Is transcranial alternating current stimulation effective for improving working memory? A three-level meta-analysis.

Working memory, an essential component of cognitive function, can be improved through specific methods. This meta-analysis evaluates the effectiveness of transcranial alternating current stimulation (tACS), an emerging technique for enhancing working memory, and explores its efficacy, influencing factors, and underlying mechanisms. A PRISMA systematic search was conducted. Hedges's g was used to quantify effect sizes. We constructed a three-level meta-analytic model to account for all effect sizes and performed subgroup analyses to assess moderating factors. Recognizing the distinct neural underpinnings of various working memory processes, we separately assessed the effects on n-back tasks and traditional working memory tasks. A total of 39 studies with 405 effect sizes were included (170 from n-back tasks and 235 from other tasks). The overall analysis indicated a net benefit of g = 0.060 of tACS on working memory. Separate analyses showed that tACS had a small positive effect on n-back tasks (g = 0.102), but almost no effect on traditional working memory tasks (g = 0.045). Further analyses revealed mainly: A moderately positive effect of theta tACS (without anti-phase stimulation) on n-back tasks (g = 0.207); and a small effect of offline stimulation on working memory maintenance (g = 0.127). Overall, tACS has minimal impact on working memory improvement, but it shows potential under certain conditions. Specifically, both online and offline theta tACS can improve n-back task performance, while only offline stimulation enhances working memory maintenance. More research is needed to understand the mechanisms behind these effects to make tACS an effective method.

Glycerol Kinase Drives Hepatic de novo Lipogenesis and Triglyceride Synthesis in Nonalcoholic Fatty Liver by Activating SREBP-1c Transcription, Upregulating DGAT1/2 Expression, and Promoting Glycerol Metabolism.

Glycerol kinase (GK) participates in triglyceride (TG) synthesis by catalyzing glycerol metabolism. Whether GK contributes to nonalcoholic fatty liver (NAFL) is unclear. The expression of hepatic Gk is found to be increased in diet-induced and genetic mouse models of NAFL and is positively associated with hepatic SREBP-1c expression and TG levels. Cholesterol and fatty acids stimulate GK expression in hepatocytes. In HFD-induced NAFL mice, knockdown of hepatic Gk decreases expression of SREBP-1c and its target lipogenic genes as well as DGAT1/2, increases serum glycerol levels, decreases serum TG levels, and attenuates hepatic TG accumulation. Overexpression of GK in hepatocytes in mice or in culture produces opposite results. Mechanistic studies reveal that GK stimulates SREBP-1c transcription directly by binding to its gene promoter and indirectly by binding to SREBP-1c protein, thereby increasing lipogenic gene expression and de novo lipogenesis. Studies with truncated GK and mutant GKs indicate that GK induces SREBP-1c transcription independently of its enzyme activity. GK contributes to lipid homeostasis under physiological conditions by catalyzing glycerol metabolism rather than by regulating SREBP-1c transcription. Collectively, these results demonstrate that increased hepatic GK promotes de novo lipogenesis and TG synthesis in NAFL by stimulating SREBP-1c transcription and DGAT1/2 expression and catalyzing glycerol metabolism.

Revealing the distinct impacts of effectiveness recognition and memory retention on the transfer of creative cognitive reappraisal.

Previous research has shown that creative cognitive reappraisal is highly effective in regulating negative emotions. We conducted three experiments to explore its transferability. In Experiment 1, we observed that free recall performance was better for creative reappraisal compared to non-creative reappraisal. Memory retention of reappraisals was associated with creativity ratings, but not with perceived effectiveness ratings. In Experiment 2, participants generated reappraisals for newly introduced unpleasant images before (pre-session) and after (post-session) exposure to creative reappraisal, non-creative reappraisal, and descriptive control interpretation. Results showed increased reflective effectiveness of self-generated reappraisals in the post-session. The level of creativity of the self-generated reappraisals was associated with differences in perceived effectiveness between creative and non-creative exposed reappraisals. In Experiment 3, we investigated how two processing approaches (effectiveness-oriented vs. memory-oriented) influenced the transferability of creative reappraisal. We observed creativity levels of self-generated reappraisals increased in both conditions. The reflective effectiveness of the self-generated reappraisals tended to increase only in the effectiveness-oriented processing condition. Our findings demonstrate that recognising the effectiveness of creative reappraisal plays a crucial role in its transfer across different situations.

Mettl1 knockdown alleviates cardiac I/R injury in mice by inactivating the Mettl1-CYLD-P53 positive feedback loop.

The N7-methylguanosine (m7G) methyltransferase Mettl1 has been recently implicated in cardiac repair and fibrosis. In this study we investigated the role of Mettl1 in mouse cardiomyocytes injury and the underlying mechanisms. Cardiac ischemia/reperfusion (I/R) I/R model was established in mice by ligation of the left anterior descending coronary artery (LAD) for 45 min followed by reperfusion for 24 h. We showed the mRNA and protein levels of Mettl1 were significantly upregulated in mouse I/R hearts and H2O2-treated neonatal mouse cardiomyocytes (NMCMs). Mettl1 knockdown markedly ameliorated cardiac I/R injury, evidenced by decreased infarct size, apoptosis, and improved cardiac function. Overexpression of Mettl1 triggered cardiomyocytes apoptosis in vivo and in vitro. By performing RNA sequencing combined with m7G methylated RNA sequencing in Mettl1-overexpressing mouse hearts, we revealed that Mettl1 catalyzed m7G modification of the deubiquitinase cylindromatosis (CYLD) mRNA to increase the expression of CYLD, which enhanced the stability of P53 via abrogating its ubiquitination degradation. Vice versa, P53 served as a transcriptional factor to positively regulate Mettl1 expression during I/R injury. Knockdown of CYLD mitigated cardiomyocytes apoptosis induced by Mettl1 overexpression or oxidative stress. From the available drug-targets databases and literature, we identified 4 small molecule inhibitors of m7G modification. Sinefungin, one of the Mettl1 inhibitors exerted profound protection against cardiac I/R injury in vivo and in vitro. Collectively, this study has identified Mettl1 as a key regulator of cardiomyocyte apoptosis, and targeting the Mettl1-CYLD-P53 positive feedback circuit may represent a novel therapeutic avenue for alleviating cardiac I/R injury.

The deficit in cognitive reappraisal capacity in individuals with anxiety or depressive disorders: meta-analyses of behavioral and neuroimaging studies.

BACKGROUND: The deficit in cognitive reappraisal capacity is a key factor in developing and maintaining emotional disorders such as anxiety disorders and depressive disorders. However, the results from both neuroimaging and behavioral studies are mixed. Therefore, we systematically conducted a series of meta-analyses based on behavioral and neuroimaging studies to clarify this issue. METHODS: In behavioral meta-analyses, we used three-level random-effects models to summarize the overall effect sizes based on Hedges' g. In neuroimaging meta-analyses, we used SDM-PSI to summarize the brain activation patterns. RESULTS: Behavioral meta-analyses found that individuals with anxiety disorders or depressive disorders could reduce negative reactivity through reappraisal; the reduction of negative emotions through reappraisal by individuals with anxiety disorders was similar to that by healthy individuals; the reduction by depressive disorders was lower than that of healthy individuals. Neuroimaging meta-analyses showed that individuals with anxiety disorders or depressive disorders activated regions of cognitive control during cognitive reappraisal; the activation in individuals with anxiety disorders was lower than in healthy individuals; while the activation in individuals with depressive disorders was similar to that in healthy individuals. CONCLUSION: Individuals with anxiety and depressive disorders showed dissociation in behaviour and neuroimaging patterns of cognitive reappraisal capacity deficit.

DeepMineLys: Deep mining of phage lysins from human microbiome.

