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Diffuse intrinsic pontine glioma (DIPG), a lethal pediatric cancer driven by H3K27M oncohistones, exhibits aberrant epigenetic regulation and stem-like cell states. Here, we uncover an axis involving H3.3K27M oncohistones, CREB5/ID1, which sustains the stem-like state of DIPG cells, promoting malignancy. We demonstrate that CREB5 mediates elevated ID1 levels in the H3.3K27M/ACVR1WT subtype, promoting tumor growth; while BMP signaling regulates this process in the H3.1K27M/ACVR1MUT subtype. Furthermore, we reveal that H3.3K27M directly enhances CREB5 expression by reshaping the H3K27me3 landscape at the CREB5 locus, particularly at super-enhancer regions. Additionally, we elucidate the collaboration between CREB5 and BRG1, the SWI/SNF chromatin remodeling complex catalytic subunit, in driving oncogenic transcriptional changes in H3.3K27M DIPG. Intriguingly, disrupting CREB5 super-enhancers with ABBV-075 significantly reduces its expression and inhibits H3.3K27M DIPG tumor growth. Combined treatment with ABBV-075 and a BRG1 inhibitor presents a promising therapeutic strategy for clinical translation in H3.3K27M DIPG treatment. Diffuse intrinsic pontine glioma (DIPG) is driven by H3K27M oncohistones, but the exact related mechanisms are poorly understood. Here, the authors identify an H3.3K27M oncohistone-driven CREB5/ID1 axis that promotes transcriptional changes and progression in DIPG, which could represent a potential therapeutic target.

The precise regulation of the RIG-I-like receptors (RLRs)-mediated type I interferon (IFN-I) activation is crucial in antiviral immunity and maintaining host immune homeostasis in the meantime. Here, we identify an E3 ubiquitin ligase, namely RNF167, as a negative regulator of RLR-triggered IFN signaling. Mechanistically, RNF167 facilitates both atypical K6- and K11-linked polyubiquitination of RIG-I/MDA5 within CARD and CTD domains, respectively, which leads to degradation of the viral RNA sensors through dual proteolytic pathways. RIG-I/MDA5 conjugated with K6-linked ubiquitin chains in CARD domains is recognized by the autophagy cargo adaptor p62, that delivers the substrates to autolysosomes for selective autophagic degradation. In contrast, K11-linked polyubiquitination in CTD domains leads to proteasome-dependent degradation of RLRs. Thus, our study clarifies a function of atypical K6- and K11-linked polyubiquitination in the regulation of RLR signaling. We also unveil an elaborate synergistic effect of dual proteolysis systems to control amplitude and duration of IFN-I activation, hereby providing insights into physiological roles of the cross-talk between these two protein quality control pathways. Type I interferon-dependent immunity is crucial for antiviral defense but must be tightly regulated to prevent tissue damage. Here, the authors present RNF167 as a negative regulator of RLR-triggered IFN activation, mediating K6- and K11-linked ubiquitination of RIG-I/MDA5 to promote proteasomal and autophagic degradation.

Background Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor with limited treatment options. Although natural killer (NK) cell-based immunotherapy is promising, its efficacy remains limited, necessitating strategies to enhance NK cell cytotoxicity. Histone deacetylase (HDAC) inhibition demonstrate potential to enhance NK-mediated killing. However, the combination of HDAC inhibitors and NK cell therapy for DMG remains unexplored. Methods Patient-derived DMG cell lines and orthotopic mouse models were used to evaluate the effects of the class I HDAC inhibitor MS-275 on cytotoxicity. NK cell-mediated lysis was measured using both luciferase and calcein AM-based assays. The downstream signaling pathways affected by MS-275 were investigated via RNA-seq, CUT&Tag assay, RT‒qPCR, and chromatin immunoprecipitation with qPCR. Results Based on bioinformatic analysis, class I HDACs are identified as therapeutic targets in DMG. The corresponding HDAC inhibitor, MS-275 upregulated NK cell-mediated cytotoxicity pathway through GSEA analysis. Pretreating DMG cells with MS-275 elevated NK cell ligand gene expression and enhanced NK cell-induced lysis. In addition to NK-activating ligands, MS-275 elevated the NK-inhibitory ligand HLA-E, thereby enhancing the efficacy of immunotherapies targeting the NKG2A–HLA-E axis. Mechanistically, MS-275 increased HLA-E expression by promoting STAT3 acetylation at lysine 685. Combining MS-275 with NK cell therapy and blockade of the NKG2A–HLA-E axis extended overall survival in orthotopic mouse models. Conclusions This study is the first to demonstrate that HDAC inhibition enhances NK cell-mediated cytotoxicity in DMG. Combining HDAC inhibition with NK cell therapy represents a promising therapeutic strategy for treating DMG by targeting NKG2A–HLA-E axis.

