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

Retrosternal goiters

Clinica 1 Chirurgie, Clinica de Endocrinologie, Spitalul „Sf.Spiridon”, UMF ”Gr.T.Popa”, Iaşi, România, Al XII-lea Congres al Asociației Chirurgilor „Nicolae Anestiadi” din Republica Moldova cu participare internațională 23-25 septembrie 2015Introducere: Noțiunea de guşă retrosternală sau substernală reprezintă coborîrea a mai mult de 50% de glanda tiroidă în cavitatea toracică. Material şi metode: A fost efectuat un studiu retrospectiv a cazurilor de guşă retrosternală sau substernală din totalul de 2482 pacienți ce au suportat tiroidectomie în Clinica 1 Chirurgie din Iaşi în perioada 2000-2010. Guşa retrosternală a fost depistată la 54 (2,17%) pacienți. Toți bolnavii au fost îndreptați la operație din Clinica de Endocrinologie. Rezultate: Vîrsta medie a pacienților la momentul instalării diagnosticului a constituit 55,3±3,58 ani, majoritatea fiind femei – 83,3%. În manifestările clinice ale guşei retrosternale au dominat fenomenele de compresie. Dereglările funcției glandei tiroide au fost determinate prin teste hormonale efectuate în Clinica de Endocrinologie în 15 (27,7%) cazuri. Diagnoza de guşă retrosternală a fost suspectată în baza examenului clinic şi confirmată imagistic: radiografie toracică, ultrasonografie, computer tomografie. Abordul cervical a fost utilizat cu siguranță, sternotomia fiind necesară doar în 8 (14,8%) cazuri. Morbiditatea postoperatorie a constituit 5,5% (3 cazuri) cu mortalitate nulă. Durata medie de spitalizare a fost 4,3 zile. Noi am comparat datele noastre recente cu raportul privind tratamentul guşei retrosternale şi toracice în Clinica 1 Chirurgie din Iaşi în perioada anilor 1950-1979, publicat în revista „Chirurgia” în 1981. Concluzii: Guşa retrosternală reprezintă o formă specifică de patologie a glandei tiroide cu o incidență scăzută. Diagnosticul şi tratamentul guşei retrosternale implică o abordare multidisciplinară. Medicul endocrinolog are un rol important în diagnosticul şi supravegherea postoperatorie. Deşi intervenția chirurgicală este o metoda curativă de elecție pentru guşa substernală, persistă controverse privind abordul chirurgical şi rata complicațiilor. Abordul cervical poate fi utilizat cu siguranță aproape în toate cazurile, sternotomia fiind efectuată fără ezitare în caz de necesitate.Introduction: The term of retrosternal or substernal goiter means that more than 50% of thyroid gland descends in the thorax. Material and methods: There is a retrospective study on retrosternal and substernal goiter and its pathological features among 2482 patients who underwent thyroidectomy between 2000 and 2010 in the First Surgery Clinic of Iasi. Retrosternal goiter was diagnosed in 54 (2.17%) patients. All patients were referred to surgery from the Clinic of Endocrinology. Results: Mean age at diagnosis was 55.3±3.58 years, and most cases were found in women – 83.3%). The clinical picture of retrosternal goiter was dominated by compressive disorders. Thyroid function abnormalities were identified by hormonal assays performed on Endocrinology Clinic Iasi in 15 (27.7%) cases. The diagnosis of retrosternal goiter was suggested by clinical examination and confirmed by imaging: chest X-ray, ultrasound, CT scan. The cervical approach was safely performed. Only in 8 cases (14.8%), sternotomy was necessary. There was no mortality, and morbidity was 5.5% (3 cases). The length of stay in the hospital was 4.3 days. We compared our recent data with a previous report on retrosternal and thoracic goiter treated in First Surgery Clinic of Iasi during 1950 to 1979 and published in the journal “Chirurgia” in 1981. Conclusions: Retrosternal goiter is a particular form of thyroid surgical pathology presented with reduced incidence. Diagnosis and treatment of retrosternal goiter involve a multidisciplinary team. The endocrinologist has an important role in diagnosis and postoperative follow-up. Surgery is the treatment of choice for substernal goiters, but there are still some controversies on surgical approach, and complication rate. The cervical approach can be safely performed in almost all cases but when required, sternotomy should be performed without hesitation

Poly‐aneuploid cancer cells promote evolvability, generating lethal cancer

Cancer cells utilize the forces of natural selection to evolve evolvability allowing a constant supply of heritable variation that permits a cancer species to evolutionary track changing hazards and opportunities. Over time, the dynamic tumor ecosystem is exposed to extreme, catastrophic changes in the conditions of the tumor—natural (e.g., loss of blood supply) or imposed (therapeutic). While the nature of these catastrophes may be varied or unique, their common property may be to doom the current cancer phenotype unless it evolves rapidly. Poly‐aneuploid cancer cells (PACCs) may serve as efficient sources of heritable variation that allows cancer cells to evolve rapidly, speciate, evolutionarily track their environment, and most critically for patient outcome and survival, permit evolutionary rescue, therapy resistance, and metastasis. As a conditional evolutionary strategy, they permit the cancer cells to accelerate evolution under stress and slow down the generation of heritable variation when conditions are more favorable or when the cancer cells are closer to an evolutionary optimum. We hypothesize that they play a critical and outsized role in lethality by their increased capacity for invasion and motility, for enduring novel and stressful environments, and for generating heritable variation that can be dispensed to their 2N+ aneuploid progeny that make up the bulk of cancer cells within a tumor, providing population rescue in response to therapeutic stress. Targeting PACCs is essential to cancer therapy and patient cure—without the eradication of the resilient PACCs, cancer will recur in treated patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156440/2/eva12929_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156440/1/eva12929.pd

