Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated colorectal cancer.

PURPOSE: BRAFV600E-mutated colorectal cancer (CRC) exhibits a strong correlation with DNA hypermethylation suggesting this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E CRC in vivo. EXPERIMENTAL DESIGN: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E CRC models. RESULTS: A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor suppressor genes. Combined inhibition of PRC activity through EZH2 inhibitor with 5-azacitidine treatment additively improved efficacies in BRAFV600E CRC cells. CONCLUSIONS: In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E CRC, and simultaneous blockade of DNMT and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated CRC.

Examining the Predictive Utility of Behavioral Economic Demand Indices and Subjective Effects on the Actualized Reinforcing Value of Menthol Cigarettes and Potential Alternatives.

INTRODUCTION: Considering recent and proposed bans on menthol cigarettes, methods are needed to understand the substitutability of potential menthol cigarette alternatives (MCAs) for menthol cigarettes. This study examined the prospective relationship between behavioral economic demand indices and subjective effects of usual brand menthol cigarettes (UBMC) and preferred MCAs with subsequent performance on a laboratory-based concurrent-choice task comparing UBMC and MCAs. METHODS: Eighty participants who typically smoked menthol cigarettes completed this clinical laboratory study. After sampling each product, participants completed the cigarette purchase task (CPT) and modified cigarette evaluation questionnaire (mCEQ). Following 1 week of substituting their preferred MCA for their UBMC, participants completed a 90-minute concurrent-choice self-administration (SA) task comparing their UBMC and preferred MCA. Linear regression models explored associations between CPT demand indices and mCEQ subjective effects in the laboratory with subsequent response effort for UBMCs on the concurrent-choice task. RESULTS: Three demand indices for UBMC were positively associated with UBMC response effort: essential value (EV; p = .02), Omax (p = .02), and breakpoint (p = .04). Four CPT demand indices for the preferred MCA significantly corresponded with UBMC response effort: EV (p = .03), price associated with maximal expenditure (Pmax) (p = .04), maximal expenditure (Omax) (p = .03), and breakpoint (p = .03). Subjective effects captured by the mCEQ were not associated with response effort. CONCLUSIONS: Demand indices reflecting Persistence (ie, sensitivity to escalating price) predicted effort to obtain UBMC puffs on the concurrent-choice task. Among this sample, the CPT captured information on the relative reinforcing value (ie, addiction potential) of combustible tobacco products similar to the longer SA task. IMPLICATIONS: In an ever-changing product market, assessing the reinforcing efficacy of menthol cigarettes and putative substitutes quickly and with validity is an important methodological tool for understanding abuse liability. Results suggest that behavioral economic demand indices of CPT efficiently capture information on the relative reinforcing value of UBMC and plausible alternative tobacco products, similar to a 90-minute in-laboratory SA task.

A bivalent Adenovirus-Vectored Vaccine induces a robust humoral response, but does not protect cynomolgus macaques against a lethal challenge with Sudan virus.

The most recent Sudan virus (SUDV) outbreak in Uganda was first detected in September 2022 and resulted in 164 laboratory-confirmed cases and 77 deaths. There are no approved vaccines against SUDV. Here, we investigated the protective efficacy of ChAdOx1-biEBOV in cynomolgus macaques using a prime or a prime-boost regimen. ChAdOx1-biEBOV is a replication-deficient simian adenovirus vector encoding SUDV and Ebola virus (EBOV) glycoproteins (GPs). Intramuscular vaccination induced SUDV and EBOV GP-specific IgG responses and neutralizing antibodies. Upon challenge with SUDV, vaccinated animals showed signs of disease like those observed in control animals, and no difference in survival outcomes were measured among all three groups. Viral load in blood samples and in tissue samples obtained after necropsy were not significantly different between groups. Overall, this study highlights the importance of evaluating vaccines in multiple animal models and demonstrates the importance of understanding protective efficacy in both animal models and human hosts.

Examining the prevalence of nicotine vaping and association of major depressive episodes among adolescents and young adults by disability type in 2021.