Background Genetic and epigenetic profiles are critical in managing brainstem gliomas (BSG), whose heterogeneity is far beyond the realm of the Diffuse midline glioma, H3K27 altered. Cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA)-based liquid biopsy provides minimally-invasive strategies to acquire molecular information for brain tumors, whereas there is a deficiency in techniques for co-detection of genetic and epigenetic alterations due to the limited yield of ctDNA. This study aims to develop a reliable minimally-invasive approach to simultaneously detect the mutation and methylation profiles in the CSF ctDNA of BSGs, thereby enhancing diagnostic accuracy, prognostic capability, and monitoring potential. Methods A cohort of 80 BSG cases with 138 CSF samples and 71 tissues was retrospectively established. Public tissue methylation profiles ( N  = 1016) were used for the development of H3K27M and IDH mutation-specific assay. The mutation and methylation co-detection classifier (BSGdiag) was trained and tested in tissue cohorts and further validated in CSF samples. CSF Methylation Risk Score (MRS) was defined and used for prognostication and monitoring. Results The methylation assay demonstrated robust three-class (H3K27M-mut, IDH-mut and double-wildtype) classification with microAUC values of 1.00, 0.973, and 0.813 across public datasets, tissue cohorts, and CSF samples, respectively. BSGdiag achieved a sensitivity of 95.6%, specificity of 83.3%, and AUC of 0.949 for the H3K27M subtype, and a microAUC of 0.990 for the three-class classification in CSFs. MRS-stratified CSF methylation risk group was an independent prognostic factor (HR = 2.61, 95% CI: 1.09–6.25, P  = 0.032). Methylation information in CSF remained even with clinical, radiological and CSF genetic indications of no disease, suggesting its utility in monitoring minimal residual disease. Conclusions The study de novo developed the first methylation assay for robust BSG molecular subtyping and introduced a novel methodology for co-detecting CSF ctDNA mutations and methylation in BSGs. The BSGdiag enhances the utility of ctDNA by leveraging both genetic and epigenetic information. Its comprehensiveness, minimal invasiveness, robustness, and reliability make it highly promising for future clinical applications and trial designs.

Rail surface cracks are widespread damage that can lead to uneven surfaces of railheads and affect traveling safety. Non-destructive testing is needed to inspect rails regularly to ensure the normal operation of railroads. This paper proposes a laser ultrasonic testing method combining variational mode decomposition and diffractive Rayleigh wave time-of-flight to detect tiny cracks on the rail surface quantitatively. The finite element method was combined with experiments to simulate and experimentally investigate cracks of different sizes numerically. In the numerical simulation, the location of the crack was determined by B-scan. Afterward, the interaction between various types of ultrasound and cracks was comparatively analyzed, and the crack size was quantitatively characterized using useful information from the ultrasound signals. The results show that the time-of-flight method can detect arbitrary cracks with low error. Therefore, the experimentally acquired ultrasound signals used the time difference between the diffracted Rayleigh wave and other ultrasound waves to detect the crack information quantitatively. The variational mode decomposition method was used to separate the ultrasonic signals and extract the best surface wave modes to improve the signal-to-noise ratio. The results show that the combination of variational mode decomposition and time-of-flight method can effectively detect the size of cracks.

A unique photonic crystal fiber with square and circular air holes (SC-PCF) is designed in this research. Three layers of circular air holes and two levels of square air holes make up the fiber cladding. The finite element approach is used to simulate the fiber construction, and numerical calculations are used to examine the transmission properties in the S+C+L band. The results reveal that the SC-PCF can sustain 86 Orbital Angular Momentum (OAM) modes in the wavelength range of 1400 nm to 1700 nm (300 nm), with an effective refractive index difference (ERID) of 5.88 × 10−3 between them, thus avoiding mode coupling. The mode purity of all modes is greater than 96% at 1550 nm, and the lowest dispersion and dispersion change are 4.939 ps/nm/km and 0.956 ps/nm/km, respectively. The confinement loss (CL) of all modes is lower than 10−9 dB/m, and the nonlinear coefficient (NC) is lower than 1.5 W−1·km−1 in the whole band. The proposed SC-PCF has important value in long-distance and large-capacity communication systems.

