m6A-related lncRNAs as potential biomarkers and the lncRNA ELFN1-AS1/miR-182-5p/BCL-2 regulatory axis in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid subtype. However, unsatisfactory survival outcomes remain a major challenge, and the underlying mechanisms are poorly understood. N6-methyladenosine (m6A), the most common internal modification of eukaryotic mRNA, participates in cancer pathogenesis. In this study, m6A-associated long non-coding RNAs (lncRNA) were retrieved from publicly available databases. Univariate, LASSO, and multivariate Cox regression analyses were performed to establish an m6A-associated lncRNA model specific to DLBCL. Kaplan-Meier curves, principal component analysis, functional enrichment analyses and nomographs were used to study the risk model. The underlying clinicopathological characteristics and drug sensitivity predictions against the model were identified. Risk modelling based on the three m6A-associated lncRNAs was an independent prognostic factor. By regrouping patients using our model-based method, we could differentiate patients more accurately for their response to immunotherapy. In addition, prospective compounds that can target DLBCL subtypes have been identified. The m6A-associated lncRNA risk-scoring model developed herein holds implications for DLBCL prognosis and clinical response prediction to immunotherapy. In addition, we used bioinformatic tools to identify and verify the ceRNA of the m6A-associated lncRNA ELFN1-AS1/miR-182-5p/BCL-2 regulatory axis. ELFN1-AS1 was highly expressed in DLBCL and DLBCL cell lines. ELFN1-AS1 inhibition significantly reduced the proliferation of DLBCL cells and promoted apoptosis. ABT-263 inhibits proliferation and promotes apoptosis in DLBCL cells. In vitro and in vivo studies have shown that ABT-263 combined with si-ELFN1-AS1 can inhibit DLBCL progression.

ITGB2 related to immune cell infiltration as a potential therapeutic target of inflammatory bowel disease using bioinformatics and functional research.

Inflammatory bowel disease (IBD) is a chronic systemic inflammatory condition regarded as a major risk factor for colitis-associated cancer. However, the underlying mechanisms of IBD remain unclear. First, five GSE data sets available in GEO were used to perform 'batch correction' and Robust Rank Aggregation (RRA) to identify differentially expressed genes (DEGs). Candidate molecules were identified using CytoHubba, and their diagnostic effectiveness was predicted. The CIBERSORT algorithm evaluated the immune cell infiltration in the intestinal epithelial tissues of patients with IBD and controls. Immune cell infiltration in the IBD and control groups was determined using the least absolute shrinkage selection operator algorithm and Cox regression analysis. Finally, a total of 51 DEGs were screened, and nine hub genes were identified using CytoHubba and Cytoscape. GSE87466 and GSE193677 were used as extra data set to validate the expression of the nine hub genes. CD4-naïve T cells, gamma-delta T cells, M1 macrophages and resting dendritic cells (DCs) are the main immune cell infiltrates in patients with IBD. Signal transducer and activator of transcription 1, CCR5 and integrin subunit beta 2 (ITGB2) were significantly upregulated in the IBD mouse model, and suppression of ITGB2 expression alleviated IBD inflammation in mice. Additionally, the expression of ITGB2 was upregulated in IBD-associated colorectal cancer (CRC). The silence of ITGB2 suppressed cell proliferation and tumour growth in vitro and in vivo. ITGB2 resting DCs may provide a therapeutic strategy for IBD, and ITGB2 may be a potential diagnostic marker for IBD-associated CRC.

Exploration of shared gene signatures and molecular mechanisms between type 2 diabetes and osteoporosis.

