PBRM1 bromodomains associate with RNA to facilitate chromatin association.

PBRM1 is a subunit of the PBAF chromatin remodeling complex, which is mutated in 40-50% of clear cell renal cell carcinoma patients. It is thought to largely function as a chromatin binding subunit of the PBAF complex, but the molecular mechanism underlying this activity is not fully known. PBRM1 contains six tandem bromodomains which are known to cooperate in binding of nucleosomes acetylated at histone H3 lysine 14 (H3K14ac). Here, we demonstrate that the second and fourth bromodomains from PBRM1 also bind nucleic acids, selectively associating with double stranded RNA elements. Disruption of the RNA binding pocket is found to compromise PBRM1 chromatin binding and inhibit PBRM1-mediated cellular growth effects.

Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy.

BACKGROUND AND AIM: The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD: Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS: Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION: Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Is there an association between non-alcoholic fatty liver disease and cognitive function? A systematic review.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is represented as the most common liver disease worldwide. NAFLD is associated with metabolic risk factors underpinned by insulin resistance, inflammation and endothelial dysfunction, leading to extrahepatic changes in central nervous diseases such as cognitive impairment, Alzheimer's disease and dementia. The aim of the review is to explore the association between NAFLD and cognitive function. METHODS: Using the PRISMA guidelines, a systematic electronic literature search was conducted in four databases: MEDLINE, PsychINFO, Embase and CINAHL from inception until March 2021. Neuropsychological tests utilised within each study were grouped into relevant cognitive domains including 'general cognition', 'reasoning', 'mental speed, attention and psychomotor speed', 'memory and learning', 'language', 'visuospatial perception' and 'ideas, abstraction, figural creations and mental flexibility'. RESULTS: Eleven observational studies that involved 7978 participants with a mean age of 51 years were included. Those with NAFLD had poor cognitive performance in three cognitive domains, including 'general cognition', 'mental speed, attention and psychomotor speed', and 'ideas, abstraction, figural creations and mental flexibility'. CONCLUSION: The observed results from the 11 included studies showed that NAFLD was associated with lower cognitive performance across several domains. However, studies conducted to date are limited to observational designs and are heterogeneous with varying diagnostic tools used to assess cognitive function. TRIAL REGISTRATION: PROSPERO Registration: CRD42020161640 .

A Potent, Selective CBX2 Chromodomain Ligand and Its Cellular Activity During Prostate Cancer Neuroendocrine Differentiation.

Polycomb group (PcG) proteins are epigenetic regulators that facilitate both embryonic development and cancer progression. PcG proteins form Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). PRC2 trimethylates histone H3 lysine 27 (H3K27me3), a histone mark recognized by the N-terminal chromodomain (ChD) of the CBX subunit of canonical PRC1. There are five PcG CBX paralogs in humans. CBX2 in particular is upregulated in a variety of cancers, particularly in advanced prostate cancers. Using CBX2 inhibitors to understand and target CBX2 in prostate cancer is highly desirable; however, high structural similarity among the CBX ChDs has been challenging for developing selective CBX ChD inhibitors. Here, we utilize selections of focused DNA encoded libraries (DELs) for the discovery of a selective CBX2 chromodomain probe, SW2_152F. SW2_152F binds to CBX2 ChD with a Kd of 80 nM and displays 24-1000-fold selectivity for CBX2 ChD over other CBX paralogs in vitro. SW2_152F is cell permeable, selectively inhibits CBX2 chromatin binding in cells, and blocks neuroendocrine differentiation of prostate cancer cell lines in response to androgen deprivation.

Detection of phenolic endocrine disrupting chemicals (EDCs) from maternal blood plasma and amniotic fluid in Indian population.

