Using Transformer-Based Topic Modeling to Examine Discussions of Delta-8 Tetrahydrocannabinol: Content Analysis.

BACKGROUND: Delta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid found in small amounts naturally in the cannabis plant; it can also be synthetically produced in larger quantities from hemp-derived cannabidiol. Most states permit the sale of hemp and hemp-derived cannabidiol products; thus, hemp-derived delta-8 THC products have become widely available in many state hemp marketplaces, even where delta-9 THC, the most prominently occurring THC isomer in cannabis, is not currently legal. Health concerns related to the processing of delta-8 THC products and their psychoactive effects remain understudied. OBJECTIVE: The goal of this study is to implement a novel topic modeling approach based on transformers, a state-of-the-art natural language processing architecture, to identify and describe emerging trends and topics of discussion about delta-8 THC from social media discourse, including potential symptoms and adverse health outcomes experienced by people using delta-8 THC products. METHODS: Posts from January 2008 to December 2021 discussing delta-8 THC were isolated from cannabis-related drug forums on Reddit (Reddit Inc), a social media platform that hosts the largest web-based drug forums worldwide. Unsupervised topic modeling with state-of-the-art transformer-based models was used to cluster posts into topics and assign labels describing the kinds of issues being discussed with respect to delta-8 THC. Results were then validated by human subject matter experts. RESULTS: There were 41,191 delta-8 THC posts identified and 81 topics isolated, the most prevalent being (1) discussion of specific brands or products, (2) comparison of delta-8 THC to other hemp-derived cannabinoids, and (3) safety warnings. About 5% (n=1220) of posts from the resulting topics included content discussing health-related symptoms such as anxiety, sleep disturbance, and breathing problems. Until 2020, Reddit posts contained fewer than 10 mentions of delta-8-THC for every 100,000 cannabis posts annually. However, in 2020, these rates increased by 13 times the 2019 rate (to 99.2 mentions per 100,000 cannabis posts) and continued to increase into 2021 (349.5 mentions per 100,000 cannabis posts). CONCLUSIONS: Our study provides insights into emerging public health concerns around delta-8 THC, a novel substance about which little is known. Furthermore, we demonstrate the use of transformer-based unsupervised learning approaches to derive intelligible topics from highly unstructured discussions of delta-8 THC, which may help improve the timeliness of identification of emerging health concerns related to new substances.

The Cholesterol Metabolite 27HC Increases Secretion of Extracellular Vesicles Which Promote Breast Cancer Progression.

Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite 27-hydroxycholesterol (27HC) as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and as a liver X receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells with neutrophils (polymorphonuclear neutrophils; PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that includes exosomes. The resulting EVs had a size distribution that was skewed slightly larger than EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across 3 different subtypes: primary murine PMNs, RAW264.7 monocytic cells, and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in 2 different syngeneic models, demonstrating the potential role of 27HC-induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages, and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their protumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV-treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively, however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.

Racial differences in lifestyle, demographic, and health factors associated with quality of life (QoL) in midlife women.

Previously, quality of life (Qol) has been defined as an individual's evaluation of a satisfactory life as a whole (i.e. physically, mentally, psychologically, and socially). Only a few studies have examined the racial differences between QoL and risk factors associated with health, demographics, and lifestyle in midlife women. Thus, the purpose of our study was to determine racial differences in QoL in menopausal women due to lifestyle, demographic, and health related risk factors. A stratified ordinal logistic regression model was applied to self-reported questionnaire data from the Midlife Women's Health Study (MWHS) to determine risk factors associated with QoL differences between White and Black women during the menopausal transition. In multivariable models, our results showed Black women who had 3 or 4 comorbidities were about 4 times as likely to have higher QoL compared to women who had 0 to 2 comorbidities (95% CI: 1.65,10.78). However, the number of comorbidities was not significantly associated with QoL in White women in univariate or multiple regression. Further, body mass index and income were not significant factors in QoL in Black women but were in White women. Overall, our results illustrate that differences in health, demographic, and lifestyle factors are associated with QoL during menopause. Also, we suggest that future studies evaluate stratified models between racial groups to determine race-specific risk factors related to quality of life.

Identification of early liver toxicity gene biomarkers using comparative supervised machine learning.