Vast shotgun metagenomics data remain an underutilized resource for novel enzymes. Artificial intelligence (AI) has increasingly been applied to protein mining, but its conventional performance evaluation is interpolative in nature, and these trained models often struggle to extrapolate effectively when challenged with unknown data. In this study, we present a framework (DeepMineLys [deep mining of phage lysins from human microbiome]) based on the convolutional neural network (CNN) to identify phage lysins from three human microbiome datasets. When validated with an independent dataset, our method achieved an F1-score of 84.00%, surpassing existing methods by 20.84%. We expressed 16 lysin candidates from the top 100 sequences in E. coli, confirming 11 as active. The best one displayed an activity 6.2-fold that of lysozyme derived from hen egg white, establishing it as the most potent lysin from the human microbiome. Our study also underscores several important issues when applying AI to biology questions. This framework should be applicable for mining other proteins.

Does working memory training improve emotion regulation and reduce internalizing symptoms? A pair of three-level meta-analyses.

BACKGROUND: Emotional dysfunction is a core feature of many mental disorders. Working memory training (WM-T) is promising to improve emotion regulation and reduce internalizing symptoms (anxiety and depressive symptoms), but the results are mixed. Therefore, we conducted meta-analyses to clarify these mixed results. METHODS: We searched Web of Science, PubMed, ScienceDirect, and EBSCO to identify relevant studies and screened the references. The effect size was calculated using Hedges' g. Three-level, random-effects models were run using metafor in R. RESULTS: The current study included 44 articles, of which 29 were involved with emotion regulation, and 30 were involved with internalizing symptoms. The results showed that WM-T could yield emotional benefits, but the benefits were confined to enhancing explicit emotional regulation capacity and reducing anxiety symptoms. For the meta-analysis regarding the effect of WM-T on emotion regulation, there was no significant moderator. For the meta-analysis regarding the effect of WM-T on internalizing symptoms, the emotional valence of the material and control group were statistically significant moderators. CONCLUSION: WM-T could yield certain emotional effects, but only to improve explicit emotion regulation capacity and reduce anxiety symptoms. In addition, some measures could enhance the effect, such as targeting specific populations, increasing the number of training sessions (≥15) or duration (>450 minutes), using negative material, and using n-back training tasks.

The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9-Mediated Splicing of NFATc4.

Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1-catalyzed RNA N7-methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non-ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac-specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC- or Mettl1-induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.

Multicomponent qualitative and quantitative analysis of Farfarae Flos in serum using UHPLC-Q TOF-MS.

Farfarae Flos is a traditional herb widely employed for treating coughs, bronchitis, and asthmatic disorders. In the current study, we utilized SWATH and IDA data acquisition modes in combination with multiple data processing techniques to identify Farfarae Flos metabolites in mice serum. A total of 56 compounds were characterized, including 31 phenolic acids, 13 flavonoids, 11 sesquiterpenoids and 1 alkaloid. Further quantitative analysis was conducted on 12 absorbed metabolites, utilizing a newly developed and rigorously validated analytical method. Our approach demonstrated an acceptable level of specificity, accuracy, precision, and stability. When applied to compare the serum of mice treated with FF, all 12 metabolites showed the highest concentration at 0.5 h. Overall, this study presented a novel strategy for unraveling the active compounds of FF via serum pharmacochemistry analysis, which made a foundation for exploring the pharmacodynamic material basis of FF.

The positive feedback loop of the NAT10/Mybbp1a/p53 axis promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury.

