Radiotherapy plus temozolomide with or without anlotinib in H3K27M-mutant diffuse midline glioma: A retrospective cohort study.

BACKGROUND: Besides the hallmark of H3K27M mutation, aberrant amplifications of receptor tyrosine kinases (RTKs) are commonly observed in diffuse midline glioma (DMG), a highly malignant brain tumor with dismal prognosis. Here, we intended to evaluate the efficacy and safety of a multitarget RTK inhibitor anlotinib in patients with H3K27M-DMG. METHODS: A total of 40 newly diagnosed H3K27M-DMG patients including 15 with anlotinib and 25 without anlotinib treatment were retrospectively enrolled in this cohort. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed and compared. RESULTS: The median PFS and OS of all patients in this cohort were 8.5 months (95% CI, 6.5-11.3) and 15.5 months (95% CI, 12.6-17.1), respectively. According to the Response Assessment in Neuro-Oncology (RANO) criteria, the disease control rate in the anlotinib group [93.3%, 95% confidence interval (CI), 70.2-98.8] was significantly higher than those without anlotinib (64%, 95% CI: 40.5-79.8, p = 0.039). The median PFS of patients with and without anlotinib was 11.6 months (95% CI, 7.8-14.3) and 6.4 months (95% CI, 4.3-10.3), respectively. Both the median PFS and OS of DMG patients treated with anlotinib were longer than those without anlotinib in the infratentorial patients (PFS: 10.3 vs. 5.4 months, p = 0.006; OS: 16.6 vs. 8.7 months, p = 0.016). Multivariate analysis also indicated anlotinib (HR: 0.243, 95% CI: 0.066-0.896, p = 0.034) was an independent prognosticator for longer OS in the infratentorial subgroup. In addition, the adverse events of anlotinib administration were tolerable in the whole cohort. CONCLUSIONS: This study first reported that anlotinib combined with Stupp regimen is a safe and feasible regimen for newly diagnosed patients with H3K27M-DMG. Further, anlotinib showed significant efficacy for H3K27M-DMG located in the infratentorial region.

GEFormerDTA: drug target affinity prediction based on transformer graph for early fusion.

Predicting the interaction affinity between drugs and target proteins is crucial for rapid and accurate drug discovery and repositioning. Therefore, more accurate prediction of DTA has become a key area of research in the field of drug discovery and drug repositioning. However, traditional experimental methods have disadvantages such as long operation cycles, high manpower requirements, and high economic costs, making it difficult to predict specific interactions between drugs and target proteins quickly and accurately. Some methods mainly use the SMILES sequence of drugs and the primary structure of proteins as inputs, ignoring the graph information such as bond encoding, degree centrality encoding, spatial encoding of drug molecule graphs, and the structural information of proteins such as secondary structure and accessible surface area. Moreover, previous methods were based on protein sequences to learn feature representations, neglecting the completeness of information. To address the completeness of drug and protein structure information, we propose a Transformer graph-based early fusion research approach for drug-target affinity prediction (GEFormerDTA). Our method reduces prediction errors caused by insufficient feature learning. Experimental results on Davis and KIBA datasets showed a better prediction of drugtarget affinity than existing affinity prediction methods.

Systematic Mendelian randomization study of the effect of gut microbiome and plasma metabolome on severe COVID-19.

Background: COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators in the human body and could contribute to the immune responses impacting the progression of COVID-19. However, the causal relationship between specific intestinal bacteria, metabolites and severe COVID-19 remains not clear. Methods: Based on two-sample Mendelian randomization (MR) framework, the causal effects of 131 intestinal taxa and 452 plasma metabolites on severe COVID-19 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated with the abundance of intestinal taxa and the concentration of plasma metabolites had been utilized as the instrument variables to infer whether they were causal factors of severe COVID-19. In addition, mediation analysis was conducted to find the potential association between the taxon and metabolite, and further colocalization analysis had been performed to validate the causal relationships. Results: MR analysis identified 13 taxa and 53 metabolites, which were significantly associated with severe COVID-19 as causal factors. Mediation analysis revealed 11 mediated relationships. Myo-inositol, 2-stearoylglycerophosphocholine, and alpha-glutamyltyrosine, potentially contributed to the association of Howardella and Ruminiclostridium 6 with severe COVID-19, respectively. Butyrivibrio and Ruminococcus gnavus could mediate the association of myo-inositol and N-acetylalanine, respectively. In addition, Ruminococcus torques abundance was colocalized with severe COVID-19 (PP.H4 = 0.77) and the colon expression of permeability related protein RASIP1 (PP.H4 = 0.95). Conclusions: Our study highlights the potential causal relationships between gut microbiome, plasma metabolome and severe COVID-19, which potentially serve as clinical biomarkers for risk stratification and prognostication and benefit the mechanism mechanistic investigation of severe COVID-19.

