Integrative analysis of single-cell and bulk RNA sequencing unveils a machine learning-based pan-cancer major histocompatibility complex-related signature for predicting immunotherapy efficacy.

Major histocompatibility complex (MHC) could serve as a potential biomarker for tumor immunotherapy, however, it is not yet known whether MHC could distinguish potential beneficiaries. Single-cell RNA sequencing datasets derived from patients with immunotherapy were collected to elucidate the association between MHC and immunotherapy response. A novel MHCsig was developed and validated using large-scale pan-cancer data, including The Cancer Genome Atlas and immunotherapy cohorts. The therapeutic value of MHCsig was further explored using 17 CRISPR/Cas9 datasets. MHC-related genes were associated with drug resistance and MHCsig was significantly and positively associated with immunotherapy response and total mutational burden. Remarkably, MHCsig significantly enriched 6% top-ranked genes, which were potential therapeutic targets. Moreover, we generated Hub-MHCsig, which was associated with survival and disease-special survival of pan-cancer, especially low-grade glioma. This result was also confirmed in cell lines and in our own clinical cohort. Later low-grade glioma-related Hub-MHCsig was established and the regulatory network was constructed. We provided conclusive clinical evidence regarding the association between MHCsig and immunotherapy response. We developed MHCsig, which could effectively predict the benefits of immunotherapy for multiple tumors. Further exploration of MHCsig revealed some potential therapeutic targets and regulatory networks.

Diagnostic performance of PIVKA-II in identifying recurrent hepatocellular carcinoma following curative resection: a retrospective cohort study.

Protein induced by vitamin K absence or antagonist II (PIVKA-II) plays a critical role in the diagnosis of hepatocellular carcinoma (HCC), however, studies on its efficacy in diagnosing recurrent HCC were rarely found. A multicenter, retrospective, and observational study was conducted. During the overall follow-up of 5 years, HCC patients who had curative resection were monitored every 3 months in the first year post-surgery and every 6 months thereafter if no recurrence occurred. Tumor markers were collected at the diagnosis of recurrence for those with recurrence and at the last follow-up for those without recurrence. The median serum levels of PIVKA-II and AFP in the recurrence group were significantly higher than those in the non-recurrence group (PIVKA-II: 84.62 vs. 18.76 mAU/ml, p < 0.001; AFP: 4.90 vs. 3.00 ng/ml, p < 0.001) and there is a significant correlation between PIVKA-II and AFP (R = 0.901, p < 0.001). PIVKA-II showed better accuracy than AFP in the diagnosis of overall recurrent HCC (AUC: 0.883 vs. 0.672; p < 0.0001), but also in patients with negative PIVKA-II before curative resection (AUC: 0.878 vs. 0.680, p = 0.001). Clinician should pay more attention to serum PIVKA-II values when following patients after curative HCC resection to detect early recurrence.Clinical trial registration: ChiCTR2300070874.

JNK signaling mediates acute rejection via activating autophagy of CD8+ T cells after liver transplantation in rats.

Background: Acute rejection (AR) after liver transplantation (LT) remains an important factor affecting the prognosis of patients. CD8+ T cells are considered to be important regulatory T lymphocytes involved in AR after LT. Our previous study confirmed that autophagy mediated AR by promoting activation and proliferation of CD8+ T cells. However, the underlying mechanisms regulating autophagy in CD8+ T cells during AR remain unclear. Methods: Human liver biopsy specimens of AR after orthotopic LT were collected to assess the relationship between JNK and CD8+ T cells autophagy. The effect of JNK inhibition on CD8+ T cells autophagy and its role in AR were further examined in rats. Besides, the underlying mechanisms how JNK regulated the autophagy of CD8+ T cells were further explored. Results: The expression of JNK is positive correlated with the autophagy level of CD8+ T cells in AR patients. And similar findings were obtained in rats after LT. Further, JNK inhibitor remarkably inhibited the autophagy of CD8+ T cells in rat LT recipients. In addition, administration of JNK inhibitor significantly attenuated AR injury by promoting the apoptosis and downregulating the function of CD8+ T cells. Mechanistically, JNK may activate the autophagy of CD8+ T cells through upregulating BECN1 by inhibiting the formation of Bcl-2/BECN1 complex. Conclusion: JNK signaling promoted CD8+ T cells autophagy to mediate AR after LT, providing a theoretical basis for finding new drug targets for the prevention and treatment of AR after LT.

Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses.

Purpose: NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. Methods: Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents. Clinical phenotype, treatment, and prognosis were analyzed. Results: Nine patients with NLRP3-AID were enrolled between December 2014 and October 2022 with an average follow-up period exceeding 30 months. The median age of onset was 12 months, and 66.7% were younger than 3 years old. The diagnosis was significantly delayed and the median delay duration was 115 months. The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7). Two cases of chronic infantile neurological cutaneous articular syndrome (CINCA) had clubbed fingers, one with interstitial lung disease, a finding rarely reported. Treatment with glucocorticoids (77.8%) and biologic agents (33.3%) yielded 66% complete remission and 33% partial remission. Genetic analysis identified eight pathogenic NLRP3 missense mutations, including one novel mutation. Conclusions: Our study illuminated the distinct clinical and genetic features of Chinese NLRP3-AID patients, emphasizing the significance of early genetic screening. Despite delayed diagnosis, treatment primarily with glucocorticoids and biologic agents, led to favorable outcomes. Genetic heterogeneity, including a novel mutation, highlighted the complexity of NLRP3-AID in this population.

Tumor-targeted delivery of copper-manganese biomineralized oncolytic adenovirus for colorectal cancer immunotherapy.

Oncolytic viral therapy (OVT) is a novel anti-tumor immunotherapy approach, specifically replicating within tumor cells. Currently, oncolytic viruses are mainly administered by intratumoral injection. However, achieving good results for distant metastatic tumors is challenging. In this study, a multifunctional oncolytic adenovirus, OA@CuMnCs, was developed using bimetallic ions copper and manganese. These metal cations form a biomineralized coating on the virus's surface, reducing immune clearance. It is known that viruses upregulate the expression of PD-L1. Copper ions in OA@CuMnCs can decrease the PD-L1 expression of tumor cells, thereby promoting immune cell-related factor release. This process involves antigen presentation and the combination of immature dendritic cells, transforming them into mature dendritic cells. It changes "cold" tumors into "hot" tumors, further inducing immunogenic cell death. While oncolytic virus replication requires oxygen, manganese ions in OA@CuMnCs can react with endogenous hydrogen peroxide. This reaction produces oxygen, enhancing the virus's replication ability and the tumor lysis effect. Thus, this multifunctionally coated OA@CuMnCs demonstrates potent amplification in immunotherapy efficacy, and shows great potential for further clinical OVT. STATEMENT OF SIGNIFICANCE: Oncolytic virus therapy (OVs) is a new anti-tumor immunotherapy method that can specifically replicate in tumor cells. Although the oncolytic virus can achieve a therapeutic effect on some non-metastatic tumors through direct intratumoral injection, there are still three major defects in the treatment of metastatic tumors: immune response, hypoxia effect, and administration route. Various studies have shown that the immune response in vivo can be overcome by modifying or wrapping the surface protein of the oncolytic virus. In this paper, a multifunctional coating of copper and manganese was prepared by combining the advantages of copper and manganese ions. The coating has a simple preparation method and mild conditions, and can effectively enhance tumor immunotherapy.

Ubiquitination-specific protease 7 enhances stemness of hepatocellular carcinoma by stabilizing basic transcription factor 3.

