Prospective Screen Research Articles

Machine learning enables high-throughput, low-replicate screening for novel anti-seizure targets and compounds using combined movement and calcium fluorescence in larval zebrafish.

Identifying new, more efficacious anti-seizure medications (ASMs) is challenging, partly due to limitations in animal-based assays. Zebrafish (Danio rerio) can serve as a model of chemical and genetic seizures, but methods for detecting seizure-like activity in zebrafish, though powerful, have been hampered by low sensitivity (locomotor/behavioral assays) or low-throughput (tectal electrophysiology or calcium fluorescence microscopy). To address these issues, we developed a novel approach to assay seizure-like activity using combined locomotor and calcium fluorescence features, measured simultaneously from unrestrained larval zebrafish using a 96-well fluorescent plate reader. Using custom software to track fish movement and changes in fluorescence (deltaF/F0) from high-speed time-series (12.6Hz), we trained logistic classifiers using elastic net regression to distinguish seizure-like activity from non-seizure related changes based on event-specific and subject-specific features in response to the GABAAR antagonist, pentylenetetrazole (PTZ). We demonstrate that a classifier trained on combined movement and fluorescence data achieves high accuracy ("PTZ M+F"; area-under-curve receiver-operator characteristic (AUC-ROC): 0.98; F1 score: 0.912) and out-performs classifiers trained on movement ("PTZ M"; AUC-ROC: 0.9, F1: 0.9) or fluorescence features alone ("PTZ F"; AUC-ROC 0.96; F1: 0.87). The rate of classified seizure-like events increases as a dose-response to PTZ (serial dose escalation, 0, 2.5mM, 15mM) and is strongly suppressed by ASM treatment (valproic acid, VPA; tiagabine, TGB). At high-dose PTZ, we show that VPA reduces seizure-like activity defined by either "PTZ M+F" or "PTZ M" classifiers. Meanwhile, TGB selectively reduces events defined by the "PTZ M+F" classifier, paralleling previous reports that TGB reduces electrographic but not locomotor seizures and highlighting the potential for our approach to combine features of previously orthogonal assays. Using ASM benchmark data, we employ bootstrap simulation to calculate the expected statistical power of our method as a function of sample size. We demonstrate that anti-seizure responses (robust strictly standardized mean difference, RSSMD, versus control) with magnitudes similar to those associated with VPA or TGB can be reliably detected (true positive rate (TPR) > 90%) with as few as N=4 biological replicates per group, while maintaining a 5% false positive rate. In a prospective test screen with 3-6 replicates per group and on-plate controls, the anti-seizure effect of 4 out of 5 tested ASMs (CBZ, LEV, LZP, TGB) was detected. In summary, we demonstrate a simple high-throughput approach to whole organism anti-seizure phenotyping combining two previously reported metrics to facilitate screens for novel anti-seizure interventions in zebrafish.

Abstract B042: Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire

Abstract B042: Feasibility of an electronic medical records based ovarian cancer symptom screening patient questionnaire

Recreational screen time trajectories during early childhood and imaging-measured body composition at age 7 in the Odense child cohort.

Children spend increasing amounts of time on recreational screen media, which may lead to an obesogenic environment. We investigated the association of trajectories of screen time across ages 3, 5 and 7 years with body composition at age 7 in the Odense Child Cohort. Data were collected in the Municipality of Odense, Denmark, between 2010 and 2019. Group-based trajectory modelling was applied to group participants into four trajectories of prospective parent-reported screen time. Body composition was assessed using dual-energy x-ray absorptiometry with calculated fat-mass index (FMI) as the primary outcome. Primary models were linear multivariable regression models adjusted for participants' sex, age, birthweight, maternal origin, maternal education, maternal body-mass-index, and maternal age. Further models were adjusted for additional possible confounders. Selection bias was addressed by inverse probability weighting. In total, 803 children (48.2% female) were included in the primary analysis. Participants with screen time at all time points were assigned to four trajectory groups [constant low screen time (12.7%), low increase (36.3%), high increase between ages 3 and 5 (33.5%) and high increase in screen time (17.5%)]. Sample characteristics differed across missing data status and trajectories. Mean FMI (kg/m2 ) and standard deviation (SD) were 3.7 (SD 1.3) and 3.9 (SD 1.6) for the constant low versus high screen time, respectively. No differences in FMI were found between screen time trajectory groups at age 7 (adjusted mean difference 0.1kg/m2 , 95% confidence interval -0.3, 0.5 for constant low versus high screen time). No consistent associations between screen time groups and secondary body composition outcomes were found. Results from this study do not suggest that recreational screen time from age 3 to 7 years is associated with adiposity or other measures of body composition.