Advances in glioma models using in vivo electroporation to highjack neurodevelopmental processes.

Glioma is the most prevalent type of neurological malignancies. Despite decades of efforts in neurosurgery, chemotherapy and radiation therapy, glioma remains one of the most treatment-resistant brain tumors with unfavorable outcomes. Recent progresses in genomic and epigenetic profiling have revealed new concepts of genetic events involved in the etiology of gliomas in humans, meanwhile, revolutionary technologies in gene editing and delivery allows to code these genetic "events" in animals to genetically engineer glioma models. This approach models the initiation and progression of gliomas in a natural microenvironment with an intact immune system and facilitates probing therapeutic strategies. In this review, we focus on recent advances in in vivo electroporation-based glioma modeling and outline the established genetically engineered glioma models (GEGMs).

Differences in survival prognosticators between children and adults with H3K27M-mutant diffuse midline glioma.

AIMS: H3K27M-mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor. The biological behavior, clinicopathological characteristics, and prognostic factors of DMG have not yet been completely uncovered, especially in adult patients. This study aims to investigate the clinicopathological characteristics and identify prognostic factors of H3K27M-mutant DMG in pediatric and adult patients, respectively. METHODS: A total of 171 patients with H3K27M-mutant DMG were included in the study. The clinicopathological characteristics of the patients were analyzed and stratified based on age. The Cox proportional hazard model was used to determine the independent prognostic factors in pediatric and adult subgroups. RESULTS: The median overall survival (OS) for the entire cohort was 9.0 months. Significant differences were found in some clinicopathological characteristics between children and adults. The median OS was also significantly different between the pediatric and adult subgroups, with 7.1 months for children and 12.3 months for adults (p < 0.001). In the overall population, the multivariate analysis identified adult patients, single lesion, concurrent chemoradiotherapy/radiotherapy, and intact ATRX expression as independent favorable prognostic factors. In the age-stratified subgroups, the prognostic factors varied between children and adults, with intact ATRX expression and single lesion being independent favorable prognostic factors in adults, while infratentorial localization was significantly associated with worse prognosis in children. CONCLUSIONS: The differences in clinicopathological features and prognostic factors between pediatric and adult patients with H3K27M-mutant DMG suggest the need for further clinical and molecular stratification based on age.

Radiotherapy and radio-sensitization in H3K27M -mutated diffuse midline gliomas.

BACKGROUND: H3K27M mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%. Radiotherapy is the only established adjuvant treatment of H3K27M DMGs; however, the radio-resistance is commonly observed. METHODS: We summarized current understandings of the molecular responses of H3K27M DMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement. RESULTS: Ionizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial-mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio-resistance. CONCLUSIONS: The advances in mechanisms of radio-resistance in H3K27M DMGs promote the potential targets to enhance the sensitivity to radiotherapy.

Cerebrospinal fluid circulating tumor DNA depicts profiling of brain metastasis in NSCLC.