BACKGROUND: Nicotine vaping is more prevalent among U.S. adults with disabilities compared to those without disabilities. However, less is known about nicotine vaping among adolescents (12-17 years) and young adults (18-25 years) by disability status. METHODS: Using data from a sample of 24,722 adolescents and young adults (AYAs) from the 2021 National Survey on Drug Use and Health, we conducted descriptive and multivariable analyses to estimate the national prevalence of nicotine vaping by disability type and examined major depressive episodes (MDEs) as a risk factor for nicotine vaping. RESULTS: A greater proportion of AYAs with disabilities engaged in past-month nicotine vaping compared to those without a disability (13.9 % vs 9.6 %, p = 0.0001). Also, when MDE was excluded from the model, AYAs with any disability had higher odds of nicotine vaping (AOR = 1.41; 95 % CI 1.15, 1.74) than those without a disability. However, disability status was no longer significant when MDE was included (AOR = 1.16; 95 % CI 0.91, 1.46) in the model. CONCLUSIONS: The higher prevalence of nicotine vaping among AYAs with disabilities suggests that tailored messages may be needed to communicate health risks and adverse outcomes of e-cigarette use. Also, MDE is associated with nicotine vaping among AYA populations. This information can be helpful to school nurses, counselors, and mental health professionals in their screening of major depression as a risk factor for e-cigarette use.

Cigarette smoking behaviors and nicotine dependence at the intersection of sexual identity and sex in the United States: Findings from the National Survey on Drug Use and Health.

INTRODUCTION: Cigarette smoking is disproportionately high among lesbian, gay, and bisexual (LGB) adults. Yet, collapsing these identities into a monolith can disguise important within group disparities (e.g., lesbian/gay versus bisexual female). The purpose of this study is to report recent national prevalence estimates and trends of cigarette smoking behaviors and nicotine dependence by sexual identity and sex. METHODS: Data were from the 2015-2019 National Survey on Drug Use and Health (n = 210,392; adults 18+), a nationally representative, repeated cross-sectional study of substance use and mental health in the U.S. We examined bivariate and multivariable associations between sexual identity and cigarette smoking measures (i.e., former smoking, lifetime smoking, current smoking, current daily smoking, nicotine dependence) by sex. We also examined linear time trends in current and former smoking. Covariates included age, race/ethnicity, education, annual household income, and survey year. RESULTS: Bisexual women had the highest unadjusted prevalence of current smoking (31 %) and lowest of former smoking (25 %). LGB females and males had higher adjusted prevalence of current smoking, daily smoking, and nicotine dependence than heterosexual adults. Bisexual females and gay and bisexual males had lower adjusted prevalence of former smoking (adjusted prevalence ratio range: 0.78-0.85) than heterosexual counterparts. DISCUSSION: This is the first study to identify disproportionately low prevalence of former smoking among bisexual females. Paired with findings of high prevalence of current cigarette smoking and nicotine dependence, these data suggest that tobacco control interventions targeted toward bisexual females are urgently needed to reduce the burden of cigarette smoking among these individuals.

Patterns of Alcohol, Marijuana, and Tobacco Use Among U.S. Adolescents and Young Adults by Disability Status: 2015-2019.

PURPOSE: To estimate the national prevalence of tobacco, marijuana, and alcohol use among U.S. adolescents (age 12-17) and young adults (aged 18-25; adolescents and young adults [AYAs]) with a disability and examine associations between disability and substance use from 2015 to 2019. METHODS: Data from the 2015-2019 National Survey on Drug Use and Health were used to estimate the prevalence of tobacco, marijuana, and alcohol use among AYAs with disabilities. Modified Poisson regression models evaluated linear time trends in past-month substance use and estimated adjusted prevalence ratios (aPRs) for past-month cigarette, any tobacco, alcohol, and marijuana use. RESULTS: Adolescents with any disability had a higher prevalence of past-month cigarette (aPR = 1.87; 95% CI 1.67-2.09), alcohol (aPR = 1.21; 95% CI 1.11-1.31), and marijuana use (aPR = 1.47; 95% CI 1.36-1.60) compared to those without disabilities. Cigarette smoking among adolescents decreased over this time period; however, the decline among adolescents without a disability was greater than those with any disability. Young adults with any disability had a higher prevalence of past-month cigarette (aPR = 1.42; 95% CI 1.35-1.48) and marijuana use (aPR = 1.39; 95% CI 1.34-1.45), but a lower prevalence of past-month alcohol use (aPR = 0.93; 95% CI 0.90-0.95) than those without disabilities. Alcohol use remained constant among young adults with any disability but decreased for those without disabilities. DISCUSSION: Population-level disparities in cigarette and marijuana use exist in AYAs with disabilities. Future studies should identify strategies tailored to AYAs with disabilities to encourage smoking cessation and prevent cannabis use disorder.