Ferroptosis is a nonapoptotic form of regulated cell death that has been reported to play a central role in cardiac ischemia‒reperfusion (I/R) injury. N-acetyltransferase 10 (NAT10) contributes to cardiomyocyte apoptosis by functioning as an RNA ac4c acetyltransferase, but its role in cardiomyocyte ferroptosis during I/R injury has not been determined. This study aimed to elucidate the role of NAT10 in cardiac ferroptosis as well as the underlying mechanism. The mRNA and protein levels of NAT10 were increased in mouse hearts after I/R and in cardiomyocytes that were exposed to hypoxia/reoxygenation. P53 acted as an endogenous activator of NAT10 during I/R in a transcription-dependent manner. Cardiac overexpression of NAT10 caused cardiomyocyte ferroptosis to exacerbate I/R injury, while cardiomyocyte-specific knockout of NAT10 or pharmacological inhibition of NAT10 with Remodelin had the opposite effects. The inhibition of cardiomyocyte ferroptosis by Fer-1 exerted superior cardioprotective effects against the NAT10-induced exacerbation of post-I/R cardiac damage than the inhibition of apoptosis by emricasan. Mechanistically, NAT10 induced the ac4C modification of Mybbp1a, increasing its stability, which in turn activated p53 and subsequently repressed the transcription of the anti-ferroptotic gene SLC7A11. Moreover, knockdown of Mybbp1a partially abolished the detrimental effects of NAT10 overexpression on cardiomyocyte ferroptosis and cardiac I/R injury. Collectively, our study revealed that p53 and NAT10 interdependently cooperate to form a positive feedback loop that promotes cardiomyocyte ferroptosis to exacerbate cardiac I/R injury, suggesting that targeting the NAT10/Mybbp1a/p53 axis may be a novel approach for treating cardiac I/R.

Familial genetic and environmental transmission of depression: A multi-informant twin family study.

The phenomenon of familial clustering in depression is well established, yet the mechanisms by which depression is transmitted within families remain poorly understood. In the current study, we investigate the familial genetic and environmental transmission of depression by incorporating data from both adolescent twins and their parents. A total of 987 twin families were recruited from the Beijing Twin Study. Depression assessments were conducted for both adolescents and their parents. Twins' depression was assessed through reports from both the twins themselves and their parents, while parental depression was assessed by parental self-report. We employed a nuclear twin family model to examine genetic and environmental influences on adolescent depression. Our results, based on both self- and parent-report, demonstrate significant additive and dominant genetic influences on depression. We also found mild yet significant sibling environmental influences, while familial environmental influences were absent. Notably, parent-reported depression showed higher heritability but lower unique environmental influences compared with self-reported depression. These results highlight the important role of genetic transmission and sibling environmental transmission in explaining depression. Our study delineates the underlying mechanism of familial transmission in depression and can inform early treatments to halt transmission during adolescence.

CRISPR RNA-Guided Transposases Facilitate Dispensable Gene Study in Phage.

Phages provide a potential therapy for multi-drug-resistant (MDR) bacteria. However, a significant portion of viral genes often remains unknown, posing potential dangers. The identification of non-essential genes helps dissect and simplify phage genomes, but current methods have various limitations. In this study, we present an in vivo two-plasmid transposon insertion system to assess the importance of phage genes, which is based on the V. cholerae transposon Tn6677, encoding a nuclease-deficient type I-F CRISPR-Cas system. We first validated the system in Pseudomonas aeruginosa PAO1 and its phage S1. We then used the selection marker AcrVA1 to protect transposon-inserted phages from CRISPR-Cas12a and enriched the transposon-inserted phages. For a pool of selected 10 open-reading frames (2 known functional protein genes and 8 hypothetical protein genes) of phage S1, we identified 5 (2 known functional protein genes and 3 hypothetical protein genes) as indispensable genes and the remaining 5 (all hypothetical protein genes) as dispensable genes. This approach offers a convenient, site-specific method that does not depend on homologous arms and double-strand breaks (DSBs), holding promise for future applications across a broader range of phages and facilitating the identification of the importance of phage genes and the insertion of genetic cargos.

Prevalence and risk factors of oral human papillomavirus infection among 4212 healthy adults in Hebei, China.

