Characterizing mitochondrial features in osteoarthritis through integrative multi-omics and machine learning analysis.

Purpose: Osteoarthritis (OA) stands as the most prevalent joint disorder. Mitochondrial dysfunction has been linked to the pathogenesis of OA. The main goal of this study is to uncover the pivotal role of mitochondria in the mechanisms driving OA development. Materials and methods: We acquired seven bulk RNA-seq datasets from the Gene Expression Omnibus (GEO) database and examined the expression levels of differentially expressed genes related to mitochondria in OA. We utilized single-sample gene set enrichment analysis (ssGSEA), gene set enrichment analysis (GSEA), and weighted gene co-expression network analysis (WGCNA) analyses to explore the functional mechanisms associated with these genes. Seven machine learning algorithms were utilized to identify hub mitochondria-related genes and develop a predictive model. Further analyses included pathway enrichment, immune infiltration, gene-disease relationships, and mRNA-miRNA network construction based on these hub mitochondria-related genes. genome-wide association studies (GWAS) analysis was performed using the Gene Atlas database. GSEA, gene set variation analysis (GSVA), protein pathway analysis, and WGCNA were employed to investigate relevant pathways in subtypes. The Harmonizome database was employed to analyze the expression of hub mitochondria-related genes across various human tissues. Single-cell data analysis was conducted to examine patterns of gene expression distribution and pseudo-temporal changes. Additionally, The real-time polymerase chain reaction (RT-PCR) was used to validate the expression of these hub mitochondria-related genes. Results: In OA, the mitochondria-related pathway was significantly activated. Nine hub mitochondria-related genes (SIRT4, DNAJC15, NFS1, FKBP8, SLC25A37, CARS2, MTHFD2, ETFDH, and PDK4) were identified. They constructed predictive models with good ability to predict OA. These genes are primarily associated with macrophages. Unsupervised consensus clustering identified two mitochondria-associated isoforms that are primarily associated with metabolism. Single-cell analysis showed that they were all expressed in single cells and varied with cell differentiation. RT-PCR showed that they were all significantly expressed in OA. Conclusion: SIRT4, DNAJC15, NFS1, FKBP8, SLC25A37, CARS2, MTHFD2, ETFDH, and PDK4 are potential mitochondrial target genes for studying OA. The classification of mitochondria-associated isoforms could help to personalize treatment for OA patients.

Initial timing of alfalfa hay supplementation manipulates blood parameters, rumen gene expression, and epithelial microbiota in pre-weaning lambs.

The present study aimed to investigate the impact of initiating alfalfa supplementation at either 14 or 42 days of age on growth performance, blood parameters, rumen tissue gene expression, and epithelial microbiota in pre-weaning lambs. A total of 42 seven-day-old male Hu lambs (3.88 ± 0.92 kg) were selected for this study. After 7 d of adjustment period, six lambs were slaughtered at 14 d of age to establish a baseline control. The remaining 36 lambs were randomly allocated to two treatment groups, every three lambs were considered a unit, including fed milk replacer, starter pellets, and either alfalfa hay fed at 14 (EAF) or 42 d of age (LAF). Body weight and feed intake were recorded for lamb until 70 d of age. Blood samples, rumen tissue samples, and epithelial microbiota samples were collected from the lambs at 42, 56, and 70 d of age. The results indicated that average daily gain, starter intake, and total dry matter intake were greater in the EAF group compared to the LAF group from 14 to 42 d of age (P < 0.01), but no significant differences from 43 to 70 d of age or during the entire trial. Treatment and age interactively affected the alfalfa intake (P = 0.02) from 43 to 70 d of age. The concentration of serum immunoglobulin A (IgA) (P < 0.01) and the expression of the rumen gene insulin-like growth factor 1 (P < 0.01) were greater in the EAF group compared to the LAF group at 42 d of age. Furthermore, the concentrations of alkaline phosphatase (P = 0.03), albumin (P < 0.01), total protein (P = 0.03), urea (P = 0.04), lipopolysaccharide (P < 0.01), ß-hydroxybutyric acid (P = 0.02), interleukin-1ß (IL-1ß) (P < 0.01), IL-4 (P < 0.01), and tumor necrosis factor α (P < 0.01) were affected by age. The abundance of Prevotella was lower (P < 0.05), whereas Megasphaera (P < 0.05) was greater in the EAF group compared to the LAF group at 42 d of age. The early addition of alfalfa promotes rumen epithelial microbiota colonization. In conclusion, this study demonstrated that alfalfa provision at 14 d of age promotes growth performance in lambs, but this effect disappeared at 43 to 70 d of age. Moreover, provision of alfalfa at 14 d of age enhances the immune response, promotes rumen tissue cell proliferation, and affects dynamical changes of rumen epithelial microbiota. Meanwhile, our findings showed that the rumen undergoes significant physiological challenges during the transition from a liquid diet to a solid diet.

