would be required. Governments and their agencies should be encouraged to prioritise the allocation of resources to put simple strategies into practice, such as different f-Hb thresholds to create equal positivity in both sexes.