Brain metastasis (BM) genetically diverges from the primary tumor in non-small-cell lung cancer (NSCLC). Hence, accurately capturing clinically relevant alterations is pivotal for the delivery of targeted therapies. Circulating tumor DNA (ctDNA) sequencing has emerged as a promising liquid biopsy in the biomarker-based clinical management of recurrent and extracranial metastatic NSCLC. However, the absence of simultaneous sequencing data from brain metastatic sites prevents the definitive evaluation of the efficacy of ctDNA in representing genetic profiles in BM. Here, we performed parallel genomic comparisons between matched BM and primary tumor DNA, plasma ctDNA, and cerebrospinal fluid (CSF) ctDNA. The results indicated that CSF ctDNA had a greater ability than plasma ctDNA to comprehensively represent the mutational landscape of BM, with CSF ctDNA detecting all BM mutations in 83.33% of patients, while plasma ctDNA was only 27.78%. Mutant allele frequency (MAF) in CSF ctDNA was highly correlated with the tumor size of BM (r = 0.95), and the mean MAF in CSF ctDNA was higher than that in plasma ctDNA (38.05% vs. 4.57%, respectively). MAF and tumor mutational burden in CSF ctDNA were strongly associated with those in BM (r = 0.96 and 0.97, respectively). Of note, CSF ctDNA had significantly higher concordance with BM than plasma ctDNA (99.33% vs. 67.44%), facilitating the identification of clinically relevant mutations. Moreover, we found that plasma ctDNA has stronger profiling performance, with a concordance of 93.01% in multiple brain metastases, equivalent to CSF ctDNA. Collectively, our study indicates that CSF ctDNA is superior to plasma ctDNA in accurately representing the profiling of single BM. Plasma ctDNA could be an alternative liquid biopsy material to be applied in multiple brain metastatic NSCLC.

Tobacco smoking associates with NF1 mutations exacerbating survival outcomes in gliomas.

Tobacco smoking is associated with increased risks of nearly 20 types of cancer. Although the association between smoking and gliomas, the most prevalent type of adult brain tumor, is still unconclusive, here, we found that the frequency of NF1 mutations was significantly increased in the glioma patients with smoking history compared to non-smoking patients (24% vs. 10%, P = 0.021). NF1 acts as a tumor suppressor gene is highly mutated in gliomas. The TCGA data analysis indicated that glioma patients carrying NF1 somatic mutations have worse overall survival (median survival time: smoking 19.9 months vs. non-smoking 36.8 month; P = 0.0018). In addition, we revealed that the NF1 and IDH1 mutations were mutually exclusive suggesting NF1 mutation has independent molecular mechanism involved in glioma biology.

Molecular insight into pentraxin-3: Update advances in innate immunity, inflammation, tissue remodeling, diseases, and drug role.

Pentraxin-3 (PTX3) is the prototype of the long pentraxin subfamily, an acute-phase protein consisting of a C-terminal pentraxin domain and a unique N-terminal domain. PTX3 was initially isolated from human umbilical vein endothelial cells and human FS-4 fibroblasts. It was subsequently found to be also produced by synoviocytes, chondrocytes, osteoblasts, smooth muscle cells, myeloid dendritic cells, epithelial cells, and tumor cells. Various modulatory factors, such as miRNAs, cytokines, drugs, and hypoxic conditions, could regulate the expression level of PTX3. PTX3 is essential in regulating innate immunity, inflammation, angiogenesis, and tissue remodeling. Besides, PTX3 may play dual (pro-tumor and anti-tumor) roles in oncogenesis. PTX3 is involved in the occurrence and development of many non-cancerous diseases, including COVID-19, and might be a potential biomarker indicating the prognosis, activity,and severity of diseases. In this review, we summarize and discuss the potential roles of PTX3 in the oncogenesis and pathogenesis of non-cancerous diseases and potential targeted therapies based on PTX3.

Novel insight into ferroptosis-related genes, molecular subtypes, and immune characteristics in intracranial aneurysms.

OBJECTIVES: This study aimed to identify the role of ferroptosis in intracranial aneurysm (IA). METHODS: GSE122897, GSE75436, GSE15629, and GSE75434 datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed ferroptosis-related genes (DEFRGs) were selected to construct a diagnostic model integrating with machine learning. Then, a consensus clustering algorithm was performed to classify IA patients into distinct ferroptosis-related clusters. Functional analyses, including GO, KEGG, GSVA, and GSEA analyses, were conducted to elucidate the underlying mechanisms. ssGSEA and xCell algorithms were performed to uncover the immune characteristics. RESULTS: We identified 28 DEFRGs between IAs and controls from the GSE122897 dataset. GO and KEGG results showed that these genes were enriched in cytokine activity, ferroptosis, and the IL-17 signaling pathway. Immune analysis showed that the IAs had higher levels of immune infiltration. A four FRGs model (MT3, CDKN1A, ZEP69B, and ABCC1) was established and validated with great IA diagnostic ability. We divided the IA samples into two clusters and found that cluster 2 had a higher proportion of rupture and immune infiltration. We identified 10 ferroptosis phenotypes-related markers in IAs. CONCLUSION: Ferroptosis and the immune microenvironment are closely associated with IAs, providing a basis for understanding the IA development.

