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Metabolomics, proteomics and DNA methylome assays, when done in tandem from the same blood sample and analyzed together, offer an opportunity to evaluate the molecular basis of post-traumatic stress disorder (PTSD) course and pathogenesis. We performed separate metabolomics, proteomics, and DNA methylome assays on blood samples from two well-characterized cohorts of 159 active duty male participants with relatively recent onset PTSD (<1.5 years) and 300 male veterans with chronic PTSD (>7 years). Analyses of the multi-omics datasets from these two independent cohorts were used to identify convergent and distinct molecular profiles that might constitute potential signatures of severity and progression of PTSD and its comorbid conditions. Molecular signatures indicative of homeostatic processes such as signaling and metabolic pathways involved in cellular remodeling, neurogenesis, molecular safeguards against oxidative stress, metabolism of polyunsaturated fatty acids, regulation of normal immune response, post-transcriptional regulation, cellular maintenance and markers of longevity were significantly activated in the active duty participants with recent PTSD. In contrast, we observed significantly altered multimodal molecular signatures associated with chronic inflammation, neurodegeneration, cardiovascular and metabolic disorders, and cellular attritions in the veterans with chronic PTSD. Activation status of signaling and metabolic pathways at the early and late timepoints of PTSD demonstrated the differential molecular changes related to homeostatic processes at its recent and multi-system syndromes at its chronic phase. Molecular alterations in the recent PTSD seem to indicate some sort of recalibration or compensatory response, possibly directed in mitigating the pathological trajectory of the disorder., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare no competing interests. KJR has provided scientific consultation to Alkermes and Biogen, is on scientific advisory boards for Jannsen and Verily, and has received sponsored research funding from Brainsway and Genomind. None of these relationships are related to the work described here., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Individuals with post-traumatic stress disorder (PTSD) who experience additional traumas or stressful life events may undergo symptomatic worsening, but no data exist on whether exposure to the COVID-19 pandemic in a high infection area worsens mental health among older adults with chronic PTSD., Methods: Seventy-six older adults (N = 46 with PTSD and N = 30 trauma-exposed comparison subjects [TE]) for whom prepandemic data were available were interviewed between April 1 and May 8, 2020 to quantify depressive (Hamilton Rating Scale for Depression [HRSD]) and PTSD symptom (Post-traumatic Stress Disorder Checklist [PCL-5]) levels. Group differences in baseline characteristics as well as pre-post pandemic symptom levels were examined, and participant characteristics were assessed as moderators of symptom change., Results: Compared to TEs, individuals with PTSD more often reported living alone and experiencing a physical illness (χ 2  = 5.1, df = 1, p = 0.02). PCL-5 scores among individuals with PTSD decreased during the COVID-19 pandemic by 7.1 points (t(69) = -3.5, p = 0.0008), whereas the TE group did not change significantly. Overall no significant differences in HRSD were found between groups, but a race or ethnicity variable was found to moderate HRSD symptom change. Non-black or Hispanic individuals with PTSD experienced significantly increased HRSD scores during the pandemic compared to black or Hispanic PTSD participants., Conclusion: The findings are indicative of complexity in the responses of older individuals with PTSD to further stressful life events as well as possibly unique aspects to the COVID-19 pandemic as a stressor. Sources of resilience may exist based on experience with prior traumas as well as increasing age promoting more adaptive coping styles., (Copyright © 2020 American Association for Geriatric Psychiatry. All rights reserved.)

War veterans are at increased risk of suicide that may be related to deployment and/or post-deployment stressors and to adjustment-related factors. The aim of this study was to examine whether levels of plasma neuropeptide Y (NPY) might distinguish combat veterans who have made a post-deployment suicide attempt from those who have never made a suicide attempt. We focused on NPY because of prior findings linking NPY with the neurobiology of resilience, stress-related and other disorders, and suicidal behavior. Demographic and clinical parameters of suicide attempters and non-attempters were assessed and plasma NPY was determined by radioimmunoassay. NPY levels were higher among attempters in comparison to non-attempters, controlling for sex and body-mass index. Suicide attempters had higher Scale for Suicidal Ideation (SSI) scores than non-attempters. There was a positive correlation between NPY levels and SSI scores among non-attempters but not among attempters. Likewise, NPY levels positively correlated with Brown-Goodwin Aggression Scale scores among suicide attempters but not among non-attempters. This is the first demonstration of altered plasma NPY levels in association with suicide attempt history and suicidal ideation in veterans. Our findings suggest that clinical differences between combat veterans with or without a history of suicide attempt may have a neurobiological origin., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier B.V.)

