A new perspective on hematological malignancies: m6A modification in immune microenvironment

Immunotherapy for hematological malignancies is a rapidly advancing field that has gained momentum in recent years, primarily encompassing chimeric antigen receptor T-cell (CAR-T) therapies, immune checkpoint inhibitors, and other modalities. However, its clinical efficacy remains limited, and drug resistance poses a significant challenge. Therefore, novel immunotherapeutic targets and agents need to be identified. Recently, N6-methyladenosine (m6A), the most prevalent RNA epitope modification, has emerged as a pivotal factor in various malignancies. Reportedly, m6A mutations influence the immunological microenvironment of hematological malignancies, leading to immune evasion and compromising the anti-tumor immune response in hematological malignancies. In this review, we comprehensively summarize the roles of the currently identified m6A modifications in various hematological malignancies, with a particular focus on their impact on the immune microenvironment. Additionally, we provide an overview of the research progress made in developing m6A-targeted drugs for hematological tumor therapy, to offer novel clinical insights

PO-240 Effects of aerobic exercise and fiber-enriched diet on gut microbiota in pre-diabetic patients with NAFLD: There is no full text article associated whit this abstract

  Objective Compelling evidence suggests that gut microbiota can play a role in the development of the metabolic syndrome, which incorporates abdominal obesity, hypertension, hyperglycaemia and dyslipidaemia. It is known that effective lifestyle intervention (including increasing physical exercise and calorie-restricted diet) is the mainstay treatment for the majority of patients with non-alcoholic fatty liver disease (NAFLD) and prediabetes. However, the effect of aerobic exercise and dietary intervention on gut microbiota in pre-diabetic patients with NAFLD is largely unknown and needs to be elucidated. Thus, the aim of the study was to investigate whether gut microbiota composition would change after aerobic exercise training and a fibre-enriched diet intervention in pre-diabetic patients with NAFLD. Methods We have conducted a randomized controlled trial in patients aged 50-65-year who have fulfilled the inclusion criteria (impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) and hepatic fat content >5.6%, NAFLD). The patients were randomly assigned to aerobic exercise (AEx), dietary intervention (Diet), aerobic exercise plus diet intervention (AED) or no intervention (NI) groups for an average period of 8.6 months (7-11 months). Among those participants, 78 provided fecal samples (AEx, n = 18, Diet, n = 22, AED = 21, and NI = 17). Progressive supervised aerobic exercise training (60-75% intensity) was given 2-3 times/week in 30-60 min/sessions, and the diet intervention was provided as lunch with 38% carbohydrate and diet fibre of 12g per day for 8.6-months. The hepatic fat content (HFC) was assessed by 1H MRS, glycated hemoglobin (HbA1c) and insulin sensitivity were assessed by conventional methods. Gut microbiota characterizations were determined with 16S rDNA-based high-throughput sequencing by Illumina Miseq platform. Results The Simpson index showed that alpha diversity was significantly different in intervention groups compared with NI group after the intervention (AEx vs NI, p=0.070; Diet vs NI, p=0.014; AED vs NI, p=0.011). Simpson index had a negative trend with HFC change % after intervention (r=-0.254, p=0.053). Weighted UniFrac PCoA analysis revealed that the structure of gut microbiota in the intervention groups was significantly differed from that of NI group (AEx vs NI, p<0.01, Diet vs NI, p<0.05, AED vs NI, p<0.001). Interestingly, we found that Erysipelotrichi (which has been reported associated with NASH) was negatively correlated VO2max (r=-0.274, p=0.040). At genus level, Clostridium and Lactobacillus were positively correlated with HFC change after intervention (r=0.273, p=0.038; r=0.273, p=0.041 respectively). Conclusions The exercise and diet intervention modified the structure of gut microbiota both in alpha and beta diversity. The Clostridium and Lactobacillus is related to energy metabolism and participated in the fermentation of carbohydrate which may be partly explain the positive correlation of gut microbiota with HFC change. However, the function of specific gut microbe needs to be further studied. &nbsp

PO-201 Aging attenuates the effect of aerobic capacity in muscle and serum metabolic profile but not in white adipose tissue