Type 2 diabetes mellitus (T2D) and osteoporosis (OP) are systemic metabolic diseases and often coexist. The mechanism underlying this interrelationship remains unclear. We downloaded microarray data for T2D and OP from the Gene Expression Omnibus (GEO) database. Using weighted gene co-expression network analysis (WGCNA), we identified co-expression modules linked to both T2D and OP. To further investigate the functional implications of these associated genes, we evaluated enrichment using ClueGO software. Additionally, we performed a biological process analysis of the genes unique in T2D and OP. We constructed a comprehensive miRNA-mRNA network by incorporating target genes and overlapping genes from the shared pool. Through the implementation of WGCNA, we successfully identified four modules that propose a plausible model that elucidates the disease pathway based on the associated and distinct gene profiles of T2D and OP. The miRNA-mRNA network analysis revealed co-expression of PDIA6 and SLC16A1; their expression was upregulated in patients with T2D and islet ß-cell lines. Remarkably, PDIA6 and SLC16A1 were observed to inhibit the proliferation of pancreatic ß cells and promote apoptosis in vitro, while downregulation of PDIA6 and SLC16A1 expression led to enhanced insulin secretion. This is the first study to reveal the significant roles of PDIA6 and SLC16A1 in the pathogenesis of T2D and OP, thereby identifying additional genes that hold potential as indicators or targets for therapy.

Association of the newly proposed dietary index for gut microbiota and depression: the mediation effect of phenotypic age and body mass index.

BACKGROUND: Gut microbiota and depression have garnered attention. The dietary index for gut microbiota (DI-GM) is a newly proposed index that reflects the diversity of gut microbiota, yet its association with depression remains unstudied. METHODS: Data from the National Health and Nutrition Examination Survey were analyzed. Depression was assessed using Patient Health Questionnaire (PHQ-9). Dietary recall data were used to calculate the DI-GM (including components beneficial and unfavorable to gut microbiota). Multivariable weighted logistic and linear regression were employed to investigate the association of DI-GM with depression and total PHQ-9 score. The potential mediating role of phenotypic age and body mass index (BMI) was explored. Secondary analyses included subgroup analyses, restricted cubic spline (RCS), and multiple imputation. RESULTS: A higher DI-GM and beneficial gut microbiota score were associated with a lower prevalence of depression (DI-GM: OR = 0.94, 95% CI = 0.89, 0.99; beneficial gut microbiota score: OR = 0.88, 95% CI = 0.82, 0.94) and lower total PHQ-9 score (DI-GM: ß=-0.09, 95% CI=-0.14, -0.04; beneficial gut microbiota: ß=-0.15, 95% CI=-0.21, -0.08). RCS indicated a non-linear relationship between DI-GM and depression. A significant mediating effect of phenotypic age (proportion of mediation: 19.81%, 95% CI: 12.86-63.00%) and BMI (proportion of mediation: 16.49%, 95% CI: 12.87-62.00%) was observed. CONCLUSIONS: The newly proposed DI-GM was negatively associated with the prevalence of depression and total PHQ-9 score. Mediation analyses demonstrated a significant mediating effect of phenotypic age and BMI.

M6A-mediated upregulation of circMDK promotes tumorigenesis and acts as a nanotherapeutic target in hepatocellular carcinoma.

BACKGROUND: Emerging evidence suggest the critical role of circular RNAs (circRNAs) in disease development especially in various cancers. However, the oncogenic role of circRNAs in hepatocellular carcinoma (HCC) is still largely unknown. METHODS: RNA sequencing was performed to identify significantly upregulated circRNAs in paired HCC tissues and non-tumor tissues. CCK-8 assay, colony formation, transwell, and xenograft mouse models were used to investigate the role of circRNAs in HCC proliferation and metastasis. Small interfering RNA (siRNA) was used to silence gene expression. RNA immunoprecipitation, biotin pull-down, RNA pull-down, luciferase reporter assay and western blot were used to explore the underlying molecular mechanisms. RESULTS: Hsa_circ_0095868, derived from exon 5 of the MDK gene (named circMDK), was identified as a new oncogenic circRNA that was significantly upregulated in HCC. The upregulation of circMDK was associated with the modification of N6-methyladenosine (m6A) and poor survival in HCC patients. Mechanistically, circMDK sponged miR-346 and miR-874-3p to upregulate ATG16L1 (Autophagy Related 16 Like 1), resulting to the activation of PI3K/AKT/mTOR signaling pathway to promote cell proliferation, migration and invasion. Poly (ß-amino esters) (PAEs) were synthesized to assist the delivery of circMDK siRNA (PAE-siRNA), which effectively inhibited tumor progression without obvious adverse effects in four liver tumor models including subcutaneous, metastatic, orthotopic and patient-derived xenograft (PDX) models. CONCLUSIONS: CircMDK could serve as a potential tumor biomarker that promotes the progression of HCC via the miR-346/874-3p-ATG16L1 axis. The PAE-based delivery of siRNA improved the stability and efficiency of siRNA targeting circMDK. The PAE-siRNA nanoparticles effectively inhibited HCC proliferation and metastasis in vivo. Our current findings offer a promising nanotherapeutic strategy for the treatment of HCC.

