Clinical and genetic architecture of a large cohort with auditory neuropathy.

Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.

Synthesis of S(IV)-Stereogenic Chiral Thio-Oxazolidinones via Palladium-Catalyzed Asymmetric [3+2] Annulations.

Organic molecules bearing chiral sulfur stereocenters exert a great impact on asymmetric catalysis and synthesis, chiral drugs, and chiral materials. Compared with acyclic ones, the catalytic asymmetric synthesis of thio-heterocycles has largely lagged behind due to the lack of efficient synthetic strategies. Here we establish the first modular platform to access chiral thio-oxazolidinones via Pd-catalyzed asymmetric [3+2] annulations of vinylethylene carbonates with sulfinylanilines. This protocol is featured by readily available starting materials, and high enantio- and diastereoselectivity. In particular, an unusual effect of a non-chiral supporting ligand on the diastereoselectivity was observed. Possible reaction mechanisms and stereocontrol models were proposed.

An oncogene regulating chromatin favors response to immunotherapy: Oncogene CHAF1A and immunotherapy outcomes.

Many biological processes related to cell function and fate begin with chromatin alterations, and many factors associated with the efficacy of immune checkpoint inhibitors (ICIs) are actually downstream events of chromatin alterations, such as genome changes, neoantigen production, and immune checkpoint expression. However, the influence of genes as chromatin regulators on the efficacy of ICIs remains elusive, especially in gastric cancer (GC). In this study, thirty out of 1593 genes regulating chromatin associated with a favorable prognosis were selected for GC. CHAF1A, a well-defined oncogene, was identified as the highest linkage hub gene. High CHAF1A expression were associated with microsatellite instability (MSI), high tumor mutation burden (TMB), high tumor neoantigen burden (TNB), high expressions of PD-L1 and immune effector genes, and live infiltration of immune cells. High CHAF1A expression indicated a favorable response and prognosis in immunotherapy of several cohorts, which was independent of MSI, TMB, TNB, PD-L1 expression, immune phenotype and transcriptome scoring, and improved patient selection based on these classic biomarkers. In vivo, CHAF1A knockdown alone inhibited tumor growth but it impaired the effect of an anti-PD-1 antibody by increasing the relative tumor proliferation rate and decreasing the survival benefit, potentially through the activation of TGF-ß signaling. In conclusion, CHAF1A may be a novel biomarker for improving patient selection in immunotherapy.

A novel biomarker associated with EBV infection improves response prediction of immunotherapy in gastric cancer.

BACKGROUND: Novel biomarkers are required in gastric cancer (GC) treated by immunotherapy. Epstein-Barr virus (EBV) infection induces an immune-active tumor microenvironment, while its association with immunotherapy response is still controversial. Genes underlying EBV infection may determine the response heterogeneity of EBV + GC. Thus, we screened hub genes associated with EBV infection to predict the response to immunotherapy in GC. METHODS: Prognostic hub genes associated with EBV infection were screened using multi-omic data of GC. EBV + GC cells were established and confirmed by EBV-encoded small RNA in situ hybridization (EBER-ISH). Immunohistochemistry (IHC) staining of the hub genes was conducted in GC samples with EBER-ISH assay. Infiltrating immune cells were stained using immunofluorescence. RESULTS: CHAF1A was identified as a hub gene in EBV + GC, and its expression was an independent predictor of overall survival (OS). EBV infection up-regulated CHAF1A expression which also predicted EBV infection well. CHAF1A expression also predicted microsatellite instability (MSI) and a high tumor mutation burden (TMB). The combined score (CS) of CHAF1A expression with MSI or TMB further improved prognostic stratification. CHAF1A IHC score positively correlated with the infiltration of NK cells and macrophages M1. CHAF1A expression alone could predict the immunotherapy response, but its CS with EBV infection, MSI, TMB, or PD-L1 expression showed better effects and improved response stratification based on current biomarkers. CONCLUSIONS: CHAF1A could be a novel biomarker for immunotherapy of GC, with the potential to improve the efficacy of existing biomarkers.

The Association Between Emotion Recognition and Internalizing Problems in Children and Adolescents: A Three-Level Meta-Analysis.

