Naturalistic psilocybin use is associated with persisting improvements in mental health and wellbeing: results from a prospective, longitudinal survey

IntroductionThe classic psychedelic psilocybin, found in some mushroom species, has received renewed interest in clinical research, showing potential mental health benefits in preliminary trials. Naturalistic use of psilocybin outside of research settings has increased in recent years, though data on the public health impact of such use remain limited.MethodsThis prospective, longitudinal study comprised six sequential automated web-based surveys that collected data from adults planning to take psilocybin outside clinical research: at time of consent, 2 weeks before, the day before, 1–3 days after, 2–4 weeks after, and 2–3 months after psilocybin use.ResultsA sample of 2,833 respondents completed all baseline assessments approximately 2 weeks before psilocybin use, 1,182 completed the 2–4 week post-use survey, and 657 completed the final follow-up survey 2–3 months after psilocybin use. Participants were primarily college-educated White men residing in the United States with a prior history of psychedelic use; mean age = 40 years. Participants primarily used dried psilocybin mushrooms (mean dose = 3.1 grams) for “self-exploration” purposes. Prospective longitudinal data collected before and after a planned psilocybin experience on average showed persisting reductions in anxiety, depression, and alcohol misuse, increased cognitive flexibility, emotion regulation, spiritual wellbeing, and extraversion, and reduced neuroticism and burnout after psilocybin use. However, a minority of participants (11% at 2–4 weeks and 7% at 2–3 months) reported persisting negative effects after psilocybin use (e.g., mood fluctuations, depressive symptoms).DiscussionResults from this study, the largest prospective survey of naturalistic psilocybin use to date, support the potential for psilocybin to produce lasting improvements in mental health symptoms and general wellbeing

Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer

A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency. Using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but its drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also inhibits triple negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

The characterization of breast anatomical metrics using dedicated breast CT

Purpose: Accurate anatomical characterization of the breast is useful in breast phantom development and computer modeling of breast imaging technologies. Capitalizing on the three-dimensional capabilities of dedicated breast CT (bCT), a number of parameters which describe breast shape and fibroglandular distribution are defined

Activation of estrogen receptor α increases and estrogen receptor β decreases apolipoprotein E expression in hippocampus in vitro and in vivo

Previous evidence indicates that, in carriers of apolipoprotein E4 (ApoE4), estrogen therapy increased the risk of late-onset Alzheimer's disease (AD), whereas in individuals carrying ApoE2/3, estrogen therapy reduced the risk of AD [Cauley JA, Zmuda JM, Yaffe K, Kuller LH, Ferrell RE, Wisniewski SR, Cummings SR (1999) J Bone Miner Res 14:1175–1181; Yaffe K, Haan M, Byers A, Tangen C, Kuller L (2000) Neurology 54:1949–1954]. Estrogen mechanisms of action are mediated by two estrogen receptors (ERs), ERα and ERβ. In this study, we determined the relationship between ER subtype and estrogen regulation of ApoE expression in HT-22 cells ectopically transfected with ERα or ERβ, in primary cultured rat hippocampal neurons in vitro and in rat hippocampus in vivo by both molecular biological and pharmacological analyses. Results of these analyses demonstrated that activation of ERα either by 17β-estradiol or a specific-agonist, propylpyrazole triol, up-regulated ApoE mRNA and protein expression. In contrast, the ERβ-selective agonist, diarylpropionitrile, down-regulated ApoE mRNA and protein expression. These results demonstrate that, in vitro and in vivo, ApoE expression can be differentially regulated depending on activation of ER subtypes. These data suggest that use of ER-selective ligands could provide therapeutic benefit to reduce the risk of AD by increasing ApoE expression in ApoE2/3 allele carriers and decreasing ApoE expression in ApoE4 allele carriers

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field