Screening agrochemicals and pharmaceuticals for potential liver toxicity is required for regulatory approval and is an expensive and time-consuming process. The identification and utilization of early exposure gene signatures and robust predictive models in regulatory toxicity testing has the potential to reduce time and costs substantially. In this study, comparative supervised machine learning approaches were applied to the rat liver TG-GATEs dataset to develop feature selection and predictive testing. We identified ten gene biomarkers using three different feature selection methods that predicted liver necrosis with high specificity and selectivity in an independent validation dataset from the Microarray Quality Control (MAQC)-II study. Nine of the ten genes that were selected with the supervised methods are involved in metabolism and detoxification (Car3, Crat, Cyp39a1, Dcd, Lbp, Scly, Slc23a1, and Tkfc) and transcriptional regulation (Ablim3). Several of these genes are also implicated in liver carcinogenesis, including Crat, Car3 and Slc23a1. Our biomarker gene signature provides high statistical accuracy and a manageable number of genes to study as indicators to potentially accelerate toxicity testing based on their ability to induce liver necrosis and, eventually, liver cancer.

Combined Targeting of Estrogen Receptor Alpha and Exportin 1 in Metastatic Breast Cancers.

The majority of breast cancer specific deaths in women with estrogen receptor positive (ER+) tumors occur due to metastases that are resistant to therapy. There is a critical need for novel therapeutic approaches to achieve tumor regression and/or maintain therapy responsiveness in metastatic ER+ tumors. The objective of this study was to elucidate the role of metabolic pathways that undermine therapy efficacy in ER+ breast cancers. Our previous studies identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression and showed that combining selinexor (SEL), an FDA-approved XPO1 antagonist, synergized with endocrine agents and provided sustained tumor regression. In the current study, using a combination of transcriptomics, metabolomics and metabolic flux experiments, we identified certain mitochondrial pathways to be upregulated during endocrine resistance. When endocrine resistant cells were treated with single agents in media conditions that mimic a nutrient deprived tumor microenvironment, their glutamine dependence for continuation of mitochondrial respiration increased. The effect of glutamine was dependent on conversion of the glutamine to glutamate, and generation of NAD+. PGC1α, a key regulator of metabolism, was the main driver of the rewired metabolic phenotype. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and our findings reveal a critical role that ERα-XPO1 crosstalk plays in reducing cancer recurrences. Combining SEL with current therapies used in clinical management of ER+ metastatic breast cancer shows promise for treating and keeping these cancers responsive to therapies in already metastasized patients.

Combined Targeting of Estrogen Receptor Alpha and XPO1 Prevent Akt Activation, Remodel Metabolic Pathways and Induce Autophagy to Overcome Tamoxifen Resistance.

A majority of breast cancer specific deaths in women with ERα (+) tumors occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and the nuclear transport protein XPO1 in overcoming endocrine resistance. Selinexor (SEL), an XPO1 antagonist, has been evaluated in multiple late stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Our transcriptomics analysis showed that 4-Hydroxytamoxifen (4-OHT), SEL alone or their combination induced differential Akt signaling- and metabolism-associated gene expression profiles. Western blot analysis in endocrine resistant cell lines and xenograft models validated differential Akt phosphorylation. Using the Seahorse metabolic profiler, we showed that ERα-XPO1 targeting changed the metabolic phenotype of TAM-resistant breast cancer cells from an energetic to a quiescent profile. This finding demonstrated that combined targeting of XPO1 and ERα rewired the metabolic pathways and shut down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies to improve therapy response in relapsed ERα (+) tumors, our findings show great promise for uncovering the role that ERα-XPO1 crosstalk plays in reducing cancer recurrences.

Urban Neighborhood and Residential Factors Associated with Breast Cancer in African American Women: a Systematic Review.

Residential characteristics in urban neighborhoods impact health and might be important factors contributing to health disparities, especially in the African American population. The purpose of this systematic review is to understand the relationship between urban neighborhood and residential factors and breast cancer incidence and prognosis in African American women. Using PubMed and Web of Science, the existing literature was reviewed. Observational, cross-sectional, cohort, and prospective studies until February 2017 were examined. Studies including populations of African American women, setting in "urban" areas, and a measure of a neighborhood or residential factor were reviewed. Four parameters related to neighborhood or residential factors were extracted including: neighborhood socioeconomic status (nSES), residential segregation, spatial access to mammography, and residential pollution. Our analysis showed that African American women living in low nSES have greater odds of late stage diagnosis and mortality. Furthermore, African American women living in segregated areas (higher percentage of Blacks) have higher odds of late stage diagnosis and mortality compared to White and Hispanic women living in less segregated areas (lower percentage of Blacks). Late stage diagnosis was also shown to be significantly higher in areas with poor mammography access and areas with higher Black residential segregation. Lastly, residential pollution did not affect breast cancer risk in African American women. Overall, this systematic review provides a qualitative synthesis of major neighborhood and residential factors on breast cancer outcomes in African American women.