Cerebrospinal Fluid Sphingomyelins in Alzheimer's Disease, Neurodegeneration, and Neuroinflammation

BACKGROUND: Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by sample size, breadth of SMs examined, and diversity of biomarkers available. OBJECTIVE: Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation. METHODS: Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models. RESULTS: No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs. CONCLUSION: The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific

Assessing the Biological Mechanisms Linking Smoking Behavior and Cognitive Function: A Mediation Analysis of Untargeted Metabolomics

(1) Smoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which have both been linked to the development of Alzheimer’s disease and related dementias (ADRD). This study identified potential mechanisms of the smoking–cognitive function relationship using metabolomics data from the longitudinal Wisconsin Registry for Alzheimer’s Prevention (WRAP). (2) 1266 WRAP participants were included to assess the association between smoking status and four cognitive composite scores. Next, untargeted metabolomic data were used to assess the relationships between smoking and metabolites. Metabolites significantly associated with smoking were then tested for association with cognitive composite scores. Total effect models and mediation models were used to explore the role of metabolites in smoking-cognitive function pathways. (3) Plasma N-acetylneuraminate was associated with smoking status Preclinical Alzheimer Cognitive Composite 3 (PACC3) and Immediate Learning (IMM). N-acetylneuraminate mediated 12% of the smoking-PACC3 relationship and 13% of the smoking-IMM relationship. (4) These findings provide links between previous studies that can enhance our understanding of potential biological pathways between smoking and cognitive function

Coevolution between harmful male genitalia and female resistance in seed beetles

Reproductive conflict between the sexes is thought to be a key force in the evolution of many reproductive characters, but persuasive evidence for its significance is still scarce. The spectacular evolution of male genitalia that impose physical injury on females during mating has often been suggested to be a product of sexually antagonistic coevolution, but our understanding of these extraordinary adaptations is very limited, and there are no direct data addressing their evolutionary elaboration. We show that more spiny male genitalia causes more harm to females during copulation and provide comparative evidence for the correlated evolution between these antagonistic adaptations in males and a female counteradaptation (the amount of connective tissue in the copulatory duct) in a group of insects. By combining comparative and experimental methods, we demonstrate that imbalance of relative armament of the sexes affects evolution of the economics of reproduction: as males evolve genitalia that are more harmful relative to the level of female counteradaptation, costs associated with mating for females increase and population fitness is depressed. Our results unveil a coevolutionary arms race between the sexes and are consistent with a proposed link between sexual conflict, species' viability, and the risk of extinction

Phase 1 study of safety, tolerability and immunogenicity of the human telomerase (hTERT)-encoded DNA plasmids INO-1400 and INO-1401 with or without IL-12 DNA plasmid INO-9012 in adult patients with solid tumors

BACKGROUND: Human telomerase reverse transcriptase (hTERT) is frequently classified as a \u27universal\u27 tumor associated antigen due to its expression in a vast number of cancers. We evaluated plasmid DNA-encoded hTERT as an immunotherapy across nine cancer types. METHODS: A phase 1 clinical trial was conducted in adult patients with no evidence of disease following definitive surgery and standard therapy, who were at high risk of relapse. Plasmid DNA encoding one of two hTERT variants (INO-1400 or INO-1401) with or without plasmid DNA encoding interleukin 12 (IL-12) (INO-9012) was delivered intramuscularly concurrent with the application of the CELLECTRA constant-current electroporation device 4 times across 12 weeks. Safety assessments and immune monitoring against native (germline, non-mutated, non-plasmid matched) hTERT antigen were performed. The largest cohort of patients enrolled had pancreatic cancer, allowing for additional targeted assessments for this tumor type. RESULTS: Of the 93 enrolled patients who received at least one dose, 88 had at least one adverse event; the majority were grade 1 or 2, related to injection site. At 18 months, 54.8% (51/93) patients were disease-free, with median disease-free survival (DFS) not reached by end of study. For patients with pancreatic cancer, the median DFS was 9 months, with 41.4% of these patients remaining disease-free at 18 months. hTERT immunotherapy induced a de novo cellular immune response or enhanced pre-existing cellular responses to native hTERT in 96% (88/92) of patients with various cancer types. Treatment with INO-1400/INO-1401±INO-9012 drove hTERT-specific IFN-γ production, generated hTERT-specific CD4+ and CD8+ T cells expressing the activation marker CD38, and induced hTERT-specific activated CD8 +CTLs as defined by cells expressing perforin and granzymes. The addition of plasmid IL-12 adjuvant elicited higher magnitudes of cellular responses including IFN-γ production, activated CD4+ and CD8+ T cells, and activated CD8+CTLs. In a subset analysis of pancreatic cancer patients, the presence of immunotherapy-induced activated CD8+ T cells expressing PD-1, granzymes and perforin correlated with survival. CONCLUSIONS: Plasmid DNA-encoded hTERT/IL-12 DNA immunotherapy was well-tolerated, immune responses were noted across all tumor types, and a specific CD8+ phenotype increased by the immunotherapy was significantly correlated with survival in patients with pancreatic cancer

Engendering healthy masculinities to prevent sexual violence: Rationale for and design of the Manhood 2.0 trial

Violence against women and girls is an important global health concern. Numerous health organizations highlight engaging men and boys in preventing violence against women as a potentially impactful public health prevention strategy. Adapted from an international setting for use in the US, “Manhood 2.0” is a “gender transformative” program that involves challenging harmful gender and sexuality norms that foster violence against women while promoting bystander intervention (i.e., giving boys skills to interrupt abusive behaviors they witness among peers) to reduce the perpetration of sexual violence (SV) and adolescent relationship abuse (ARA). Manhood 2.0 is being rigorously evaluated in a community-based cluster-randomized trial in 21 lower resource Pittsburgh neighborhoods with 866 adolescent males ages 13–19. The comparison intervention is a job readiness training program which focuses on the skills needed to prepare youth for entering the workforce, including goal setting, accountability, resume building, and interview preparation. This study will provide urgently needed information about the effectiveness of a gender transformative program, which combines healthy sexuality education, gender norms change, and bystander skills to interrupt peers\u27 disrespectful and harmful behaviors to reduce SV/ARA perpetration among adolescent males. In this manuscript, we outline the rationale for and evaluation design of Manhood 2.0

Engendering healthy masculinities to prevent sexual violence: Rationale for and design of the Manhood 2.0 trial

Violence against women and girls is an important global health concern. Numerous health organizations highlight engaging men and boys in preventing violence against women as a potentially impactful public health prevention strategy. Adapted from an international setting for use in the US, “Manhood 2.0” is a “gender transformative” program that involves challenging harmful gender and sexuality norms that foster violence against women while promoting bystander intervention (i.e., giving boys skills to interrupt abusive behaviors they witness among peers) to reduce the perpetration of sexual violence (SV) and adolescent relationship abuse (ARA). Manhood 2.0 is being rigorously evaluated in a community-based cluster-randomized trial in 21 lower resource Pittsburgh neighborhoods with 866 adolescent males ages 13–19. The comparison intervention is a job readiness training program which focuses on the skills needed to prepare youth for entering the workforce, including goal setting, accountability, resume building, and interview preparation. This study will provide urgently needed information about the effectiveness of a gender transformative program, which combines healthy sexuality education, gender norms change, and bystander skills to interrupt peers\u27 disrespectful and harmful behaviors to reduce SV/ARA perpetration among adolescent males. In this manuscript, we outline the rationale for and evaluation design of Manhood 2.0