This study aims to explore the molecular regulation mechanism of ubiquitination-specific protease 7 (USP7) in facilitating the stemness properties of hepatocellular carcinoma (HCC). Gain-of-function and loss-of-function assays were conducted in SK-Hep1 and HepG2 cells transfected with USP7 overexpression/knockdown plasmids and USP7 inhibitor P22077. The proliferation, migration, invasion, and self-renewal capacity of hepatocellular carcinoma cells were detected by CCK-8, colony formation, Transwell, scratch, and tumor sphere formation, respectively. MS was performed to identify the potential substrate of USP7 following P22077 treatment. Co-IP assay was used to verify the interaction between USP7 and basic transcription factor 3 (BTF3) in HCC cells. The overexpression of USP7 could promote the proliferation, migration, invasion, and colony formation capacity of SK-Hep1 and HepG2 cells. Additionally, ectopic UPS7 enhanced the epithelial-mesenchymal transition (EMT) and stem-like characteristics of the HCC cells. In contrast, USP7 depletion by knockdown of USP7 or administrating inhibitor P22077 significantly inhibited these malignant phenotypes of SK-Hep1 and HepG2 cells. Following MS analysis, BTF3 was identified as a potential substrate for USP7. USP7 could interact with BTF3 and upregulate its protein level, while USP7 depletion significantly upregulated the ubiquitination levels. Overexpression of BTF3 partially rescue the inhibitory effects of USP7 depletion on the malignant phenotypes and stemness properties of SK-Hep1 and HepG2 cells. USP7 can promote the stemness and malignant phenotype of HCC by stabilizing BTF3.

Featured lncRNA-based signature for discriminating prognosis and progression of hepatocellular carcinoma.

Long non-coding RNAs (lncRNAs) have been implicated in carcinogenesis and progression of hepatocellular carcinoma (HCC). This study aimed to identify a robust lncRNA signature for predicting the survival of HCC patients. We performed an integrated analysis of the lncRNA expression profiling in The Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma database to identify the prognosis-related lncRNA for the HCC. The HCC cohort was randomly divided into a training set (n = 250) and a testing set (n = 113). Following a two-step screening, we identified an 18-lncRNA signature risk score. The high-risk subgroups had significantly shorter survival time than the low-risk group in both the training set (P < 0.0001) and the testing set (P = 0.005). Stratification analysis revealed that the prognostic value of the lncRNA-based signature was independent of the tumor stage and pathologic stage. The area under the receiver operating characteristic curve (AUROC) of the 18-lncRNA signature risk score was 0.826 (95%CI, 0.764-0.888), 0.817 (95%CI, 0.759-0.876), and 0.799 (95%CI, 0.731-0.867) for 1-year, 3-year, and 5-year follow-up, respectively. Bioinformatics analyses indicated that the 18 lncRNA might mediate cell cycle, DNA replication processes, and canonical cancer-related pathways, in which MCM3AP-AS1 was a potential target for HCC. In conclusion, the 18-lncRNA signature was a robust predictive biomarker for the prognosis and progression of HCC.

Clinical characteristics of hypertrophic cranial pachymeningitis in granulomatosis with polyangiitis: a retrospective single-center study in China.

BACKGROUND: Hypertrophic cranial pachymeningitis (HCP) is uncommon but a poorly understood complication of granulomatosis with polyangiitis (GPA). OBJECTIVES: We conducted this retrospective study to elucidate the clinical characteristics and factors independently associated with granulomatosis with polyangiitis (GPA) complicated by hypertrophic cranial pachymeningitis (HCP) in China. METHODS: We collected the medical records of 78 patients diagnosed with GPA who were admitted to the inpatient department of Peking Union Medical College Hospital between January 2003 and September 2021. Clinical features, laboratory and radiological findings, and Birmingham Vasculitis Activity Scores (excluding meningitis score) were recorded. A binary logistic regression analysis was performed to analyze factors independently associated with GPA-related HCP. RESULTS: Headache (100%) and cranial nerve palsy (61.5%) were common manifestations of HCP. Compared to 52 GPA patients without HCP, 26 patients with HCP required more time from initial symptoms to diagnosis, with a lower ratio of pulmonary and renal involvement, a higher ratio of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) positivity, conductive or sensorineural hearing loss, mastoiditis, and decreased vision or sudden visual loss. Binary logistic regression analysis indicated that proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) negativity (OR 10.698, p = 0.001), conductive or sensorineural hearing loss (OR 10.855, p = 0.005), and decreased vision or sudden visual loss (OR 8.647, p = 0.015) were significantly associated with GPA-related HCP. Of the 26 patients, 18 received methylprednisolone pulse treatment, and 18 received intrathecal injections of dexamethasone and methotrexate. CONCLUSIONS: HCP was a severe manifestation of GPA in our study. Independent factors associated with the occurrence of HCP in patients with GPA included PR3-ANCA negativity, conductive or sensorineural hearing loss, and decreased vision or sudden visual loss. Furthermore, GPA-related HCP was associated with higher disease activity, requiring more intensive treatments.