A practical guide to large-scale docking.

Structure-based docking screens of large compound libraries have become common in early drug and probe discovery. As computer efficiency has improved and compound libraries have grown, the ability to screen hundreds of millions, and even billions, of compounds has become feasible for modest-sized computer clusters. This allows the rapid and cost-effective exploration and categorization of vast chemical space into a subset enriched with potential hits for a given target. To accomplish this goal at speed, approximations are used that result in undersampling of possible configurations and inaccurate predictions of absolute binding energies. Accordingly, it is important to establish controls, as are common in other fields, to enhance the likelihood of success in spite of these challenges. Here we outline best practices and control docking calculations that help evaluate docking parameters for a given target prior to undertaking a large-scale prospective screen, with exemplification in one particular target, the melatonin receptor, where following this procedure led to direct docking hits with activities in the subnanomolar range. Additional controls are suggested to ensure specific activity for experimentally validated hit compounds. These guidelines should be useful regardless of the docking software used. Docking software described in the outlined protocol (DOCK3.7) is made freely available for academic research to explore new hits for a range of targets.

Property-Unmatched Decoys in Docking Benchmarks.

Enrichment of ligands versus property-matched decoys is widely used to test and optimize docking library screens. However, the unconstrained optimization of enrichment alone can mislead, leading to false confidence in prospective performance. This can arise by over-optimizing for enrichment against property-matched decoys, without considering the full spectrum of molecules to be found in a true large library screen. Adding decoys representing charge extrema helps mitigate over-optimizing for electrostatic interactions. Adding decoys that represent the overall characteristics of the library to be docked allows one to sample molecules not represented by ligands and property-matched decoys but that one will encounter in a prospective screen. An optimized version of the DUD-E set (DUDE-Z), as well as Extrema and sets representing broad features of the library (Goldilocks), is developed here. We also explore the variability that one can encounter in enrichment calculations and how that can temper one's confidence in small enrichment differences. The new tools and new decoy sets are freely available at http://tldr.docking.org and http://dudez.docking.org.

Supporting SARS-CoV-2 Papain-Like Protease Drug Discovery: In silico Methods and Benchmarking.

The coronavirus disease 19 (COVID-19) is a rapidly growing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its papain-like protease (SARS-CoV-2 PLpro) is a crucial target to halt virus replication. SARS-CoV PLpro and SARS-CoV-2 PLpro share an 82.9% sequence identity and a 100% sequence identity for the binding site reported to accommodate small molecules in SARS-CoV. The flexible key binding site residues Tyr269 and Gln270 for small-molecule recognition in SARS-CoV PLpro exist also in SARS-CoV-2 PLpro. This inspired us to use the reported small-molecule binders to SARS-CoV PLpro to generate a high-quality DEKOIS 2.0 benchmark set. Accordingly, we used them in a cross-benchmarking study against SARS-CoV-2 PLpro. As there is no SARS-CoV-2 PLpro structure complexed with a small-molecule ligand publicly available at the time of manuscript submission, we built a homology model based on the ligand-bound SARS-CoV structure for benchmarking and docking purposes. Three publicly available docking tools FRED, AutoDock Vina, and PLANTS were benchmarked. All showed better-than-random performances, with FRED performing best against the built model. Detailed performance analysis via pROC-Chemotype plots showed a strong enrichment of the most potent bioactives in the early docking ranks. Cross-benchmarking against the X-ray structure complexed with a peptide-like inhibitor confirmed that FRED is the best-performing tool. Furthermore, we performed cross-benchmarking against the newly introduced X-ray structure complexed with a small-molecule ligand. Interestingly, its benchmarking profile and chemotype enrichment were comparable to the built model. Accordingly, we used FRED in a prospective virtual screen of the DrugBank1 database. In conclusion, this study provides an example of how to harness a custom-made DEKOIS 2.0 benchmark set as an approach to enhance the virtual screening success rate against a vital target of the rapidly emerging pandemic.