CircRNA-001241 mediates sorafenib resistance of hepatocellular carcinoma cells by sponging miR-21-5p and regulating TIMP3 expression.

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and its incidence is on the rise, closely related to advanced liver disease. Sorafenib chemotherapy is one of the main treatment options for patients with advanced HCC. Despite several reports on HCC multidrug resistance, the underlying regulatory mechanisms are still unclear. In this study, we found circ-001241 was significantly upregulated in HCC tissues and cells. Knockdown of circ-001241 markedly inhibited HCC cell proliferation and decreased sorafenib-resistance. More importantly, circRNA acts as a ceRNA to suppress the expression and activity of miR-21-5p, leading to the increase in TIMP3 expression. In addition, circRNA-001241 facilitated HCC sorafenib-resistance by regulating the miR-21-5p/TIMP3 axis. Taken together, our study elucidated the oncogenic role of circ-001241 in mediating sorafenib resistance in HCC, providing insights and opportunities to overcome sorafenib resistance in patients with advanced hepatocellular carcinoma.

Truncated tests for combining evidence of summary statistics.

To date, thousands of genetic variants to be associated with numerous human traits and diseases have been identified by genome-wide association studies (GWASs). The GWASs focus on testing the association between single trait and genetic variants. However, the analysis of multiple traits and single nucleotide polymorphisms (SNPs) might reflect physiological process of complex diseases and the corresponding study is called pleiotropy association analysis. Modern day GWASs report only summary statistics instead of individual-level phenotype and genotype data to avoid logistical and privacy issues. Existing methods for combining multiple phenotypes GWAS summary statistics mainly focus on low-dimensional phenotypes while lose power in high-dimensional cases. To overcome this defect, we propose two kinds of truncated tests to combine multiple phenotypes summary statistics. Extensive simulations show that the proposed methods are robust and powerful when the dimension of the phenotypes is high and only part of the phenotypes are associated with the SNPs. We apply the proposed methods to blood cytokines data collected from Finnish population. Results show that the proposed tests can identify additional genetic markers that are missed by single trait analysis.

Phase transition and higher order analysis of Lq regularization under dependence.

We study the problem of estimating a [Formula: see text]-sparse signal [Formula: see text] from a set of noisy observations [Formula: see text] under the model [Formula: see text], where [Formula: see text] is the measurement matrix the row of which is drawn from distribution [Formula: see text]. We consider the class of [Formula: see text]-regularized least squares (LQLS) given by the formulation [Formula: see text], where [Formula: see text]  [Formula: see text] denotes the [Formula: see text]-norm. In the setting [Formula: see text] with fixed [Formula: see text] and [Formula: see text], we derive the asymptotic risk of [Formula: see text] for arbitrary covariance matrix [Formula: see text] that generalizes the existing results for standard Gaussian design, i.e. [Formula: see text]. The results were derived from the non-rigorous replica method. We perform a higher-order analysis for LQLS in the small-error regime in which the first dominant term can be used to determine the phase transition behavior of LQLS. Our results show that the first dominant term does not depend on the covariance structure of [Formula: see text] in the cases [Formula: see text] and [Formula: see text] which indicates that the correlations among predictors only affect the phase transition curve in the case [Formula: see text] a.k.a. LASSO. To study the influence of the covariance structure of [Formula: see text] on the performance of LQLS in the cases [Formula: see text] and [Formula: see text], we derive the explicit formulas for the second dominant term in the expansion of the asymptotic risk in terms of small error. Extensive computational experiments confirm that our analytical predictions are consistent with numerical results.