There is a widespread exposure of general population, including pregnant women and developing fetuses, to the endocrine disrupting chemicals (EDCs). These chemicals have been reported to be present in urine, blood serum, breast milk and amniotic fluid. We aimed to investigate the association between the maternal exposure and in utero fetal exposure levels of these chemicals to study their transfer from maternal to fetal unit indicating prenatal exposure. Samples of maternal blood and amniotic fluid were collected as set from 53 pregnant women at full term. Nine phenolic EDCs, methyl paraben (MP; 20.92ng/mL and 18.92ng/mL), ethyl paraben (EP; 1.97ng/ mL and 1.89ng/mL), propyl paraben (PP; 19.22ng/mL and 18.82ng/mL), butyl paraben (BP; 1.11ng/mL and 1.37ng/mL), p-hydroxybenzoic acid (PHBA; 29.99ng/mL and 26.15ng/mL), bisphenol A (BPA; 7.43ng/mL and 7.75ng/mL), triclosan (TCS; 7.17ng/mL and 7.04ng/mL), octyl phenol (OP; 5.46ng/mL and 5.72ng/mL) and nonyl phenol (NP; 9.38ng/mL and 8.44ng/mL), were simultaneously detected in samples of maternal blood plasma and amniotic fluid respectively using Gas Chromatography-Mass Spectrometry (GC-MS). Highest positive correlation was found for total concentration of 4-nonyl phenol, NP (r=0.575, p<0.001), whereas the lowest positive correlation was found for free form of bisphenol A, BPA (r=0.343, p<0.05), when compared between the two matrices. Our results suggest that maternal exposure to several EDCs is positively associated with in utero exposure to the developing fetus. Future studies should focus on collection of amniotic fluid at different trimesters and the corresponding maternal samples to better characterize the pharmacokinetics and the associated disease etiologies of these EDCs during fetal development.

Diet Overall and Hypocaloric Diets Are Associated With Improvements in Depression but Not Anxiety in People With Metabolic Conditions: A Systematic Review and Meta-Analysis.

The risk of depression and anxiety is higher in people with metabolic conditions, but whether dietary approaches, which are central to the management of metabolic conditions, can also improve depression and anxiety is uncertain. The primary aim of this systematic review and meta-analysis was to evaluate the effects of dietary interventions on depression and anxiety in adults with metabolic conditions. The secondary aim was to evaluate the effects of hypocaloric and isocaloric dietary interventions on these outcomes. Four databases (MEDLINE, PsychINFO, EMBASE, and CINAHL) were searched from inception to March 2023. Randomized controlled trials (RCTs) including dietary interventions in adults with metabolic conditions (type 2 diabetes mellitus, hyperlipidemia, hypertension, and/or overweight/obesity) that assessed depression and/or anxiety as outcomes were included. Overall, 13 RCTs were included in the systematic review, ≤13 of which were included in the meta-analysis. Estimates were pooled using random-effect meta-analysis for dietary interventions compared with controls. Improvements in depression scores were found in meta-analytic models including all dietary interventions [pooled estimate for the standardized mean difference (SMD) = -0.20 (95% CI: -0.35, -0.05); P = 0.007] and hypocaloric only diets [SMD = -0.27 (95% CI: -0.44, -0.10); P = 0.002]. There were no improvements in depression scores with isocaloric dietary interventions only [SMD = -0.14 (95% CI: -0.38, 0.10); P = 0.27]. In addition, there were no significant effects of any dietary interventions on anxiety scores. In adults with metabolic conditions, all dietary interventions and hypocaloric diets improved depression, but not anxiety. These findings suggest that dietary interventions including hypocaloric diets can play an important role in the management of depression in people with metabolic conditions. This systematic review and meta-analysis has been registered with PROSPERO (CRD42021252307).

Investigating the efficacy and feasibility of using a whole-of-diet approach to lower circulating levels of C-reactive protein in postmenopausal women: a mixed methods pilot study.

OBJECTIVE: Chronic inflammation is associated with obesity and is an underlying pathophysiology for cardiovascular disease (CVD) development in postmenopausal women. This study aims to determine feasibility and efficacy of an anti-inflammatory dietary intervention to lower levels of C-reactive protein in weight stable postmenopausal women with abdominal obesity. METHODS: This mixed-methods pilot study used a single arm pre-post design. Thirteen women followed a 4-week anti-inflammatory, dietary intervention, optimizing consumption of healthy fats, low glycemic index wholegrains, and dietary antioxidants. Quantitative outcomes included change in inflammatory and metabolic markers. Focus groups were undertaken and thematically analyzed to explore participants lived experience of following the diet. RESULTS: There was no significant change in plasma high-sensitivity C-reactive, protein. Despite discouraging weight loss, median (Q1-Q3) body weight decreased by -0.7 (-1.3 to 0 kg, P = 0.02). This was accompanied by reductions in plasma insulin (0.90 [-0.05 to 2.20] mmol/L), Homeostatic Model Assessment of Insulin Resistance (0.29 [-0.03 to 0.59]), and low-density lipoprotein:high-density lipoprotein ratio (0.18 [-0.01 to 0.40]) ( P ≤ 0.023 for all). Thematic analysis revealed that postmenopausal women have a desire to improve meaningful markers of health status that do not focus on weight. Women were highly engaged with learning about emerging and innovative nutrition topics, favoring a detailed and comprehensive nutrition education style that challenged their proficient health literacy and cooking skills. CONCLUSIONS: Weight-neutral dietary interventions targeting inflammation can improve metabolic markers and may be a viable strategy for CVD risk reduction in postmenopausal women. To determine effects on inflammatory status, a fully powered and longer-term randomized controlled trial is required.