The diagnostic value of [18F]FAPI-42 PET/CT for pulmonary artery masses: comparison with [18F]FDG PET/CT.

OBJECTIVES: To investigate the potential utility of [18F]fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) for evaluating pulmonary artery (PA) masses, and compare it with [18F]fluorodeoxyglucose (FDG) PET/CT. METHODS: Participants with clinically suspected PA malignancy were prospectively enrolled and underwent dual-tracer PET/CT ([18F]FAPI-42 and [18F]FDG) imaging. Visual analysis and semi-quantitative parameters were compared between the two types of radiotracers. The tissue specimen underwent immunohistochemical staining to verify FAP expression in the tissue. RESULTS: Thirty-three patients (18 males/15 females; mean age 53.1 ± 15.4 years) were enrolled. All 21 patients with malignant PA masses were FDG-positive (100%), whereas 20 out of 21 patients were FAPI-positive (95.2%). All 12 patients with benign PA masses were both negative in FDG and FAPI PET. The mean maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) of FAPI and FDG in malignant PA masses were significantly higher than those of benign masses. Although there was no significant difference in SUVmax between FDG and FAPI in malignant PA masses (11.36 vs. 9.18, p = 0.175), the TBR (liver) and TBR (left ventricle) were more favorable for FAPI than for FDG (13.04 vs. 5.17, p < 0.001); (median: 7.75 vs. 2.75, p = 0.007). Immunohistochemical analysis (n = 16) validated that the level of FAP expression corresponded strongly to the uptake of FAPI in PET/CT scans (rs = 0.712, p = 0.002). For clinical management, FAPI PET found more metastatic lesions than FDG PET in 4 patients, with 2 patients upgrading and 1 patient changing treatment decisions. CONCLUSIONS: FAPI PET/CT is feasible in the diagnosis of PA masses. Although not superior to FDG PET/CT, FAPI PET/CT showed better target-to-background contrast. CLINICAL RELEVANCE STATEMENT: This study found that FAPI PET/CT is not superior to FDG PET/CT in diagnosing PA masses, but FAPI PET/CT displays better target-to-background contrast and more positive lesions, which may help improve disease management. KEY POINTS: Pulmonary malignancies lack specificity in clinical manifestations, laboratory tests, and routine imaging examinations. FAPI PET/CT is not diagnostically better than FDG PET/CT but displays better target-to-background contrast and more positive lesions. Dual-tracer PET/CT ([18F]FAPI-42 and [18F]FDG) imaging improves clinical management of pulmonary artery masses.

Alfalfa supplementation timing changes the rumen archaeal and fungal community composition and colonization in pre-weaning lambs.

The establishment of the rumen microbiota plays an important role in the rumen development. However, little is known about the effects of alfalfa supplementation time on rumen microbiota establishment. Here, a total of 42 Hu lambs, seven-day-old, were chosen for the study. After a week of adjustment, six lambs were sacrificed to establish a baseline. The remaining 36 lambs were randomly split into two groups: one receiving alfalfa hay at 14 days (EAF), the other at 42 days (LAF), both groups received milk replacer and starter pellets. Introducing alfalfa at 14 days of age significantly improved total dry matter intake between 28 and 42 days (p = 0.04) and average daily gain from both 14 to 28 days (p = 0.04) and 28 to 42 days (p < 0.01), but this effect disappears from 56 to 70 days (p > 0.05). At 42 days, the abundances of Naganishia, Ascochyta, and Neosetophoma in the EAF group were significantly higher (p < 0.05) than those in the LAF group (17.8% vs. 3.97, 10.89% vs. 1.77, and 1.27% vs. 0.09%, respectively). At 56 days, the abundances of Ascochyta, Wallemia, and Aspergillus in the EAF group were significantly lower (p < 0.05) than in the LAF group (3.53% vs. 16.40, 8.78% vs. 18.89, and 2.14% vs. 4.69%). At 70 days, Aspergillus abundance in the EAF group was significantly higher (p < 0.05) than in the LAF group (2.69% vs. 0.85%). The LEfSe analysis showed that Methanobrevibacter_smithii was the archaeal biomarker at 14 days in both groups. Methanobrevibacter_sp_AbM4 was enriched at 56 days in the LAF group. Compared to the LAF group, the specific fungal biomarkers in the EAF group included Sporobolomyces and Bullera at 14 days, Naganishia, Didymella, Cleistothelebolus, and Alloleptosphaeria at 42 days, Ascochyta, Neoascochyta, and Alfaria at 70 days. Correlation analysis results showed strong patterns of association both within and between archaea and fungi, which were influenced by alfalfa supplementation time. In summary, alfalfa supplementation at 14 days of age promotes the growth performance of lambs before weaning, and alfalfa supplementation timing significantly affects rumen archaeal and fungal communities and dynamical changes.