Maintaining Excellent Mechanical Properties via Additive Manufacturing of Low-N 25Cr-Type Duplex Stainless Steel.

Duplex stainless steel (DSS) exhibits good mechanical properties and corrosion resistance, and has attracted more and more attention within the fields of both science and technology. However, the increasing levels of N and of Cr, Mo, etc., as alloying elements in DSS increase production difficulty. In particular, the N element increases the risk of Cr2N precipitation, which can seriously deteriorate the thermal plasticity of DSS, while increasing its strength. For this reason, a low-N-content 25Cr-type DSS was designed in order to adapt additive manufacturing processes. With regard to the nano-inclusions of oxide precipitation and effective grain refinement, and considering the benefits of selective laser melting fabrication, a low-N 25Cr-type duplex stainless steel with a 0.09 wt.% N content achieved high mechanical properties, with a yield strength of 712 MPa and an elongation of 27.5%, while the V-notch impact toughness was 160 J/cm2. The microstructure evolution and the reasons behind the improvement in mechanical properties will be discussed in detail.

NLRC4 gain-of-function variant is identified in a patient with systemic lupus erythematosus.

NLRC4 gain-of-function variants are known to cause various autoinflammatory phenotypes, including familial cold autoinflammatory syndrome (FCAS4) and NLRC4 macrophage activation syndrome (NLRC4-MAS). However, to date, no study has linked NLRC4 gain-of-function variants to systemic lupus erythematosus (SLE). In this study, we identified a novel NLRC4 W655S variant in an SLE patient and her son, who had neonatal lupus complicated with macrophage activation syndrome. Our in vitro experiments demonstrated that the W655S NLRC4 increased ASC speck formation and mature IL-1ß secretion compared to the wild-type NLRC4. In addition, the patient had elevated levels of IL-1ß and IL-18 in both serum and PBMCs. RNA sequencing showed that NF-κB and interferon signaling pathways were significantly activated in the patient compared to healthy controls. Furthermore, gene set enrichment analysis revealed upregulation of NLRC4-related pathways in patient PBMCs. In conclusion, our study identified the NLRC4 W655S variant in a patient with SLE. This is the first report linking inflammasomopathy to monogenic SLE. Our findings suggest that inflammasome activation may be a critical driver in the pathogenicity of lupus, and autoinflammatory pathways may play important roles in the development of the disease.

Minichromosome maintenance protein family member 6 mediates hepatocellular carcinoma progression by recruiting UBE3A to induce P53 ubiquitination.

With limited therapeutic options for hepatocellular carcinoma (HCC), it is of great significance to investigate the underlying mechanisms and identifying tumor drivers. MCM6, a member of minichromosome maintenance proteins (MCMs), was significantly elevated in HCC progression and associated with poor prognosis. Knockdown of MCM6 significantly inhibited the proliferation and migration of HCC cells with the increased apoptosis ratio and cell cycle arrest, whereas overexpression of MCM6 induced adverse effects. Mechanistically, MCM6 could decrease the P53 activity by inducing the degradation of P53 protein. In addition, MCM6 enhanced the ubiquitination of P53 by recruiting UBE3A to form a triple complex. Furthermore, overexpression of UBE3A significantly rescued the P53 activation and suppression of malignant behaviors mediated by MCM6 inhibition. In conclusion, MCM6 facilitated aggressive phenotypes of HCC cells by UBE3A/P53 signaling, providing potential biomarkers and targets for HCC.

Long Term Outcomes and Potential Risk Factors for Endovascular Repair of Aortic Pseudoaneurysms in Vascular Behçet's Disease.