BACKGROUND: Human papillomavirus (HPV) infection is an essential cause of oropharyngeal squamous cell carcinoma that is increasing in incidence worldwide. However, little is known about the epidemiology of oral HPV infection among healthy adults in China. METHODS: A study in northern China was conducted in 2021 as baseline data of Diverse Life-Course Cohort (DLCC). Residents who aged above 20 were eligible to participate. Oral swab specimens and questionnaires were collected from 4226 participants. HPV DNA in oral exfoliated cells was tested by Nested Polymerase Chain Reaction approach and sequencing. Univariate and multivariate analyses were performed to assess the associations between exposure factors and oral HPV infection. RESULTS: Overall prevalence of oral HPV infection was 4.08% (95%CI, 3.69%-4.68%). The most prevalent HPV type detected was HPV-81 (1.35%; 95% CI, 1.00%-1.70%), followed by HPV-16 (0.64%; 95% CI, 0.40%-0.88%). Oral HPV infection presented a bimodal pattern with respect to age in male and female participants. Oral HPV prevalence of male participants was significantly higher than prevalence of female participants (5.0% versus 3.6%, P = 0.041). Prevalence of oral HPV was higher among current smokers (OR = 1.59; 95% CI, 1.11-2.29; P = 0.039) and current drinkers (OR = 1.60; 95% CI, 1.14-2.25; P = 0.023). Current alcohol consumption was independently associated with oral HPV infection (OR = 1.74; 95% CI, 1.22-2.50; P = 0.010). CONCLUSIONS: Among healthy adults aged above 20 in Hebei, China, the prevalence of high-risk HPV infection was 1.92% (95%CI, 1.51%-2.34%). Oral HPV prevalence was independently associated with alcohol consumption. More tailored prevention strategies are needed to prevent oral HPV infection through smoking cessation, reduction of alcohol consumption, and HPV vaccination.

Epidemiology of Oral Human Papillomavirus Infection among Diverse Chinese Adults in Typical Areas of China: Findings from the DLCC Study.

BACKGROUND: Human papillomavirus (HPV) infection is a predominant cause of oropharyngeal squamous cell carcinoma. However, there is limited knowledge about the epidemiology of oral HPV infections among adults in China. METHODS: We collected data from a prospective cohort that enrolled participants in Mainland China. A total of 9,867 participants ages at least 20 years provided oral swab specimens in typical areas of China (Hebei and Guangdong provinces) in 2021. HPV DNA in oral exfoliated cells was tested using nested PCR and sequencing. Prevalence among subpopulations was compared. Multivariable logistic regression models were employed to assess possible factors influencing oral HPV infection. RESULTS: The overall prevalence of oral HPV infection was 3.0% [95% confidence interval (CI): 2.68-3.36]. Among those infected, 1.3% (1.08-1.53) were infected with high-risk HPV types. Men had a higher age-standardized HPV infection prevalence (3.6%, 2.96-4.29) compared with their female counterparts (2.7%, 2.35-3.12). People in Hebei had a higher age- and sex-standardized prevalence (4.1%, 3.50-4.70) than those in Guangdong (2.2%, 1.80-2.56). Generally, men (OR and 95% CI: 1.42, 1.09-1.85) and people in Hebei (2.01, 1.53-2.65) had higher odds of any type of HPV infection. In addition, people living in urban areas had a 2.15-fold (1.43-3.26) higher odds of high-risk HPV infection. CONCLUSIONS: This study reveals a low prevalence of oral HPV infection with significant geographic and sex differences among Chinese population. IMPACT: This is the first study to report the epidemiologic characteristics of oral HPV infection among Chinese adults in diverse geographic areas with large sample size.

Mettl13 protects against cardiac contractile dysfunction by negatively regulating C-Cbl-mediated ubiquitination of SERCA2a in ischemic heart failure.