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer.

Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromodomain-containing protein 7 (BRD7) is implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two inhibitors with increased selectivity toward BRD7, 1-78 and 2-77, which bind with submicromolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands occupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.

The burden of type 2 diabetes in Australia during the period 1990-2019: Findings from the global burden of disease study.

AIMS: To describe morbidity and mortality trends of type 2 diabetes in Australia, from 1990 to 2019, compared with similar sociodemographic index (SDI) countries. METHODS: Australia-specific Global Burden of Diseases data were used to estimate age-standardised, age-specific, and sex-specific rates for prevalence, years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life years (DALYs), and deaths due to type 2 diabetes between 1990 and 2019. Australian data were compared with 14 similar SDI countries. RESULTS: Type 2 diabetes increased in Australia between 1990 and 2019. The age-standardised prevalence increased from 1,985 [95% Confidence Interval (CI): 1,786.7-2195.3] per 100,000 population, to 3,429 [95% CI 3,053.3-3,853.7]. Cases tripled, from 379,532 [342,465-419,475] to 1,307,261 [1,165,522-1,461,180]. The age-standardised death rates doubled, from 2,098 [1,953-2,203] per 100,000, to 4,122 [3,617-4,512]. DALYs doubled, from 70,348 [59,187-83,500] to 169,763 [129,792-216,150], with increases seen in YLDs and YLLs. Men displayed higher rates. Compared to similar SDI countries, Australia ranked 4th in terms of burden for type 2 diabetes. CONCLUSIONS: The burden of type 2 diabetes in Australia has increased considerably over three decades. There is an urgent need to prioritise resource allocation for prevention programs, screening initiatives to facilitate early detection, and effective and accessible management strategies for the large proportion of the population impacted by type 2 diabetes.

The Evidence Surrounding Non-Alcoholic Fatty Liver Disease in Individuals with Cancer: A Systematic Literature Review.

Emerging evidence indicates an association between non-alcoholic fatty liver disease (NAFLD), cancer development and mortality. Cancer treatment-induced metabolic and hepatic dysfunction may be associated with increased rates of NAFLD. The review aims to investigate current evidence surrounding NAFLD in adults (≥18 years) with cancer including prevalence, effect of cancer treatments, metabolic co-morbidities, and mortality. Embase, Scopus, PubMed, and CINAHL were searched from inception to December 2021 including randomized controlled trials and observational studies. Twenty-three articles were included, comprising 142,218 participants. The overall risk of bias for observational studies was determined as low for 10 studies and neutral for 12 studies, and the RCT was determined as some concerns. The prevalence of NAFLD, based on imaging or histology, in adults with cancer ranged from 0.5 to 81.3%, with higher prevalence in breast, colorectal and gynecological cancers. Higher rates of NAFLD were also seen in patients who (i) underwent treatments-including chemotherapy and hormone therapy and/or who (ii) had higher BMI or other metabolic co-morbidities. NAFLD was associated with an increase in all-cause and cancer-related mortality. Based on review results, it is recommended that further assessment is carried out to determine whether liver screening in high-risk patients is cost effective and if interventions can be implemented to improve hepatic and health outcomes in adults with cancer.

Ethnic differences in response to lifestyle intervention for the prevention of type 2 diabetes in adults: A systematic review and meta-analysis.

The risk of type 2 diabetes mellitus (T2DM) varies by ethnicity, but ethnic differences in response to diabetes prevention interventions remain unclear. This systematic review and meta-analysis assessed ethnic differences in the effects of lifestyle interventions on T2DM incidence, glycemic outcomes (fasting glucose, 2-h glucose, HbA1c ), anthropometric measures (weight, BMI, waist circumference), and lifestyle behaviors (physical activity, energy intake, energy from fat, fiber intake). MEDLINE, EMBASE, and other databases were searched (to June 15, 2020) for randomized and non-randomized controlled trials on lifestyle interventions (diet and/or physical activity) in adults at risk of T2DM. Ethnicity was categorized into European, South Asian, East and Southeast Asian, Middle Eastern, Latin American, and African groups. Forty-four studies were included in meta-analyses. Overall, lifestyle interventions resulted in significant improvement in T2DM incidence, glycemic outcomes, anthropometric measures, physical activity, and energy intake (all P < 0.01). Significant subgroup differences by ethnicity were found for 2-h glucose, weight, BMI, and waist circumference (all P < 0.05) but not for T2DM incidence, fasting glucose, HbA1c , and physical activity (all P > 0.05). Few studies in non-European groups reported dietary intake. Lifestyle interventions in different ethnic groups may have similar effects in reducing incidence of T2DM although this needs to be confirmed in further studies.