OBJECTIVE: This study aimed to analyse long term outcomes and risk factors for endovascular repair of aortic pseudoaneurysms in patients with vascular Behçet's disease (BD). METHODS: Medical records of 26 aortic vascular BD patients who underwent endovascular treatment at the vascular department of Peking Union Medical College Hospital between January 2002 and December 2021 were reviewed retrospectively. Erythrocyte sedimentation rate (ESR) and C reactive protein were used to assess BD activity. Computed tomography angiography (CTA) was obtained pre- and post-operatively for almost all patients. Univariable logistic regression analysis was used to analyse risk factors for endovascular repair, such as inflammatory indicators, drug usage, and stent graft parameters. RESULTS: The abdominal aorta (n = 17) was the most common site of 27 vascular BD pseudoaneurysms in this study. CTA also revealed one aortic arch pseudoaneurysm, seven descending thoracic aortic pseudoaneurysms, one thoraco-abdominal aortic pseudoaneurysm, and one pseudoaneurysm at the aortic bifurcation. Most of the pseudoaneurysms were treated with covered stent grafts. The technical success rate was 96% and no deaths occurred during hospital stay. The mean follow up was 5.8 ± 5.5 years and 31% (8/26) experienced post-operative complications. Overall one, three, and five year event free survival rates were 87%, 78%, and 74%, respectively. Univariable logistic regression analysis revealed that pre-operative ESR ≥ 16.0 mm/h (p = .040), pre-operative glucocorticoid (GC) use ≤ 11.5 days (p = .024), pre-operative immunosuppressant use ≤ 15.5 days (p = .028), and length of proximal landing zone ≤ 1.95 cm (p = .034) were associated with a worse prognoses following endovascular treatment. Proximal oversize ≥ 9.5% (p = .074) was also regarded as a risk factor, although not statistically significant. CONCLUSION: This study further confirmed the feasibility of endovascular repair for aortic vascular BD patients. Risk factors predicting poor prognoses included elevated pre-operative ESR, insufficient pre-operative GC use or immunosuppressant use, inadequate proximal landing zone, and larger proximal oversize percentage.

An immune-related signature for optimizing prognosis prediction and treatment decision of hepatocellular carcinoma.

BACKGROUND: An immune-related gene signature (IGS) was established for discriminating prognosis, predicting benefit of immunotherapy, and exploring therapeutic options in hepatocellular carcinoma (HCC). METHODS: Based on Immune-related hub genes and The Cancer Genome Atlas (TCGA) LIHC dataset (n = 363), an immune-related gene signature (IGS) was established by least absolute shrinkage and selection operator (LASSO) analysis. The prognostic significance and clinical implications of IGS were verified in International Cancer Genome Consortium (ICGC) and Chinese HCC (CHCC) cohorts. The molecular and immune characteristics and the benefit of immune checkpoint inhibitor (ICI) therapy in IGS-defined subgroups were analyzed. In addition, by leveraging the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing datasets, we determined the potential therapeutic agents for high IGS-risk patients. RESULTS: The IGS was constructed based on 8 immune-related hub genes with individual coefficients. The IGS risk model could robustly predict the survival of HCC patients in TCGA, ICGC, and CHCC cohorts. Compared with 4 previous established immune genes-based signatures, IGS exhibited superior performance in survival prediction. Additionally, for immunological characteristics and enriched pathways, a low-IGS score was correlated with IL-6/JAK/STAT3 signaling, inflammatory response and interferon α/γ response pathways, low TP53 mutation rate, high infiltration level, and more benefit from ICI therapy. In contrast, high IGS score manifested an immunosuppressive microenvironment and activated aggressive pathways. Finally, by in silico screening potential compounds, vindesine, ispinesib and dasatinib were identified as potential therapeutic agents for high-IGS risk patients. CONCLUSIONS: This study developed a robust IGS model for survival prediction of HCC patients, providing new insights into integrating tailored risk stratification with precise immunotherapy and screening potentially targeted agents.