Smoking cessation interventions for U.S. adults with disabilities: A systematic review.

INTRODUCTION: People with disabilities disproportionately use tobacco products. However, little is known about cessation interventions tailored for people with disabilities. The objective of this study was to conduct a systematic review of smoking cessation interventions for adults with disabilities. METHODS: Six electronic databases (Cochrane, CINAHL Plus [EBSCOhost], Embase [Ovid], Medline [Ovid], PsycINFO [Ovid], and Web of Science) were searched to identify eligible interventions for people with disabilities (e.g., vision, hearing, mobility, communication, cognition, self-care) through July 2023. Two independent coders evaluated the records and extracted data from studies that met inclusion criteria. Qualitative synthesis was conducted on the included studies in 2023. RESULTS: One randomized controlled trial and one nonrandomized study met the inclusion criteria. Both studies used mindfulness-based procedures to reduce cigarette use in adults with mild intellectual disability. The outcome was defined as self-reported cigarette use at follow-up, which ranged from 1 year to 3 years. Limited information was provided on how the interventions were tailored to meet the unique needs of people with disabilities in either study. CONCLUSION: Two interventions conducted in adults with mild intellectual disability showed promising results using mindfulness-based procedures; however, the studies did not address barriers reported by people with disabilities, nor tailor the interventions to meet the needs of the target population. Research is needed to address tobacco use disparities among people with a range of disabilities. Current cessation interventions would be enhanced by integrating disability identifiers alongside other demographic information in future studies and reporting subgroup analyses in adults with disabilities.

Substitutability of menthol cigarette alternatives: a clinical trial.

INTRODUCTION: This study assessed the substitutability of plausible combustible menthol cigarette alternatives (MCAs) for usual brand menthol cigarettes (UBMCs) in adults who smoke menthol cigarettes. METHODS: Following three in-lab sampling sessions, 80 adults aged 21-50 who smoke menthol cigarettes chose their preferred MCA: (1) a menthol roll-your-own cigarette (mRYO), (2) a menthol filtered little cigar (mFLC) or (3) a non-menthol cigarette (NMC). Participants were instructed to completely substitute their preferred MCA for their UBMC for 1 week and complete daily diaries documenting adherence and subjective effects. At the final lab visit, participants completed concurrent choice and cross-price elasticity tasks with their substitute product and UBMC as the comparator. RESULTS: Most (65%) participants chose mRYO as their preferred product, followed by NMC and mFLC. Adherence to MCA was high for all products across the week (range: 63%-88%). Positive subjective effects for mRYO decreased over time but remained numerically higher than the other MCA products; craving reduction also decreased for NMC across phases. In the progressive ratio task, participants chose their UBMC in 61.7% of choices; this did not differ by preferred MCA, although the median breakpoint was highest for mRYO and similar for mFLC and NMC. Cross-price elasticity comparing UBMC and the preferred product indicated high substitutability of each MCA at phase 3 (I values -0.70 to -0.82). CONCLUSIONS AND RELEVANCE: mRYOs were the most preferred MCA among the study products, but all MCAs were acceptable substitutes for UBMC using behavioural and economic measures in a short-term trial period.Trial registration number NCT04844762.

Smoking cessation interventions for US adults with disabilities: protocol for a systematic review.

INTRODUCTION: People with disabilities have a higher prevalence of cigarette smoking than people without disabilities. However, little information exists on smoking cessation interventions tailored to address the unique needs of people with disabilities. This paper describes a systematic review protocol to identify and evaluate tobacco smoking cessation interventions designed to improve outcomes for people with disabilities. METHODS AND ANALYSIS: We will conduct a systematic review of the literature using the procedures outlined by Cochrane. We will search four electronic databases (CINAHL Plus (EBSCO), Embase (Ovid), Medline (Ovid) and PsycINFO (Ovid)) with no date restriction to identify tobacco cessation interventions tailored to meet the needs of people with disabilities. We will extract data and assess risk of bias using the RoB2 and ROBINS-I for included studies using Covidence systematic review software. Quantitative and qualitative syntheses will summarise key study characteristics and outcomes with text, tables and forest plots; a meta-analysis will be conducted, if appropriate. ETHICS AND DISSEMINATION: Ethical approval is not required as there are no primary data associated with the study. Data will be disseminated through a peer-reviewed articles and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42022337434.

