Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population.

BACKGROUND: There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. METHODS: Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. RESULTS: Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. CONCLUSION: Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.

CRISPR and KRAS: a match yet to be made.

CRISPR (clustered regularly interspaced short palindromic repeats) systems are one of the most fascinating tools of the current era in molecular biotechnology. With the ease that they provide in genome editing, CRISPR systems generate broad opportunities for targeting mutations. Specifically in recent years, disease-causing mutations targeted by the CRISPR systems have been of main research interest; particularly for those diseases where there is no current cure, including cancer. KRAS mutations remain untargetable in cancer. Mutations in this oncogene are main drivers in common cancers, including lung, colorectal and pancreatic cancers, which are severe causes of public health burden and mortality worldwide, with no cure at hand. CRISPR systems provide an opportunity for targeting cancer causing mutations. In this review, we highlight the work published on CRISPR applications targeting KRAS mutations directly, as well as CRISPR applications targeting mutations in KRAS-related molecules. In specific, we focus on lung, colorectal and pancreatic cancers. To date, the limited literature on CRISPR applications targeting KRAS, reflect promising results. Namely, direct targeting of mutant KRAS variants using various CRISPR systems resulted in significant decrease in cell viability and proliferation in vitro, as well as tumor growth inhibition in vivo. In addition, the effect of mutant KRAS knockdown, via CRISPR, has been observed to exert regulatory effects on the downstream molecules including PI3K, ERK, Akt, Stat3, and c-myc. Molecules in the KRAS pathway have been subjected to CRISPR applications more often than KRAS itself. The aim of using CRISPR systems in these studies was mainly to analyze the therapeutic potential of possible downstream and upstream effectors of KRAS, as well as to discover further potential molecules. Although there have been molecules identified to have such potential in treatment of KRAS-driven cancers, a substantial amount of effort is still needed to establish treatment strategies based on these discoveries. We conclude that, at this point in time, despite being such a powerful directed genome editing tool, CRISPR remains to be underutilized for targeting KRAS mutations in cancer. Efforts channelled in this direction, might pave the way in solving the long-standing challenge of targeting the KRAS mutations in cancers.

KRAS AND THE REALITY OF PERSONALIZED MEDICINE IN NON-SMALL CELL LUNG CANCER.

Lung cancer is the leading cause of mortality among all cancer types, worldwide. Latest available global statistics of World Health Organization report 1.59 million casualities in 2012 alone. Worldwide, 1 in 5 cancer deaths are caused by lung cancer. In 2016, in USA alone, estimated new cases of lung cancer are 224,390, of which 158,080 are expected to result in death as reported by National Cancer Institute. Non-small cell lung cancer (NSCLC), a histological subtype, comprises of about 85% of all cases, which is nearly 9 out of 10 lung cancer patients. Efforts are underway to develop and improve targeted therapy strategies. Certain mutations are being clinically targeted such as those in EGFR and ALK genes. However, one of the most frequently mutated genes in NSCLC is the KRAS oncogene, which is currently untargetable. Approximately 25% of all types of NSCLC tumors contain KRAS mutations, which remain as an undruggable challenge. These mutations are indicative of poor prognosis and confer negative response to standard chemotherapy. Furthermore, tumors harboring KRAS mutations are unlikely to respond to currently available targeted treatments such as Tyrosine Kinase Inhibitors. Therefore, there is a definitive, urgent need to generate new targeted therapy approaches for KRAS mutations. Current strategies have major limitations and evolve around targeting molecules upstream and downstream of KRAS. Direct targeting is not available in the clinic. Combination therapies of multiple agents are being sought. Concentrated efforts are needed to accelerate basic research and consecutive clinical trials to achieve effective targeting of KRAS.

Predictors and trends of Caesarean section and breastfeeding in the Eastern Mediterranean region: Data from the cross-sectional Cyprus Women's Health Research (COHERE) Initiative.