Identification of acetyl-CoA carboxylase alpha as a prognostic and targeted candidate for hepatocellular carcinoma.

PURPOSE: The de novo lipogenesis has been a longstanding observation in hepatocellular carcinoma (HCC). However, the prognostic value and carcinogenic roles of the enzyme Acetyl-CoA carboxylase alpha (ACACA) in HCC remains unknown. METHODS: The proteins with remarkable prognostic significance were screened out from The Cancer Proteome Atlas Portal (TCPA) database. Furthermore, the expression characteristics and prognostic value of ACACA were evaluated in multiple databases and the local HCC cohort. The loss-of-function assays were performed to uncover the potential roles of ACACA in steering malignant behaviors of HCC cells. The underlying mechanisms were conjectured by bioinformatics and validated in HCC cell lines. RESULTS: ACACA was identified as a crucial factor of HCC prognosis. Bioinformatics analyses showed that HCC patients with higher expression of ACACA protein or mRNA levels had poor prognosis. Knockdown of ACACA remarkably crippled the proliferation, colony formation, migration, invasion, epithelial-mesenchymal transition (EMT) process of HCC cells and induced the cell cycle arrest. Mechanistically, ACACA might facilitate the malignant phenotypes of HCC through aberrant activation of Wnt/ß-catenin signaling pathway. In addition, ACACA expression was associated with the dilute infiltration of immune cells including plasmacytoid DC (pDC) and cytotoxic cells by utilization of relevant database analysis. CONCLUSION: ACACA could be a potential biomarker and molecular target for HCC.

Identification of potential LncRNAs as papillary thyroid carcinoma biomarkers based on integrated bioinformatics analysis using TCGA and RNA sequencing data.

The roles and mechanisms of long non-coding RNAs (lncRNAs) in papillary thyroid cancer (PTC) remain elusive. We obtained RNA sequencing (RNA-seq) data of surgical PTC specimens from patients with thyroid cancer (THCA; n = 20) and identified differentially expressed genes (DEGs) between cancer and cancer-adjacent tissue samples. We identified 2309 DEGs (1372 significantly upregulated and 937 significantly downregulated). We performed Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment, and protein-protein interaction network analyses and screened for hub lncRNAs. Using the same methods, we analyzed the RNA-seq data from THCA dataset in The Cancer Genome Atlas (TCGA) database to identify differentially expressed lncRNAs. We identified 15 key differentially expressed lncRNAs and pathways that were closely related to PTC. Subsequently, by intersecting the differentially expressed lncRNAs with hub lncRNAs, we identified LINC02407 as the key lncRNA. Assessment of the associated clinical characteristics and prognostic correlations revealed a close correlation between LINC02407 expression and N stage of patients. Furthermore, receiver operating characteristic curve analysis showed that LINC02407 could better distinguish between cancerous and cancer-adjacent tissues in THCA patients. In conclusion, our findings suggest that LINC02407 is a potential biomarker for PTC diagnosis and the prediction of lymph node metastasis.

A Cohort Study on Deficiency of ADA2 from China.

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2), an autosomal recessive autoinflammatory disorder caused by biallelic loss-of-function variants in adenosine deaminase 2 (ADA2), has not been systemically investigated in Chinese population yet. We aim to further characterize DADA2 cases in China. METHODS: A retrospective analysis of patients with DADA2 identified through whole exome sequencing (WES) at seventeen rheumatology centers across China was conducted. Clinical characteristics, laboratory findings, genotype, and treatment response were analyzed. RESULTS: Thirty patients with DADA2 were enrolled between January 2015 and December 2021. Adenosine deaminase 2 enzymatic activity was low in all tested cases to confirm pathogenicity. Median age of disease presentation was 4.3 years and the median age at diagnosis was 7.8 years. All but one patient presented during childhood and two subjects died from complications of their disease. The patients most commonly presented with systemic inflammation (92.9%), vasculitis (86.7%), and hypogammaglobinemia (73.3%) while one patient presented with bone marrow failure (BMF) with variable cytopenia. Twenty-three (76.7%) patients were treated with TNF inhibitors (TNFi), while two (6.7%) underwent hematopoietic stem cell transplantation (HSCT). They all achieved clinical remission. A total of thirty-nine ADA2 causative variants were identified, six of which were novel. CONCLUSION: To establish early diagnosis and improve clinical outcomes, genetic screening and/or testing of ADA2 enzymatic activity should be performed in patients with suspected clinical features. TNFi is considered as first line treatment for those with vascular phenotypes. HSCT may be beneficial for those with hematological disease or in those who are refractory to TNFi.