Using machine learning to improve our understanding of injury risk and prediction in elite male youth football players

ObjectivesThe purpose of this study was to examine whether the use of machine learning improved the ability of a neuromuscular screen to identify injury risk factors in elite male youth football players. DesignProspective cohort study. Methods355 elite youth football players aged 10–18 years old completed a prospective pre-season neuromuscular screen that included anthropometric measures of size, as well as single leg countermovement jump (SLCMJ), single leg hop for distance (SLHD), 75% hop distance and stick (75%Hop), Y-balance anterior reach and tuck jump assessment. Injury incidence was monitored over one competitive season. Risk profiling was assessed using traditional regression analyses and compared to supervised machine learning algorithms constructed using decision trees. ResultsUsing continuous data, multivariate logistic analysis identified SLCMJ asymmetry as the sole significant predictor of injury (OR 0.94, 0.92–0.97, p<0.001), with a specificity of 97.7% and sensitivity of 15.2% giving an AUC of 0.661. The best performing decision tree model provided a specificity of 74.2% and sensitivity of 55.6% with an AUC of 0.663. All variables contributed to the final machine model, with asymmetry in the SLCMJ, 75%Hop and Y-balance, plus tuck jump knee valgus and anthropometrics being the most frequent contributors. ConclusionsAlthough both statistical methods reported similar accuracy, logistic regression provided very low sensitivity and only identified a single neuromuscular injury risk factor. The machine learning model provided much improved sensitivity to predict injury and identified interactions of asymmetry, knee valgus angle and body size as contributing factors to an injurious profile in youth football players.

Homeless status documentation at a metropolitan hospital emergency department.

This study compared the prevalence of homelessness in consecutive patients presenting to a metropolitan hospital ED measured via a prospective housing screen with the prevalence of homelessness determined via retrospective audit of hospital data. Factors that altered the odds of patients being homeless and service outcomes that differed were examined for screened patients. All patients presenting to the ED during a 7 day period in 2017 were invited to complete a housing screen. A retrospective audit of all ED presentations during the same period also occurred. Demographic (e.g. age, gender), clinical (e.g. reason for presentation, ED presentation history) and arrival mode (e.g. time, how arrived) predictors of homeless status were examined alongside care outcomes (e.g. ED length of stay, admission and 28 day re-presentation). Of 1208 presenting patients, 504 were prospectively screened and 7.9% were homeless. This compared with 0.8% of ED presentations coded as homeless in the Victorian Emergency Minimum Dataset and 2.3% of the 704 non-screened patients identified as homeless using Victorian Emergency Minimum Dataset Usual Accommodation alongside primary diagnosis and registration address. Within the screened sample, homeless patients were more likely to be male, arrive by emergency ambulance/with police, have a psychosocial diagnosis, and be frequent presenters. Re-presentation within 28 days occurred for 43% of homeless and 15% of not-homeless patients. Hospital ED administrative data substantially under-recognises the prevalence of homelessness in presenting patients. Standardised use of brief housing screens could improve identification of and provision of support to this often highly vulnerable population.

The impact of psychosocial distress on survival in patients diagnosed with gastrointestinal (GI) malignancies.

654 Background: A cancer diagnosis can cause psychological distress that adversely affects patients’ emotional, social, spiritual and physical capabilities. The aim of this study is to identify factors associated with increased risk for psychosocial distress and to evaluate the influence of anxiety and depression on survival of GI cancer patients. Methods: All patients with GI cancer referred to BC Cancer from 2011-2015 who completed a prospective Psychosocial Screen for Cancer – Revised within 6 months of cancer diagnosis were included in the study. Baseline characteristics were collected from the BC Cancer registry. Patient groups were compared using the Chi-squared Fisher’s exact test. OS was calculated using the Kaplan Meier method, compared using the log rank test and Cox proportional hazards model. Results: 8722 patients were included in the analysis. Baseline characteristic: median age 67, male 60% , metastatic disease 29%. Colorectal/anal cancers (60%) were the most common followed by pancreatic cancer (11%). Patients with anxiety and depression were more likely to be younger (aged 64 and less), female and have metastatic disease. Patients with anxiety were more likely to get chemotherapy. Depression was associated with less chemotherapy use. Anxiety and depression were associated with increased psychosocial needs including emotional, informational, physical, spiritual, social/family concerns (p &lt; 0.001). Psychological distress was not influenced by the patient’s geographic location or socioeconomic status. Median OS for patients with anxiety was 20 m vs no symptoms 27 m (p &lt; 0.001) and depression 17 m vs no symptoms 27m (p &lt; 0.001). The impact on OS remained significant for anxiety and depression in a multivariate model that included age, sex, metastatic status and chemotherapy use. Conclusions: Patients with GI malignancies who are female, younger than 64 and have metastatic disease are at risk for psychological distress. Anxiety and depression were associated with poorer survival outcomes even when controlling for age, sex, metastatic status and chemotherapy. Mobilizing resources to meet patients’ needs is important and should be implemented as part of patients’ comprehensive care.