The comprehensive landscape of prognosis, immunity, and function of the GLI family by pan-cancer and single-cell analysis.

The Hedgehog (Hh) signaling pathway has been implicated in the pathogenesis of various cancers. However, the roles of the downstream GLI family (GLI1, GLI2, and GLI3) in tumorigenesis remain elusive. This study aimed to unravel the genetic alterations of GLI1/2/3 in cancer and their association with the immune microenvironment and related signaling pathways. Firstly, we evaluated the expression profiles of GLI1/2/3 in different cancer types, analyzed their prognostic and predictive values, and assessed their correlation with tumor-infiltrating immune cells. Secondly, we explored the relationships between GLI1/2/3 and genetic mutations, epigenetic modifications, and clinically relevant drugs. Finally, we performed enrichment analysis to decipher the underlying mechanisms of GLI1/2/3 in cancer initiation and progression. Our results revealed that the expression levels of GLI1/2/3 were positively correlated in most cancer tissues, suggesting a cooperative role of these factors in tumorigenesis. We also identified tissue-specific expression patterns of GLI1/2/3, which may reflect the distinct functions of these factors in different cell types. Furthermore, GLI1/2/3 expression displayed significant associations with poor prognosis in several cancers, indicating their potential as prognostic biomarkers and therapeutic targets. Importantly, we found that GLI1/2/3 modulated the immune microenvironment by regulating the recruitment, activation, and polarization of cancer-associated fibroblasts, endothelial cells, and macrophages. Additionally, functional enrichment analyses indicated that GLI1/2/3 are involved in the regulation of epithelial-mesenchymal transition (EMT). Together, our findings shed new light on the roles of GLI1/2/3 in tumorigenesis and provide a potential basis for the development of novel therapeutic strategies targeting GLI-mediated signaling pathways in cancer.

Characterizing hedgehog pathway features in senescence associated osteoarthritis through Integrative multi-omics and machine learning analysis.

Purpose: Osteoarthritis (OA) is a disease of senescence and inflammation. Hedgehog's role in OA mechanisms is unclear. This study combines Bulk RNA-seq and scRNA-seq to identify Hedgehog-associated genes in OA, investigating their impact on the pathogenesis of OA. Materials and methods: Download and merge eight bulk-RNA seq datasets from GEO, also obtain a scRNA-seq dataset for validation and analysis. Analyze Hedgehog pathway activity in OA using bulk-RNA seq datasets. Use ten machine learning algorithms to identify important Hedgehog-associated genes, validate predictive models. Perform GSEA to investigate functional implications of identified Hedgehog-associated genes. Assess immune infiltration in OA using Cibersort and MCP-counter algorithms. Utilize ConsensusClusterPlus package to identify Hedgehog-related subgroups. Conduct WGCNA to identify key modules enriched based on Hedgehog-related subgroups. Characterization of genes by methylation and GWAS analysis. Evaluate Hedgehog pathway activity, expression of hub genes, pseudotime, and cell communication, in OA chondrocytes using scRNA-seq dataset. Validate Hedgehog-associated gene expression levels through Real-time PCR analysis. Results: The activity of the Hedgehog pathway is significantly enhanced in OA. Additionally, nine important Hedgehog-associated genes have been identified, and the predictive models built using these genes demonstrate strong predictive capabilities. GSEA analysis indicates a significant positive correlation between all seven important Hedgehog-associated genes and lysosomes. Consensus clustering reveals the presence of two hedgehog-related subgroups. In Cluster 1, Hedgehog pathway activity is significantly upregulated and associated with inflammatory pathways. WGCNA identifies that genes in the blue module are most significantly correlated with Cluster 1 and Cluster 2, as well as being involved in extracellular matrix and collagen-related pathways. Single-cell analysis confirms the significant upregulation of the Hedgehog pathway in OA, along with expression changes observed in 5 genes during putative temporal progression. Cell communication analysis suggests an association between low-scoring chondrocytes and macrophages. Conclusion: The Hedgehog pathway is significantly activated in OA and is associated with the extracellular matrix and collagen proteins. It plays a role in regulating immune cells and immune responses.

