Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

Innate lymphoid cell subsets in the pathogenesis of primary biliary cholangitis.

BACKGROUND AND AIM: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by destructive lymphocytic cholangitis and specific anti-mitochondrial antibodies. Innate lymphoid cells (ILCs) have been reported to play a role in liver homeostasis and autoimmunity. METHODS: We evaluated the features of peripheral ILC1s and ILC3 in patients with PBC and hepatic ILC1 and ILC3 in two different PBC mouse models (dominant-negative transforming growth factor-beta receptor II [dnTGFßRII] and 2-octynoic acid-bovine serum albumin [2OA-BSA]). RESULTS: A total of 115 patients and 18 healthy controls were enrolled in the study. Decreased circulating ILC1/3s were observed in early-stage PBC patients, and the numbers of ILC1/3s were negatively correlated with specific parameters and the proportion of T-helper (Th) 1 and Th17 cells. Reduced numbers of ILC1s were observed in PBC mouse models with different etiologies. ILC1-deficient mice had more severe hepatic inflammation after inducing the 2OA-BSA model. Continuous low-dose injections of lipopolysaccharide (LPS) reduced ILC1 levels in mice, consistent with the lower level of ILC1s in PBC patients with high LPS (> 50 ng/mL), and aggravated hepatic lymphocyte infiltration. CONCLUSION: Patients with PBC had decreased ILC1s, which were negatively correlated with CD4+ T cells. Deficient ILC1 populations led to disease exacerbations in mice. Our results indicated that ILC1s may participate in the pathogenesis of PBC.

Double hydrogen bonding-induced compact H-type π-π stacking enhancing rapid carrier transfer in perylene diimide supramolecules achieving high oxygen evolution performance.

Perylene diimides (PDI) are widely used in photocatalytic oxygen evolution due to their deep valence band potentials. Here, we report the synthesis of a unique supramolecular photocatalyst (designated s-PDI-P1) by introducing hydroxyl and carboxyl groups at the imide position of PDI. This modification allows the formation of intermolecular double hydrogen bond structures between the hydroxyl groups, oxygen atoms on the perylene cores and the carboxyl groups. The resulting double hydrogen bonding structures reduce lateral slip and promote the formation of supramolecular structures with H-type π-π stacking. In addition, the intermolecular hydrogen bonding interactions between the hydroxyl groups and the oxygen atoms on the perylene cores bring the PDI molecules closer together, enhancing the conjugation of the PDI supramolecules and facilitating the formation of ultrathin nanosheet-like structures. In this study, we successfully constructed ultrathin nanosheets of the supramolecular photocatalyst s-PDI-P1 with a compact H-type π-π stacking structure, which exhibited enhanced charge transfer capability, shorter charge migration distance, and achieved a high photocatalytic oxygen evolution rate of 3.23 mmolg-1h-1. These results highlight the potential of intermolecular double hydrogen bond structures to improve the separation and migration driving force of photogenerated charges, thus providing a novel design strategy for organic photocatalysts.

Growth patterns of caudal fin rays are informed by both external signals from the regenerating organ and remembered identity autonomous to the local tissue.

Regenerating tissues must remember or interpret their spatial position, using this information to restore original size and patterning. The external skeleton of the zebrafish caudal fin is composed of 18 rays; after any portion of the fin is amputated, position-dependent regenerative growth restores each ray to its original length. We tested for transcriptional differences during regeneration of proximal versus distal tissues and identified 489 genes that differed in proximodistal expression. Thyroid hormone directs multiple aspects of ray patterning along the proximodistal axis, and we identified 364 transcripts showing a proximodistal expression pattern that was dependent on thyroid hormone context. To test what aspects of ray positional identity are directed by extrinsic cues versus remembered identity autonomous to the tissue itself, we transplanted distal portions of rays to proximal environments and evaluated regeneration within the new location. While neighboring proximal tissue showed robust expression of scpp7, a transcript with thyroid-regulated proximal enrichment, regenerating rays originating from transplanted distal tissue showed reduced (distal-like) expression during outgrowth. These distal-to-proximal transplants regenerated far beyond the length of the graft itself, indicating that cues from the proximal environment promoted additional growth. Nonetheless, these transplants initially regenerated at a much slower rate compared to controls, suggesting retained memory of distal identity. This early growth retardation caused rays that originated from transplants to become noticeably shorter than their native neighboring rays. While several aspects of fin ray morphology (bifurcation, segment length) were found to be determined by the environment, regeneration speed and ray length are remembered autonomously by tissues, persisting across multiple rounds of amputation and regeneration.