Bidirectional crosstalk between the epithelial-mesenchymal transition and immunotherapy: A bibliometric study.

Immunotherapy has recently attracted considerable attention. However, currently, a thorough analysis of the trends associated with the epithelial-mesenchymal transition (EMT) and immunotherapy is lacking. In this study, we used bibliometric tools to provide a comprehensive overview of the progress in EMT-immunotherapy research. A total of 1,302 articles related to EMT and immunotherapy were retrieved from the Web of Science Core Collection (WOSCC). The analysis indicated that in terms of the volume of research, China was the most productive country (49.07%, 639), followed by the United States (16.89%, 220) and Italy (3.6%, 47). The United States was the most influential country according to the frequency of citations and citation burstiness. The results also suggested that Frontiers in Immunotherapy can be considered as the most influential journal with respect to the number of articles and impact factors. "Immune infiltration," "bioinformatics analysis," "traditional Chinese medicine," "gene signature," and "ferroptosis" were found to be emerging keywords in EMT-immunotherapy research. These findings point to potential new directions that can deepen our understanding of the mechanisms underlying the combined effects of immunotherapy and EMT and help develop strategies for improving immunotherapy.

Methodological and reporting quality assessment of systematic reviews and meta-analyses in the association between sleep duration and hypertension.

OBJECTIVE: It is crucial to conduct systematic reviews (SRs) and meta-analyses (MAs) to make causal references, in order to inform the clinical guidelines and decision-making. The high reporting quality of reviews through compliance with the guidelines Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Assessing the Methodological Quality of Systematic Reviews-2 (AMSTAR-2) could promote the consistency and reproducibility across the published articles. The purpose of this meta-epidemiological study is to evaluate the reporting methodological quality of SRs on the association between sleep duration and hypertension. METHODS: An electronic search in an online database was performed to retrieve systematic reviews and meta-analyses published up to 31st December 2022. Data screening and extraction were conducted by two investigators. The reporting quality of each included article was measured with reference to the 27-item 2020 PRISMA checklist, and methodological quality was evaluated using the AMSTAR-2. PRISMA evaluation was determined by total scores of individual SR and items scores and AMSTAR-2 assessment was also conducted using four categories. RESULTS: Of 2269 articles captured in the initial search, 15 SRs were included in the final analyses. All SRs had more than one incomplete PRISMA item. The mean of total scores was 20.5 (range 14-25), and the results of the AMSTAR-2 assessment were critically low to low. The reporting quality of "rationale," "objectives," "selection process," "study selection," "discussion," and 'support' was fully reported. SRs that reported registration information and protocol had a higher PRISMA score than articles that reported certain deficiencies. From the results of the AMSTAR-2 assessment, the methodological quality of these SRs and MAs was critically low to low. None of the included literature provided a list of excluded articles, and the report of the search strategy was incomplete; half of the SRs did not use appropriate tools to assess the risk of bias in each included study. CONCLUSIONS: Both the reporting and methodological quality of overall studies are less than ideal, with several key items being consistently under-reported. The quality measured by AMSTAR-2 is mainly consistent with the quality of reporting. Authors, reviewers, and journal editors should raise awareness and move forward to encourage completeness of SR reporting based on the results, which can aid in enhancing the quality of evidence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023459901.

Phthalate and gallstones: the mediation of insulin.