Background: The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial., Patients and Methods: Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized., Results: Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%-62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%-51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%-46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain., Conclusions: TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification., Competing Interests: Disclosure JF has received honoraria from Genentech. AL has received research funding from Bristol Myers Squibb and NantOmics and holds equity in Sanofi. MO has served on advisory boards for PharmaMar, Novartis, and Targeted Oncology, and received travel expenses from Bristol Myers Squibb and Merck. YRM-G has received travel expenses from AstraZeneca. BTL holds two institutional patents (US62/685,057, US62/514,661), and has served on advisory boards for Genentech (subsidiary of Roche), Eli Lilly, Guardant Health, Hengrui Therapeutics, Mersana Therapeutics, and Thermo Fisher Scientific, received travel expenses from MORE Health and Resolution Bioscience, and received research funding from Amgen, AstraZeneca, BioMedValley Discoveries, Daiichi Sankyo, Genentech, GRAIL, Guardant Health, Eli Lilly, Hengrui Therapeutics, Illumina, and MORE Health. JJH has received consulting fees from Bristol Myers Squibb, Cytomx, Eli Lilly, Eisai, Exelixis, Imvax, QED, and research funding from Bristol Myers Squibb. GI has received research funding from Janssen, Mirati Therapeutics, and Novartis, and consulting fees from Mirati Therapeutics. MMG has received honoraria from Bayer and Flatiron Health, served on advisory boards for Bayer, Boehringer Ingelheim, Epizyme, Daiichi Sankyo, Karyopharm, and Springworks Therapeutics, served on a speakers’ bureau for Amgen, and received travel expenses from Epizyme. AS has received research funding from Eli Lilly, Kura Oncology, Merus, Northern Biologics, and Surface Oncology. DMH owns stock in Fount Therapeutics, has served on advisory boards for ArQule, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, CytomX, Debiopharm, Fount Therapeutics, Genentech, Eli Lilly, Janssen, Jazz Pharma, Pfizer, and Puma Biotechnology, received research funding from AstraZeneca, Bayer, Loxo Oncology, and Puma Biotechnology, and received travel expenses from Chugai Pharma and Genentech; he is currently employed by and holds equity in Loxo Oncology, a subsidiary of Eli Lilly. AD has received honoraria and/or served on advisory boards for 14ner/Elevation Oncology, Abbvie, ArcherDX, AstraZeneca, Axis Pharma, Bayer, Beigene, BergenBio, Blueprint Medicines, Exelixis, Helsinn, Hengrui Therapeutics, Loxo Oncology (subsidiary of Eli Lilly), Monopteros, MORE Health, Remedica, Roche (subsidiaries Genentech and Ignyta), Pfizer, Takeda (subsidiaries Ariad and Millennium), TP Therapeutics, Tyra Biosciences, and Verastem; and received research funding from Exelixis, Foundation Medicine GlaxoSmithKline, Pfizer, PharmaMar, Teva, and Taiho. All research funding was provided to the institution. All other authors report no financial relationships., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include attention-deficit/hyperactivity disorder (ADHD) and more notably comorbid ADHD and conduct disorder (CD). Despite existing evidence for the purported role of abnormal serotonergic function in aggressive youth and adults, little evidence exists on the role of serotonin in the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relation between serotonergic function in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood would predict the development of adult ASPD. Towards this goal we divided 40 adults (M = 37, F = 3), ages 23-26 (m-24.57, sd-2.33) diagnosed with childhood ADHD into 2 groups: participants with (n = 21) and without (n = 19) ASPD. We used logistic regression to assess whether serotonergic measures in childhood assessed via prolactin and cortisol responses to a fenfluramine challenge, would selectively predict the development of ASPD in early adulthood. Logistic regression models showed that low central serotonergic response in childhood indexed by cortisol response significantly predicted adult ASPD (Wald = 4.427, p = .035) but not ADHD diagnosis in adulthood. Adults without ASPD had the highest serotonergic response whereas adults with adolescent ASPD (i.e. early onset ASPD) had the lowest response. Thus we provide new evidence of the link between low serotonergic function in childhood and the development of ASPD in adulthood, particularly for boys with adolescent onset of ASPD. These findings are relevant for understanding the contribution of childhood neurobiology to risk for later ASPD., (Copyright © 2018. Published by Elsevier B.V.)