Integrated investigation of the clinical implications and targeted landscape for RNA methylation modifications in hepatocellular carcinoma.

BACKGROUND: RNA methylation (RM) is a crucial post-translational modification (PTM) that directs epigenetic regulation. It mostly consists of N1-methyladenosine (m1A), 5-methylcytosine (m5C), N3-methylcytidine (m3C), N6-methyladenosine (m6A), and 2'-O-methylation (Nm). The "writers" mainly act as intermediaries between these modifications and associated biological processes. However, little is known about the interactions and potential functions of these RM writers in hepatocellular carcinoma (HCC). METHODS: The expression properties and genetic alterations of 38 RM writers were assessed in HCC samples from five bioinformatic datasets. Two patterns associated with RM writers were identified using consensus clustering. Then, utilizing differentially expressed genes (DEGs) from different RM subtypes, we built a risk model called RM_Score. Additionally, we investigated the correlation of RM_Score with clinical characteristics, tumor microenvironment (TME) infiltration, molecular subtypes, therapeutic response, immunotherapy effectiveness, and competing endogenous RNA (ceRNA) network. RESULTS: RM writers were correlated with TME cell infiltration and prognosis. Cluster_1/2 and gene.cluster_A/B were shown to be capable of distinguishing the HCC patients with poor prognosis after consensus and unsupervised clustering of RNA methylation writers. Additionally, we constructed RNA modification pattern-specific risk model and subdivided the cases into RM_Score high and RM_Score low subgroups. In individual cohorts or merged datasets, the high RM_Score was related to a worse overall survival of HCC patients. RM_Score also exhibited correlations with immune and proliferation related pathways. In response to anti-cancer treatments, the RM_Score had a negative correlation (drug sensitive) with drugs that focused on the MAPK/ERK and metabolism signaling, and a positive correlation (drug resistant) with compounds targeting RKT and PI3K/mTOR signaling pathway. Notably, the RM_Score was connected to the therapeutic effectiveness of PD-L1 blockage, implying that RM writers may be the target of immunotherapy to optimize clinical outcomes. Additionally, a ceRNA network was generated including 2 lncRNAs, 4 miRNAs, and 7 mRNAs that was connected to RM writers. CONCLUSIONS: We thoroughly investigated the potential functions of RNA methylation writers and established an RM_patterns-based risk model for HCC patients. This study emphasized the critical functions of RM modification in TME infiltration, targeted therapy, and immunotherapy, providing potential targets for HCC.

Tumor Organoid Model and Its Pharmacological Applications in Tumorigenesis Prevention.

Cancer is a leading cause of death and a severe threat to global public health. Organoid, as a novel 3D in vitro model, has been applied in various tumor related studies due to its apparent advantages. The organoid is mainly constructed by Matrigel-depended 3D culture system, Air-Liquid Interface (ALI) culture, and Microfluidic culture or Organ-on-chips platform. For the application in carcinogenesis studies, the organoid model may favor depicting initiative hallmarks and identifying potential intervening targets, investigating driver genes of carcinogenesis, and identifying known or unknown risk or protective factors. In this review, we discussed different organoid construction methods and their properties. We also noted that tumor organoids can portray initiative hallmarks and identify possible intervening targets, as well as explore carcinogenesis driver genes and uncover known or unknown risks or protective factors. Organoid systems have been used to identify tumor-preventive drugs such as oligomeric proanthocyanidins, Vitamin D, n-3 PUFAs, and pomegranate. The current evidence underscores the organoid model's potential importance in developing innovative tumorprevention techniques.