Numerous studies have explored the link between how well youth recognize emotions and their internalizing problems, but a consensus remains elusive. This study used a three-level meta-analysis model to quantitatively synthesize the findings of existing studies to assess the relationship. A moderation analysis was also conducted to explore the sources of research heterogeneity. Through a systematic literature search, a total of 42 studies with 201 effect sizes were retrieved for the current meta-analysis, and 7579 participants were included. Emotion recognition was negatively correlated with internalizing problems. Children and adolescents with weaker emotion recognition skills were more likely to have internalizing problems. In addition, this meta-analysis found that publication year had a significant moderating effect. The correlation between emotion recognition and internalizing problems decreased over time. The degree of internalizing problems was also found to be a significant moderator. The correlation between emotion recognition and internalizing disorders was higher than the correlation between emotion recognition and internalizing symptoms. Deficits in emotion recognition might be relevant for the development and/or maintenance of internalizing problems in children and adolescents. The overall effect was small and future research should explore the clinical relevance of the association.

Lipidomics reveals immune-related adverse events in NSCLC patients receiving immune checkpoint inhibitor.

There is a lack of reliable biomarkers to predict and identify the risk of immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) treatment. This study aims to explore potential biomarkers using lipidomics to identify and predict the risk of irAEs in NSCLC patients receiving ICI treatment. This prospective study enrolled 94 NSCLC patients with IIIB/IV stage NSCLC who underwent first-line chemotherapy in combination with ICI treatment. The prediction cohort consisted of plasma samples collected from 60 patients before ICI treatment, and the occurrence of irAE was monitored within 6 months of initiating first-line ICI therapy. The validation cohort comprised 34 patients, with plasma samples obtained from 15 patients who did not develop irAE at 6 months of ICI treatment and plasma samples collected from 19 irAE patients at the onset of irAE. Through non-targeted lipidomics and semi-targeted lipid quantification analysis, we identify 11 differentially metabolized lipids and further screened these lipids with the area under the curve (AUC) > 0.7 to predict the occurrence of irAEs in NSCLC patients following ICI treatment. The results showed that the biomarker panel consisting of 9 lipids (LPC-18:2, PC-40:6, LPC-22:6, LPC-O-18:0, PS-38:0, PC-38:6, PC-37:6, PC-36:5,LPC-17:0) exhibited a good AUC of 0.859 in the prediction and 0.940 in the validation cohort phase of the receiver operating characteristic curve; The study utilizes plasma lipidomics to develop a rapid and effective prediction model for identifying irAEs in advanced NSCLC patients who treatment with first-line chemotherapy combined with immunotherapy.

Inhibiting NF-κB-S100A11 signaling and targeting S100A11 for anticancer effects of demethylzeylasteral in human colon cancer.

Colon cancer is a common and deadly malignancy of the gastrointestinal tract. Targeting proteins that inhibit tumor proliferation could lead to innovative treatment strategies for this disease. Demethylzeylasteral, extracted naturally from Tripterygium wilfordii Hook. f., demonstrates incredible anti-colon cancer activity. However, the molecular mechanism behind this requires further investigation. This study aims to identify crucial targets and mechanisms of demethylzeylasteral in treating colon cancer, making it a promising candidate for anti-tumor therapy. Through gene knockout, overexpression techniques, and double Luciferase experiments, we confirmed that demethylzeylasteral reduces S100A11 expression in HT29 cells and in vivo tumor models to anti-colon cancer. By conducting Surface Plasmon Resonance, immunofluorescence staining, and confocal laser microscopy observations, we verified the direct interaction between demethylzeylasteral and S100A11, and explored the impact of S100A11's subcellular localization on cell proliferation. Demethylzeylasteral inhibited S100A11 expression and exhibited anti-cancer activity in both in vitro and in vivo colon cancer models. Conversely, overexpression of S100A11 hindered apoptosis induced by demethylzeylasteral. Additionally, we found that knockdown or overexpression of NF-κB respectively decreased or increased S100A11 expression, subsequently affecting cell proliferation. The dual Luciferase reporting experiment revealed that NF-κB is an upstream transcription factor regulating S100A11 expression. And Surface plasmon resonance confirmed that S100A11 can directly interact with demethylzeylasteral, this interaction limited the transport of S100A11 from the cytoplasm to nucleus, attenuation S100A11 mediated cell proliferation effect.