Background: Exposure to a mixture of environmental chemicals may cause gallstone, but the evidence remains equivocal. The current study aims to investigate the association between phthalate metabolites and gallstones, and to explore their mediators. Methods: Data from the National Health and Nutrition Examination Survey 2017-2018 on U.S. adults (≥20 years) were analyzed to explore the association between phthalate metabolites and gallstones by employed survey-weighted logistic regression, restricted cubic spline (RCS), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR). Mediation analyses examined the role of oxidative stress markers, inflammatory markers, metabolic syndrome, body composition, diabetes, and insulin. Results: The current study included 1,384 participants, representing 200.6 million U.S. adults. Our results indicated a significant association between phthalate metabolites, particularly high molecular weight metabolites such as Di(2-ethylhexyl) phthalate (DEHP) and 1,2-Cyclohexane dicarboxylic acid diisononyl ester (DINCH), and gallstones. Furthermore, mediation analyses indicated that phthalate metabolites may play a role in the development of gallstones by influencing insulin secretion. Subgroup analyses did not reveal significant interaction. Conclusion: The association between exposure to phthalates and the occurrence of gallstones, potentially mediated by hyperinsulinemia from a nationally representative epidemiological perspective. These insights contribute to a better understanding of the potential health implications of plasticizers, emphasizing the need for proactive management measures.

Association between biological aging and diabetic retinopathy.

The impact of aging on diabetic retinopathy (DR) remains underestimated. The current study aimed to investigate the association between biological aging and DR, in contrast to chronological age (CA). Using the National Health and Nutrition Survey data from 2005 to 2008. Biological aging was evaluated through the biological age (BA) and phenotypic age (PA), which were calculated from clinical markers. DR was identified in participants with diabetes mellitus (DM) when they exhibited one or more retinal microaneurysms or retinal blot hemorrhages under retinal imaging, with or without the presence of more severe lesions. Survey-weighted multivariable logistic regression was performed, and the regression model was further fitted using restricted cubic splines. The discriminatory capability and clinical utility of the model were evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Based on weighted analyses, of the 3100 participants included in this study, of which 162 had DR. In the adjusted model, BA (odds ratio [OR] = 1.12, 95% CI, 1.06-1.18) and PA (OR = 1.11, 95% CI, 1.07-1.14) were associated with DR, while CA was not significantly (OR = 1.01, 95% CI, 0.99-1.03). Narrowing the analysis to DM participants and adjusting for factors like insulin showed similar results. ROC and DCA analyses indicate that BA/PA predicted DR better than CA and offer greater clinical utility. The positive association between BA/PA and DR was consistent across subgroups despite potential interactions. Biological aging heightens DR risk, with BA/PA showing a stronger association than CA. Our findings underscored the importance of timely anti-aging interventions for preventing DR.

Increased altitudes change sleep status among Chinese population.

Sleep is integral to human health. Accumulating evidence has revealed that sleep characteristics could be influenced by altitudes. However, few studies explored what the trajectories of sleep status are along with the altitudes. Therefore, this study aims to find the relationship between altitudes and sleep status using data from CHARLS, a nationwide survey data from China. The generalized additive model and generalized additive mixed-effects model were used to explore the association between sleep status and altitudes. Age, gender, education level, and other common confounding factors were included in the models as covariates. The sleep duration showed a rapid increase trend after the altitude of 1600 m. The probabilities of long sleep duration were increased with the evaluation of altitudes (edf = 1.945, P = 0.004), while the similar statistically significant change was not observed for short sleep duration (edf = 2.204, P = 0.193). Gender, residence, and ethnicity were the main influencing factors for the increase in sleep duration as altitude increased. The high-altitude environment could have effects on the sleep status of individuals, especially on the sleep duration. Long sleep duration was found more prevalent among highlanders. This study shed light on the underlying relationship between altitudes and sleep status which could provide clues for further mechanism studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-024-00527-y.

Association between flavonoid intake and rheumatoid arthritis among US adults.

