Project description:As part of current harm reduction strategies, candidate modified risk tobacco products (MRTP)s are developed to offer adult smokers who want to continue using tobacco products as an alternative to cigarettes while potentially reducing individual risk and population harm compared to smoking cigarettes. One of these candidate MRTPs is the Tobacco Heating System (THS) 2.2 which does not burn tobacco, but instead heats it, thus producing significantly reduced levels of harmful and potentially harmful constituents (HPHC)s compared with combustible cigarettes (CC). The assessment of MRTPs against combustible cigarettes requires the establishment of exposure-response markers. Biomarkers derived from blood offer for the general population a less invasive alternative than sampling the primary site, such as the airways. Various diseases and exposures, including cigarette smoke, have been shown to alter the molecular profile of the blood. Leveraging this fact, a whole blood derived gene signature that can distinguish current smokers from either non-smokers or former smokers with high specificity and sensitivity was previously reported. Four controlled, parallel randomized groups, open-label clinical studies were conducted with subjects randomized to three groups: (1) switching from CCs to THS2.2 (or its mentholated version, respectively); (2) continuous use of CC; or (3) smoking abstinence. These studies had an investigational period of five days in confinement which was followed by an 85 day ambulatory period for two of them. By measuring biomarkers of exposure to selected HPHCs, these studies showed a consistent reduced exposure in subjects that either stopped smoking or switched to THS2.2 (including mentholated version), compared with subjects who continued smoking their own cigarettes at both day 5 and at day 90. To complement the classical exposure measurements, we tested the small signature consisting of only 11 genes on the blood transcriptome of subjects enrolled in the clinical studies. We show that in all four clinical studies tested, the signature scores were consistently reduced in subjects that either stopped smoking or switched to THS2.2 compared with subjects who continued smoking their conventional tobacco products at both day 6 and at day 91.

Project description:The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD. We used RNA-Sequencing gene expression to characterize both prognostic and diagnostic molecular signatures associated to PTSD risk and PTSD status compared to control subjects. Peripheral blood luekocytes gene expression was subject to transcriptional analysis for 94 service members both prior-to and following-deployment to conflict zones. Half of the subjects returned with Post-traumatic stress disorder (PTSD), while the other half did not.

Dataset Information

E-MTAB-6558

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