Prognostic significance of liver stiffness in patients with primary biliary cholangitis: validation of Baveno VII criteria.

BACKGROUND: The role of liver stiffness measurements (LSM) in patients with primary biliary cholangitis (PBC) remains to be further elucidated. AIMS: To clarify the prognostic role of LSM and to validate the "novel concepts" proposed by the Baveno VII Working Group. METHODS: An analysis of the prognostic significance of LSM was performed involving 672 patients. RESULTS: LSM and ΔLSM/ΔT were independent risk factors for liver decompensation, liver transplantation, or liver-related death (primary outcomes, p < 0.001, both). A rule of 5 kPa for LSM (10-15-20 kPa) could be used to denote progressively higher relative risks of primary outcomes. Patients with LSM < 10 kPa have a negligible 3-year risk of primary outcomes (< 1%). Cut-off values of 10 and 15 kPa can be used to classify PBC patients into low-, medium-, and high-risk groups. A clinically significant decrease in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially reduced risk of primary outcomes (p < 0.05, all), which can be defined as a decrease in LSM of > - 20% associated with LSM < 20 kPa or any decrease to LSM < 10 kPa. A clinically significant increase in LSM, evaluated at 6, 12, or 24 months elastography tests, was associated with a substantially raised risk of primary outcomes (p < 0.05, all), which can be defined as an increase in LSM of ≥ + 20% or any increase to LSM ≥ 15 kPa. CONCLUSIONS: LSM can be used to monitor disease progression and predict long-term prognosis in patients with PBC.

Integrative bioinformatics analysis and experimental validation of key biomarkers for risk stratification in primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is an autoimmune liver disease, whose etiology is yet to be fully elucidated. Currently, ursodeoxycholic acid (UDCA) is the only first-line drug. However, 40% of PBC patients respond poorly to it and carry a potential risk of disease progression. So, in this study, we aimed to explore new biomarkers for risk stratification in PBC patients to enhance treatment. METHODS: We first downloaded the clinical characteristics and microarray datasets of PBC patients from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis. Hub genes were further validated in multiple public datasets and PBC mouse model. Furthermore, we also verified the expression of the hub genes and developed a predictive model in our clinical specimens. RESULTS: A total of 166 DEGs were identified in the GSE79850 dataset, including 95 upregulated and 71 downregulated genes. Enrichment analysis indicated that DEGs were significantly enriched in inflammatory or immune-related process. Among these DEGs, 15 risk-related genes were recognized and further validated in the GSE119600 cohort. Then, TXNIP, CD44, ENTPD1, and PDGFRB were identified as candidate hub genes. Finally, we proceeded to the next screening with these four genes in our serum samples and developed a three-gene panel. The gene panel could effectively identify those patients at risk of disease progression, yielding an AUC of 0.777 (95% CI, 0.657-0.870). CONCLUSIONS: In summary, combining bioinformatics analysis and experiment validation, we identified TXNIP, CD44, and ENTPD1 as promising biomarkers for risk stratification in PBC patients.

Association of family sequence similarity gene 13A gene polymorphism and interstitial lung disease susceptibility: A systematic review and meta-analysis.