Ischemic heart failure (HF) remains a leading cause of morbidity and mortality. Maintaining homeostasis of cardiac function and preventing cardiac remodeling deterioration are critical to halting HF progression. Methyltransferase-like protein 13 (Mettl13) has been shown to regulate protein translation efficiency by acting as a protein lysine methyltransferase, but its role in cardiac pathology remains unexplored. This study aims to characterize the roles and mechanisms of Mettl13 in cardiac contractile function and HF. We found that Mettl13 was downregulated in the failing hearts of mice post-myocardial infarction (MI) and in a cellular model of oxidative stress. Cardiomyocyte-specific overexpression of Mettl13 mediated by AAV9-Mettl13 attenuated cardiac contractile dysfunction and fibrosis in response to MI, while silencing of Mettl13 impaired cardiac function in normal mice. Moreover, Mettl13 overexpression abrogated the reduction in cell shortening, Ca2+ transient amplitude and SERCA2a protein levels in the cardiomyocytes of adult mice with MI. Conversely, knockdown of Mettl13 impaired the contractility of cardiomyocytes, and decreased Ca2+ transient amplitude and SERCA2a protein expression in vivo and in vitro. Mechanistically, Mettl13 impaired the stability of c-Cbl by inducing lysine methylation of c-Cbl, which in turn inhibited ubiquitination-dependent degradation of SERCA2a. Furthermore, the inhibitory effects of knocking down Mettl13 on SERCA2a protein expression and Ca2+ transients were partially rescued by silencing c-Cbl in H2O2-treated cardiomyocytes. In conclusion, our study uncovers a novel mechanism that involves the Mettl13/c-Cbl/SERCA2a axis in regulating cardiac contractile function and remodeling, and identifies Mettl13 as a novel therapeutic target for ischemic HF.

Oral-microbiome-derived signatures enable non-invasive diagnosis of laryngeal cancers.

BACKGROUND: Recent studies have uncovered that the microbiota in patients with head and neck cancers is significantly altered and may drive cancer development. However, there is limited data to explore the unique microbiota of laryngeal squamous cell carcinoma (LSCC), and little is known regarding whether the oral microbiota can be utilized as an early diagnostic biomarker. METHODS: Using 16S rRNA gene sequencing, we characterized the microbiome of oral rinse and tissue samples from 77 patients with LSCC and 76 control patients with vocal polyps, and then performed bioinformatic analyses to identify taxonomic groups associated with clinicopathologic features. RESULTS: Multiple bacterial genera exhibited significant differences in relative abundance when stratifying by histologic and tissue type. By exploiting the distinct microbial abundance and identifying the tumor-associated microbiota taxa between patients of LSCC and vocal polyps, we developed a predictive classifier by using rinse microbiota as key features for the diagnosis of LSCC with 85.7% accuracy. CONCLUSION: This is the first evidence of taxonomical features based on the oral rinse microbiome that could diagnose LSCC. Our results revealed the oral rinse microbiome is an understudied source of clinical variation and represents a potential non-evasive biomarker of LSCC.

Quality of Life in Patients With Benign Lateral Skull Base Neoplasms Following Infratemporal Fossa Approaches.

Objectives: Infratemporal fossa approaches (IFAs) allow the total resection of certain lateral skull base neoplasms. To date, no studies have explored the change of patient-reported quality of life (QoL) after total resection of benign lateral skull base neoplasms through IFA. The present study aimed to give a comprehensive understanding of QoL among patients after IFA through general and disease-specific QoL questionnaires. Methods: Forty-seven patients with benign lateral skull base neoplasms were enrolled. The Short Form 36 (SF-36), World Health Organization Quality of Life-BREF (WHOQOL-BREF), and the University of Washington Head and Neck Quality of Life (UW-QOL) were chosen as tools to assess QoL before and after surgeries through IFA. Results: Patients had significantly lower scores in appearance, chewing, and speech after surgeries through IFA. However, change in health from SF-36 and physical health from WHOQOL-BREF scored higher after surgery. In multivariate linear regression analysis, age, gender, mood, speech, appearance, swallowing, and chewing contributed independently to general QoL. Conclusion: Patients were shown to benefit with regard to overall QoL after gross tumor resection from IFA, despite the impact of appearance, speech, and chewing. Function preservation and restoration are critical since their correlation with postoperative QoL.