INTRODUCTION: Caesarean section (C-section) is a life-saving procedure when medically indicated but unmet need and overuse can add to avoidable morbidity and mortality. It is not clear whether C-section has a negative impact on breastfeeding and there is limited data available on rates of C-section or breastfeeding from Northern Cyprus, an emerging region in Europe. This study aimed to investigate prevalence, trends and associations of C-section and breastfeeding in this population. METHODS: Using self-reported data from the representative Cyprus Women's Health Research (COHERE) Initiative, we used 2,836 first pregnancies to describe trends in C-section and breastfeeding between 1981 and 2017. Using modified Poisson regression, we examined the relationship between year of pregnancy and C-section and breastfeeding, as well as the association between C-section and breastfeeding prevalence and duration. RESULTS: C-section prevalence in first pregnancies increased from 11.1% in 1981 to 72.5% in 2017 with a relative risk of 2.60 (95%CI; 2.14-2.15) of babies being delivered by C-section after 2005 compared to before 1995, after full adjustment for demographic and maternal medical and pregnancy related factors. Prevalence of ever breastfeeding remained steady throughout the years at 88.7% and there was no significant association between breastfeeding initiation and the year of pregnancy, or demographic and maternal medical and pregnancy related variables. After full adjustment, women who gave birth after 2005 were 1.24 (95%CI; 1.06-1.45) times more likely to breastfeed for >12 weeks compared to women who gave birth before 1995. There was no association between C-section and breastfeeding prevalence or length. CONCLUSION: Prevalence of C-section in this population is much higher than WHO recommendations. Public awareness campaigns surrounding choice during pregnancy and change in legal framework to allow for midwife-led continuity models of birthing care should be implemented. Further research is required to understand the reasons and drivers behind this high rate.

Biomedical impact of splicing mutations revealed through exome sequencing.

Splicing is a cellular mechanism, which dictates eukaryotic gene expression by removing the noncoding introns and ligating the coding exons in the form of a messenger RNA molecule. Alternative splicing (AS) adds a major level of complexity to this mechanism and thus to the regulation of gene expression. This widespread cellular phenomenon generates multiple messenger RNA isoforms from a single gene, by utilizing alternative splice sites and promoting different exon-intron inclusions and exclusions. AS greatly increases the coding potential of eukaryotic genomes and hence contributes to the diversity of eukaryotic proteomes. Mutations that lead to disruptions of either constitutive splicing or AS cause several diseases, among which are myotonic dystrophy and cystic fibrosis. Aberrant splicing is also well established in cancer states. Identification of rare novel mutations associated with splice-site recognition, and splicing regulation in general, could provide further insight into genetic mechanisms of rare diseases. Here, disease relevance of aberrant splicing is reviewed, and the new methodological approach of starting from disease phenotype, employing exome sequencing and identifying rare mutations affecting splicing regulation is described. Exome sequencing has emerged as a reliable method for finding sequence variations associated with various disease states. To date, genetic studies using exome sequencing to find disease-causing mutations have focused on the discovery of nonsynonymous single nucleotide polymorphisms that alter amino acids or introduce early stop codons, or on the use of exome sequencing as a means to genotype known single nucleotide polymorphisms. The involvement of splicing mutations in inherited diseases has received little attention and thus likely occurs more frequently than currently estimated. Studies of exome sequencing followed by molecular and bioinformatic analyses have great potential to reveal the high impact of splicing mutations underlying human disease.

An RNA map predicting Nova-dependent splicing regulation.

Nova proteins are a neuron-specific alternative splicing factors. We have combined bioinformatics, biochemistry and genetics to derive an RNA map describing the rules by which Nova proteins regulate alternative splicing. This map revealed that the position of Nova binding sites (YCAY clusters) in a pre-messenger RNA determines the outcome of splicing. The map correctly predicted Nova's effect to inhibit or enhance exon inclusion, which led us to examine the relationship between the map and Nova's mechanism of action. Nova binding to an exonic YCAY cluster changed the protein complexes assembled on pre-mRNA, blocking U1 snRNP (small nuclear ribonucleoprotein) binding and exon inclusion, whereas Nova binding to an intronic YCAY cluster enhanced spliceosome assembly and exon inclusion. Assays of splicing intermediates of Nova-regulated transcripts in mouse brain revealed that Nova preferentially regulates removal of introns harbouring (or closest to) YCAY clusters. These results define a genome-wide map relating the position of a cis-acting element to its regulation by an RNA binding protein, namely that Nova binding to YCAY clusters results in a local and asymmetric action to regulate spliceosome assembly and alternative splicing in neurons.

Protocol for the Cultural Translation and Adaptation of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project Endometriosis Participant Questionnaire (EPHect).