Basic research shows that flavonoids have anti-inflammatory effects that influence rheumatoid arthritis (RA) in rats. Investigating potential dietary interventions for RA helps prevent the onset and progression of the disease. Clinical evidence on the association of flavonoid and subclass intake with RA is lacking. Using three survey cycles of 2007-2008, 2009-2010, and 2017-2018 from the National Health and Nutrition Survey and the United States Department of Agriculture's Food and Nutrient Database for Dietary Studies (FNDDS), we analyzed 7,419 American adults (≥20 years old). The values of flavonoid and subclass intake were calculated using FNDDS. The status questions for self-reported RA were from the NHANES codebook. Weighted analyses, revealed that among the 7,419 participants included in this study (mean age of 44.69 years [standard error, 0.40] and 3,584 [48.31%] were female), 408 met the classification criteria for RA. According to the multivariable logistic regression model, compared with the risk of RA in the first quartile (Q1), the risks of RA in the second quartile (Q2), the third quartile (Q3) and the fourth quartile (Q4) were lower (Q2: OR=0.55, 95% CI: 0.38-0.80; Q3: OR=0.66, 95% CI: 0.44-0.97; Q4: OR=0.64, 95% CI: 0.46-0.89; trend: P=.03). The association between total flavonoids and RA remained significant after full consideration of confounding factors. With regard to the subclasses of flavonoids, high flavanones intake was associated with low RA prevalence in Model 3 (Q3: OR= 0.60, 95% CI:0.39-0.92; Q4: OR = 0.56, 95% CI: 0.32-0.99, trend: P=.02), but no such association was found in the other subclasses. Total flavonoids intake protected against RA, and the risk of developing RA decreased significantly with increasing intake of total flavonoids. Total flavonoids and flavanones were significantly associated with reduced RA risk for the American adult population. We highlighted the importance of employing diverse methodologies to assess the health effects of flavonoids.

tsRNA-GlyGCC promotes colorectal cancer progression and 5-FU resistance by regulating SPIB.

BACKGROUND: tRNA-derived small RNAs (tsRNAs) are newly discovered non-coding RNA, which are generated from tRNAs and are reported to participate in several biological processes in diseases, especially cancer; however, the mechanism of tsRNA involvement in colorectal cancer (CRC) and 5-fluorouracil (5-FU) is still unclear. METHODS: RNA sequencing was performed to identify differential expression of tsRNAs in CRC tissues. CCK8, colony formation, transwell assays, and tumor sphere assays were used to investigate the role of tsRNA-GlyGCC in 5-FU resistance in CRC. TargetScan and miRanda were used to identify the target genes of tsRNA-GlyGCC. Biotin pull-down, RNA pull-down, luciferase assay, ChIP, and western blotting were used to explore the underlying molecular mechanisms of action of tsRNA-GlyGCC. The MeRIP assay was used to investigate the N(7)-methylguanosine RNA modification of tsRNA-GlyGCC. RESULTS: In this study, we uncovered the feature of tsRNAs in human CRC tissues and confirmed a specific 5' half tRNA, 5'tiRNA-Gly-GCC (tsRNA-GlyGCC), which is upregulated in CRC tissues and modulated by METTL1-mediated N(7)-methylguanosine tRNA modification. In vitro and in vivo experiments revealed the oncogenic role of tsRNA-GlyGCC in 5-FU drug resistance in CRC. Remarkably, our results showed that tsRNA-GlyGCC modulated the JAK1/STAT6 signaling pathway by targeting SPIB. Poly (ß-amino esters) were synthesized to assist the delivery of 5-FU and tsRNA-GlyGCC inhibitor, which effectively inhibited tumor growth and enhanced CRC sensitive to 5-FU without obvious adverse effects in subcutaneous tumor. CONCLUSIONS: Our study revealed a specific tsRNA-GlyGCC-engaged pathway in CRC progression. Targeting tsRNA-GlyGCC in combination with 5-FU may provide a promising nanotherapeutic strategy for the treatment of 5-FU-resistance CRC.

Cuproptosis-related lncRNAs as potential biomarkers of AML prognosis and the role of lncRNA HAGLR/miR-326/CDKN2A regulatory axis in AML.

