Precision medicine for suicidality: from universality to subtypes and personalization

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator

Stepwise quantum decay of self-localized solitons

The two-phonon decay of self-localized soliton in a one-dimensional monatomic anharmonic lattice caused by cubic anharmonicity is considered. It is shown that the decay takes place with emission of phonon bursts. The average rate of emission of phonons is of the order of vibrational quantum per vibrational period. Characteristic time of the relaxation is determined by the quantum anharmonicity parameter; this time may vary from a few (quantum lattices, large anharmonicity) to thousands (ordinary lattices, small anharmonicity) of vibrational periods.Comment: 6 pages, 3 figure

Asymmetric gap soliton modes in diatomic lattices with cubic and quartic nonlinearity

Nonlinear localized excitations in one-dimensional diatomic lattices with cubic and quartic nonlinearity are considered analytically by a quasi-discreteness approach. The criteria for the occurence of asymmetric gap solitons (with vibrating frequency lying in the gap of phonon bands) and small-amplitude, asymmetric intrinsic localized modes (with the vibrating frequency being above all the phonon bands) are obtained explicitly based on the modulational instabilities of corresponding linear lattice plane waves. The expressions of particle displacement for all these nonlinear localized excitations are also given. The result is applied to standard two-body potentials of the Toda, Born-Mayer-Coulomb, Lennard-Jones, and Morse type. The comparison with previous numerical study of the anharmonic gap modes in diatomic lattices for the standard two-body potentials is made and good agreement is found.Comment: 24 pages in Revtex, 2 PS figure

Factors associated with quality of life in systemic sclerosis: a cross-sectional study

© 2019, The Author(s). Introduction: Systemic sclerosis (SSc) is a connective tissue disease characterized by progressive fibrosis of the skin and internal organs, leading to their failure and disturbances in the morphology and function of blood vessels. The disease affects people in different ways, and identifying how the difficulties and limitations are related to quality of life may contribute to designing helpful interventions. The aim of this study was to identify factors associated with quality of life in people with SSc. Methods: This was a cross-sectional study conducted in 11 rheumatic centres in Poland. Patients diagnosed with SSc were included. Quality of life was measured using the SSc Quality of Life Questionnaire (SScQoL). The following candidate factors were entered in preliminary multivariable analysis: age, place of residence, marital status, occupational status, disease type, disease duration, pain, fatigue, intestinal problems, breathing problems, Raynaud’s symptoms, finger ulcerations, disease severity, functional disability, anxiety and depression. Factors that achieved statistical significance at the 10% level were then entered into a final multivariable model. Factors achieving statistical significance at the 5% level in the final model were considered to be associated with quality of life in SSc. Results: In total, 231 participants were included. Mean age (SD) was 55.82 (12.55) years, disease duration 8.39 (8.18) years and 198 (85.7%) were women. Factors associated with quality of life in SSc were functional disability (β = 2.854, p < 0.001) and anxiety (β = 0.404, p < 0.001). This model with two factors (functional disability and anxiety) explained 56.7% of the variance in patients with diffuse SSc and 73.2% in those with localized SSc. Conclusions: Functional disability and anxiety are significantly associated with quality of life in SSc. Interventions aimed at improving either of these factors may contribute towards improving the quality of life of people with SSc

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.ope