BACKGROUND: Among present reports, the T/G allelic variation at the rs2609255 locus of the family sequence similarity gene 13A (FAM13A) was considerable associated with susceptibility to interstitial lung diseases (ILDs). In this study, we summarized relevant studies and applied a meta-analysis to explore whether the polymorphism of rs2609255 site of the FAM13A gene can be utilized to predict susceptibility to idiopathic pulmonary fibrosis (IPF) patients or rheumatoid arthritis-associated interstitial lung disease (RA-ILD) or silicosis patients in different populations for the first time. METHODS: We compared the frequency of G allele on rs2609255 site of FAM13A between the control subjects and IPF or RA-ILD or silicosis patients from different races by using meta-analysis. Nine studies were involved in this meta-analysis, including five IPF studies, two RA-ILD studies, and two silicosis studies, and containing 14 subgroups. We conducted separate meta-analyses for different races. RESULTS: In all individuals, a substantial link between the G allele of the FAM13A rs2609255 polymorphism and IPF (OR: 1.47, 95% CI: 1.33-1.63, p < 0.00001) was indicated. After dividing by ethnicity, the G allele was illustrated to be considerable correlation with IPF in Asian (OR: 2.63, 95% CI: 1.81-3.81, p < 0.00001) and with RA-ILD individuals (OR: 3.27, 95% CI: 1.26-8.49, p = 0.01). Conversely, there was no correlation with the G allele and IPF in European individuals (OR: 1.27, 95% CI: 0.89-1.83, p = 0.13) or silicosis in Chinese individuals (OR: 1.20, 95% CI: 0.99-1.46, p = 0.07). CONCLUSION: This is the first meta-analysis that provides evidence that the rs2609255 of FAM13A might increase susceptibility to RA-ILD, and IPF especially in Asian but not in European individuals, and not be correlated with silicosis in Chinese individuals, which indicated the differences in susceptibility to disease by race were noteworthy.

Magnetometer-Detected Nuclear Magnetic Resonance of Photochemically Hyperpolarized Molecules.

Photochemically induced dynamic nuclear polarization (photo-CIDNP) enables nuclear spin ordering by irradiating samples with light. Polarized spins are conventionally detected via high-field chemical-shift-resolved NMR (above 0.1 T). In this Letter, we demonstrate in situ low-field photo-CIDNP measurements using a magnetically shielded fast-field-cycling NMR setup detecting Larmor precession via atomic magnetometers. For solutions comprising mM concentrations of the photochemically polarized molecules, hyperpolarized 1H magnetization is detected by pulse-acquired NMR spectroscopy. The observed NMR line widths are about 5 times narrower than normally anticipated in high-field NMR and are systematically affected by light irradiation during the acquisition period, reflecting a reduction of the transverse relaxation time constant, T2*, on the order of 10%. Magnetometer-detected photo-CIDNP spectroscopy enables straightforward observation of spin-chemistry processes in the ambient field range from a few nT to tens of mT. Potential applications of this measuring modality are discussed.

Clinical characteristics of hypersensitivity pneumonitis: non-fibrotic and fibrotic subtypes.

BACKGROUND: The presence of fibrosis is a criterion for subtype classification in the newly updated hypersensitivity pneumonitis (HP) guidelines. The present study aimed to summarize differences in clinical characteristics and prognosis of non-fibrotic hypersensitivity pneumonitis (NFHP) and fibrotic hypersensitivity pneumonitis (FHP) and explore factors associated with the presence of fibrosis. METHODS: In this prospective cohort study, patients diagnosed with HP through a multidisciplinary discussion were enrolled. Collected data included demographic and clinical characteristics, laboratory findings, and radiologic and histopathological features. Logistic regression analyses were performed to explore factors related to the presence of fibrosis. RESULTS: A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP patients and 115 (56.9%) FHP patients. Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP. Serum levels of carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 153, gastrin-releasing peptide precursor, squamous cell carcinoma antigen, and antigen cytokeratin 21-1, and count of bronchoalveolar lavage (BAL) eosinophils were higher in the FHP group than in the NFHP group. BAL lymphocytosis was present in both groups, but less pronounced in the FHP group. Multivariable regression analyses revealed that older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors for the development of FHP. Twelve patients developed adverse outcomes, with a median survival time of 12.5 months, all of whom had FHP. CONCLUSIONS: Older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors associated with the development of FHP. Prognosis of patients with NFHP was better than that of patients with FHP. These results may provide insights into the mechanisms of fibrosis in HP.