Purpose Over the past several decades, numerous articles have been published on brainstem tumors. However, there has been limited bibliometric analysis in this field. Therefore, we conducted a bibliometric analysis to elucidate the evolution and current status of brainstem tumor research. Methods We retrieved 5525 studies published in English between 1992 and 2023 from the Web of Science Core Collection database. We employed bibliometric tools and VOSviewer to conduct the analysis. Results We included a total of 5525 publications for further analysis. The annual publications have exhibited steady growth over time. The United States accounted for the highest number of publications and total citations. Among individual researchers, Liwei Zhang had the highest number of publications, while Cynthia Hawkins and Chris Jones shared the most citations, closely followed by Eric Bouffet in this field. The study titled “Diffuse brainstem glioma in children: critical review of clinical trials” stood out as the most cited work in this field. Keyword analysis revealed that immune therapy and epigenetic research are the focal points of this field. Conclusions Our bibliometric analysis underscores the enduring significance of brainstem tumors in the realm of neuro-oncology research. The field’s hotspots have transitioned from surgery and radiochemotherapy to investigating epigenetic mechanisms and immune therapy.

Vascular dementia (VD) is characterized with vascular cognitive impairment (VCI), which currently has few effective therapies in clinic. Neuronal damage and white matter injury are involved in the pathogenesis of VCI. Citicoline has been demonstrated to exhibit neuroprotection and neurorepair to improve cognition in cerebrovascular diseases. Nicotinamide adenine dinucleotide (NAD + )-dependent sirtuin (SIRT) signaling pathway constitutes a strong intrinsic defense system against various stresses including neuroinflammation in VCI. Our hypothesis is that the combined use of citicoline and the precursor of NAD + , nicotinamide mononucleotide (NMN), could enhance action on cognitive function in VCI. We investigated the synergistic effect of these two drugs in the rat model of VCI by bilateral common carotid artery occlusion (BCCAO). Citicoline significantly enhanced neurite outgrowth in Neuro-2a cells, and the combination of citicoline and NMN remarkably induced neurite outgrowth in Neuro-2a cells and primary cortical neuronal cells with an optimal proportion of 4:1. In the rat model of BCCAO, when two drugs in combination of 160 mg/kg citicoline and 40 mg/kg NMN, this combination administrated at 7 days post-BCCAO significantly improved the cognitive impairment in BCCAO rats compared with vehicle group by the analysis of the Morris water maze and the novel object recognition test. This combination also decreased microglial activation and neuroinflammation, and protected white matter integrity indicated by the increased myelin basic protein (MBP) expression through activation of SIRT1/TORC1/CREB signaling pathway. Our results suggest that the combination of citicoline and NMN has a synergistic effect for the treatment of VD associated with VCI.

Downregulated expression levels of microRNA-320a (miR-320a) were found in primary breast cancers and colorectal cancer. Previous findings indicated that miRNA-320a may involve in the cancer development. In this study, we explored the roles of miR-320a by targeting c-Myc in the tumor growth of hepatocellular carcinoma (HCC). Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-320a in 50 HCC tissues and four HCC cells. Luciferase reporter assay was conducted to confirm the direct downstream target of miR-320a in HEK-293 cells. The effect of miR-320a on endogenous c-Myc expression was investigated by transfecting miR-320a mimics into HepG2 and QGY-7703 cell lines. The c-Myc and miR-320a expressions were analyzed by immunohistochemistry (IHC) and qRT-PCR in the same HCC tissues. Furthermore, the biological functional correlation of miR-320a with c-Myc was determined by studying the effect of miR-320a mimics or c-Myc small interfering RNA (siRNA) on HCC cell proliferation and invasion. The expression of miR-320a was downregulated in 50 HCC tissues and 4 HCC cells. Luciferase assay revealed that c-Myc is a direct target of miR-320a. IHC and Western blot analysis showed that the c-Myc expression was inhibited by miR-320a in HCC tissues and cell lines. Upregulation of miR-320a suppressed the HCC cell proliferation and invasion capacity induced by inhibiting c-Myc, and the results were consistent with the effects of c-Myc siRNA on tumor suppression. These results revealed that miRNA-320a inhibits tumor proliferation and invasion by targeting c-Myc in HCC cells. Our results showed that miR-320a functions as a tumor suppressor in HCC. By targeting c-Myc directly, miR-320a inhibits the HCC cell growth. Our studies provide evidence of miR-320a as a potentially target for HCC treatment.

Interleukin 6 (IL-6) is a major pro-inflammatory cytokine and dysregulation of IL-6 is relevant to many inflammatory diseases. Endotoxin induced tolerance of IL-6 is an important mechanism to avoid the excessive immune reaction. But to date, the molecular mechanisms of endotoxin tolerance of IL-6 remain unclear. Here we reported that IL-6 secretion and microRNA-181b (miR-181b) expression were inversely correlated following LPS stimulation. We also demonstrated that miR-181b targeting the 3′-UTR of IL-6 transcripts and up-regulation of miR-181b was associated with NF-kB. We further demonstrated that up-regulation of miR-181b in response to LPS was required for inducing IL-6 tolerance in macrophage. Our results suggested that the post-transcriptional control mediated by miR-181b could be involved in fine tuning the critical level of IL-6 expression in endotoxin tolerance.