Effectiveness of Internet-delivered self-help acceptance and commitment therapy (iACT) on nurses' obsessive-compulsive symptoms and sleep quality: A randomized controlled trial with 3-month follow-up.

BACKGROUND: Frontline nurses suffered unprecedented mental distress during the COVID-19 pandemic. It's essential to explore new and more accessible alternatives to improve the availability of psychological treatments. This study aimed to investigate the influence of online self-help iACT linear intervention and iACT loop intervention on sleep quality (SQ), obsessive-compulsive symptoms (OCS), and psychological flexibility (PF) in nurses. METHODS: A randomized controlled trial was conducted at a hospital in China. 602 participants were randomly assigned to the iACT linear intervention, iACT loop intervention, or wait list control group, and required to complete the questionnaires of OCS, PF and SQ. The linear mixed effects analysis (LMM) was used to analyze the impact of the intervention on outcome variables. RESULTS: LMM analyses demonstrated that both two intervention had significant improvement on OCS (t = -38.235, p < 0.001), PF (t = 28.156, p < 0.001), as well as SQ (t = -16.336, p < 0.001). There were significant differences between the linear group and loop group on the PF in T2 (t = -8.271, p < 0.001), T3 (t = -8.366, p < 0.001), T4 (t = -8.302, p < 0.001), with the iACT loop model (Cohen's d = 1.652) showing a slight advantage over the iACT linear model (Cohen's d = 1.134). CONCLUSIONS: The findings indicate that two interventions positively impact OCS, PF, and SQ. Compared to the iACT linear psychotherapy model, the iACT loop model shows greater effectiveness in enhancing PF, making it helpful to promote significant improvements in psychotherapy planning.

Metabolomics Study Revealing Purines as Potential Diagnostic Biomarkers of Acute Respiratory Distress Syndrome in Patients with Community─Acquired Pneumonia.

Community-acquired pneumonia (CAP) is a significant threat to human health and the leading cause of acute respiratory distress syndrome (ARDS). We aimed to reveal the metabolic profiling whether can be used for assessing CAP with or without ARDS (nARDS) and therapeutic effects on CAP patients after treatment. Urine samples were collected at the onset and recovery periods, and metabolomics was employed to identify robust biomarkers. 19 metabolites were significantly changed in the ARDS relative to nARDS, mainly involving purines and fatty acids. After treatment, 7 metabolites in the nARDS and 14 in the ARDS were found to be significantly dysregulated, including fatty acids and amino acids. In the validation cohort, we observed that the biomarker panel consisted of N2,N2-dimethylguanosine, 1-methyladenosine, 3-methylguanine, 1-methyladenosine, and uric acid exhibited better AUCs of 0.900 than pneumonia severity index and acute physiology and chronic health evaluation II (APACHE II) scores between the ARDS and nARDS. Combining L-phenylalanine, phytosphingosine, and N-acetylaspartylglutamate as biomarkers for discriminating the nARDS and ARDS patients after treatment exhibited good AUCs of 0.811 and 0.821, respectively. The metabolic pathway and defined biomarkers may serve as crucial indicators for predicting the development of ARDS in CAP patients and for assessing therapeutic effects.

Home confinement's impact on myopia control by using orthokeratology in school-aged children.

BACKGROUND: Home confinement during the epidemic has a significant impact on the lifestyle and behavior of school-aged children, who have exhibited an increase in the prevalence and development of myopia. Our research will look at if home confinement will affect school-aged children on myopia control with orthokeratology. METHOD: Data on axial length was gathered from school-aged children who had received OK lenses treatment. The entire data was separated into subgroups based on gender, age, and initial refraction, and the AL changes for each period were calculated using the formula defined in our study. Finally, the acquired data will be examined using various statistical approaches, and the ideas of slow, moderate, and rapid myopia progression will be applied to our study. RESULT: A total of 258 study subjects met the requirements to be included in the study. We discovered that the percentage of rapid myopia growth increased during the epidemic. In addition, the AL changes before and during the epidemic were found to be statistically significant in 171 subjects in the overall data. (P = 0.041) In the high age group, the AL changes before and during the epidemic、(P = 0.033) before and after the epidemic (P = 0.023) were found to be statistically significant. The AL changes before and during the epidemic (P = 0.035) were shown to be statistically significant in the moderate myopia group. Finally, we did not find statistically significant results for other groups. CONCLUSION: We cannot conclude that home confinement did have a negative impact on myopia control with orthokeratology in school-aged children. But we found there was an increase in the percentage of patients with OK treatment that had fast myopia progression during the confinement. We also observed that older children with higher initial refraction were more likely to be affected by home confinement.