Trends in cigarette smoking prevalence and status among U.S. adults with disabilities, 2015-2019.

INTRODUCTION: The prevalence of current cigarette smoking is higher in people with disabilities compared to those without. However, little is known about smoking status and trends in smoking by disability functioning domain. METHODS: Data from the 2015-2019 National Surveys on Drug Use and Health were used to estimate the prevalence of past-month and daily cigarette smoking, former smoking, and nicotine dependence for people with any disability and six disability functioning domains. Logistic regression models estimated the odds of each outcome by disability domain compared to no disability, adjusting for sociodemographic factors. RESULTS: From 2015-2019, the overall prevalence of current cigarette smoking (23.3% vs. 16.7%) and the proportion of those with nicotine dependence (14.6% vs 8.0%) was higher in people with any disability compared to those without (ps < 0.001). The prevalence of current cigarette smoking decreased while the prevalence of former cigarette smoking increased from 2015 to 2019 (ps < 0.05). People with any disability had higher odds of current smoking (AOR=1.20; 95% CI 1.16, 1.25) and similar odds of former smoking (AOR=1.00; 95% CI 0.95, 1.06) compared to people without disabilities. Odds of current and former smoking varied by domain. CONCLUSION: The prevalence of cigarette smoking among people with any disability decreased over time but remained higher than those without. People with any disability had similar odds of former smoking, though differences existed by disability domain. Future research should explore additional smoking and quit behaviors by disability functioning domain.

Addiction potential of combustible menthol cigarette alternatives: a randomised cross-over trial.

INTRODUCTION: The Food and Drug Administration (FDA) has issued proposed product standards banning menthol as a characterising flavour in cigarettes and cigars. The public health benefits of these product standards may be attenuated by the role of plausible substitutes in the marketplace. Therefore, the present study examined the addiction potential of plausible combustible menthol alternatives compared with usual brand menthol cigarettes (UBMC). METHODS: Ninety-eight adult menthol cigarette smokers completed four visits, smoking their UBMC at the first session and three menthol cigarette alternatives in random order at the subsequent visits: (1) a preassembled menthol roll-your-own (mRYO) cigarette using menthol pipe tobacco and mentholated cigarette tube, (2) a menthol filtered little cigar (mFLC) and (3) a non-menthol cigarette (NMC). Measures of smoking topography, exhaled carbon monoxide (CO), craving and withdrawal, subjective effects and behavioural economic demand indices were assessed. RESULTS: Compared with UBMC, menthol cigarette alternatives resulted in different puffing topography and CO exposure (except mRYO), and lower levels of positive subjective experience and behavioural economic demand indices. Among the alternative products, participants reported the highest level of positive subjective experience and higher demand for mRYO, compared with mFLC and NMC. Similarly, participants were significantly more likely to want to try again, purchase and use the mRYO product regularly compared with mFLC and NMC. CONCLUSIONS AND RELEVANCE: mRYO cigarettes were the most highly rated cigarette alternative among study products, suggesting their potential appeal as a menthol cigarette substitute and needed inclusion of menthol pipe tobacco and cigarette tubes in FDA's proposed ban.

Tailored text message and web intervention for smoking cessation in U.S. socioeconomically-disadvantaged young adults: A randomized controlled trial.