The Effects of Housing on Growth, Immune Function and Antioxidant Status of Young Female Lambs in Cold Conditions.

Cold conditions in northern China during winter may reduce sheep growth and affect their health, especially if they are young, unless housing is provided. We allocated 45 two-month-old female lambs to be housed in an enclosed building, a polytunnel, or kept outdoors, for 28 days. The daily weight gain and scalp and ear skin temperature of outdoor lambs were less than those of lambs that were housed in either a house or polytunnel; however, rectal temperature was unaffected by treatment. There was a progressive change in blood composition over time, and by the end of the experiment, outdoor lambs had reduced total antioxidant capacity (T-AOC), catalase (CAT), glutathione peroxidase (GSH-Px) and total superoxide dismutase (T-SOD) and increased malondialdehyde compared to those in the house or polytunnel. In relation to immune responses in the lambs' serum, in the polytunnel, immunoglobulin A (IgA), tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) were higher and immunoglobulin G (IgG) lower compared with the concentrations in lambs that were outdoors. Over the course of the experiment, genes expressing heat shock proteins and antioxidant enzymes increased in lambs in the outdoor treatment, whereas they decreased in lambs in the indoor treatments. It is concluded that although there were no treatment effects on core body temperature, the trends for progressive changes in blood composition and gene expression indicate that the outdoor lambs were not physiologically stable; hence, they should not be kept outdoors in these environmental conditions for long periods.

A better method to evaluate the reliability of echocardiography for assessment of pulmonary hypertension: comparison of tricuspid regurgitant spectrum quality grading and tricuspid valve regurgitation degree.

Background: Transthoracic echocardiography (TTE) is recommended as the most important noninvasive screening tool for the diagnosis of pulmonary hypertension (PH), sonographers usually measure the volume of regurgitant flow rather than evaluating the spectral quality, so physicians will determine whether the ultrasound measurements of pulmonary arterial systolic pressure (US-PASP) are reliable based on the volume of tricuspid regurgitation (TR). Therefore, for the first time, we grade the quality of TR spectrum (TRS) based on its integrity and clarity, aiming to assess clinical application value of different tricuspid regurgitant spectrum quality grades (TR-SQG), and investigate whether the accuracy of US-PASP is more trustworthy than TR. Methods: We retrospectively analyzed 108 patients with chronic thromboembolic PH (CTEPH) to compare the correlation and agreement between US-PASP and right heart catheterization measurements of PASP (RHC-PASP). TR area (TRA) and TRS were measured in each patient, and TR-SQG was performed. Results: The correlation coefficients between US-PASP and RHC-PASP were r=0.622 (P<0.001), r=0.754 (P<0.001), r=0.595 (P<0.001) in mild, moderate, severe TR, and r=0.301 (P=0.135), r=0.747 (P<0.001), r=0.739 (P<0.001), r=0.828 (P<0.001) in TR-SQG I-IV, respectively. Bland-Altman analysis revealed the mean biases of 5.05, 3.06, 7.62 mmHg in mild, moderate, severe TR, and -16.47, -8.07, 1.82, 6.09 mmHg in TR-SQG I-IV, respectively. In mild TR with the TR-SQG III and IV, the correlation coefficients between US-PASP and RHC-PASP were r=0.779 (P<0.001), intraclass correlation coefficient (ICC) =0.774, paired t-test P=0.160, respectively; and the consistency was significantly higher than that of mild TR without considering TR-SQG. In moderate TR with the TR-SQG III and IV, the r=0.749, ICC =0.746, paired t-test P=0.298 between US-PASP and RHC-PASP. Conclusions: The US-PASP with TR-SQG III or IV is trustworthy, and its accuracy and consistency are better than those predicted by the traditional severity of TR. The establishment of the ultrasound evaluation system of TR-SQG helps clinicians to judge whether the US-PASP is accurate, credible, and reliable.

Systematic analysis of the prognostic value and immunological function of LTBR in human cancer.

Lymphotoxin beta receptor (LTBR) is a positive T cell proliferation regulator gene. It is closely associated with the tumor immune microenvironment. However, its role in cancer and immunotherapy is unclear. Firstly, the expression level and prognostic value of LTBR were analyzed. Secondly, the expression of LTBR in clinical stages, immune subtypes, and molecular subtypes was analyzed. The correlation between LTBR and immune regulatory genes, immune checkpoint genes, and RNA modification genes was then analyzed. Correlations between LTBR and immune cells, scores, cancer-related functional status, tumor stemness index, mismatch repair (MMR) genes, and DNA methyltransferase were also analyzed. In addition, we analyzed the role of LTBR in DNA methylation, mutational status, tumor mutation burden (TMB), and microsatellite instability (MSI). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to explore the role of LTBR in pan-cancer. Finally, the drugs associated with LTBR were analyzed. The expression of LTBR was confirmed using quantitative real-time PCR and Western blot. LTBR is significantly overexpressed in most cancers and is associated with low patient survival. In addition, LTBR expression was strongly correlated with immune cells, score, cancer-related functional status, tumor stemness index, MMR genes, DNA methyltransferase, DNA methylation, mutational status, TMB, and MSI. Enrichment analysis revealed that LTBR was associated with apoptosis, necroptosis, and immune-related pathways. Finally, multiple drugs targeting LTBR were identified. LTBR is overexpressed in several tumors and is associated with a poor prognosis. It is related to immune-related genes and immune cell infiltration.

Preliminary study on the short-term changes of pulmonary perfusion after a single balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: Little is known about immediate responses of blood perfusion to the balloon pulmonary angioplasty (BPA) procedure. OBJECTIVES: To investigate the changes in pulmonary perfusion of balloon-dilated vessels and untreated vessels with before, immediately after a single BPA and at follow-up. DESIGN: Retrospective single-center cohort study. METHODS: Patients who had chronic thromboembolic pulmonary hypertension (CTEPH) and completed the pulmonary perfusion single photon emission computed tomography (SPECT) imaging before, immediately after BPA and at follow-up were included. We evaluated the perfusion defects of both-lung, BPA target (balloon dilated) and non-target (untreated) vessel segments according to Begic 3-point scale in each lung segment. RESULTS: Forty patients (40 BPA procedures) were included and were given next BPA after 89 (62-125) days. The hemodynamic parameters including mPAP, PVR, and RAP were significantly improved after a single BPA. Visual scoring results of pulmonary perfusion imaging in 40 BPAs showed the perfusion defect scores of target vessels reduced from 5.6 ± 2.6 to 4.2 ± 2.2 (p < 0.001) immediately after BPA, and then further diminished to 3.1 ± 1.9 (p < 0.001) at follow-up. While in the non-target vessels, the post-BPA perfusion defect scores did not change significantly (13.4 ± 4.7 versus 12.8 ± 4.6, p = 0.182), but tended to decrease at follow-up (12.2 ± 4.2). However, there were 17 BPAs of which the post-BPA perfusion defect scores of non-target vessels increased significantly (p < 0.001), but decreased at follow-up. CONCLUSION: In addition to improving the blood perfusion of target vessels, BPA also has a certain effect on the perfusion of some non-target vessels.

Corrigendum: Systematic pan-cancer analysis of the potential tumor diagnosis and prognosis biomarker P4HA3.

[This corrects the article DOI: 10.3389/fgene.2023.1045061.].

Percutaneous endovascular biopsy for the diagnosis of pulmonary artery masses: A preliminary study of single-center.

Percutaneous endovascular biopsy (PEB) including forceps biopsy and catheter aspiration has been used to make a pretreatment diagnosis for pulmonary artery (PA) masses. This retrospective study aims to describe the procedure of PEB and compare the diagnostic yield of forceps biopsy and catheter aspiration for a definite diagnosis in patients with PA masses. All consecutive 22 patients (53 ± 14 years), 11 males and 11 females, who underwent PEB for pathologic confirmation between November 2018 and November 2022 were enrolled. All 22 patients performed computed tomography pulmonary angiography or positron emission tomography-computed tomography to confirm the filling defects suspicious for PA malignancy before intervention. And then, all patients underwent PEB successfully without acute or fatal complications, including both forceps biopsy and catheter aspiration in 15 cases, only forceps biopsy in 5 cases, and only catheter aspiration in 2 cases. Histopathological analysis provided a definite diagnosis in all PEBs with a clinical success of 91.0% (20/22). Among them, in 15 patients who underwent both forceps biopsy and aspiration biopsy, the technical success using forceps biopsy was 93.3% (14/15), and aspiration biopsy was 6.7% (1/15), and there was a significant difference in diagnostic accuracy when comparing two techniques. Twenty-one out of 22 PA masses (95.5%) were malignant, of which, the most frequent malignant lesion observed was PA sarcoma (66.7%, 14/21). Benign lesion included one thrombus (4.5%, 1/22). In conclusion, PEB is an effective and safe diagnostic method for differentiating benign and malignant PA masses and could be peformed when PA masses appeared clinically malignant.

Aetiological distribution of pulmonary hypertension and the value of transthoracic echocardiography screening in the respiratory department: A retrospective analysis from China.

METHODS: The aetiological composition and clinical characteristics of patients with pulmonary hypertension (PH) hospitalised in the respiratory department were retrospectively analysed, as well as the correlation between transthoracic echocardiography (TTE) and right heart catheterization (RHC) for evaluating pulmonary artery systolic pressure (PASP) and mean pulmonary artery pressure (mPAP). RESULTS: Of 731 patients, 544 (74.42%) were diagnosed with PH by RHC. Pulmonary arterial hypertension (PAH) was the most common type of PH, accounting for 30.10%; PH due to lung disease and/or hypoxia accounted for 20.79%, and PH due to pulmonary artery obstructions accounted for 19.29%. TTE has the highest specificity for diagnosing PH due to pulmonary artery obstructions. The specificity was 0.9375, the sensitivity was 0.7361 and the area under the ROC curve (AUC) was 0.836. PASP, and mPAP estimated by TTE were different for various types of PH. In terms of PASP, TTE overestimated PASP in PH due to lung disease and/or hypoxia, but there was no significant difference compared with RHC (P > 0.05). TTE underestimates PAH patients' PASP compared with RHC. In terms of mPAP, TTE underestimated the mPAP of all types of PH, as there was a significant difference in the TTE-estimated mPAP of patients with PAH compared with RHC but not on other types of PH. Pearson correlation analysis of TTE and RHC showed a moderate overall correlation (rPASP 0.598, P < 0.001; rmPAP 0.588, P < 0.001). CONCLUSIONS: Among the patients with PH in the respiratory department, patients with PAH accounted for the majority. TTE has high sensitivity and specificity for the diagnosis of PH due to pulmonary artery obstructions in the respiratory department.

Systematic pan-cancer analysis of the potential tumor diagnosis and prognosis biomarker P4HA3.

Purpose: Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) is implicated in several cancers' development. However, P4HA3 has not been reported in other cancers, and the exact mechanism of action is currently unknown. Materials and methods: First, the expression profile of P4HA3 was analyzed using a combination of the University of California Santa Cruz (UCSC) database, Cancer Cell Line Encyclopedia (CCLE) database, and Genotype-Tissue Expression (GTEx) database. UniCox and Kaplan-Meier were used to analyze the predictive value of P4HA3. The expression of P4HA3 was analyzed in clinical staging, immune subtypes, and Molecular subtypes. Secondly, the correlation of P4HA3 with immunomodulatory genes, immune checkpoint genes, RNA modification genes, immune cell infiltration, cancer-related functional status, tumor stemness index, DNA mismatch repair (MMR) genes and DNA Methyltransferase was examined. The role of P4HA3 in DNA methylation, copy number variation (CNV), mutational status, tumor mutational burden (TMB), and microsatellite instability (MSI) was also analyzed. In addition, gene set enrichment analysis (GSEA) was used to explore the potential functional mechanisms of P4HA3 in pan-cancer. Finally, P4HA3-related drugs were searched in CellMiner, Genomics of Drug Sensitivity in Cancer (GDSC), and Cancer Therapeutics Response Portal (CTRP) databases. Results: P4HA3 is significantly overexpressed in most cancers and is associated with poor prognosis. P4HA3 is strongly associated with clinical cancer stage, immune subtypes, molecular subtypes, immune regulatory genes, immune checkpoint genes, RNA modifier genes, immune cell infiltration, cancer-related functional status, tumor stemness index, MMR Gene, DNA Methyltransferase, DNA methylation, CNV, mutational status, TMB, and MSI are closely related. Available enrichment analysis revealed that P4HA3 is associated with the epithelial-mesenchymal transition and immune-related pathways. There are currently 20 drugs associated with P4HA3. Conclusion: In human pan-cancer, P4HA3 is associated with poor patient prognosis and multiple immune cells and may be a novel immunotherapeutic target. It may act on tumor progression through the epithelial-mesenchymal transition (EMT) pathway.

Homocysteine impedes neurite outgrowth recovery after intracerebral haemorrhage by downregulating pCAMK2A.

Hyperhomocysteinemia (HHcy) is independently associated with poorer long-term prognosis in patients with intracerebral haemorrhage (ICH); however, the effect and mechanisms of HHcy on ICH are still unclear. Here, we evaluated neurite outgrowth and neurological functional recovery using simulated models of ICH with HHcy in vitro and in vivo. We found that the neurite outgrowth velocity and motor functional recovery in the ICH plus HHcy group were significantly slower than that in the control group, indicating that homocysteine (Hcy) significantly impedes the neurite outgrowth recovery after ICH. Furthermore, phosphoproteomic data and signalome analysis of perihematomal brain tissues suggested that calmodulin-dependent protein kinases 2 (CAMK2A) kinase substrate pairs were significantly downregulated in ICH with HHcy compared with autologous blood injection only, both western blot and immunofluorescence staining confirmed this finding. Additionally, upregulation of pCAMK2A significantly increased neurite outgrowth recovery in ICH with HHcy. Collectively, we clarify the mechanism of HHcy-hindered neurite outgrowth recovery, and pCAMK2A may serve as a therapeutic strategy for promoting neurological recovery after ICH.

Successful chemotherapy with continuous immunotherapy for primary pulmonary endovascular epithelioid hemangioendothelioma: A case report.

RATIONALE: Epithelioid hemangioendothelioma (EHE) is a rare, low to moderate-grade malignancy, even less in pulmonary endovascular neoplasm. Patients with pulmonary EHE have no optimal treatment, resulting in poor prognoses. PATIENT CONCERNS: We reported a 42-year-old man with multiple mild metabolic uptakes in pulmonary endovascular filling defect with a maximum standardized uptake value of 4.5 by 18-fluorodeoxyglucose/fibroblast associated protein inhibitor-positron emission tomography/ computed tomography. Anticoagulant treatment was not effective with the diagnosis of acute pulmonary embolism. DIAGNOSES: A primary endovascular EHE pulmonary endovascular epithelioid hemangioendothelioma was diagnosed by endovascular biopsy with positive stains for molecular CD31, CD34 and CAMTA1, and it had low proliferative capacity characterized by Ki-67 of 5%. The mutation gene MSH2 (p.Y656 in exon 12) (mutation abundance of 0.07%) from peripheral blood indicates the potential benefit of an immune checkpoint inhibitor, pembrolizumab. INTERVENTIONS AND OUTCOMES: The patient was treated with tri-weekly paclitaxel (175mg/m2) and carboplatin (AUC 5) chemotherapy regimen. He exerted a remarkable response after 5 cycles (21 days per cycle) and Pembrolizumab (200mg once monthly) as maintenance treatment. LESSONS: This case highlights the diagnostic challenge of differentiating endovascular lesions and optimal therapy for pulmonary EHE. Importantly, it indicated that the mutation gene MSH2 (p.Y656) might influence the pathogenesis of EHE.

Implication of Cerebral Small-Vessel Disease on Perihematomal Edema Progress in Patients With Hypertensive Intracerebral Hemorrhage.

BACKGROUND: Perihematomal edema (PHE) is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to cerebral small vessel disease (CSVD). However, it is not known to date whether the severity of CSVD is associated with the extent of PHE progression in the acute phase. PURPOSE: To investigate the association between the magnetic resonance imaging (MRI) marker of severe chronic-ischemia cerebral small vessel changes (sciSVC) and PHE growth or hematoma absorption among ICH patients with hypertension. STUDY TYPE: Retrospective. POPULATION: Three hundred and sixty-eight consecutive hypertensive ICH patients without surgical treatment. FIELD STRENGTH/SEQUENCE: 3 T; spin-echo echo-planar imaging-diffusion-weighted imaging (DWI); T2-weighted, fluid-attenuated inversion recovery (FLAIR), T2*-weighted gradient-recalled echo and T1-weighted. ASSESSMENT: The hematoma and PHE volumes at 24 hours and 5 days after symptom onset were measured in 121 patients with spontaneous ICH who had been administered standard medical treatment. Patients were grouped into two categories: those with sciSVC and those without. The imaging marker of sciSVC was defined as white matter hyperintensities (WMHs) Fazekas 2-3 combined cavitating lacunes. STATISTICAL TESTS: Univariable analyses, χ2 test, Mann-Whitney U test, and multiple linear regression. RESULTS: The presence of sciSVC (multiple lacunes and confluent WMH) had a significant negative influence on PHE progress (Beta = -5.3 mL, 95% CI = -10.3 mL to -0.3 mL), and hematoma absorption (Beta = -3.2 mL, 95% CI = -5.9 mL to -0.4 mL) compared to that observed in the absence of sciSVC, as determined by multivariate linear regression analysis. DATA CONCLUSIONS: The presence of sciSVC (multiple lacunes and confluent WMH) negatively influenced hematoma absorption and PHE progress in ICH patients. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 3.

Efficacy of computed tomography in diagnosing pulmonary hypertension: A systematic review and meta-analysis.

Objective: This study seeks to evaluate the diagnostic value of computed tomography (CT) in pulmonary hypertension. Method: PubMed, Embase, Scopus, and Web of Science databases were searched to obtain the relevant English literature, and the retrieval time until June 2022. The quality of the included studies is evaluated using the QUADAS-2 tool. The quality of the included studies was assessed, followed by a meta-analysis, analyze heterogeneity, summarize sensitivity and specificity, draw the comprehensive subject working characteristics (sROC) curve, calculate the area under the curve and conduct subgroup analysis and sensitivity analysis to find the source of the heterogeneity. Results: A total of 12 articles were included, all with pulmonary artery diameter/liter aortic diameter >1 or 1 as the diagnostic criteria for pulmonary hypertension, and a total of 1,959 patients were included. Deek's funnel plot analysis suggests that there is no significant publication bias (P = 0.102). The combined sensitivity was 0.652 (95% CI: 0.579, 0.719), combined specificity was 0.830 (95% CI: 0.796, 0.880), positive likelihood ratio was 3.837 (95% CI: 3.215, 4.579), negative likelihood ratio was 0.419 (95% CI: 0.346, 0.507), diagnostic odds ratio was 9.157 (95% CI: 6.748, 12.427) and area under the summary receiver operating characteristic (SROC) curve was 0.84 (95% CI: 0.81, 0.87). Conclusion: The CT examination of pulmonary artery diameter/aortic artery hypertension is worthy of clinical application.

Bioinformatics analysis of genomic and immune infiltration patterns in autism spectrum disorder.

Background: Autism spectrum disorder (ASD) is a specific type of pervasive developmental disorder, and most studies suggest that the onset of autism may be related to genetic and immune factors. The etiology of autism and the underlying molecular events need to be further addressed. Methods: The ASD-related dataset GSE18123 was downloaded from the Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) was used to screen for Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that may be associated with autism. The top 5,000 genes with an absolute median difference were obtained, and a co-expression network was constructed using weighted correlation network analysis (WGCNA). In addition, GO and KEGG enrichment analyses were performed for genes in the modules most closely related to ASD. Hub genes were found in the significant modules, and the expression values and receiver operating characteristic (ROC) curves of the hub genes were analyzed and validated. Immune cell infiltration in ASD was calculated using the CIBERSORT algorithm, and the relationship between hub genes and immune cells was analyzed. Finally, GSEA was used to explore the potential pathways of hub genes affecting ASD. Results: The 5,000 DEGs were divided into eight significant modules by WGCNA. The green module was most significantly associated with ASD, and two hub genes [fatty acid-binding protein 2 (FABP2) and Janus kinase 2 (JAK2)] were found. Immune cell infiltration showed that resting dendritic cells and monocytes differed significantly in ASD and healthy individuals. FABP2 was significantly associated with memory B cells and CD8 T cells. JAK2 was significantly associated with monocytes, CD4 activated memory T cells, CD4 resting memory T cells, activated dendritic cells, gamma delta T cells, regulatory T cells (Tregs), CD8 T cells, and naïve CD4 T cells. FABP2 and JAK2 were found to affect multiple pathways of immunity. Conclusions: FABP2 and JAK2 may influence the immune microenvironment of ASD by regulating immune cells and immune-related pathways and are candidate molecular markers for the development of ASD.