Intermittent fasting alleviates type 1 diabetes-induced cognitive dysfunction by improving the frontal cortical metabolic disorder.

Intermittent fasting (IF) is an ecological strategy to control various metabolic disorder symptoms, but its protective effect on type 1 diabetes (T1D)-induced cognitive dysfunction and the underlying mechanisms remain poorly defined. Herein, we examined the efficacy of IF in altering the behaviors and brain metabolome in T1D mice and investigated the potential molecular mechanisms. We demonstrated that IF remarkably improved frontal cortical-dependent memory in T1D mice and reduced the loss of neuronal cells. Metabolomics and targeted mass spectrometry assays showed that IF reprogrammed the composition of the frontal cortical metabolome in T1D mice, including activating the aspartate and glutamate pathway and reversing glycerophospholipid and sphingolipid depositions. Mechanistically, IF attenuated the levels of oxidative stress proteins, like NOX2, NOX4, 8-OHdG, and 4-HNE, and inhibited the levels of pro-apoptotic factors Bax and cleaved Caspase-3, ultimately improving the memory ability of T1D mice. In vitro studies confirmed the protective effect of the supplemented N-acetylaspartate, a pivotal metabolite involved in IF-regulated T1D-induced cognitive dysfunction, in high glucose-stimulated SH-SY5Y cells by eliminating toxic lipids accumulation, oxidative stress, and apoptosis. To conclude, the frontal cortical metabolites mediated the protective effects of IF against T1D-induced cognitive dysfunction by attenuating oxidative stress and apoptotic signaling. Thus, IF can be a potential therapeutic strategy for T1D-induced cognitive dysfunction.

Lipid metabolism reprogramming in tumor-associated macrophages and implications for therapy.

The tumormicroenvironment (TME) plays a key role in tumor progression. Tumor-associated macrophages (TAMs), which are natural immune cells abundantin the TME, are mainly divided into the anti-tumor M1 subtype and pro-tumor M2 subtype. Due to the high plasticity of TAMs, the conversion of the M1 to M2 phenotype in hypoxic and hypoglycemic TME promotes cancer progression, which is closely related to lipid metabolism. Key factors of lipid metabolism in TAMs, including peroxisome proliferator-activated receptor and lipoxygenase, promote the formation of a tumor immunosuppressive microenvironment and facilitate immune escape. In addition, tumor cells promote lipid accumulation in TAMs, causing TAMs to polarize to the M2 phenotype. Moreover, other factors of lipid metabolism, such as abhydrolase domain containing 5 and fatty acid binding protein, have both promoting and inhibiting effects on tumor cells. Therefore, further research on lipid metabolism in tumors is still required. In addition, statins, as core drugs regulating cholesterol metabolism, can inhibit lipid rafts and adhesion of tumor cells, which can sensitize them to chemotherapeutic drugs. Clinical studies on simvastatin and lovastatin in a variety of tumors are underway. This article provides a comprehensive review of the role of lipid metabolism in TAMs in tumor progression, and provides new ideas for targeting lipid metabolism in tumor therapy.

Dearomatization-Rearomatization Reaction of Metal-Polarized Aza-ortho-Quinone Methides.

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs.

[Analysis of audiological features in infants with unilateral hearing loss].