The prevalence of cigarette smoking in young adults is higher among those with socioeconomic disadvantage than those without. Low treatment-seeking among young adult smokers is compounded by few efficacious smoking cessation interventions for this group, particularly socioeconomically-disadvantaged young adults (SDYA) who smoke cigarettes. The goal of this study was to test a tailored smoking-cessation intervention for SDYA. 343 SDYA aged 18-30 living in the U.S. (85% female) who smoke cigarettes with access to a smartphone and interest in quitting smoking in the next six months were recruited online in Spring 2020 and randomized to referral to online quit resources (usual care control; n = 171) or a 12-week tailored text message smoking-cessation program with a companion web-based intervention (n = 172). Intent to treat analyses examined associations between study condition, self-reported 30-day point prevalence abstinence (PPA), and confidence to quit smoking at 12 weeks, controlling for potential confounders. Intervention group participants had greater self-reported 30-day PPA at 12-weeks than controls (adjusted relative risk 3.93, 95% CI 2.14-7.24). Among those who continued smoking, the intervention increased confidence to quit (0.81 points, 95% confidence interval 0.08-1.53). Weekly engagement in the intervention predicted greater cessation. A tailored text message intervention for SDYA increased smoking abstinence and confidence to quit at the end-of-treatment. Findings may have been influenced by recruitment at the start of the COVID pandemic but suggest that text messaging is an acceptable and efficacious cessation strategy for SDYA smokers. Future studies should examine the impact on longer-term smoking-cessation and importance of intervention tailoring for SDYA.

ChAdOx1 nCoV-19 (AZD1222) or nCoV-19-Beta (AZD2816) protect Syrian hamsters against Beta Delta and Omicron variants.

ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirus-vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 has been shown to have 74% vaccine efficacy against symptomatic disease in clinical trials. However, variants of concern (VoCs) have been detected, with substitutions that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial, even though current real-world data is suggesting good efficacy following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluate the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. Minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 3- or 5- days post inoculation, in contrast to lungs of control animals. In Omicron-challenged hamsters, a single dose of AZD2816 or AZD1222 reduced virus shedding. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.

High enhancer activity is an epigenetic feature of HPV negative atypical head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with significant mortality and frequent recurrence. Prior efforts to transcriptionally classify HNSCC into groups of varying prognoses have identified four accepted molecular subtypes of the disease: Atypical (AT), Basal (BA), Classical (CL), and Mesenchymal (MS). Here, we investigate the active enhancer landscapes of these subtypes using representative HNSCC cell lines and identify samples belonging to the AT subtype as having increased enhancer activity compared to the other 3 HNSCC subtypes. Cell lines belonging to the AT subtype are more resistant to enhancer-blocking bromodomain inhibitors (BETi). Examination of nascent transcripts reveals that both AT TCGA tumors and cell lines express higher levels of enhancer RNA (eRNA) transcripts for enhancers controlling BETi resistance pathways, such as lipid metabolism and MAPK signaling. Additionally, investigation of higher-order chromatin structure suggests more enhancer-promoter (E-P) contacts in the AT subtype, including on genes identified in the eRNA analysis. Consistently, known BETi resistance pathways are upregulated upon exposure to these inhibitors. Together, our results identify that the AT subtype of HNSCC is associated with higher enhancer activity, resistance to enhancer blockade, and increased signaling through pathways that could serve as future targets for sensitizing HNSCC to BET inhibition.

Disparities in Tobacco Use by Disability and Type: Findings From the 2019 National Health Interview Survey.

INTRODUCTION: People with disabilities report a higher prevalence of cigarette use than people without disabilities. However, evidence is limited on the relationships between disability type, degree of functional difficulty, and other tobacco product use. METHODS: Data from the 2019 U.S. National Health Interview Survey were used to estimate the prevalence and odds of tobacco product use for 6 disability types and degree of functional difficulty. Bivariate and multivariable analyses conducted in 2021 examined the associations between tobacco product use and disability type. RESULTS: Compared to adults who reported no difficulty, current cigarette use prevalence was higher for adults who reported a lot of difficulty/cannot do at all to vision (21.5% vs 13.1%), hearing (19.6% vs 13.6%), mobility (20.0% vs 12.9%), and cognitive (25.4% vs 12.9%) disability questions. The odds of current cigarette (AOR=1.32), pipe (AOR=1.85), and smokeless tobacco (AOR=1.57) use were significantly higher for adults who reported a lot of difficulty/cannot do at all to any disability question and significantly higher for current cigarette (AOR=1.24), e-cigarette (AOR=1.33), pipe (AOR=1.45), and smokeless tobacco (AOR=1.29) use for adults who reported some difficulty to any disability question than those who reported no difficulty. Pipe use was correlated with mobility difficulty (AOR=1.68), and smokeless tobacco use was correlated with hearing difficulty (AOR=1.95). CONCLUSIONS: People who reported difficulty with vision, hearing, mobility, or cognition had a higher cigarette use prevalence than people without disabilities. Other tobacco use differed by disability type. Future research should tailor tobacco interventions to reduce these disparities.