867: Impact of maternal and paternal factors on fetal nasal bone visualization during first trimester screening

Ultrasound visualization of the fetal nasal bone (NB) is integrated into aneuploidy screening at 11-14 weeks gestation (T1 screen). Demographic factors unrelated to aneuploidy have been suggested to influence first trimester NB ossification and therefore visualization at this gestational age. We aimed to evaluate relationships between maternal and paternal factors and T1 screen NB visualization. Secondary analysis of a prospective T1 screen cohort study. All ultrasounds were performed by Fetal Medicine Foundation certified personnel. Fetal NB were characterized as “present” or “absent” if ultrasound quality criteria were met, and characterized as “not adequately visualized” (NAV) if quality criteria were not met. Maternal history, demographics ,body mass index (BMI), and paternal demographics were compared across three groups of NB visualization. Statistical analysis was performed with Mann-Whitney U and Kruskal-Wallis Test. Multivariate logistic regression was used to evaluate the primary determinant of inability to identify the NB. ROC curve and Youden’s J statistic were used to calculate clinical relevance. In 2173 participants, NB was absent in 25 (1.2%) and NAV in 54 fetuses (2.5%). While patients with absent or NAV NB were predominantly African American (14/25 [56%] and 33/54 [61%], respectively) the overall distribution of maternal and paternal ethnicity was similar across NB visualization categories (Table 1). Women with NAV NB had a significantly higher BMI (p <.001, Table 1). When participants with NAV and absent NB were combined and compared to those with present NB, differences in race distribution reached significance for maternal and paternal race (p <0.05, respectively). Logistic regression identified BMI as the primary determinant of NAV NB (p <0.01), but failed to identify determinants of an absent NB. ROC analysis showed that maternal BMI >35 predicted NAV of the NB with 42% sensitivity and 84% specificity (p = .001). In a population with stringent imaging criteria for NB visualization, maternal or paternal factors were not associated with an absent NB, though increased maternal BMI led to inadequate NB visualization. It is possible that failure to distinguish an inadequately visualized NB from an absent NB may be responsible for associations with ethnicity reported in other studies. In patients with BMI >35, a T1 screen scheduled closer to 14 weeks may improve likelihood of successful NB evaluation.

Matrix-based Molecular Descriptors for Prospective Virtual Compound Screening.

Molecular descriptors capture diverse structural information of molecules and are a prerequisite for ligand-based similarity searching. In this study, we introduce topological matrix-based descriptors to virtual screening for hit discovery. We evaluated the usefulness of matrix-based descriptors in a retrospective setting and compared them with topological pharmacophore descriptors. Special attention was given to the influence of data pre-processing and the applied similarity metric on the virtual screening performance. Overall, the MB descriptors showed a competitive and complementary performance to other descriptors. A prospective screen of a commercial compound library led to the discovery of a novel natural-product-derived cyclooxygenase-2 inhibitor predicted to interact differently with the target protein compared to the query compound ibuprofen. The results of our study motivate the use of matrix-based descriptors for molecular similarity-based virtual screening and scaffold hopping.

A comprehensive approach to the molecular determinants of lifespan using a Boolean model of geroconversion.

SummaryAltered molecular responses to insulin and growth factors (GF) are responsible for late‐life shortening diseases such as type‐2 diabetes mellitus (T2DM) and cancers. We have built a network of the signaling pathways that control S‐phase entry and a specific type of senescence called geroconversion. We have translated this network into a Boolean model to study possible cell phenotype outcomes under diverse molecular signaling conditions. In the context of insulin resistance, the model was able to reproduce the variations of the senescence level observed in tissues related to T2DM's main morbidity and mortality. Furthermore, by calibrating the pharmacodynamics of mTOR inhibitors, we have been able to reproduce the dose‐dependent effect of rapamycin on liver degeneration and lifespan expansion in wild‐type and HER2–neu mice. Using the model, we have finally performed an in silico prospective screen of the risk–benefit ratio of rapamycin dosage for healthy lifespan expansion strategies. We present here a comprehensive prognostic and predictive systems biology tool for human aging.