Objective:To investigate the audiological characteristics and possible causes of unilateral hearing loss in infants and young children. Methods:105 infants from Beijing Maternal and Child Health Care Institution who failed the newborn hearing screening and were referred to the Children's Hearing Diagnosis Center of PLA General Hospital for hearing diagnosis. They were diagnosed with unilateral hearing loss and underwent clinical data collection. A full set of audiological examinations included ABR, 40 Hz auditory event related potential, ASSR, DPOAE, tympanometry. Results:①In initial diagnosis, 45 cases（42.86%） had mild hearing loss, 19 cases（18.10%） had moderate hearing loss, 14 cases（13.33%） had severe hearing loss, and 27 cases（25.71%） had severe hearing loss; Among them, 65 cases（61.90%） were conductive hearing loss or mixed hearing loss, and 40 cases（38.10%） were sensorineural hearing loss. ②83 of 105 cases had follow-up visits: 24 cases were normal, 15 cases with mild hearing loss, 4 cases with moderate hearing loss, 12 cases with severe hearing loss, and 26 cases with extremely severe hearing loss, 2 cases of hearing loss in both ears. ③From the initial diagnosis to the follow-up diagnosis, the change of mild hearing loss was the largest, followed by moderate hearing loss, severe and extremely severe hearing loss basically did not change; the number of mild and severe conductive hearing loss which recovered to normal hearing was most, the number of sensorineural hearing loss changed little. Conclusion:The infants who failed the newborn hearing screening and were diagnosed with unilateral hearing loss were mainly mild to moderate conductive hearing loss and severe to extremely severe sensorineural hearing loss. The hearing of children with hearing loss gradually improved, and severe and extremely severe sensorineural hearing loss remained unchanged.

[Application of behavioral audiometry in subjective hearing assessment of children].

Objective:To explore the value and influencing factors of behavioral audiometry in subjective hearing assessment of children. Methods:The results of behavioral audiometry（visual reinforcement audiometry or play audiometry） of 1944 children（3888 ears） in the outpatient department from January 2012 to December 2015 were retrospectively analyzed. The subjective performance（" good ", "moderate", "poor", " unfinished "） was compared according to age and hearing level. SPSS 27.0 software was used for statistical analysis. Results:The subjective performance of children was "good" in 2791 ears（71.8%）, "moderate" in 411 ears（10.6%）, "poor" in 309 ears（7.9%） and " unfinished " in 377 ears（9.7%）. In visual reinforcement audiometry, the proportion of children who subjectively performed as "good" gradually increased with age, reaching the peak at 2 years old, and decreased with age after 2 years old. In play audiometry, the proportion of children who subjectively performed as "good" gradually increased with age, peaking at 4-5 years of age. The children who did not finish the test were mainly 1-3 years old. The reasons included uncooperation for 148 ears, crying for 95 ears, refusing to wear headphones for 57 ears, fatigue for 42 ears, lack of interest for 20 ears, not understanding for 14 ears, and distraction for 1 ear. Conclusion:Behavioral audiometry was helpful to assess children's subjective hearing, and children's subjective performance was good. In clinical work, more novel and attractive test materials and methods should be adopted or developed according to the physical and mental characteristics of young children.

[The follow-up study on patients of children with auditory neuropathy].

Objective:To analyse the audiological characteristics of patients of children with auditory neuropathy（AN） for gaining a better understanding of the audiological characteristics prognosis of patients with AN. Methods:58 patients（108 ears） of children with AN were enrolled, all of whom had received further consultation within 10 years after the first consultation. Behavioral audiometry test, tympanogram test, distortion product otoacoustic emission（DPOAE）, auditory brainstem response（ABR）, cochlear microphonics（CM）, auditory steady-state response（ASSR） were performed on these patients. Results:①There were no significant changes in behavioral audiometry threshold between first and further consultation（P>0.05）；②Tympanograms were mostly of type A or As； ③The patients had worse DPOAE results in the further consultation, while the elicitation rate of other frequencies were higher except for the lower elicitation rate of 750 Hz and 1000 Hz；④There were 7 ears that had present ABR and CM in the first consultation, while three ears had present ABR and CM in the further consultation；⑤Except for 500 Hz, other frequency thresholds of ASSR in the further consultation were statistically significant compared with those in the first consultation（P<0.01）；⑥The threshold of behavioral audiometry at 4000 Hz was higher than that of ASSR, and there was no obvious correlation between the other frequencies（P>0.05）. Conclusion:There is a tendency of hearing deterioration in patients of children with AN. Patients with no DPOAE elicitation and no ABR elicitation or serious abnormalities need CM test to avoid misdiagnosis. The hearing status and speech communication ability of patients should be continuously monitored. Parents should pay attention to the changes in the behavioral ability of the children in daily life and make regular subsequent visits.

The Effect of Social Support on Depression among Economically Disadvantaged College Students: The Mediating Role of Psychological Resilience and the Moderating Role of Geography.