Thyroid hormone regulates proximodistal patterning in fin rays.

Processes that regulate size and patterning along an axis must be highly integrated to generate robust shapes; relative changes in these processes underlie both congenital disease and evolutionary change. Fin length mutants in zebrafish have provided considerable insight into the pathways regulating fin size, yet signals underlying patterning have remained less clear. The bony rays of the fins possess distinct patterning along the proximodistal axis, reflected in the location of ray bifurcations and the lengths of ray segments, which show progressive shortening along the axis. Here, we show that thyroid hormone (TH) regulates aspects of proximodistal patterning of the caudal fin rays, regardless of fin size. TH promotes distal gene expression patterns, coordinating ray bifurcations and segment shortening with skeletal outgrowth along the proximodistal axis. This distalizing role for TH is conserved between development and regeneration, in all fins (paired and medial), and between Danio species as well as distantly related medaka. During regenerative outgrowth, TH acutely induces Shh-mediated skeletal bifurcation. Zebrafish have multiple nuclear TH receptors, and we found that unliganded Thrab-but not Thraa or Thrb-inhibits the formation of distal features. Broadly, these results demonstrate that proximodistal morphology is regulated independently from size-instructive signals. Modulating proximodistal patterning relative to size-either through changes to TH metabolism or other hormone-independent pathways-can shift skeletal patterning in ways that recapitulate aspects of fin ray diversity found in nature.

Exploring construction workers' brain connectivity during hazard recognition: a cognitive psychology perspective.

Monitoring brain activity is a novel development for hazard recognition in the construction industry. However, very few empirical studies have investigated the causal connections within the brain. This study aimed to explore the brain connectivity of construction workers during hazard recognition. Electroencephalogram data were collected from construction workers to perform image-based hazard recognition tasks. The Granger causality-based adaptive directed transfer function was used to simulate directed and time-variant information flow across the observed brain activity from the perspective of cognitive psychology. The results suggested a top-down modulation of behavioral goals originating from the dorsal attention network during hazard relocation. The sensory cortex predominantly serves as the information outlet center and interacts extensively with the frontal and visual cortices, reflecting a top-down attention reorientation mechanism for processing threatening stimuli. Our findings of brain effective connectivity supplement new evidence underpinning parallel distributed processing theory for workplace hazard recognition.

Erratum: Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition: Erratum.

[This corrects the article DOI: 10.7150/thno.61085.].

Biomagnetic signals recorded during transcranial magnetic stimulation (TMS)-evoked peripheral muscular activity.

Transcranial magnetic stimulation (TMS) has widespread clinical applications from diagnosis to treatment. We combined TMS with non-contact magnetic detection of TMS-evoked muscle activity in peripheral limbs to explore a new diagnostic modality that enhances the utility of TMS as a clinical tool by leveraging technological advances in magnetometry. We recorded measurements in a regular hospital room using an array of optically pumped magnetometers (OPMs) inside a portable shield that encloses only the forearm and hand of the subject. We present magnetomyograms (MMG)s of TMS-evoked movement in a human hand, together with a simultaneous surface electromyograph (EMG) data. The biomagnetic signals recorded in the MMG provides detailed spatial and temporal information that is complementary to that of the electric signal channels. Moreover, we identify features in the magnetic recording beyond that of the EMG. This system demonstrates the value of biomagnetic signals in TMS-based clinical approaches and widens its availability and practical potential.

Endogenous Follistatin-like 1 guarantees the immunomodulatory properties of mesenchymal stem cells during liver fibrotic therapy.