Acute myeloblastic leukemia (AML) is the most prevalent form of AML in adults. Despite the availability of various treatment options, including radiotherapy and chemotherapy, many patients fail to respond to treatment or relapse. Copper is a necessary cofactor for all organisms; however, it turns toxic when concentrations reach a certain threshold maintained by homeostatic systems that have been conserved through evolution. However, the mechanism through which excess copper triggers cell death remains unknown. In this study, data on long non-coding RNAs (lncRNAs) related to cuproptosis were retrieved from publicly available databases. LASSO and univariate and multivariate Cox regression analyses were performed to establish an lncRNA model associated with cuproptosis specific to AML. To investigate the risk model, the Kaplan-Meier curve, principal component analysis, functional enrichment analysis, and nomographs were employed. The underlying clinicopathological characteristics were determined, and drug sensitivity predictions against the model were identified. Six cuproptosis-related lncRNA-based risk models were identified as the independent prognostic factors. By regrouping patients using a model-based method, we were able to more accurately differentiate patients according to their responses to immunotherapy. In addition, prospective compounds targeting AML subtypes have been identified. Using qRT-PCR, we examined the expression levels of six cuproptosis-associated lncRNAs in 30 clinical specimens. The cuproptosis-associated lncRNA risk-scoring model developed herein has implications in monitoring AML prognosis and in the clinical prediction of the response to immunotherapy. Furthermore, we identified and verified the ceRNA of the cuproptosis-related lncRNA HAGLR/miR-326/CDKN2A regulatory axis using bioinformatic tools. HAGLR is highly expressed in AML and AML cell lines. HAGLR inhibition significantly reduced the proliferation of AML cells and promoted apoptosis. Elesclomol promotes the degradation of CDKN2A and inhibits the proliferation of AML cells. Elesclomol combined with si-HAGLR inhibited the AML progression of AML both in vitro and in vivo.

Exosomal circRNA-001264 promotes AML immunosuppression through induction of M2-like macrophages and PD-L1 overexpression.

Exosomes can help to effectively regulate the crosstalk between cancer cells and normal cells in the tumor microenvironment. They also regulate cancer cell proliferation and apoptosis by virtue of their cargo molecules. Transmission electron microscopy (TEM) together with differential ultracentrifugation served for verifying the presence of exosomes. In vivo and in vitro assays served for determining the role of exosomal circ_001264. RNA pull-down and dual-luciferase reporter assays assisted in the classification of the mechanism of exosomal circ_001264-mediated regulation of the crosstalk between Acute myeloid leukemia (AML) cells and M2 macrophages. Furthermore, we adopted a programmed death ligand 1 antibody (aPD-L1) in combination with exosomal circ_001264 siRNA for antitumor treatment in vitro and in vivo mouse models served for validating the in vivo outcomes. Out study illustrated the aberrant overexpression of circ_001264 in AML patients and its correlation with poor patient prognosis. AML cell-derived exosomal circ_001264 regulated the RAF1 expression and activated the p38-STAT3 signaling pathway, thereby inducing the M2 macrophage polarization. Polarized M2 macrophages can induce PD-L1 overexpression by secreting PD-L1. Here, a programmed death ligand (aPD-L1) was adopted for preventing the immunosuppression, which was able to achieve the desired therapeutic effect at the tumor site. Indeed, in the mouse model, leukemia tumor load decreased remarkably in the exosomal circ_001264 siRNA plus aPD-L1 combination group. Taken together, our study contributed to a theoretical basis for AML treatment. The co-administration of exosomal circ_001264 siRNA and aPD-L1 exhibited an obvious anti-cancer effectiveness in AML.

Immunological significance of prognostic markers for breast cancer based on alternative splicing.