Incorporation of protein flexibility and conformational energy penalties in docking screens to improve ligand discovery.

Proteins fluctuate between alternative conformations, which presents a challenge for ligand discovery because such flexibility is difficult to treat computationally owing to problems with conformational sampling and energy weighting. Here, we describe a flexible-docking method that samples and weights protein conformations using experimentally-derived conformations as a guide. The crystallographically refined occupancies of these conformations, which are observable in an apo receptor structure, define energy penalties for docking. In a large prospective library screen, we identified new ligands that target specific receptor conformations of a cavity in Cytochrome c Peroxidase, and we confirm both ligand pose and associated receptor conformation predictions by crystallography. The inclusion of receptor flexibility led to ligands with new chemotypes and physical properties. By exploiting experimental measures of loop and side chain flexibility, this method can be extended to the discovery of new ligands for hundreds of targets in the Protein Data Bank where similar experimental information is available.

Identification of dosage‐sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a fetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in fetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and, more recently, chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive. We propose that chromosomal microarray analysis will identify copy number variations (CNVs) associated with isolated CDH. We perform a prospective genome-wide screen for CNVs using chromosomal microarrays on 75 fetuses referred with apparently isolated CDH, six of which were later reclassified as non-isolated CDH. The results pinpoint haploinsufficiency of NR2F2 as a cause of CDH and cardiovascular malformations. In addition, the 15q25.2 and 16p11.2 recurrent microdeletions are associated with isolated CDH. By using gene prioritisation and network analysis, we provide strong evidence for several novel dosage-sensitive candidate genes associated with CDH. Chromosomal microarray analysis detects submicroscopic CNVs associated with isolated CDH or CDH with cardiovascular malformations.

Adolescents’ prospective screen time by gender and parental education, the mediation of parental influences

BackgroundThe present study investigated associations in gender dyads of parents’ and adolescents’ time spent on television and video viewing (TV/DVD), and computer and electronic game use (PC/games) at the ages of 11 and 13 years. Possible mediating effects of parental modelling and parental regulation in the relationship between parental education and adolescents’ prospective TV/DVD and PC/game time were further examined.MethodsA total of 908 adolescents, participating at both ages 11 and 13 years in the Norwegian HEalth In Adolescents (HEIA) cohort study (2007–2009), were included in the analyses. Data on adolescents’, mothers’ and fathers’ self reported time spent on TV/DVD and PC/games were measured at both time points by questionnaires. Correlation coefficients were used to examine gender dyads of parents’ and adolescents’ reports. Mediation analyses using linear regression investigated possible mediation effects of parental modelling and parental regulation in the prospective relationship between parental education and adolescents’ time spent on TV/DVD and PC/games between the ages of 11 and 13 years.ResultsCorrelations of screen time behaviours in gender dyads of parents and adolescents showed significant associations in time spent on TV/DVD at the age of 11 and 13 years. Associations between mothers and sons and between fathers and daughters were also observed in time spent on PC/games at the age of 11 years. Maternal and paternal modelling was further found to mediate the relationship between parental education and adolescents’ prospective TV/DVD time between the ages of 11 and 13 years. No mediation effect was observed for parental regulation, however a decrease in both maternal and paternal regulation at the age of 11 years significantly predicted more TV/DVD time among adolescents at the age of 13 years.ConclusionCross-sectional and longitudinal relationships were observed in gender dyads of parents’ and adolescents’ screen time behaviours at the ages of 11 and 13 years, and further studies including both parents and their children should be emphasized. Moreover, maternal and paternal modelling were found to be important target variables in interventions aiming to reduce social differences by parental education in adolescents’ prospective time spent on TV/DVD.

Prospective memory and glycemic control in children with type 1 diabetes mellitus: a cross-sectional study

BackgroundProspective memory is that memory which is required to carry out intended actions and is therefore essential in carrying out the daily activities required in the self-management of type 1 diabetes mellitus (T1DM). This study aimed to identify the relationships between prospective memory and diabetic control in children with T1DM.Method94 children aged 6–18 years with T1DM completed an innovative prospective memory screen, PROMS, and a series of cognitive tests. Parents answered questionnaires about their children's diabetic histories and cognitive skills.ResultsNo association between total PROMS score and glycemic control was found. Lower HbA1C was associated with higher (better) scores on the 20 minute event-based task on the PROMS. Parental concerns about working memory and metacognition in their children were mirrored by higher HbA1C.ConclusionsThis study suggests that there may be an association between glycemic control and prospective memory for event based tasks. Additional studies need to be done to determine reproducibility, causality, and if prospective memory based interventions can improve diabetic control.