Higher Adherence to a Mediterranean Diet Is Associated with Improved Insulin Sensitivity and Selected Markers of Inflammation in Individuals Who Are Overweight and Obese without Diabetes.

Insulin resistance (IR) and chronic low-grade inflammation are risk factors for chronic diseases including type 2 diabetes (T2D) and cardiovascular disease. This study aimed to investigate two dietary indices: Mediterranean Diet Score (MDS) and Dietary Inflammatory Index (DII®), and their associations with direct measures of glucose metabolism and adiposity, and biochemical measures including lipids, cytokines and adipokines in overweight/obese adults. This cross-sectional study included 65 participants (males = 63%; age 31.3 ± 8.5 years). Dietary intake via 3-day food diaries was used to measure adherence to MDS (0-45 points); higher scores indicating adherence. Energy-adjusted DII (E-DII) scores were calculated with higher scores indicating a pro-inflammatory diet. IR was assessed using hyperinsulinemic euglycemic clamps, insulin secretion by intravenous glucose tolerance test, adiposity by dual-energy X-ray absorptiometry, and circulating cytokine and adipokine concentrations by multiplex assays. Higher MDS was associated with greater insulin sensitivity (ß = 0.179; 95%CI: 0.39, 0.318) after adjusting for age, sex and % body fat, and lower NF-κB, higher adiponectin and adipsin in unadjusted and adjusted models. Higher E-DII score was associated with increased total cholesterol (ß = 0.364; 95%CI: 0.066, 0.390) and LDL-cholesterol (ß = 0.305; 95%CI: 0.019, 0.287) but not with adiposity, glucose metabolism, cytokines or adipokines. Greater MDS appears to be associated with decreased IR and inflammatory markers in overweight/obese adults.

At the Crossroad of Gene Regulation and Genome Organization: Potential Roles for ATP-Dependent Chromatin Remodelers in the Regulation of CTCF-Mediated 3D Architecture.

In higher order organisms, the genome is assembled into a protein-dense structure called chromatin. Chromatin is spatially organized in the nucleus through hierarchical folding, which is tightly regulated both in cycling cells and quiescent cells. Assembly and folding are not one-time events in a cell's lifetime; rather, they are subject to dynamic shifts to allow changes in transcription, DNA replication, or DNA damage repair. Chromatin is regulated at many levels, and recent tools have permitted the elucidation of specific factors involved in the maintenance and regulation of the three-dimensional (3D) genome organization. In this review/perspective, we aim to cover the potential, but relatively unelucidated, crosstalk between 3D genome architecture and the ATP-dependent chromatin remodelers with a specific focus on how the architectural proteins CTCF and cohesin are regulated by chromatin remodeling.

The Association between Diet and Hepatocellular Carcinoma: A Systematic Review.

Globally, liver cancer is the sixth most common cause of cancer mortality, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. Emerging evidence states that diet is recognised as a potential lifestyle-related risk factor for the development of HCC. The aim of this systematic review is to determine whether there is an association between diet and the development of HCC. Using the PRISMA guidelines, three databases (MEDLINE Complete, CINAHL and Embase) were systematically searched, and studies published until July 2020 were included. Thirty observational studies were selected. The protocol was registered with PROSPERO (CRD42019135240). Higher adherence to the Mediterranean dietary pattern, Alternative Healthy Eating Index-2010, the Urban Prudent Dietary Pattern, the Traditional Cantonese Dietary Pattern, intake of vegetables, wholegrains, fish, poultry, coffee, macronutrients such as monounsaturated fats and micronutrients such as vitamin E, vitamin B9, ß-carotene, manganese and potassium were associated with a reduced risk of HCC. The results suggest a potential role of diet in the development of HCC. Further quantitative research needs to be undertaken within a range of populations to investigate diet and the relationship with HCC risk.

The Effect of Lifestyle Intervention on Diabetes Prevention by Ethnicity: A Systematic Review of Intervention Characteristics Using the TIDieR Framework.