Objective Aerobic capacity is a quantitative predictor of the morbidity and mortality in many diverse patient populations. While aging is the main factor affecting aerobic capacity. The present study aimed to assess the effect of aerobic capacity and aging on metabolic profile in rats and to investigate the metabolic interactions between white adipose tissue (WAT), muscle and serum. Methods In this study, we used rat models that were selectively bred to differ in maximal running capacity (High capacity runners (HCR) and Low capacity runners (LCR)). Part of the rats were sacrificed after 9 months and the rest at 21 months. The effect of aerobic capacity on metabolic profile was assessed from 9 months old young rats (HCR-Y and LCR-Y), while the effect of aging on the metabolic profile in different capacity rats was determined comparing 9 months to 21 months old rats (HCR-O and LCR-O). Nuclear magnetic resonance (NMR) spectroscopy was performed to detect the metabolomics of WAT, muscle and serum. Partial least-squares-discriminant analysis (PLS-DA) was used for pattern recognition between HCR-Y and LCR-Y and between HCR-O and LCR-O. Metabolites with variable influence on projection (VIP) >1.0 and p<0.05 were classified as significantly different metabolites between groups. Spearman correlation was used to assess the metabolic interactions between white adipose tissue (WAT), muscle and serum. Results  HCR-Y rats had significantly higher skeletal muscle mass-to-body mass ratio (p<0.001), while lower body mass (p<0.001), fat mass (p<0.001), skeletal muscle mass (p=0.035) and fat mass to body mass ratio (p=0.004) than LCR-Y rats. The running capacity of HCR-Y rats was 132.7% (best running speed) better than LCR-Y rats (p<0.001). However, with age, the difference between body compositions between the two capacity groups became insignificant. HCR-O only had significantly lower body mass than the LCR-O (p=0.02). Running capacity (p=0.06) was 86.4% (best running speed) higher in the HCR-O rats than that of the LCR-O rats. PLS-DA revealed marked effects of aerobic capacity on metabolic profile in all three tissue types between HCR-Y and LCR-Y. The metabolic profile classification and prediction was best (i.e. sharper) in muscle than in WAT and serum. In addition, muscle and serum contained more significantly different metabolites than WAT in HCR-Y than in LCR-Y. Pathway analysis of the significantly different metabolites between HCR-Y and LCR-Y revealed that all the pathways belong to the lipid metabolism and amino acid metabolism in muscle while in serum it is only amino acid metabolism. However, in the case of the old groups, the PLS-DA gave reversed results. It revealed that WAT performed best in terms of classification and prediction of metabolites between HCR-O and LCR-O and had the most significantly different metabolites out of the three tissue types. The significantly different metabolites’ pathways belong to lipid metabolism in WAT. When assessing the metabolic interaction between different tissue types, all significantly different metabolites between HCR and LCR rats in young and old groups were moderately or strongly correlated (Spearman correlation between 0.45-0.9) with one or more metabolites in any of the three tissues. Conclusions In this study, we assessed the metabolic profile and body composition of WAT, muscle and serum in young and old rats with different aerobic capacities. We found that aerobic capacity greatly impacts body composition and the metabolic profile in muscle and serum in young rats, however the impact is attenuated with age. In addition, it is aging and not aerobic capacity that had the most influence on WAT metabolites. This suggest that WAT has more important role in aging process than previously assumed

Interactive effects of aging and aerobic capacity on energy metabolism-related metabolites of serum, skeletal muscle, and white adipose tissue

Aerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial beta-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Enhancing Electrochemical Sensing through Molecular Engineering of Reduced Graphene Oxide–Solution Interfaces and Remote Floating-Gate FET Analysis

Two-dimensional nanomaterials such as reduced graphene oxide (rGO) have captured significant attention in the realm of field-effect transistor (FET) sensors due to their inherent high sensitivity and cost-effective manufacturing. Despite their attraction, a comprehensive understanding of rGO–solution interfaces (specifically, electrochemical interfacial properties influenced by linker molecules and surface chemistry) remains challenging, given the limited capability of analytical tools to directly measure intricate solution interface properties. In this study, we introduce an analytical tool designed to directly measure the surface charge density of the rGO–solution interface leveraging the remote floating-gate FET (RFGFET) platform. Our methodology involves characterizing the electrochemical properties of rGO, which are influenced by adhesion layers between SiO2 and rGO, such as (3-aminopropyl)trimethoxysilane (APTMS) and hexamethyldisilazane (HMDS). The hydrophilic nature of APTMS facilitates the acceptance of oxygen-rich rGO, resulting in a noteworthy pH sensitivity of 56.8 mV/pH at the rGO–solution interface. Conversely, hydrophobic HMDS significantly suppresses the pH sensitivity from the rGO–solution interface, attributed to the graphitic carbon-rich surface of rGO. Consequently, the carbon-rich surface facilitates a denser arrangement of 1-pyrenebutyric acid N-hydroxysuccinimide ester linkers for functionalizing capturing probes on rGO, resulting in an enhanced sensitivity of lead ions by 32% in our proof-of-concept test