Endometriosis affects 10% of women worldwide and is one of the most common causes of chronic pelvic pain and infertility. However, causal mechanisms of this disease remain unknown due to its heterogeneous presentation. In order to successfully study its phenotypic variation, large sample sizes are needed. Pooling of data across sites is not always feasible given the large variation in the complexity and quality of the data collected. The World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect) have developed an endometriosis participant questionnaire (EPQ) to harmonize non-surgical clinical participant characteristic data relevant to endometriosis research, allowing for large-scale collaborations in English-speaking populations. Although the WERF EPHect EPQs have been translated into different languages, no study has examined the cross-cultural translation and adaptation for content and face validity. In order to investigate this, we followed the standard guidelines for cross-cultural adaptation and translation of the minimum version of the EPQ (EPQ-M) using 40 patients who underwent laparoscopic surgery in Turkey and 40 women in Northern Cyprus, aged between 18 and 55. We assessed the consistency by using cognitive testing and found the EPHect EPQ-M to be comprehensive, informative, and feasible in these two Turkish-speaking populations. The translated and adapted questionnaire was found to be epidemiologically robust, taking around 30-60 min to complete; furthermore, participants reported a similar understanding of the questions, showing that common perspectives were explored. Results from the cognitive testing process led to minor additions to some items such as further descriptive and/or visuals in order to clarify medical terminology. This paper illustrates the first successful cross-cultural translation and adaptation of the EPHect EPQ-M and should act as a tool to allow for further studies that wish to use this questionnaire in different languages. Standardized tools like this should be adopted by researchers worldwide to facilitate collaboration and aid in the design and conduction of global studies to ultimately help those affected by endometriosis and its associated symptoms.

Host Genetics at the Intersection of Autoimmunity and COVID-19: A Potential Key for Heterogeneous COVID-19 Severity.

COVID-19 presentation is very heterogeneous across cases, and host factors are at the forefront for the variables affecting the disease manifestation. The immune system has emerged as a key determinant in shaping the outcome of SARS-CoV-2 infection. It is mainly the deleterious unconstrained immune response, rather than the virus itself, which leads to severe cases of COVID-19 and the associated mortality. Genetic susceptibility to dysregulated immune response is highly likely to be among the host factors for adverse disease outcome. Given that such genetic susceptibility has also been observed in autoimmune diseases (ADs), a number of critical questions remain unanswered; whether individuals with ADs have a significantly different risk for COVID-19-related complications compared to the general population, and whether studies on the genetics of ADs can shed some light on the host factors in COVID-19. In this perspective, we discuss the host genetic factors, which have been under investigation in association with COVID-19 severity. We touch upon the intricate link between autoimmunity and COVID-19 pathophysiology. We put forth a number of autoimmune susceptibility genes, which have the potential to be additional host genetic factors for modifying the severity of COVID-19 presentation. In summary, host genetics at the intersection of ADs and COVID-19 may serve as a source for understanding the heterogeneity of COVID-19 severity, and hence, potentially holds a key in achieving effective strategies in risk group identification, as well as effective treatments.

Neurotransmitter receptor genotypes associated with mental and behavioral disorders.

AIM: Investigation of association studies within the field of mental and behavioral disorders is of value given their complex molecular etiology including epistatic interactions of multiple genes with small effects. MATERIALS & METHODS: Utilizing biomedical text mining, associations are uncovered for all mental and behavioral conditions listed in Diagnostic and Statistical Manual of Mental Disorders Text Revision. Specifically, a computational pipeline is designed to retrieve neurotransmitter receptor variations from biomedical literature with a text mining approach, where unique polymorphisms are also mined. RESULTS: Analyses of 1337 unique neurotransmitter receptors and 465 distinct conditions yield 1568 unique gene-disease associations. CONCLUSION: This study takes an unconventional approach to association studies and generates a novel dataset of associations for disorders such as major depression and schizophrenia, which provides a global perspective for their genetic etiology.

Genotype-based prevention of psychosis onset and schizophrenia: a personalized approach in a target population.

Schizophrenia imposes a significant burden on public health, affecting approximately 25 million individuals worldwide and generating an extensive healthcare burden. It is important to consider that the disease onset in schizophrenia stems from gene-environment interactions. Early interventions in order to prevent schizophrenia are of high clinical interest, and this is where personalized healthcare and medicine comes in. In this article, we bring a genotype-based personalized, preventive perspective to psychosis onset and schizophrenia. Our objective relies on the possibility of making use of a specific gene-environment interaction in the emergence of schizophrenia as a personalized preventive tool. In particular, we discuss screening of a specific AKT1 allelic variation and its interaction with cannabis use as a preventive approach in a target population with early symptoms of psychosis.

A new public health genomics model for common complex diseases, with an application to common behavioral disorders.