Expression of OLR1 gene on tumor-associated macrophages of head and neck squamous cell carcinoma, and its correlation with clinical outcome.

Head and neck squamous cell carcinoma (HNSCC) is one of the most heavily immune infiltrated human tumors, having distinct immune subtypes associated with different molecular characteristics and clinical outcomes. The tumor microenvironment (TME) of HNSCC which was dominated by tumor-associated macrophages (TAMs) had a relatively inferior prognosis. High levels of oxidized low-density lipoprotein receptor 1 (OLR1) expression are associated with more aggressive and metastatic characteristics in multiple cancers. However, the link between the OLR1 expression and immunosuppression of TME, and the molecular mechanisms which govern intratumoral TAMs behavior are unclear. Here, we performed the transcriptional analysis based on a single-cell RNA-sequencing (scRNA-seq) dataset of HNSCC, and found that the OLR1 expression was specifically enriched on the TAMs. Evaluation of protein expression within histologic sections of primary HNSCC patient samples showed a co-expression pattern of OLR1 and CD68 on macrophages. A total of 498 tumor samples of HNSCC patients from The Cancer Genome Atlas (TCGA) database were also analyzed. Remarkably, OLR1 expression was dramatically higher in HNSCC tissues than that in adjacent normal tissues, and the patients with high levels of OLR1 expression had significantly unfavorable overall survival (Hazard Ratio = 1.724, log-rank P-value = 0.0066) when compared to patients harboring low expression levels of OLR1. In summary, we reported that the specific expression of OLR1 on the TAMs was significantly correlated with poor survival outcomes, revealing that OLR1 could serve as a potential prognosis marker and promising target for immunotherapy in HNSCC.

Exosomes secreted from cardiomyocytes suppress the sensitivity of tumor ferroptosis in ischemic heart failure.

Heart failure (HF) patients in general have a higher risk of developing cancer. Several animal studies have indicated that cardiac remodeling and HF remarkably accelerate tumor progression, highlighting a cause-and-effect relationship between these two disease entities. Targeting ferroptosis, a prevailing form of non-apoptotic cell death, has been considered a promising therapeutic strategy for human cancers. Exosomes critically contribute to proximal and distant organ-organ communications and play crucial roles in regulating diseases in a paracrine manner. However, whether exosomes control the sensitivity of cancer to ferroptosis via regulating the cardiomyocyte-tumor cell crosstalk in ischemic HF has not yet been explored. Here, we demonstrate that myocardial infarction (MI) decreased the sensitivity of cancer cells to the canonical ferroptosis activator erastin or imidazole ketone erastin in a mouse model of xenograft tumor. Post-MI plasma exosomes potently blunted the sensitivity of tumor cells to ferroptosis inducers both in vitro in mouse Lewis lung carcinoma cell line LLC and osteosarcoma cell line K7M2 and in vivo with xenograft tumorigenesis model. The expression of miR-22-3p in cardiomyocytes and plasma-exosomes was significantly upregulated in the failing hearts of mice with chronic MI and of HF patients as well. Incubation of tumor cells with the exosomes isolated from post-MI mouse plasma or overexpression of miR-22-3p alone abrogated erastin-induced ferroptotic cell death in vitro. Cardiomyocyte-enriched miR-22-3p was packaged in exosomes and transferred into tumor cells. Inhibition of cardiomyocyte-specific miR-22-3p by AAV9 sponge increased the sensitivity of cancer cells to ferroptosis. ACSL4, a pro-ferroptotic gene, was experimentally established as a target of miR-22-3p in tumor cells. Taken together, our findings uncovered for the first time that MI suppresses erastin-induced ferroptosis through releasing miR-22-3p-enriched exosomes derived from cardiomyocytes. Therefore, targeting exosome-mediated cardiomyocyte/tumor pathological communication may offer a novel approach for the ferroptosis-based antitumor therapy.