Immune checkpoint modulators in cancer immunotherapy: recent advances and emerging concepts.

The discovery of immune checkpoint inhibitors (ICIs) has now been universally acknowledged as a significant breakthrough in tumor therapy after the targeted treatment of checkpoint molecules: anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on several cancer types achieved satisfying results. However, there are still quite a lot of patients suffering from severe side effects and ineffective treatment outcomes. Although the current ICI therapy is far from satisfying, a series of novel immune checkpoint molecules with remarkable preclinical and clinical benefits are being widely investigated, like the V-domain Ig suppressor of T cell activation (VISTA), which can also be called PD-1 homolog (PD-1H), and ectonucleotidases: CD39, CD73, and CD38, which belong to the ribosyl cyclase family, etc. In this review, we systematically summarized and discussed these molecules' biological structures, molecular features, and the corresponding targeted drugs, aiming to help the in-depth understanding of immune checkpoint molecules and promote the clinical practice of ICI therapy.

A Pan-Cancer Analysis Reveals CLEC5A as a Biomarker for Cancer Immunity and Prognosis.

Background: CLEC5A is a member of the C-type lectin superfamily. It can activate macrophages and lead to a series of immune-inflammation reactions. Previous studies reveal the role of CLEC5A in infection and inflammation diseases. Method: We acquire and analyze data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database, and other comprehensive databases via GSCALite, cBioPortal, and TIMER 2.0 platforms or software. Single-cell sequencing analysis was performed for quantifying the tumor microenvironment of several types of cancers. Results: CLEC5A is differentially expressed in a few cancer types, of which overexpression accompanies low overall survival of patients. DNA methylation mainly negatively correlates with CLEC5A expression. Moreover, CLEC5A is positively related to immune infiltration, including macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs). Immune checkpoint genes are significantly associated with CLEC5A expression in diverse cancers. In addition, CLEC5A expression correlates with mismatch repair (MMR) in several cancers. Tumor mutation burden (TMB), microsatellite instability (MSI), and neoantigens show a positive association with CLEC5A expression in several cancers. Furthermore, CLEC5A in cancer correlates with signal transduction, the immune system, EMT, and apoptosis process. The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B. Conclusion: CLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy.

JMJD8 Is an M2 Macrophage Biomarker, and It Associates With DNA Damage Repair to Facilitate Stemness Maintenance, Chemoresistance, and Immunosuppression in Pan-Cancer.

Background: JMJD8 has recently been identified as a cancer-related gene, but current studies provide limited information. We aimed to clarify its roles and the potential mechanisms in pan-cancer. Methods: Pan-cancer bulk sequencing data and online web tools were applied to analyze JMJD8's correlations with prognosis, genome instability, cancer stemness, DNA repair, and immune infiltration. Moreover, single-cell datasets, SpatialDB database, and multiple fluorescence staining were used to validate the association between JMJD8 expression and M2 macrophages. Further, we utilized ROCplotter and cMap web tool to analyze the therapeutic responses and screened JMJD8-targeted compounds, respectively, and we used AlphaFold2 and Discovery Studio to conduct JMJD8 homology modeling and molecular docking. Results: We first noticed that JMJD8 was an oncogene in many cancer types. High JMJD8 was associated with lower genome stability. We then found that high JMJD8 correlated with high expression of mismatch repair genes, stemness, homologous repair gene signature in more than 9 cancers. ESTIMATE and cytokine analyses results presented JMJD8's association with immunosuppression. Also, immune checkpoint CD276 was positively relevant to JMJD8. Subsequently, we validated JMJD8 as the M2 macrophage marker and showed its connection with other immunosuppressive cells and CD8+ T-cell depression. Finally, potential JMJD8-targeted drugs were screened out and docked to JMJD8 protein. Conclusion: We found that JMJD8 was a novel oncogene, and it correlated with immunosuppression and DNA repair. JMJD8 was highly associated with immune checkpoint CD276 and was an M2 macrophage biomarker in many cancers. This study will reveal JMJD8's roles in pan-cancer and its potential as a novel therapeutic target.

The Coordination of mTOR Signaling and Non-Coding RNA in Regulating Epileptic Neuroinflammation.