The study examined the influence of social support on depression, including the mediating role of psychological resilience and the moderating role of geography. Questionnaires were completed by 424 economically disadvantaged college students in two provinces, X, a coastal province, and Y, an inland province. The results indicated that (1) the social support of economically disadvantaged college students was positively correlated to psychological resilience (ß = 0.62, t = 11.22, p < 0.001); (2) the psychological resilience of economically disadvantaged college students was negatively correlated with depression (ß = -0.24, t = -10.3, p < 0.001); (3) the social support of economically disadvantaged college students was negatively correlated with depression (ß = -0.08, t = -2.85, p < 0.001); (4) the psychological resilience of economically disadvantaged college students played a partial mediating role between social support and depression; and (5) geography played a moderating role in the effect of social support on depression.

Optimized integration of metabolomics and lipidomics reveals brain region-specific changes of oxidative stress and neuroinflammation in type 1 diabetic mice with cognitive decline.

INTRODUCTION: Type 1 diabetes (T1D) causes cognitive decline and has been associated with brain metabolic disorders, but its potential molecular mechanisms remain unclear. OBJECTIVES: The purpose of this study was to explore the molecular mechanisms underlying T1D-induced cognitive impairment using metabolomics and lipidomics. METHODS: We developed an optimized integration approach of metabolomics and lipidomics for brain tissue based on UPLC-Q-TOF-MS and analyzed a comprehensive characterization of metabolite and lipid profiles in the hippocampus and frontal cortex of T1D male mice with cognitive decline (T1DCD) and age-matched control (CONT) mice. RESULTS: The results show that T1DCD mice had brain metabolic disorders in a region-specific manner relative to CONT mice, and the frontal cortex exhibited a higher lipid peroxidation than the hippocampus in T1DCD mice. Based on metabolic changes, we found that microglia was activated under diabetic condition and thereby promoted oxidative stress and neuroinflammation, leading to neuronal injury, and this event was more pronounced in the frontal cortex than the hippocampus. CONCLUSION: Our results suggest that brain region-specific shifts in oxidative stress and neuroinflammation may contribute to diabetic cognitive decline, and the frontal cortex could be the more vulnerable brain region than the hippocampus.

m6A methylation modification and immune cell infiltration: implications for targeting the catalytic subunit m6A-METTL complex in gastrointestinal cancer immunotherapy.

N6-methyladenosine (m6A) methylation modification is a ubiquitous RNA modification involved in the regulation of various cellular processes, including regulation of RNA stability, metabolism, splicing and translation. Gastrointestinal (GI) cancers are some of the world's most common and fatal cancers. Emerging evidence has shown that m6A modification is dynamically regulated by a complex network of enzymes and that the catalytic subunit m6A-METTL complex (MAC)-METTL3/14, a core component of m6A methyltransferases, participates in the development and progression of GI cancers. Furthermore, it has been shown that METTL3/14 modulates immune cell infiltration in an m6A-dependent manner in TIME (Tumor immune microenvironment), thereby altering the response of cancer cells to ICIs (Immune checkpoint inhibitors). Immunotherapy has emerged as a promising approach for treating GI cancers. Moreover, targeting the expression of METTL3/14 and its downstream genes may improve patient response to immunotherapy. Therefore, understanding the role of MAC in the pathogenesis of GI cancers and its impact on immune cell infiltration may provide new insights into the development of effective therapeutic strategies for GI cancers.

ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers.

The long-chain fatty acyl CoA synthetase (ACSLs) family of enzymes contributes significantly to lipid metabolism and produces acyl-coenzyme A by catalyzing fatty acid oxidation. The dysregulation of ACSL3 and ACSL4, which belong to the five isoforms of ACSLs, plays a key role in cancer initiation, development, metastasis, and tumor immunity and may provide several possible therapeutic strategies. Moreover, ACSL3 and ACSL4 are crucial for ferroptosis, a non-apoptotic cell death triggered by the accumulation of membrane lipid peroxides due to iron overload. Here, we present a summary of the current knowledge on ACSL3 and ACSL4 and their functions in various cancers. Research on the molecular mechanisms involved in the regulation of ferroptosis is critical to developing targeted therapies for cancer.