Super-enhancer omics in stem cell

Abstract The hallmarks of stem cells, such as proliferation, self-renewal, development, differentiation, and regeneration, are critical to maintain stem cell identity which is sustained by genetic and epigenetic factors. Super-enhancers (SEs), which consist of clusters of active enhancers, play a central role in maintaining stemness hallmarks by specifically transcriptional model. The SE-navigated transcriptional complex, including SEs, non-coding RNAs, master transcriptional factors, Mediators and other co-activators, forms phase-separated condensates, which offers a toggle for directing diverse stem cell fate. With the burgeoning technologies of multiple-omics applied to examine different aspects of SE, we firstly raise the concept of “super-enhancer omics”, inextricably linking to Pan-omics. In the review, we discuss the spatiotemporal organization and concepts of SEs, and describe links between SE-navigated transcriptional complex and stem cell features, such as stem cell identity, self-renewal, pluripotency, differentiation and development. We also elucidate the mechanism of stemness and oncogenic SEs modulating cancer stem cells via genomic and epigenetic alterations hijack in cancer stem cell. Additionally, we discuss the potential of targeting components of the SE complex using small molecule compounds, genome editing, and antisense oligonucleotides to treat SE-associated organ dysfunction and diseases, including cancer. This review also provides insights into the future of stem cell research through the paradigm of SEs

Association of leisure time physical activity and NMR-detected circulating amino acids in peripubertal girls:a 7.5-year longitudinal study

Abstract This study investigated the longitudinal associations of physical activity and circulating amino acids concentration in peripubertal girls. Three hundred ninety-six Finnish girls participated in the longitudinal study from childhood (mean age 11.2 years) to early adulthood (mean age 18.2 years). Circulating amino acids were assessed by nuclear magnetic resonance spectroscopy. LTPA was assessed by self-administered questionnaire. We found that isoleucine, leucine and tyrosine levels were significantly higher in individuals with lower LTPA than their peers at age 11 (p < 0.05 for all), independent of BMI. In addition, isoleucine and leucine levels increased significantly (~15%) from childhood to early adulthood among the individuals with consistently low LTPA (p < 0.05 for both), while among the individuals with consistently high LTPA the level of these amino acids remained virtually unchanged. In conclusion, high level of physical activity is associated lower serum isoleucine and leucine in peripubertal girls, independent of BMI, which may serve as a mechanistic link between high level of physical activity in childhood and its health benefits later in life. Further studies in peripubertal boys are needed to assess whether associations between physical activity and circulating amino acids in children adolescents are sex-specific

Timing of exercise affects glycemic control in type 2 diabetes patients treated with metformin

Objective. The purpose of the study was to examine the acute effects of the timing of exercise on the glycemic control during and after exercise in T2D. Methods. This study included 26 T2D patients (14 women and 12 men) who were treated with metformin. All patients were tested on four occasions: metformin administration alone (Metf), high-intensity interval training (HIIT) performed at 30 minutes (EX30), 60 minutes (EX60), and 90 minutes (EX90) postbreakfast, respectively. Glucose, insulin, and superoxide dismutase (SOD) activity were examined. Results. Glucose decreased significantly after the exercise in EX30, EX60, and EX90. Compared with Metf, the decline in glucose immediately after the exercise was larger in EX30 (−2.58 mmol/L; 95% CI, −3.36 to −1.79 mmol/L; ), EX60 (−2.13 mmol/L; 95% CI, −2.91 to −1.34 mmol/L; ), and EX90 (−1.87 mmol/L; 95% CI, −2.65 to −1.08 mmol/L; ), respectively. Compared with Metf, the decrease in insulin was larger in EX30 and EX60 (both ). Conclusions. Timing of exercise is a factor to consider when prescribing exercise for T2D patients treated with metformin. This trial is registered with ChiCTR-IOR-16008469 on 13 May 2016.peerReviewe

High expression of EBP is an adverse prognostic factor for de novo acute myeloid leukemia

Background: Acute myeloid leukemia (AML) is a heterogeneous disease, for which identifying reliable prognostic markers is critical for accurate clinical prognosis and treatment optimization. The inhibition of emopamil-binding protein gene (EBP) expression has been demonstrated to induce cancer cell death via depleting downstream sterols. Nevertheless, no comprehensive studies have been conducted specifically in tumors, including AML.Method: Herein, survival analyses were performed on the dataset obtained from The Cancer Genome Atlas (TCGA). Besides, the EBP levels were quantified using real-time qPCR in a cohort of 120 AML patients, and the value of EBP was further assessed using our clinical data.Results: Patients with high EBP expression had worse overall survival (OS) and event-free survival (EFS) than patients with low EBP expression, both in the TCGA dataset and our clinical data. Additionally, white blood cell (WBC) counts were higher in patients with high EBP expression (P = 0.032). Moreover, in patients with intermediate-risk AML, it was discovered that elevated EBP expression was linked to a worse EFS (P = 0.038). Multivariate analysis demonstrated that high EBP expression was an independent prognostic factor in AML patients and was associated with a shorter OS and EFS (OS: P = 0.041; EFS: P = 0.017). Furthermore, the data revealed that transplantation in the high-EBP group led to an improvement in survival (OS: P = 0.001; EFS: P = 0.001). The same benefit was also observed in intermediate-risk AML patients (OS: P = 0.026; EFS: P = 0.026).Conclusion: Collectively, our findings indicated that high expression of EBP in AML patients was an adverse prognostic factor, but transplantation had the otential to alleviate its negative effects