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.

Infliximab for parenchymal neuro-Behçet's syndrome: case series and meta-analysis.

OBJECTIVES: This study aims to evaluate the efficacy and safety of infliximab (IFX) in patients with parenchymal neuro-Behçet's syndrome (p-NBS). METHODS: We retrospectively analysed eleven p-NBS patients treated with IFX at our institution and combined them with studies from database searches for a meta-analysis. Pooled estimates of clinical response (complete and partial remission) and MRI improvement at months 3, 6, and 12 were calculated. RESULTS: One patient achieved CR and the other ten patients achieved PR at our institution. 8 studies (77 patients) were included in the meta-analysis. At 3, 6, and 12 months, 97% (95%CI 61.9-100%), 89.6% (95%CI 45.9-100%), 100% (95%CI 96.0-100%) of patients showed clinical response and 100% (95%CI 89.7-100%), 89.1% (95% CI 26.3-100%), 99.5% (95% CI 96.0-100%) of patients showed radiological improvement, respectively. Severe adverse events were observed in 7 patients. CONCLUSIONS: IFX was effective and relatively safe for p-NBS. Patients should be re-evaluated after 3 months of IFX to determine further therapy.

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.

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.

Significance of immunoglobulins synthesis with central nervous system involvement in Neuro-Behçet's disease.

OBJECTIVES: Demyelination and immunocyte-infiltrated lesions have been found in neuro-Behçet's disease (NBD) pathology. Lacking satisfying laboratory biomarkers in NBD impedes standard clinical diagnostics. We aim to explore the ancillary indicators for NBD diagnosis unveiling its potential etiology. METHODS: 28 NBD with defined diagnosis, 29 patients with neuropsychiatric lupus erythematosus, 30 central nervous system idiopathic inflammatory demyelination diseases (CNS-IIDD), 30 CNS infections, 30 cerebrovascular diseases, and 30 noninflammatory neurological diseases (NIND) were retrospectively enrolled. Immunoglobulins (Ig) in serum and cerebral spinal fluid (CSF) were detected by immunonephelometry and myelin basic protein (MBP) by quantitative enzyme-linked immunosorbent assay. RESULTS: IgA index is almost twice enhanced in NBD than NIND with an accuracy of 0.8488 in differential diagnosis, the sensitivity and specificity of which were 75.00 % and 90.00 % when the cutoff was > 0.6814. The accuracy of CSF Ig and quotient of Ig all exceed 0.90 in discerning NBD with damaged and intact blood-brain barrier (BBB). Clustering analyses divided NBD into two different phenotypes: one with BBB damage has lower Ig synthesis, the other with extra-synthesis in parenchymal sites but with intact BBB. MBP index is significantly correlated with kappa (KAP) index and lambda (LAM) index (r = 0.358, 0.575, P < 0.001), hinting the NBD pathogenesis of CNS demyelination in triggering excessive intrathecal Ig productions and humoral responses. CONCLUSIONS: IgA index acts as a potential diagnostic indicator in differentiating NBD from NIND and CNS-IIDD. Excessive immunoglobulin production induced by CNS inflammation and demyelination might be latent immunopathogenesis of NBD.

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.

Application Progress of Culturomics in the Isolated Culture of Rhizobacteria: A Review.

Comprehending the structure and function of rhizobacteria components and their regulation are crucial for sustainable agricultural management. However, obtaining comprehensive species information for most bacteria in the natural environment, particularly rhizobacteria, presents a challenge using traditional culture methods. To obtain diverse and pure cultures of rhizobacteria, this study primarily reviews the evolution of rhizobacteria culturomics and associated culture methods. Furthermore, it explores new strategies for enhancing the application of culturomics, providing valuable insights into efficiently enriching and isolate target bacterial strains/groups from the environment. The findings will help improve rhizobacteria's culturability and enrich the functional bacterial library.

Safety of an inactivated COVID-19 vaccine (CoronaVac) in children aged 7-14 years in Taizhou, China.