Efficacy of ChAdOx1 vaccines against SARS-CoV-2 Variants of Concern Beta, Delta and Omicron in the Syrian hamster model.

ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient simian adenovirusâ€"vectored vaccine encoding the spike (S) protein of SARS-CoV-2, based on the first published full-length sequence (Wuhan-1). AZD1222 was shown to have 74% vaccine efficacy (VE) against symptomatic disease in clinical trials and over 2.5 billion doses of vaccine have been released for worldwide use. However, SARS-CoV-2 continues to circulate and consequently, variants of concern (VoCs) have been detected, with substitutions in the S protein that are associated with a reduction in virus neutralizing antibody titer. Updating vaccines to include S proteins of VoCs may be beneficial over boosting with vaccines encoding the ancestral S protein, even though current real-world data is suggesting good efficacy against hospitalization and death following boosting with vaccines encoding the ancestral S protein. Using the Syrian hamster model, we evaluated the effect of a single dose of AZD2816, encoding the S protein of the Beta VoC, and efficacy of AZD1222/AZD2816 as a heterologous primary series against challenge with the Beta or Delta variant. We then investigated the efficacy of a single dose of AZD2816 or AZD1222 against the Omicron VoC. As seen previously, minimal to no viral sgRNA could be detected in lungs of vaccinated animals obtained at 5 days post inoculation, in contrast to lungs of control animals. Thus, these vaccination regimens are protective against the Beta, Delta, and Omicron VoCs in the hamster model.

Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer.

OBJECTIVE: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described. DESIGN: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin. RESULTS: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFßi, mTORi and SRCi) for EpiC groups. CONCLUSION: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.

High-Fat High-Sugar Diet-Induced Changes in the Lipid Metabolism Are Associated with Mildly Increased COVID-19 Severity and Delayed Recovery in the Syrian Hamster.

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an altered, but not significantly different, systemic IL-10 and IL-6 profile, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, partially recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.

Machine Learning in Epigenomics: Insights into Cancer Biology and Medicine.

The recent deluge of genome-wide technologies for the mapping of the epigenome and resulting data in cancer samples has provided the opportunity for gaining insights into and understanding the roles of epigenetic processes in cancer. However, the complexity, high-dimensionality, sparsity, and noise associated with these data pose challenges for extensive integrative analyses. Machine Learning (ML) algorithms are particularly suited for epigenomic data analyses due to their flexibility and ability to learn underlying hidden structures. We will discuss four overlapping but distinct major categories under ML: dimensionality reduction, unsupervised methods, supervised methods, and deep learning (DL). We review the preferred use cases of these algorithms in analyses of cancer epigenomics data with the hope to provide an overview of how ML approaches can be used to explore fundamental questions on the roles of epigenome in cancer biology and medicine.

Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models.

ChAdOx1 nCoV-19/AZD1222 is an approved adenovirus-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently being deployed globally. Previous studies in rhesus macaques revealed that intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 provided protection against pneumonia but did not reduce shedding of SARS-CoV-2 from the upper respiratory tract. Here, we investigated whether intranasally administered ChAdOx1 nCoV-19 reduces detection of virus in nasal swabs after challenging vaccinated macaques and hamsters with SARS-CoV-2 carrying a D614G mutation in the spike protein. Viral loads in swabs obtained from intranasally vaccinated hamsters were decreased compared to control hamsters, and no viral RNA or infectious virus was found in lung tissue after a direct challenge or after direct contact with infected hamsters. Intranasal vaccination of rhesus macaques resulted in reduced virus concentrations in nasal swabs and a reduction in viral loads in bronchoalveolar lavage and lower respiratory tract tissue. Intranasal vaccination with ChAdOx1 nCoV-19/AZD1222 reduced virus concentrations in nasal swabs in two different SARS-CoV-2 animal models, warranting further investigation as a potential vaccination route for COVID-19 vaccines.