AIM: In the light of common forms of gene-environment interplay, particularly epigenomics and ecogenetics, the incorporation of envirome data into public health genomics models becomes necessary. Developing and restructuring public health genomics models is essential within the context of common complex diseases. MATERIALS & METHODS: We developed a novel theoretical model integrating a gene-environment interaction paradigm into public health genomics, which integrates four main sources of data: personal genome data, personal envirome data, molecular genetic/genomic evidence and environmental factors implicated in gene-environment interactions underlying common complex disease phenotypes. Collectively, this knowledge is fed into public health policy development. RESULTS: This model is the first public health genomics model that incorporates gene-environment interactions within the context of common complex disorders, and is applied to behavioral conditions. CONCLUSION: Our model proposes, for the first time, an understanding of behavioral disorders from the genomic perspective, combining it with known environmental factors within the framework of public health. Application of this model will enable evidence-based behavioral interventions at the public health level and facilitate genome-based public health policy development for behavioral conditions.

Is there room for ethics within bioinformatics education?

When bioinformatics education is considered, several issues are addressed. At the undergraduate level, the main issue revolves around conveying information from two main and different fields: biology and computer science. At the graduate level, the main issue is bridging the gap between biology students and computer science students. However, there is an educational component that is rarely addressed within the context of bioinformatics education: the ethics component. Here, a different perspective is provided on bioinformatics education, and the current status of ethics is analyzed within the existing bioinformatics programs. Analysis of the existing undergraduate and graduate programs, in both Europe and the United States, reveals the minimal attention given to ethics within bioinformatics education. Given that bioinformaticians speedily and effectively shape the biomedical sciences and hence their implications for society, here redesigning of the bioinformatics curricula is suggested in order to integrate the necessary ethics education. Unique ethical problems awaiting bioinformaticians and bioinformatics ethics as a separate field of study are discussed. In addition, a template for an "Ethics in Bioinformatics" course is provided.

Cancer incidence in North Cyprus (1990-2004) relative to European rates.

Cancer incidence in North Cyprus (NC), deemed an interesting epidemiological case due to possible contrasting prevailing factors in relation to South and North Europe (SE and NE), was evaluated for the period 1990-2004. Age standardized rates (ASRs) and average age of incidence (AAI) values were determined for 12 different cancers, separately for males and females. Annual trends were analyzed using linear regression slopes. Absolute values were compared by two-tailed t-tests. The order of prevalence for incidences of male (M) cancers were: lung, skin, colorectal, prostate, brain, bladder, liver and stomach. Similarly, for females (F) they were: breast, gynaecological, skin, colorectal, lung, liver, brain, stomach and bladder. The following cancer cases were more common than in SE and NE: lung (M) and skin (both genders). Breast (F), prostate, stomach (F), bladder (both sexes), cervix and corpus were less frequent; the rest were comparable. There was no difference in the annual trends of ASR or AAI for NC, compared with SE or NE. Thus cancer incidence in NC shares many quantitative features with the rest of Europe. The worst cases could be improved by reducing smoking and protection from the sun.

Alternative splicing of mouse transcription factors affects their DNA-binding domain architecture and is tissue specific.

BACKGROUND: Analyzing proteins in the context of all available genome and transcript sequence data has the potential to reveal functional properties not accessible through protein sequence analysis alone. To analyze the impact of alternative splicing on transcription factor (TF) protein structure, we constructed a comprehensive database of splice variants in the mouse transcriptome, called MouSDB3 containing 461 TF loci. RESULTS: Our analysis revealed that 62% of these loci in MouSDB3 have variant exons, compared to 29% of all loci. These variant TF loci contain a total of 324 alternative exons, of which 23% are in-frame. When excluded, 80% of in-frame alternative exons alter the domain architecture of the protein as computed by SMART (simple modular architecture research tool). Sixty-eight % of these exons directly affect the coding regions of domains important for TF function. Seventy-five % of the domains affected are DNA-binding domains. Tissue distribution analyses of variant mouse TFs reveal that they have more alternatively spliced forms in 14 of the 18 tissues analyzed when compared to all the loci in MouSDB3. Further, TF isoforms are homogenous within a given single tissue and are heterogeneous across different tissues, indicating their tissue specificity. CONCLUSIONS: Our study provides quantitative evidence that alternative splicing preferentially adds or deletes domains important to the DNA-binding function of the TFs. Analyses described here reveal the presence of tissue-specific alternative splicing throughout the mouse transcriptome. Our findings provide significant biological insights into control of transcription and regulation of tissue-specific gene expression by alternative splicing via creation of tissue-specific TF isoforms.