Significance Estimation For Sequence-Based Chemical Similarity Searching (PhAST) And Application To AuroraA Kinase Inhibitors

Chemical similarity searching allows the retrieval of preferred screening molecules from a compound database. Candidates are ranked according to their similarity to a reference compound (query). Assessing the statistical significance of chemical similarity scores helps prioritizing significant hits, and identifying cases where the database does not contain any promising compounds. Our text-based similarity measure, Pharmacophore Alignment Search Tool (PhAST), employs pair-wise sequence alignment. We adapted the concept of E-values as significance estimates and employed a sampling technique that incorporates the principle of importance sampling in a Markov chain Monte Carlo simulation to generate distributions of random alignment scores. These distributions were used to compute significance estimates for similarity scores in a preliminary prospective virtual screen for inhibitors of Aurora A kinase. Assessing the significance of compound similarity computed with PhAST allows for a statistically motivated identification of candidate screening compounds. Inhibitors of Aurora A kinase were retrieved from a large compound library.

On the relevance of script writing basics in audiovisual translation practice and training

Audiovisual texts possess characteristics that clearly differentiate audiovisual translation from both oral and written translation, and prospective screen translators are usually taught about the issues that typically arise in audiovisual translation. This article argues for the development of an interdisciplinary approach that brings together Translation Studies and Film Studies, which would prepare future audiovisual translators to work with the nature and structure of a script in mind, in addition to the study of common and diverse translational aspects. Focusing on film, the article briefly discusses the nature and structure of scripts, and identifies key points in the development and structuring of a plot. These key points and various potential hurdles are illustrated with examples from the films Chinatown and La habitación de Fermat. The second part of this article addresses some implications for teaching audiovisual translation.

Geriatric screening in first opinion practice - results from 45 dogs.

ObjectivesTo evaluate and report the results of screening geriatric dogs in a first opinion practice.MethodsA prospective health screen of dogs over nine-years-old involving history taking, physical examination and urinalysis.ResultsAt least one previously unrecognised problem was identified in 80% of 45 dogs and 353 findings (mean 7·8 per dog) were recorded. Owners often failed to recognise and report serious signs of age-related disease. However, they most often reported increased sleeping (31%), loss of hearing (29%) or sight (20%), stiffness or lameness (22%) and “slowing down” (20%). Increased lens opacity (64%), increased thirst (58%), pain (24%), increased frequency of urination (24%), signs of osteoarthritis (24%) and dental disease (22%) were most frequently identified at the time of consultation. Potentially, life-threatening findings included respiratory distress, palpable abdominal masses and metastatic lung disease. Screening resulted in 29 further diagnostic procedures, including 10 dental procedures, seven medical treatments, two surgical procedures and euthanasia of two dogs.Clinical SignificanceScreening elderly dogs identified unrecognised and unreported health risk factors resulting in lifestyle modification and ongoing monitoring, as well as signs of age-related diseases resulting in diagnostic investigations, early diagnoses and surgical and medical interventions to improve quality of life.

Serum and pleural fluid biomarkers for mesothelioma

Malignant mesothelioma is an asbestos-induced, aggressive tumour. In centres across the world, research has focused on evaluating biomarkers for malignant mesothelioma screening, diagnosis, prognostication and monitoring. With the incidence of malignant mesothelioma expected to increase, it is timely to review the current status of biomarkers in this field. The majority of recent studies have evaluated the commercial MESOMARK assay in a diagnostic setting. Studies have clarified that soluble-shed mesothelin as well as mesothelin-related peptide are targets of the assay. The assay sensitivity ranges from 50% at diagnosis to 84% in advanced disease. The assay has a high level of specificity relative to benign lung and pleural conditions and is positive in 10-15% of other malignancies. In a prospective screen of 538 asbestos-exposed workers, 2.8% were positive; one had lung cancer that was subsequently successfully treated. The biomarkers megakaryocyte potentiating factor, osteopontin and CA125, either alone or in combination with soluble mesothelin, have also been assessed. To date, soluble mesothelin remains the best available biomarker for malignant mesothelioma. However, a lack of sensitivity for early-stage disease and for all malignant mesothelioma histologies provides motivation for the search of novel malignant mesothelioma biomarkers with greater sensitivity, especially for very early disease.