Epilepsy accounts for a significant proportion of the burden of neurological disorders. Neuroinflammation acting as the inflammatory response to epileptic seizures is characterized by aberrant regulation of inflammatory cells and molecules, and has been regarded as a key process in epilepsy where mTOR signaling serves as a pivotal modulator. Meanwhile, accumulating evidence has revealed that non-coding RNAs (ncRNAs) interfering with mTOR signaling are involved in neuroinflammation and therefore articipate in the development and progression of epilepsy. In this review, we highlight recent advances in the regulation of mTOR on neuroinflammatory cells and mediators, and feature the progresses of the interaction between ncRNAs and mTOR in epileptic neuroinflammation.

Knowledge Discovery-Based Analysis of Health Factors of Urinary Infections in Elderly Cardiology Inpatients.

A set of semantic similarity calculation methods combining full-text text and domain knowledge topics is proposed for the current study of entity association relations such as disease-gene in medical texts combined with topics in knowledge discovery, which is insufficient to reveal the deep semantic association relations of medical domain knowledge at topic level. Taking urinary infections in elderly inpatients as the research subject, word embedding representation of word vectors and topic vectors is performed by the TWE model, and similarity calculation is performed by combining text and domain knowledge topics based on Siamese Network framework. The urinary microbiological culture results of both groups were dominated by Escherichia coli, accounting for 34.65% and 47.92%, respectively; the use of antimicrobial drugs in the symptomatic urinary infection group was 94.19% higher than that in the asymptomatic bacteriuria group, 77.27% (x 2 = 8.158, P=0.004).

Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.

Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.

Three-year observations on the effect of different cusp inclinations on the restoration of short maxillary first molar implants: A randomized controlled trial.

Objective: To investigate the effect of different cusp inclination on short implant prosthesis of maxillary first molar after 3 years of weight-bearing in biology and mechanics. Methods: The clinical patients were randomly selected from the database and divided into four groups A, B, C, and D according to the cusp inclination of the maxillary first molar short implant restoration (4.8 mm × 8 mm, Dentium). 20 cases in each group. The cusp inclination was 10 degrees-15 degrees, 15 degrees-20 degrees, 20 degrees-25 degrees, 25 degrees-30 degrees. After 3 years of weight-bearing, cone beam computed tomography (CBCT) and Florida probe were used to measure and observe the height of alveolar bone (H), periodontal probing depth (PD) and modified sulcus bleeding index (MBI). Visual analogue scale (VAS) was used to evaluate the overall satisfaction of patients, and the mechanical complications of each group within 3 years of implant weight-bearing were counted. Results: The H and PD of group D were 1.09 ± 0.23 and 2.19 ± 0.11 respectively, which were significantly higher than those of group A, B and C (p < 0.05). There was no significant difference in MBI between groups A-D (p > 0.05). The VAS scores of group B and group C were 88.36 ± 5.12 and 88.70 ± 4.52 respectively, which were higher than those of group A and group D (p < 0.05). The incidence of food impaction, porcelain collapse and abutment loosening in group D were 40.0%, 25.0% and 15.0% respectively, which were higher than those in group B and C (p < 0.05). Conclusion: The risk of biological and mechanical complications increases after long-term weight-bearing of maxillary first molar short implant prostheses with high cusp inclination. The cusp inclination of short implant prostheses should be designed as low as 25 degrees.

Preimplantation factor modulates oligodendrocytes by H19-induced demethylation of NCOR2.

Failed or altered gliogenesis is a major characteristic of diffuse white matter injury in survivors of premature birth. The developmentally regulated long noncoding RNA (lncRNA) H19 inhibits S-adenosylhomocysteine hydrolase (SAHH) and contributes to methylation of diverse cellular components, such as DNA, RNA, proteins, lipids, and neurotransmitters. We showed that the pregnancy-derived synthetic PreImplantation Factor (sPIF) induces expression of the nuclear receptor corepressor 2 (NCOR2) via H19/SAHH-mediated DNA demethylation. In turn, NCOR2 affects oligodendrocyte differentiation markers. Accordingly, after hypoxic-ischemic brain injury in rodents, myelin protection and oligodendrocytes' fate are in part modulated by sPIF and H19. Our results revealed an unexpected mechanism of the H19/SAHH axis underlying myelin preservation during brain recovery and its use in treating neurodegenerative diseases can be envisioned.