BACKGROUND: Mesenchymal stem cell (MSC) therapy has been shown to be a promising option for liver fibrosis treatment. However, critical factors affecting the efficacy of MSC therapy for liver fibrosis remain unknown. Follistatin-like 1 (FSTL1), a TGF-ß-induced matricellular protein, is documented as an intrinsic regulator of proliferation and differentiation in MSCs. In the present study, we characterized the potential role of FSTL1 in MSC-based anti-fibrotic therapy and further elucidated the mechanisms underlying its action. METHODS: Human umbilical cord-derived MSCs were characterized by flow cytometry. FSTL1low MSCs were achieved by FSTL1 siRNA. Migration capacity was evaluated by wound-healing and transwell assay. A murine liver fibrotic model was created by carbon tetrachloride (CCl4) injection, while control MSCs or FSTL1low MSC were transplanted via intravenous injection 12 weeks post CCl4 injection. Histopathology, liver function, fibrosis degree, and inflammation were analysed thereafter. Inflammatory cell infiltration was evaluated by flow cytometry after hepatic nonparenchymal cell isolation. An MSC-macrophage co-culture system was constructed to further confirm the role of FSTL1 in the immunosuppressive capacity of MSCs. RNA sequencing was used to screen target genes of FSTL1. RESULTS: FSTL1low MSCs had comparable gene expression for surface markers to wildtype but limited differentiation and migration capacity. FSTL1low MSCs failed to alleviate CCl4-induced hepatic fibrosis in a mouse model. Our data indicated that FSTL1 is essential for the immunosuppressive action of MSCs on inflammatory macrophages during liver fibrotic therapy. FSTL1 silencing attenuated this capacity by inhibiting the downstream JAK/STAT1/IDO pathway. CONCLUSIONS: Our data suggest that FSTL1 facilitates the immunosuppression of MSCs on macrophages and that guarantee the anti-fibrotic effect of MSCs in liver fibrosis.

Deep Image Watermarking to JPEG Compression Based on Mixed-Frequency Channel Attention.

Deep blind watermarking algorithms based on an end-to-end encoder-decoder architecture have recently been extensively studied as an important technology for protecting copyright. However, none of the existing algorithms can fully utilize the channel features of the image to improve the robustness against JPEG compression while obtaining high visual quality. Therefore, we propose firstly a mixed-frequency channel attention method in the encoder, which utilizes different frequency components of the 2D-DCT domain as weight coefficients during channel squeezing and excitation. Its essence is to suppress the useless feature maps and enhance the feature maps suitable for watermarking embedding by introducing frequency analysis in the channel dimension. The experimental results indicate that the PSNR of our method reaches over 38 and the BER is less than 0.01% under the JPEG compression with quality factor Q = 50. Besides, the proposed framework also obtains excellent robustness for a variety of common distortions, including Gaussian filter, crop, crop out, and drop out.

Relayed hyperpolarization for zero-field nuclear magnetic resonance.

Zero- to ultralow-field nuclear magnetic resonance (ZULF NMR) is a rapidly developing form of spectroscopy that provides rich spectroscopic information in the absence of large magnetic fields. However, signal acquisition still requires a mechanism for generating a bulk magnetic moment for detection, and the currently used methods only apply to a limited pool of chemicals or come at prohibitively high cost. We demonstrate that the parahydrogen-based SABRE (signal amplification by reversible exchange)-Relay method can be used as a more general means of generating hyperpolarized analytes for ZULF NMR by observing zero-field J-spectra of [13C]-methanol, [1-13C]-ethanol, and [2-13C]-ethanol in both 13C-isotopically enriched and natural abundance samples. We explore the magnetic field dependence of the SABRE-Relay efficiency and show the existence of a second maximum at 19.0 ± 0.3 mT. Despite presence of water, SABRE-Relay is used to hyperpolarize ethanol extracted from a store-bought sample of vodka (%PH ~ 0.1%).

Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages.

BACKGROUND: Despite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs. METHODS: Carbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot. RESULTS: MSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis. CONCLUSIONS: These findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis.

