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AbstractThe peripheral immune system has a key pathophysiologic role in Frontotemporal degeneration (FTD). We sought a comprehensive transcriptome-wide evaluation of gene expression alterations unique to the peripheral immune system in FTD compared to healthy controls and amyotrophic lateral sclerosis.Nineteen subjects with FTD with 19 matched healthy controls and 9 subjects with amyotrophic lateral sclerosis underwent isolation of peripheral blood mononuclear cells (PBMCs) which then underwent bulk ribonucleic acid sequencing.There was increased expression in genes associated with CD19+ B-cells, CD4+ T-cells, and CD8+ T-cells in FTD participants compared to healthy controls. In contrast, there was decreased expression in CD33+ myeloid cells, CD14+ monocytes, BDCA4+ dendritic cells, and CD56+ natural killer cells in FTD and healthy controls. Additionally, there was decreased expression is seen in associated with 2 molecular processes: autophagy with phagosomes and lysosomes, and protein processing/export. Significantly downregulated in PBMCs of FTD subjects were genes involved in antigen processing and presentation as well as lysosomal lumen formation compared to healthy control PBMCs.Our findings that the immune signature based on gene expression in PBMCs of FTD participants favors adaptive immune cells compared to innate immune cells. And decreased expression in genes associated with phagosomes and lysosomes in PBMCs of FTD participants compared to healthy controls.

BackgroundFragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by intention tremor, cerebellar ataxia, and executive dysfunction in carriers of a CGG repeat expansion premutation (55-200 repeats) in the fragile X mental retardation 1 (FMR1) gene. Given reports of poor insight in FXTAS, we postulated that patients with FXTAS would be less likely to exhibit placebo response.ObjectiveTo analyze placebo response from the first randomized controlled trial in FXTAS that evaluated cognitive and motor outcomes after 1 year of treatment with memantine.MethodsData from the placebo arm of the first randomized controlled trial in FXTAS were analyzed. There were 2 coprimary outcomes. Based on studies in Parkinson's disease, placebo responders were defined as individuals with an improvement of at least 50% in the coprimary outcomes. Improvements of 20% and 30% served as secondary cutoff values based on the suggested magnitude of placebo response in other movement disorders.ResultsA total of 36 participants in the placebo group completed baseline and follow-up evaluations. The average age was 66 ± 7 years, and 60% were men. Average CGG repeat size was 86 ± 18. A total of 19 participants had stage 3 disease. Only 1 patient showed 50% improvement in both coprimary outcomes. At 30% and 20% improvement, there were 2 and 3 patients showing placebo response in the coprimary outcomes, respectively.ConclusionsPatients with FXTAS exhibited low rates of placebo response in a randomized controlled trial. Further studies on the relationship between baseline insight and placebo responsivity are applicable to FXTAS and other disorders exhibiting cognitive impairment.

Ongoing biomarker development programs have been designed to identify serologic or imaging signatures of clinico-pathologic entities, assuming distinct biological boundaries between them. Identified putative biomarkers have exhibited large variability and inconsistency between cohorts, and remain inadequate for selecting suitable recipients for potential disease-modifying interventions. We launched the Cincinnati Cohort Biomarker Program (CCBP) as a population-based, phenotype-agnostic longitudinal study. While patients affected by a wide range of neurodegenerative disorders will be deeply phenotyped using clinical, imaging, and mobile health technologies, analyses will not be anchored on phenotypic clusters but on bioassays of to-be-repurposed medications as well as on genomics, transcriptomics, proteomics, metabolomics, epigenomics, microbiomics, and pharmacogenomics analyses blinded to phenotypic data. Unique features of this cohort study include (1) a reverse biology-to-phenotype direction of biomarker development in which clinical, imaging, and mobile health technologies are subordinate to biological signals of interest; (2) hypothesis free, causally- and data driven-based analyses; (3) inclusive recruitment of patients with neurodegenerative disorders beyond clinical criteria-meeting patients with Parkinson's and Alzheimer's diseases, and (4) a large number of longitudinally followed participants. The parallel development of serum bioassays will be aimed at linking biologically suitable subjects to already available drugs with repurposing potential in future proof-of-concept adaptive clinical trials. Although many challenges are anticipated, including the unclear pathogenic relevance of identifiable biological signals and the possibility that some signals of importance may not yet be measurable with current technologies, this cohort study abandons the anchoring role of clinico-pathologic criteria in favor of biomarker-driven disease subtyping to facilitate future biosubtype-specific disease-modifying therapeutic efforts.

This pilot randomized controlled trial tested the potential efficacy of a brief internet-based, passive psychoeducation intervention, Free From Abuse, in promoting healthy relationships among young adults. Participants aged 18 to 24 years were randomly assigned to an intervention treatment (n = 71) or a placebo control condition (n = 77). Participants in the treatment arm had a larger increase in recognition of abusive behavior and reduction in domestic violence myth acceptance scores than participants in the control arm postintervention and after one week. This study provides preliminary evidence that brief internet-based passive psychoeducation is potentially useful in promoting healthy relationships among young adults. [ABSTRACT FROM AUTHOR]

The Greenland Ice Sheet contributed 10.6 mm to global sea level rise between 1992 and 2018, and it is projected to be the largest glacial contributor to sea level rise by 2100. Here we assess the relative importance of two major sources of uncertainty in 21st century ice loss projections: (1) the choice of sliding law and (2) the surface mass balance (SMB) forecast. Specifically, we used the ice flow model Úa to conduct an ensemble of runs for 48 combinations of sliding law and SMB forecast for three major Greenland outlet glaciers (Kangerlussuaq (KG), Humboldt (HU) and Petermann (PG) glaciers) with differing characteristics and evaluated how the sensitivity to these factors varied between the study glaciers. Overall, our results show that SMB forecasts were responsible for 4.45 mm of the variability in sea level rise by 2100 compared with 0.33 mm sea level equivalent (SLE) due to sliding law. HU had the largest absolute contribution to sea level rise and the largest range (2.16–7.96 mm SLE), followed by PG (0.84–5.42 mm SLE), and these glaciers showed similar patterns of ice loss across the SMB forecasts and sliding laws. KG had the lowest range and absolute values (- 0.60 to 3.45 mm SLE) of sea level rise, and the magnitude of mass loss by SMB forecast differed markedly between HU and PG. Our results highlight SMB forecasts as a key focus for improving estimates of Greenland's contribution to 21st century sea level rise. [ABSTRACT FROM AUTHOR]

AimTo investigate the in vivo effects of 3-indolylmethanamines 31B and PS121912 in treating ovarian cancer and leukemia, respectively.Materials and methodsTerminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and western blotting were applied to demonstrate the induction of apoptosis. Xenografted mice were investigated to show the antitumor effects of 3-indolylmethanamines. (13)C-Nuclear magnetic resource (NMR) and western blotting were used to demonstrate inhibition of glucose metabolism.Results31B inhibited ovarian cancer cell proliferation and activated caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1), and phosphorylated mitogen-activated protein kinases (MAPK), JUN N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38. 31B reduced ovarian cancer xenograft tumor growth and PS121912 inhibited the growth of HL-60-derived xenografts without any sign of toxicity. Compound 31B inhibited de novo glycolysis and lipogenesis mediated by the reduction of fatty acid synthase and lactate dehydrogenase-A expression.Conclusion3-Indolylmethanamines represent a new class of antitumor agents. We have shown for the first time the in vivo anticancer effects of 3-indolylmethanamines 31B and PS121912.