Introduction: Post-traumatic stress disorder (PTSD) has been associated with immune disturbances, including a higher incidence of infections and autoimmune diseases as well as a net pro-inflammatory state. Natural killer (NK) cells, a key component of the innate immune system, have been less well-studied in PTSD despite their importance in immunity., Methods: We studied two independent samples of combat-exposed male war veterans with or without PTSD, the first ("Discovery Sample") to generate hypotheses, and the second ("Validation Sample") to replicate the findings. The Discovery Sample was comprised of 42 PTSD subjects and 42 controls. The Validation Sample was comprised of 25 PTSD subjects and 30 controls. Participants had fasting, morning blood samples collected for examination of the frequency of NK cell subsets, determined by flow cytometry. The current and lifetime Clinician Administered PTSD Scale (CAPS) was used to assess symptom severity. Statistical analyses were adjusted for age and BMI., Results: PTSD subjects compared to controls had (i) a significantly higher relative frequency of atypical CD56(-)CD16(+) NK cells in the Discovery Sample (p=0.027), which was replicated in the Validation Sample (p=0.004) and the combined sample (p<0.001), and (ii) a non-significantly lower relative frequency of CD56(bright)CD16(-) NK cells in the two samples (p=0.082; p=0.118), which became statistically significant in the combined sample (p=0.020). Further, within subjects with PTSD of both samples, the relative frequency of atypical CD56(-)CD16(+) NK cells was near significantly positively correlated with lifetime PTSD severity (p=0.074)., Discussion: This study is the first to characterize NK cell subsets in individuals with PTSD. The results suggest that combat-exposed men with PTSD exhibit an aberrant profile of NK cells with significantly higher frequencies of an atypical population of CD56(-)CD16(+) cells and possibly lower frequencies of the functional CD56(bright)CD16(-) NK cell subsets. Higher proportions of dysfunctional CD56(-)CD16(+) cells have been reported in certain chronic viral infections and in senescent individuals. It is possible that this could contribute to immune dysfunctions and prematurely senescent phenotypes seen in PTSD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Psychiatric, physical and biological aspects of posttraumatic stress disorder (PTSD) may be associated with dysfunctions in several cellular processes including nitric oxide (NO) production. NO is synthesized from arginine in a reaction carried out by NO synthase (NOS) enzymes. The recently introduced "global arginine bioavailability ratio" (GABR; ratio of arginine to [ornithine+citrulline]) has been proposed as a reliable approximation of NO synthetic capacity in vivo. The objectives of the present study were to test the hypotheses that (i) subjects with combat-related PTSD have lower GABR scores than combat controls, (ii) GABR score is inversely associated with the severity of psychopathological measures, (iii) GABR score is inversely associated with markers of inflammation., Methods: Metabolic profiling for plasma samples (i.e. arginine, citrulline and ornithine) and inflammation markers (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon [IFN]-γ and C-reactive protein [CRP]) were assessed in 56 combat-exposed males with PTSD and 65 combat-exposed males without PTSD. We assessed severity of PTSD (Clinician Administered PTSD Scale [CAPS]) and depression (Beck Depression Inventory-II [BDI-II]) as well as history of early life trauma (Early Trauma Inventory [ETI]) and affectivity (Positive and Negative Affect Schedule [PANAS])., Results: The GABR value was (i) significantly lower in PTSD subjects compared to controls (p=0.001), (ii) significantly inversely correlated with markers of inflammation including IL6 (p=0.04) and TNFα (p=0.02), and (iii) significantly inversely correlated with CAPS current (p=0.001) and lifetime (p<0.001) subscales, ETI (p=0.045) and PANAS negative (p=0.006). Adding antidepressant use or MDD diagnosis as covariates led to similar results. Adding age and BMI as covariates also led to similar results, with the exception of IL6 and ETI losing their significant association with GABR., Discussion: This study provides the first evidence that global arginine bioavailability, a marker of NO synthetic capacity in vivo, is lower in veterans with PTSD and is negatively associated with some markers of inflammation as well as with measures of PTSD symptom severity, negative affectivity and childhood adverse experiences. These findings add to the accumulating evidence that specific cellular dysfunction may be associated with the symptomatology of PTSD and may help to explain the higher burden of cardio-metabolic disturbances seen in this disorder., (Copyright © 2015 Elsevier Inc. All rights reserved.)

recA protein promotes homologous pairing and strand exchange by an ordered reaction in which the protein first polymerizes on single-stranded DNA. This presynaptic intermediate, which can be formed either in the presence or absence of Escherichia coli single-stranded binding protein (SSB), has been isolated by gel filtration and characterized. At saturation, purified complexes contained one molecule of recA protein per 3.6 nucleotide residues of single-stranded DNA. Complexes that had been formed in the presence of SSB contained up to one molecule of SSB per 15 nucleotide residues, but the content of SSB in different preparations of isolated complexes appeared to be inversely related to the content of recA protein. Even when they have lost as much as a third of their recA protein, presynaptic complexes can retain activity, because the formation of stable joint molecules depends principally on the binding of recA protein to the single-stranded DNA in the localized region that corresponds to the end of the duplex substrate.