Local Duality Predictions for x ~ 1 Structure Functions

Recent data on the proton F_2 structure function in the resonance region suggest that local quark-hadron duality works remarkably well for each of the low-lying resonances, including the elastic, to rather low values of Q^2. We derive model-independent relations between structure functions at x ~ 1 and elastic electromagnetic form factors, and predict the x -> 1 behavior of nucleon polarization asymmetries and the neutron to proton structure function ratios from available data on nucleon electric and magnetic form factors.Comment: 10 pages, 2 figures, typos in Eq. (2) correcte

Nuclear transparency and effective kaon-nucleon cross section from the A(e, e'K+) reaction

We have determined the transparency of the nuclear medium to kaons from $A(e,e^{'} K^{+})$ measurements on $^{12}$C, $^{63}$Cu, and $^{197}$Au targets. The measurements were performed at the Jefferson Laboratory and span a range in four-momentum-transfer squared Q$^2$=1.1 -- 3.0 GeV$^2$. The nuclear transparency was defined as the ratio of measured kaon electroproduction cross sections with respect to deuterium, ($\sigma^{A}/\sigma^{D}$). We further extracted the atomic number ($A$) dependence of the transparency as parametrized by $T= (A/2)^{\alpha-1}$ and, within a simple model assumption, the in-medium effective kaon-nucleon cross sections. The effective cross sections extracted from the electroproduction data are found to be smaller than the free cross sections determined from kaon-nucleon scattering experiments, and the parameter $\alpha$ was found to be significantly larger than those obtained from kaon-nucleus scattering. We have included similar comparisons between pion- and proton-nucleon effective cross sections as determined from electron scattering experiments, and pion-nucleus and proton-nucleus scattering data.Comment: 7 pages, 5 figure

Scaling study of the pion electroproduction cross sections and the pion form factor

The $^{1}$H($e,e^\prime \pi^+$)n cross section was measured for a range of four-momentum transfer up to $Q^2$=3.91 GeV$^2$ at values of the invariant mass, $W$, above the resonance region. The $Q^2$-dependence of the longitudinal component is consistent with the $Q^2$-scaling prediction for hard exclusive processes. This suggests that perturbative QCD concepts are applicable at rather low values of $Q^2$. Pion form factor results, while consistent with the $Q^2$-scaling prediction, are inconsistent in magnitude with perturbative QCD calculations. The extraction of Generalized Parton Distributions from hard exclusive processes assumes the dominance of the longitudinal term. However, transverse contributions to the cross section are still significant at $Q^2$=3.91 GeV$^2$.Comment: 6 pages, 3 figure

Measurement of Nuclear Transparency for the A(e,e' pi^+) Reaction

We have measured the nuclear transparency of the A(e,e' pi^+) process in ^{2}H,^{12}C, ^{27}Al, ^{63}Cu and ^{197}Au targets. These measurements were performed at the Jefferson Laboratory over a four momentum transfer squared range Q^2 = 1.1 - 4.7 (GeV/c)^2. The nuclear transparency was extracted as the super-ratio of $(\sigma_A/\sigma_H)$ from data to a model of pion-electroproduction from nuclei without pi-N final state interactions. The Q^2 and atomic number dependence of the nuclear transparency both show deviations from traditional nuclear physics expectations, and are consistent with calculations that include the quantum chromodynamical phenomenon of color transparency.Comment: 5 pages, 3 figs Changes to figure 2 and 3 (error band updated and theory curves updated

Study of the A(e,e'π+\pi^+) Reaction on 1^1H, 2^2H, 12^{12}C, 27^{27}Al, 63^{63}Cu and 197^{197}Au

Cross sections for the p($e,e'\pi^{+}$)n process on $^1$H, $^2$H, $^{12}$C, $^{27}$Al, $^{63}$Cu and $^{197}$Au targets were measured at the Thomas Jefferson National Accelerator Facility (Jefferson Lab) in order to extract the nuclear transparencies. Data were taken for four-momentum transfers ranging from $Q^2$=1.1 to 4.8 GeV$^2$ for a fixed center of mass energy of $W$=2.14 GeV. The ratio of $\sigma_L$ and $\sigma_T$ was extracted from the measured cross sections for $^1$H, $^2$H, $^{12}$C and $^{63}$Cu targets at $Q^2$ = 2.15 and 4.0 GeV$^2$ allowing for additional studies of the reaction mechanism. The experimental setup and the analysis of the data are described in detail including systematic studies needed to obtain the results. The results for the nuclear transparency and the differential cross sections as a function of the pion momentum at the different values of $Q^2$ are presented. Global features of the data are discussed and the data are compared with the results of model calculations for the p($e,e'\pi^{+}$)n reaction from nuclear targets.Comment: 28 pages, 19 figures, submited to PR