Dihydromyricetin Alleviates Pulmonary Fibrosis by Regulating Abnormal Fibroblasts Through the STAT3/p-STAT3/GLUT1 Signaling Pathway.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with a poor prognosis. Although dihydromyricetin (DHM), extracted from vine tea and other Ampelopsis species, has been proven to have anti-inflammatory and antioxidant functions, the effects of DHM on IPF remain unclear. Methods: The effects of DHM on the differentiation, migration, proliferation, and respiratory functions of primary mouse lung fibroblasts (PMLFs) and primary human lung fibroblasts (PHLFs) were detected by western blotting, the Transwell assay, EdU staining, and the Mito Stress test. Then, the impacts of DHM on bleomycin (BLM)-induced pulmonary fibrosis were evaluated by pathological staining, western blotting, and coimmunofluorescence staining. The signaling pathway influenced by DHM was also investigated. Results: DHM could regulate the differentiation of fibroblasts to myofibroblasts and suppress the abnormal migration, proliferation, and respiratory functions of myofibroblasts induced by TGF-ß1 or myofibroblasts from IPF patients. DHM could also alleviate pulmonary fibrosis induced by BLM. All these effects were achieved by regulating the STAT3/p-STAT3/GLUT1 signaling pathway. Conclusion: DHM could regulate the abnormal functions of myofibroblasts induced by TGF-ß1 and myofibroblasts from IPF patients and alleviate pulmonary fibrosis induced by BLM; thus, DHM might be a candidate medicinal treatment for IPF.

A novel immune checkpoint-related gene signature for hepatocellular carcinoma to predict clinical outcomes and therapeutic response.

Immune checkpoint genes (ICGs) have recently been proven to perform instrumental functions in the maintenance of immune homeostasis and represent a promising therapeutic strategy; however, their expression patterns and prognostic values are not fully elucidated in hepatocellular carcinoma (HCC). In this investigation, we focused on establishing and validating a prognostic gene signature to facilitate decision-making in clinical practice. Clinical information, as well as transcriptome data, was obtained from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox method were employed to build a multi-gene signature in the TCGA database, while the ICGC database was used for validation. Subsequently, utilizing the six-gene signature, we were able to categorize patients into high- and low-risk groups. In two cohorts, survival analysis findings revealed a dismal outlook for the high-risk group. The receiver operating characteristic curves were utilized to estimate the gene signature's prediction ability. Moreover, correlation analysis showed high-risk group was linked to advanced pathological stage, infiltration of immune cells and therapeutic response. In summary, this unique gene profile might serve not only as a useful prognostic indicator but also as a marker of therapy responsiveness in HCC.

Bioinformatics Analysis Combined With Experiments Predicts PUDP as a Potential Prognostic Biomarker for Hepatocellular Carcinoma Through Its Interaction With Tumor Microenvironment.

Hepatocellular carcinoma (HCC) is one of the deadliest tumors in the world and is notorious for poor prognosis. There is mounting evidence that pseudouridine performs key functions in the initiation and progression of several cancers. A previous study demonstrated that Pseudouridine 5'-phosphatase (PUDP) may be a novel prognostic biomarker in colorectal cancer. However, in the past, we have paid little attention to PUDP and we are still not clear about its function and role in cancer. In this study, a pan-cancer analysis of PUDP expression and prognosis was performed firstly using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data and we found that PUDP may be a potential oncogene for HCC. Then the most potential upstream microRNA contributing to PUDP was identified as let-7c-5p through expression analysis, correlation analysis, and survival analysis. Subsequently, the result of single cell RNA sequencing (scRNA-seq) demonstrated that PUDP was significantly highly expressed on malignant cells. In addition, there are significantly positive correlations between PUDP and tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression, especially with tumor-promoting immune cells such as T cell regulatory (Treg), Myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF). Moreover, we found the methylation level of three loci was positively correlated with PUDP expression and four loci were negatively correlated. 15 pairs of HCC and normal adjacent tissues from HCC patients who were treated at our center were used to verify the results of the bioinformatics analysis and the results of experiments are similar to the bioinformatics analysis. Our study demonstrated that HCC patients with high PUDP expression are less likely to benefit from immunotherapy, and in addition, we explored the relationship between PUDP and anticancer drugs. Finally, we explored the clinical relevance of PUDP, identified PUDP as an independent risk factor for HCC patients and constructed a prognostic model, used International Cancer Genome Consortium (ICGC) data to do external validation. Collectively, our study demonstrated that high expression of PUDP suggested a poor prognosis and low response to immunotherapy, providing new insight into the treatment and prognosis of HCC.