Lifestyle intervention is effective in preventing type 2 diabetes mellitus (T2DM), but the efficacy of intervention components across different ethnic groups is less clear. This systematic review examined the effects of intervention characteristics of lifestyle interventions on diabetes incidence and weight loss by ethnicity using the Template for Intervention Description and Replication (TIDieR) framework. MEDLINE, EMBASE and other databases were searched for randomized and non-randomized controlled trials on lifestyle interventions (diet and/or physical activity) in adults at risk of T2DM. Ethnicity was categorized into European, South Asian, East and Southeast Asian, Middle Eastern, Latin American and African groups. Forty-five studies (18,789 participants) were included in the systematic review and 41 studies in meta-analysis. Meta-analysis showed a high number of intervention sessions was significantly associated with a greater reduction in diabetes incidence (P = 0.043) and weight (P = 0.015), while other intervention characteristics including intervention provider and delivery format did not alter the outcomes (all P > 0.05). Additionally, narrative synthesis showed long-term interventions (≥12 months) were associated with significant diabetes risk reduction for all ethnic groups, while short-term interventions (<12 months) were more effective in weight loss in most ethnic groups. There may be ethnic preferences for the optimal number of intervention sessions.

Peer-supported lifestyle interventions on body weight, energy intake, and physical activity in adults: A systematic review and meta-analysis.

There is an increasing interest in peer interventions in the management of chronic conditions, but evidence on peer interventions for body weight is lacking. The aim of this study was to examine the efficacy of peer interventions on body weight, energy intake, and physical activity in adults. Interventions delivered by peer (lay member that participants identify with) were included. We searched 14 databases. Outcomes were combined in the meta-analysis using the inverse variance random-effects model. From 2435 articles, 65 articles were included in the systematic review and meta-analysis (n = 15,673). Peer interventions resulted in significant reduction in weight (mean difference [MD] -1.05 kg; 95% confidence interval [CI] -1.68, -0.43; 95% prediction interval [PI] -3.25, 1.14; 28 studies; 7142 participants), BMI (MD -0.24 kg/m2 ; 95% CI -0.44, -0.04; 95% PI -0.92, 0.45; 25 studies; 6672 participants), waist circumference (MD -0.75 cm; 95% CI -1.29, -0.21; 95% PI -1.36, -0.14; 12 studies; 4280 participants), and significant increase in physical activity (SMD 0.20; 95% CI 0.09, 0.32; 95% PI -0.46, 0.86; 41 studies; 10,778 participants) with no significant effect on energy intake. This study suggests peer interventions are effective in reducing waist circumference, but further research is needed to confirm its effect on other obesity-related outcomes.

Inflaming Public Interest: A Qualitative Study of Adult Learners' Perceptions on Nutrition and Inflammation.

Research suggests national dietary guidelines are losing public resonance, with consumers actively seeking alternate nutrition advice from unregulated online platforms that often propagate misinformation. Improved diet quality can beneficially affect inflammation, and with science relating to nutrition and inflammation also appealing to consumers, this emerging topic provides an opportunity to consider how novel engagement strategies can be used to increase public support of expert-generated advice. This study aimed to qualitatively explore MOOC learners' perceptions and experiences of following diets believed to help manage inflammation. Data were collected from an evidence-based nutrition-focused Massive Open Online Course (MOOC), which included a unit titled Foods and Inflammation. The Framework method was used to analyze 12,622 learner comments, taken from the MOOC's online discussion forum and questionnaire. Learners identified avoidance of core food groups, such as dairy and grains, as key in managing inflammation. Dietary advice came mainly from the internet, and health professionals reportedly lacked an appreciation of the learners' underlying nutrition knowledge, providing oversimplified advice that did not satisfy their scientific curiosity. To help build consumer trust and increase engagement, health professionals need to consider innovative education strategies that utilize novel topics such as nutrition and inflammation, in a safe and accurate manner.

Dimorphic placental stress: A repercussion of interaction between endocrine disrupting chemicals (EDCs) and fetal sex.

Placental homeostasis is critical for fetal development as it determines the health of mother and fetus during pregnancy and in later life. Interestingly even the fetus, in a sexually dimorphic manner, influences the pedantic growth and development of placenta. Although placenta is thought to act as a protective barrier against chemical exposures, certain endocrine disrupting chemicals (EDCs) that are circulating in mother's blood tend to cross placenta. These EDCs have been reported to cause changes in expression levels of certain genes, immunogenic factors and non-coding RNAs such as micro RNA (miRNA) and long non-coding RNA (lncRNA) leading to placental stress. We hypothesize that these changes in placenta occur in a sexually dimorphic manner as a result of interaction between EDC exposure and fetal sex. Therefore, we propose that the ability of placenta to respond and buffer EDC exposure depends on fetal sex and, hence the EDC associated disease susceptibility of one sex differs from the other.