OBJECTIVES: Breast cancer (BC) currently has the highest incidence rate. Epigenetic regulation could alter gene expression and is closely related to BC initiation. This study aimed to develop an alternative splicing (AS)-based prognostic signature and clarify its relevance to the tumor immune microenvironment (TIME) status and immunotherapy of BC. METHODS: Cox regression analysis was conducted to screen for prognosis-related AS events. Thereafter, LASSO with Cox regression analyses was designed to construct a prognostic signature model. Kaplan-Meier survival analysis, receiver operating characteristic curves, and proportional hazard model were then utilized to confirm the prognostic value. Multiple methods were employed to reveal the context of TIME in BC. QPCR, western blotting and immunofluorescence microscopy were carried out to detect myc-associated zinc finger protein (MAZ) expression in different cell lines, and BC and paracancerous tissues. RESULTS: A total of 1,787 prognosis-related AS events were screened. Eight AS prognostic signatures were constructed with robust predictive accuracy based on the splicing subtypes. Furthermore, the establishment of a quantitative prognostic nomogram and consolidated signature was significantly correlated with TIME diversity and immune checkpoint blockade-related genes. MAZ was detected to be upregulated in BC. Finally, a newly constructed splicing regulatory network model revealed the potential functions of splicing factors. CONCLUSIONS: AS-splicing factor networks may enable a new approach to investigating potential regulatory mechanisms. Moreover, pivotal players in AS events with regards to TIME and efficiency of immunotherapy were uncovered and could facilitate clinical decision-making and individual determination of BC prognosis.

Ferroptosis synergistically sensitizes wee1 inhibitors: a bibliometric study.

Synthetic lethality (SL) is a lethal phenomenon with an important role in cancer treatment. This study was conducted to analyze the hotspots and frontiers in SL research. The Web of Science Core Collection (WOSCC) was used to identify the 100 top-cited articles related to SL research. Additionally, wee1 inhibitors combined with erastin were used to determine the effectiveness of SL in vitro and in vivo. Relevant articles were published mainly from 2009 to 2021, reaching a peak in 2020; articles published in 2010 were most frequently cited among the 100-top cited papers. Most studies (54%) were performed in the United States. Articles in Nature Chemical Biology were cited more frequently than articles in other journals, whereas Nature published the largest number of reports on SL. Among the 88 corresponding authors, CJ Lord was the most productive. Overlay visualization of keyword analysis revealed that the hotspots in SL research were PARP inhibitors, BRCA mutations, DNA damage repair, and carcinogenesis. CRISPR, ferroptosis, wee1, double-strand break (dsb) repair, myc, immunotherapy, and replication stress are emerging topics in SL research, whereas ovarian cancer, prostate stress, acute myeloid leukemia, and other topics have been used as disease models in recent years. The application and therapeutic strategy of SL in cancer is an emerging trend. Significantly, experiments verified that the wee1 inhibitor AZD1775 and ferroptosis activator erastin have synergistic effects on ovarian cancer in vitro and in vivo. Combining bibliometric analysis with experimental verification is a useful approach for SL research.

A simple method for lodging resistance evaluation of maize in the field.

The increase of planting density is a dominant approach for the higher yield of maize. However, the stalks of some varieties are prone to lodging under high density conditions. Much research has been done on the evaluation of maize lodging resistance. But there are few comprehensive reports on the determination of maize lodging resistance in situ without injury under field conditions. This study introduces a non-destructive in situ tester to determine the lodging resistance of the different maize varieties in the field. The force value can be obtained by pulling the stalk to different angles with this instrument, which is used to evaluate the lodging resistance of maize varieties. From 2018 to 2020, a total of 1,172 sample plants from 113 maize varieties were tested for the lodging resistance of plants. The statistical results show that the values of force on maize plants at 45° inclination angles (F45) are appropriate to characterize maize lodging resistance in situ by nondestructive testing in the field. According to the F45 value, the maximum lodging resistance Fmax can be inferred. The formula is: Fmax =1.1354 F45 - 0.3358. The evaluation results of lodging resistance of different varieties of this study are basically consistent with the test results of three-point bending method, moving wind tunnel and other methods. Therefore, the F45 value is the optimal index for nondestructive evaluation of maize stalk-lodging resistance under the field-planting conditions.