Our study aimed to evaluate the safety of CoronaVac, an inactivated vaccine made by Sinovac, in children aged 7-14. We conducted a parent-administered online survey to monitor adverse reactions after vaccinating children in Taizhou, China, from February 15, 2021, to January 19, 2022. 767 parents completed the survey after receiving a questionnaire via WeChat. Overall, 15.3 % (117/767) of children experienced adverse effects after the first dose, and 12.2 % (88/724) after the second. Muscle pain was the most common adverse reaction post-first dose (10.0 %), while localized pain or itching at the injection site was most common after the second dose (7.6 %). In conclusion, the vaccine has a low incidence of side effects. The mild to moderate, transient, and common nature of these effects further boosts parents' confidence in vaccinating their children.

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.

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.

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.

Communication and group size on bank run games.

This study examines the impact of communication and group size on bank run games, with a strategic focus on three-player games. In the baseline treatment group, communication is not allowed in two-player and three-player games. The main treatment consists of costless communication, cheap communication, and costly communication. The sender's action becomes more predictable with the increasing communication costs due to a lack of incentives to deceive. We find that in the non-cooperative, two-player bank run game, communication fosters cooperative behavior with the learning effect in the repeated interaction. However, coordination is far more difficult to achieve with Nash Pareto dominant equilibrium in three-player games due to its complexity in decision-making in larger groups. The ultimate result presents the limitation of communication as an efficiency-enhancing mechanism. A public recommendation is that policymakers should increase public transparency and ensure public confidence in banking systems to mitigate the risks and uncertainty of bank runs. In sum, the study presents the following:•In a three-player bank run game, communication is less effective than in a two-player scenario.•Policymakers should ensure public confidence and increase public transparency of banking systems.

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.

Shelterin Dysfunction Promotes CD4+ T Cell Senescence in Behçet's Disease.

OBJECTIVES: To investigate the potential role of shelterin dysfunction in naïve CD4+ T cells in the pathogenesis of Behçet's disease (BD). METHODS: Naïve CD4+ T cells were isolated from 40 BD patients and 40 sex- and age-matched healthy controls (HC). Senescent profiles, shelterin subunits expression, telomere length, telomerase activity, and critical DNA damage response (DDR) was evaluated. TRF2 silencing was conducted for further validation. RESULTS: Compared to HC, BD patients had significantly decreased naïve CD4+ T cells, increased cell apoptosis, senescence, and productions of TNF-α and IFN-γ upon activation. Notably, BD naïve CD4+ T cells had shortened telomere, impaired telomerase activity, and expressed lower levels of shelterin subunits TRF2, TIN2, and RAP1. Furthermore, BD naïve CD4+ T cells exhibited significantly increased DDR, evidenced by elevated phosphorylated ataxia telangiectasia (AT) mutated (pATM), pp53, and p21. Finally, TRF2-silencing markedly upregulated DDR, apoptosis, and proinflammatory cytokines production in HC naïve CD4+ T cells. CONCLUSION: Our study demonstrated that TRF2 deficiency in BD naïve CD4+ T cells promoted cell apoptosis and senescence, leading to proinflammatory cytokines overproduction. Therefore, restoring TRF2 might be a promising therapeutic strategy for BD.

Identifying Dental Pulp Stem Cell as A Novel Therapeutic Strategy for Digestive Diseases.

Mesenchymal stem cells (MSCs) have been identified as potential therapeutics for various diseases. In contrast to other sources of MSCs, dental stem cells (DSCs) have received increased attention due to their high activity and easy accessibility. Among them, dental pulp stem cells (DPSCs) exhibit superior self-renewal, multipotency, immunomodulatory, and regenerative capacities. Following their inspiring performance in animal models and clinical trials, DPSCs show pharmacological potential in regenerative medicine. In this review, we have generalized the sources, heterogeneity, and biological characteristics of DPSCs, as well as compared them with other types of dental stem cells. In addition, we summarized the application of DPSCs in digestive diseases (such as liver, esophageal, and intestinal diseases), highlighting their regenerative and pharmacological potential based on the existing preclinical and clinical evidence. Specifically, DPSCs can be> home to injured or inflamed tissues and exert repair and regeneration functions by> facilitating immune regulation, anti-inflammation, and directional differentiation. Although DPSCs have a rosy prospect, future studies should handle the underlying drawbacks and pave the way for the identification of DPSCs as novel regenerative medicine.

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.

Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis.

BACKGROUND: Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. METHODS: The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-ß1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. RESULTS: TGF-ß1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-ß1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). CONCLUSION: Pd-MSCs-EVs ameliorated TGF-ß1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis.