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Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis, and its dysregulation can lead to glycometabolic disorders. This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment. Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA), machine learning techniques, and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus (T2DM) patients were employed to assess the clinical relevance of these DEGs. Subsequently, we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders, investigated potential correlations with immune cell types, and validated expression using quantitative polymerase chain reaction in the mouse models. Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors. However, these DEGs were consistently associated with cytokine regulation and oxidative stress (OS). Enrichment analysis highlighted significant alterations in terms related to cytokines and OS. Importantly, osteomodulin ( OMD ), apolipoprotein A4 ( APOA4 ), and insulin like growth factor binding protein 6 ( IGFBP6 ) were identified with potential clinical significance in T2DM patients. These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells. Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity, yet changes in cytokine regulation and OS are universally present. OMD , APOA4 , and IGFBP6  may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart Show less

The quality of eggshells holds substantial economic significance and serves as a critical selection criterion in poultry breeding. Eggshell translucency significantly impairs their aesthetic quality, which is structurally attributed to the thinning of the eggshell membrane or reduced tensile strength. In this study, 836 dwarf white hens were selected, with 45 hens each assigned to the opaque group and the translucent group. Grading for eggshell translucency was conducted at 75, 80, and 85 weeks of age. Based on the results from these three gradings, 35 hens that consistently produced translucent eggs and 35 hens that consistently produced opaque eggs were reclassified into the translucent group and the opaque group, respectively. The thickness of the eggshell membrane, latitudinal and longitudinal tensile force and length, and other indicators related to eggshell membrane quality were measured. Correlation analysis was performed using RNA-seq genomics and DIA proteomics based on the relationships among these indicators. Transcriptome analysis revealed 179 significantly differentially expressed genes, indicating that the causes of translucent eggshells are associated with metabolism, signal transduction, the immune system, molecular binding, transport, and catabolism. Seven potential candidate genes, including Show less

Chronic renal allograft injury (CRAI) is a major cause of allograft loss in kidney transplant recipients (KTRs). The aim of this study was to evaluate the associations of urinary apolipoprotein A4 (ApoA-IV) levels with renal function and rapid renal function decline in KTRs. This study included 50 KTRs. Proteomic analysis via liquid chromatography‒mass spectrometry and tandem mass spectrometry (LC-MS/MS) was performed to identify potential urinary biomarkers. The SWATH (sequential window acquisition of all theoretical mass spectra) method was used for protein quantification. Urinary ApoA-IV levels were validated by enzyme-linked immunosorbent assay (ELISA). Rapid renal function decline was defined as an estimated glomerular filtration rate (GFR) decrease of >3 mL/min/1.73 m2 per year or initiation of dialysis. The log-transformed urinary ApoA-IV levels measured by ELISA had a significantly inverse correlation with the estimated GFR (r = -0.72, P < 0.001). Moreover, urinary ApoA-IV levels were higher in patients with rapid renal function decline than in those with stable renal function (215.4 ± 181.8 μg/mL vs. 42.5 ± 72.4 μg/mL, P = 0.001). Univariate logistic regression analysis revealed that log-transformed urinary ApoA-IV levels were significantly associated with rapid renal function decline (odds ratio [OR] 6.70, 95% confidence interval [CI] 2.56-22.83; P < 0.001). Multiple logistic regression showed urinary ApoA-IV levels remained a significant risk factor for rapid renal function decline (OR 4.10, 95% CI 1.10-19.55; P = 0.047). ROC curve analysis revealed the area under the curve (AUC) of 0.834 (95% CI 0.722-0.945, P < 0.001) for urinary ApoA-IV levels in predicting rapid renal function decline. Our results suggest that urinary ApoA-IV levels might be a potential biomarker for renal allograft function and could be used as a predictor for rapid renal function decline in KTRs. Show less

Diabetic retinopathy (DR) is one of the major complications of diabetes, resulting in severe vision loss. Traction retinal detachment (TRD) is the main factor affecting the effect of proliferative diabetic retinopathy (PDR) surgery. Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) was adopted to analyze the proteomes of the vitreous in the TRD, vitreous hemorrhage (VH) and macular hole (MH) groups. By employing bioinformatics tools for GO and KEGG pathway annotation, as well as conducting protein-protein interaction(PPI) network analysis, we investigated the functional enrichment of proteins in the TRD vitreous and their associated pathways. Additionally, peptide center analysis was performed on the proteomic data to identify key differentially expressed proteins based on screening results. Bioinformatics analysis showed that DEPs is mainly enriched in the complement, the coagulation cascade systems and regulation of actin cytoskeleton. The protein interaction network analysis showed that the central proteins were mainly related to sphingolipid metabolism. APOA4, CHI3L1, LTBP2 were significantly up-regulated in TRD, which were related to the complement system, coagulation cascade and platelet activation, sphingolipid metabolism and other pathways. APOA4 and CHI3L1 protein in patients with TRD group raised significantly in the vitreous humor, shows the potential biomarkers for TRD. Show less

Apolipoprotein A-IV (apoA-IV), the largest member of the exchangeable apolipoprotein family, is a common constituent of amyloid deposits in renal and cardiac amyloidosis. In this study, we characterized the aggregation propensity of the apoA-IV N-terminal fragment to form amyloid fibrils using a variety of biophysical techniques. Thioflavin T fluorescence assay, circular dichroism measurement, and microscopic observations revealed that the N-terminal 1-70 amino acid fragment of apoA-IV readily forms amyloid fibrils by a transition from a random coil to a β-sheet-rich structure. Sequence-based analysis indicated that residues 7-16 and 38-42 are the major aggregation-prone segments within the N-terminal 1-70 residues of apoA-IV. Consistent with this, deletion of these residues strongly inhibited the β-transition and fibril formation of apoA-IV 1-70. Kinetic and thermodynamic analyses of fibril formation by the apoA-IV 1-70 fragment demonstrated that primary nucleation is the dominant step in fibril formation, for which the activation energy barrier is entirely entropic. In addition, we found that the presence of heparin, a representative glycosaminoglycan, accelerated fibril formation kinetics and enhanced the yield of apoA-IV 1-70 fibrils, and the positively charged residues K58-K59 play a critical role in heparin interaction. Overall, our results suggest that the strong amyloid-forming propensity of the N-terminal fragment of apoA-IV may play a key role in amyloid deposition associated with apoA-IV amyloidosis. Show less

Cholesterol synthesis and gallstone formation are promoted by trimethylamine-N-oxide (TMAO), a derivative of trimethylamine, which is a metabolite of gut microbiota. However, the underlying mechanisms of TMAO-induced lithogenesis remain incompletely understood. This study aimed to explore the specific molecular mechanisms through which TMAO promotes gallstone formation. Enzyme-linked immunosorbent assays were used to compare serum concentrations of TMAO, apolipoprotein A4 (APOA4), and proprotein convertase subtilisin/kexin type 9 (PCSK9) between patients with cholelithiasis and normal controls. A murine model of TMAO-induced cholelithiasis was employed, incorporating assays of gallstone weight and bile cholesterol content, along with RNA sequencing of murine hepatic tissue. A TMAO-induced AML12 hepatocyte line was constructed and transfected with targeted small interfering RNAs and overexpression plasmids. Serum TMAO and PCSK9 levels were elevated, whereas APOA4 levels were reduced in patients with cholelithiasis. Furthermore, our murine model demonstrated that TMAO upregulated hepatic expression of PCSK9, 3-hydroxy-3-methylglutaryl-CoA reductase, and ATP-binding cassette sub-family G member 5/8, while reducing APOA4 expression, thereby modulating cholesterol metabolism and promoting lithogenesis. TMAO upregulated hepatic Show less

As the most common primary malignant bone tumor, further investigation into risk stratification for osteosarcoma (OS) prognosis is of significant clinical importance. Copper is essential for bone metabolism; however, its specific role in OS remains unclear. The expression characteristics of copper metabolism related genes (CORGs) in OS were revealed by single cell sequencing. Prognosis-associated CORGs were identified, and a CORG-related scoring system and risk model were established using bioinformatics approaches, including univariate and multivariate Cox regression analyses and LASSO analysis. We further analyzed immune microenvironment infiltration, molecular subtypes and clinicopathological characteristics. The impact of selected CORG with high-risk coefficient on OS cells was tested by qRT-PCR, western blot, siRNA, colony formation analysis and Transwell in vitro. We successfully developed an OS scoring system related to copper metabolism and validated its independent prognostic value in patients with OS. The potential clinical value of CORG scoring system was analyzed. APOA4 was selected for in vitro experiments and its effect on the proliferation and invasion ability of OS cells was verified. We established a copper metabolism-related scoring system to effectively stratify the risk of OS patients. Our results provide a new basis for the role of copper metabolism in OS and provide new potential targets for the treatment of OS. Show less

Pulmonary nodule with diameters ranging 8-30 mm has a high occurrence rate, and distinguishing benign from malignant nodules can greatly improve the patient outcome of lung cancer. However, sensitive and specific liquid-biopsy methods have yet to achieve satisfactory clinical goals. We enrolled three cohorts and a total of 185 patients diagnosed with benign (BE) and malignant (MA) pulmonary nodules. Utilizing data-independent acquisition (DIA) mass spectrometry, we quantified plasma proteome from these patients. We then performed logistic regression analysis to classify benign from malignant nodules, using cohort 1 as discovery data set and cohort 2 and 3 as independent validation data sets. We also developed a targeted multi-reaction monitoring (MRM) method to measure the concentration of the selected six peptide markers in plasma samples. We quantified a total of 451 plasma proteins, with 15 up-regulated and 5 down-regulated proteins from patients diagnosed as having malignant nodules. Logistic regression identified a six-protein panel comprised of APOA4, CD14, PFN1, APOB, PLA2G7, and IGFBP2 that classifies benign and malignant nodules with improved accuracy. In cohort 1, the area under curve (AUC) of the training and testing reached 0.87 and 0.91, respectively. We achieved a sensitivity of 100%, specificity of 40%, positive predictive value (PPV) of 62.5%, and negative predictive value (NPV) of 100%. In two independent cohorts, the 6-biomarker panel showed a sensitivity, specificity, PPV, and NPV of 96.2%, 35%, 65.8%, and 87.5% respectively in cohort 2, and 91.4%, 54.2%, 74.4%, and 81.3% respectively in cohort 3. We performed a targeted LC-MS/MS method to quantify plasma concentration of the six peptides and applied logistic regression to classify benign and malignant nodules with AUC of the training and testing reached 0.758 and 0.751, respectively. Our study identified a panel of plasma protein biomarkers for distinguishing benign from malignant pulmonary nodules that worth further development into a clinically valuable assay. Show less

Accurate diagnosis of Crohn's disease (CD) is paramount due to its resemblance to other inflammatory bowel diseases. Early and precise diagnosis plays a pivotal role in tailoring personalized treatments, thereby enhancing the quality of life for CD patients. Differential gene expression analysis was conducted to identify genes from the mRNA expression profiles of CD samples, followed by pathway enrichment analysis. The immune cell infiltration levels of each CD patient sample were assessed. Using weighted gene co-expression network analysis, key gene modules linked to CD were found. Hub gene identification was made easier by the construction of protein-protein interaction networks. Next, utilizing the Least Absolute Shrinkage and Selection Operator on the hub genes in the training set, a diagnostic model was created. The accuracy of the model was then confirmed using a different validation set. Our analysis revealed 651 differentially expressed genes, enriched in leukocyte chemotaxis and inflammation-related pathways. Immunization results showed a higher abundance of T cells CD4 memory resting, macrophages M2, and plasma cells in CD patients. Weighted gene co-expression network analysis linked the turquoise module with macrophages M2. Eight hub genes (APOA1, APOA4, CYP2C8, CYP2C9, CYP2J2, EPHX2, HSD3B1, and LPL) formed the diagnostic model, exhibiting excellent diagnostic performance with area under curve values of 0.94 (training set) and 0.941 (validation set). The CD diagnostic model, based on hub genes, shows exceptional diagnostic accuracy, providing a valuable reference for CD diagnosis. Show less

Renal fibrosis is a prominent pathophysiologic change seen with the progression of chronic kidney disease. Angiotensin II (Ang II), the central peptide of the renin-angiotensin aldosterone system (RAAS), is known to cause fibrosis under various disease conditions. Fibroblast growth factor receptor-1 (FGFR1) plays a critical role in epithelial to mesenchymal transition and tubulointerstitial fibrosis, but its role in Ang II-induced fibrosis in renal epithelial cells (RECs) and renal fibroblasts (RFbs) remains poorly understood. Our study aimed to investigate the role of FGFR1 in Ang II-induced fibrosis in both REC, RFbs and explore the potential of chimeric peptide (CP) in attenuating it. We developed a time-dependent in vitro fibrosis model using REC exposed to Ang II and analyzed the expression of FGFR1 and fibrotic markers by qPCR. Oxidative stress and profibrotic markers were measured using confocal imaging and flow cytometry. In RFbs, we also examined fibrotic cell proliferation and collagen deposition using proliferation assays and Sirius red staining. Our findings show that Ang II significantly increases FGFR1, AT Show less

Elevated levels of lipoprotein(a) have been linked to an increased risk of Atherosclerotic Cardiovascular Disease (ASCVD). Conventional lipid-lowering medications have modest to no impact on Lp(a) levels. Emerging RNA-based modalities significantly decrease Lp(a) by silencing the apo(a) mRNA at the post-transcriptional level. Pelacarsen (TQJ230) is a GalNAc-conjugated novel Antisense Oligonucleotide (ASO) that selectively inhibits apo(a) synthesis in hepatocytes. This updated review aims to elucidate the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of Pelacarsen (TQJ230), with a focused appraisal of its potential role in the prevention of Atherosclerotic Cardiovascular Disease (ASCVD). We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Pelacarsen", "antisense oligonucleotide" OR "ASO", and "lipoprotein(a)" from inception to March 2025. Pelacarsen demonstrated a dose-dependent sustained reduction in Lp(a) levels, achieving up to a 97% reduction at the highest dose in Phase 1 and 2 trials. It was well-tolerated with a favorable safety profile. Phase 3 trials are underway to provide robust data on its long-term safety and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes. Pelacarsen (TQJ230) is a potent Lp(a)-lowering agent with promising efficacy and a favorable safety profile. However, its definitive role in reducing atherosclerotic cardiovascular events remains to be established. Ongoing Phase 3 trials will be critical in determining whether its lipid-lowering effects translate into meaningful long-term cardiovascular outcomes. Show less

Fibroblast growth factor receptors (FGFRs; FGFR1, FGFR2, FGFR3, FGFR4) are frequently mutated oncogenes in solid cancers. The oncogenic potential of FGFR rearrangements and few hotspot point mutations is well established, but the majority of variants resulting from point mutations especially outside of the tyrosine kinase domain are currently considered variants of unknown significance (VUS). Recurrent nonkinase domain FGFR VUS variants were collected from the Catalog of Somatic Mutations in Cancer and their oncogenic potential was assessed in vitro by different functional assays. We compiled published clinical and preclinical data on FGFR variants and compared the data with results from our functional assays and pathogenicity predictions of state-of-the-art artificial intelligence (AI) models. We identified 12 novel FGFR extracellular small variants with potential driver function. Comparison of clinical and preclinical data on FGFR variants with pathogenicity predictions of state-of-the-art AI models showed limited usefulness of the AI predictions. Sensitivity profiles of activating FGFR variants to targeted inhibitors were recorded and showed good targetability of FGFR nonkinase domain variants. The collected results extend the spectrum of suitable FGFR variants for potential treatment with FGFR inhibitors in the context of clinical trials and beyond. Current AI models for variant pathogenicity prediction require further refinement for use in oncogenic decision making. Show less

Radiation-induced lung injury (RILI), manifesting in its initial phase as radiation pneumonitis (RP) and progressing over time to radiation-induced pulmonary fibrosis (RIPF), represents a significant adverse consequence associated with thoracic radiation therapy. Currently, there are limited therapeutic options for RILI. Anlotinib was confirmed the efficacy of pulmonary fibrosis. Therefore, anlotinib has the potential to treat RILI. To investigate the therapeutic role of anlotinib in RILI. RILI model in mice was successfully developed for evaluating the therapeutic efficacy of anlotinib. We used network pharmacology to find six target genes and analysed the correlation between these genes and RILI-related cytokines. Molecular docking further validates the binding ability of these target genes and anlotinib. We found the importance of TGF-β in anlotinib treatment of RILI by the results of network pharmacology and correlation analysis. We then used immunohistochemistry to demonstrate that anlotinib treats RILI by lowering TGF-β. Through enrichment analysis, we obtained potential therapeutic pathways and validated them with WB. In vivo investigations demonstrated that anlotinib is able to treat RILI: Inflammation, fibrosis, and apoptosis are reduced. This result is likely to be related to the reduction of TGF-β: The therapeutic mechanism potentially involves six genes, namely, FLT1, AKT1, KDR, TGFB2, PDGFRB1, and FGFR1; these targets bind well to anlotinib; we found that the expression of most of cytokines affecting the particular processes of RILI was closely associated with the six genes, in particular TGF-β1-3; immunohistochemistry further demonstrates that anlotinib treats RILI by lowering TGF-β1-3. In addition, KEGG enrichment analysis reveals possible pathways involving in therapeutic effects, including the PI3K-Akt, MAPK, Rap1, and Ras pathway. WB showed that anlotinib treatment significantly inhibited the PI3K/Akt signalling pathway. Therefore, anlotinib has the potential for treating RILI. Our results indicated the potential targets and molecular mechanism of anlotinib against RILI. Show less

FGFR alterations are known to be driver alterations in several tumor types. We aimed to assess the efficacy of pemigatinib, an oral FGFR1-3 inhibitor, in patients with metastatic or unresectable colorectal cancer whose tumors harbored FGF/FGFR alterations. The ACCRU-GI-1701 is a single-arm phase II trial which enrolled patients with previously treated FGF/FGFR-altered metastatic colorectal cancer to receive oral pemigatinib daily in 21-day cycles. The primary endpoint is objective response. Secondary endpoints include clinical benefit, progression-free survival, overall survival, quality of life, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04096417). Of the 14 patients included in the interim analysis, the objective response rate as well as clinical benefit rate were 0%. Given these results, the trial closed to enrollment after stage one due to futility. A total of 42.9% of patients had at least one grade 3 or higher AE, the most common being anemia and fatigue. Pemigatinib monotherapy did not lead to objective responses in patients with chemorefractory metastatic colorectal cancer harboring FGF/FGFR alterations, although it was overall relatively well tolerated with no new safety signals. Notably, 93% (n = 13) of patients had only FGF/FGFR mutations and amplifications; one patient had an FGFR3-WHSC1 fusion at a low cfDNA percentage (0.02%). Show less

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with a poor prognosis and lacks effective targeted therapies. Six-transmembrane epithelial antigen of prostate 3(STEAP3) is specifically overexpressed in TNBC, but its precise role and molecular mechanisms remain unclear. Here, we show that STEAP3 is positively correlated with proliferation markers in TNBC, but not in non-TNBC. Further assays revealed that STEAP3 significantly enhances TNBC cell proliferation, invasion, and metastasis Show less

Uterine fibroids, or leiomyomas, are noncancerous tumors of the myometrium and the most common tumors in women, with a cumulative incidence of approximately 80% by age 50. Currently, hysterectomy is the only definitive cure, and effective non-hormonal therapeutics are lacking. Understanding the etiology of fibroids may lead to alternative, less invasive treatments. Several obstetric disorders, including polycystic ovary syndrome (PCOS), have been linked to uterine fibroids, and women with PCOS often exhibit hormonal imbalances, particularly elevated serum testosterone levels. However, the impact of testosterone on the myometrium remains poorly understood. We hypothesize that elevated testosterone may increase the risk of developing uterine fibroids. Using RNA sequencing and MethylationEPIC array analyses, we compared myometrial tissue from women without fibroids (MyoN, n = 33), with fibroids (MyoF, n = 66), and after testosterone therapy as part of clinical care for gender dysphoria (MyoT, n = 7). The transcriptomic and methylation profiles of MyoT clustered with MyoF and were distinct from MyoN. We identified 1,321 differentially expressed protein-coding genes between MyoT and MyoN, while only 494 were found between MyoT and MyoF. Disease ontology analysis of MyoT vs. MyoN revealed enrichment of the fibroid tumor gene set. Fibroid associated genes including TGFβ3, CCND1, SERPINE1, and FGFR1 were upregulated in MyoT and MyoF samples compared to MyoN samples. The DNA methylation profiles of MyoT were closer to those of MyoF, but no correlation was observed between methylation status and gene expression. Our preliminary data suggest that exogenous testosterone induces transcriptional and methylation changes in the myometrium consistent with those observed in MyoF tissues. These findings suggest that elevated testosterone may be associated with an increased risk of developing uterine fibroids. Show less

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor with a poor prognosis, despite the emergence of chemotherapies such as gemcitabine plus albumin-bound paclitaxel (nab-paclitaxel, AG), unmet medical needs still exist for patients with metastatic PDAC (mPDAC). Surufatinib is a small-molecule tyrosine kinase inhibitor targets vascular endothelial growth factor (VEGFR) 1, 2, 3, fibroblast growth factor receptor 1 (FGFR1), and colony stimulating factor 1 receptor (CSF-1R). This single-center, retrospective study evaluates the potential efficacy of combination therapy containing Surufatinib in advanced or metastatic pancreatic cancer. We conducted a real world retrospective study of mPDAC patients who received the Surufatinib between July 2022 and July 2023 at Zhejiang Cancer Hospital. In addition, patients who received first line chemotherapy at the same period were analyzed as comparison. As of November 20, 2024, 20 eligible patients were identified in this retrospective study. The median progression-free survival (mPFS) of patients who received Surufatinib treatment was 5.27 months (95% CI, 2.55-7.98), and the median overall survival(mOS) was 9.93 months (95% CI,6.55-13.32). For fist line treatment, 9 patients received Surufatinib combined with immune checkpoint inhibitors (ICIs) and chemo and the mPFS was 7.5 months (95% CI, 3.14-11.85), compared with an mPFS of 5.43 months (95% CI, 3.89-6.96) for 52 mPDAC patients received chemotherapy at the same period. Grade 3 or above Treatment Related Adverse Event (TRAE) were neutrophil count decreased (10%), and white blood cell count decreased (5%). Preliminary data suggest that surufatinib shows potential therapeutic benefit in mPDAC, but its efficacy needs to be further validated. This combination strategy may provide a new treatment option for patients, especially in the first-line setting. Future studies will expand the sample size and include additional evaluation parameters to fully assess its efficacy and safety. ClinicalTrials, identifier NCT06378580. Show less

Parkinson's disease (PD), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca Show less

Hemangioblastoma is a highly vascularized, benign tumor in the central nervous system, frequently associated with von Hippel-Lindau (VHL) disease. Hemangioblastoma may cause tumor-associated hemorrhage or exert pressure on nearby structures, leading to life-threatening complications. Although surgical resection is the primary treatment, complete removal is not always feasible. Accordingly, there is a need to explore targeted or anti-angiogenic therapies. The fibroblast growth factor receptor (FGFR) family has roles in tumorigenesis and angiogenesis, making it a potential target in personalized therapy. The distribution and significance of FGFRs in hemangioblastoma have yet to be investigated. We examined 139 formalin-fixed, paraffin-embedded hemangioblastoma samples from 111 patients, including sporadic cases and those associated with VHL disease. Immunohistochemistry revealed positive staining for FGFR2 (95%) and FGFR4 (61%), while FGFR1 (0%) and FGFR3 (12%) were mainly negative. FGFR2 expression was significantly increased in VHL-mutated tumors (75%, p = 0.034) and in male patients (68%, p = 0.020). Tumors located in the cerebrum (n = 6, 5%) had a higher likelihood of positive FGFR4 staining (100%, p = 0.009). Additionally, a larger tumor diameter was associated with a higher likelihood of FGFR4 expression (median 12.0 mm vs 17.5 mm, p = 0.018), suggesting its contribution in tumor growth. Our study revealed the expression of FGFR2 and FGFR4 in a significant number of hemangioblastomas. This finding demonstrates the potential of FGFRs as promising therapeutic targets for patients with hemangioblastoma. Show less

Atherosclerosis is an active interaction between lipoproteins and inflammatory cells. Monocytes and macrophages are the most important immune cells involved in the process of atherosclerosis. They interact with atherogenic lipoproteins, in particular low density lipoprotein (LDL) cholesterol and lipoprotein(a) (Lp(a)). The increased concentration of the LDL cholesterol and Lp(a) accelerates the polarization of monocytes and macrophages toward proinflammatory phenotype and the formation of the foam cells. These cells then release large quantities of inflammatory cytokines that stimulate the oxidation of atherogenic lipoproteins that are even more atherogenic and contribute to the formation of foam cells and the secretion of the pro-inflammatory cytokines, thus creating a vicious circle. Surface marker C-C chemokine receptor type 2, expressed on monocytes/macrophages, enables their adhesion and migration into the subendothelial layer. The rupture of the atherosclerotic plaque on one hand, and the ability of the oxidized LDL cholesterol and Lp(a) to trigger arterial thrombosis by different mechanisms on the other hand, result in acute cardiovascular event. Here, we summarize the role of the monocytes and macrophages in atherosclerosis and explore the influence of LDL cholesterol and Lp(a) on monocytes and macrophages during the entire process of atherosclerosis, from its initiation to progression. Show less

Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes. The objective of the study is to identify key genes and cellular mechanisms driving DFU pathogenesis and healing using multi-omics integration. We used differential expression analysis and weighted co-expression network analysis (WGCNA) to identify key genes in DFU. We constructed protein-protein interaction (PPI) networks through STRING and Cytoscape. Support vector machine-recursive feature elimination (SVM-RFE) was used to screen out potential diagnostic biomarkers. Single-cell transcriptomic analysis detected differences in the cellular landscape, and intercellular communication analysis deciphered the key intercellular signaling pathway. We first found 388 differentially expressed genes that are closely related to DFU (fold change > 2 and WGCNA-derived module significantly correlated with DFU, R = 0.78). We further constructed a PPI network and identified 15 hub genes and 10 diagnostic biomarkers (including FGF7) for DFU. FGF7 is lowly expressed in DFU and enriched in stromal cells and fibroblasts in DFU, and participates in the immune microenvironment of DFU. FGF7-FGFR1 is the main pathway for intercellular communication involving fibroblasts and stromal cells in the healing process of DFU. These results provide an in-depth understanding of the multifactorial mechanisms underlying DFU progression and healing, offering a theoretical basis for optimizing clinical treatment. Show less

Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. Here, we addressed this gap by analysing the influence of HLA variation on longevity in Europeans. We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Associations were evaluated with logistic regression, adjusting for multiple testing and population structure. Subsequently, significant associations (adjusted P ≤ 0.05) were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank. Furthermore, epitope binding and immunogenicity predictions were performed to detect potential mechanisms linking HLA alleles to longevity. Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity (adjusted P = 2.80 × 10 The novel male-specific association between HLA-DRB1*15:01 and longevity has been observed in three independent cohorts. The anti-longevity effect of this association is perhaps a consequence of an increase in Alzheimer's disease (AD)-related mortality in men carrying this allele. This hypothesis is based on prior research that has identified a male-specific association between HLA-DRB1*15:01:01 and AD. Additionally, it is likely that this link is mediated by increased immune reactivity against APOB-100, which is promoted by HLA-DRB1*15:01:01. Show less

We assessed the coverage of molecular drug susceptibility testing (mDST) among patients with pulmonary multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in South Korea and identified factors influencing the lack of mDST implementation. This retrospective study included patients with pulmonary MDR/RR-TB who initiated tuberculosis (TB) treatment between January 2015 and September 2021. Data were obtained from the K-TB-N cohort, an integrated national TB database linking three datasets. We assessed mDST coverage, temporal trends and factors associated with the lack of mDST implementation. mDST was defined as the use of the Xpert MTB/RIF assay or line probe assay (LPA) for isoniazid and rifampicin (first-line LPA). In total, 4637 patients were included in the analysis. Of the 4637 patients, 1342 (28.9%) did not undergo mDST; whereas, 3295 (71.1%) underwent mDST. Over the study period, a statistically significant annual increase in mDST coverage was observed, escalating from 49.1% in 2015 to 96.9% in 2021 (p<0.001). Throughout the study, the coverage of the Xpert MTB/RIF assay remained lower than that of LPA (22.1% vs 64.2%, p<0.001). Multivariable logistic regression analysis identified several factors independently associated with a decreased likelihood of mDST being conducted, including TB treatment initiation in secondary general hospitals, small hospitals or primary clinics, as well as in non-public-private mix (PPM) participating institutions. In addition, transfers between PPM-participating and non-participating institutions during the treatment period and sputum acid-fast bacilli smear-negative status were significantly associated with lower mDST uptake. Although the increasing mDST coverage is a positive development, further efforts are needed to achieve nationwide and universal implementation, particularly for the Xpert MTB/RIF assay, in South Korea. Show less

The development of tendinous xanthomas in childhood with a low-density lipoprotein (LDL) cholesterol level >400 mg/dL is characteristic of homozygous familial hypercholesterolemia (FH). We present the case of a patient with a severely elevated LDL cholesterol level and childhood-onset xanthomas who fulfilled clinical criteria for homozygous FH. However, genetic and absorption testing clarified his phenotype to be a unique digenic overlap of both heterozygous FH and heterozygous sitosterolemia with marked elevations in cholesterol absorption indices. Treatment with ezetimibe 10 mg daily resulted in a dramatic reduction in LDL cholesterol. Sitosterolemia, a rare autosomal recessive disorder of plant sterol hyperabsorption, can also result in xanthomatosis and thus can mimic FH. Although it is usually a homozygous disease, heterozygotes may exhibit intermediary phenotypes. Patients with severe hypercholesterolemia should undergo genetic and biochemical profiling for diagnostic confirmation and for ensuring that they receive optimal, personalized therapy. Show less

Ischemia-reperfusion (IR) and adriamycin (also named doxorubicin, DOX)-induced acute myocardial injuries have a significant impact on health, causing serious economic and medical burdens. Therefore, we need to explore and identify drugs with potential therapeutic value for treating I/R- and DOX-induced myocardial injury. In the present study, we explored the therapeutic potential of FGF4 for I/R and DOX-induced myocardial injury. We found that FGF4 showed good improvement in acute cardiac injury. However, due to the short half-life of FGF4, we further prepared a myocardial-targeted FGF4-sustained release nanoliposome (named FGF4-NANO-IMTP). We investigated the effect of FGF4-NANO-IMTP on myocardial injury caused by I/R and DOX. Show less

Chronic lymphocytic leukemia (CLL) is divided into unmutated (UM-CLL) and mutated (M-CLL) subtypes depending on somatic hypermutation (SHM) frequency in their immunoglobulin heavy chain V (IGHV) region. We previously demonstrated that CD27bright memory B cells (MBCs) are germinal center (GC)-dependent with higher mutation rate, whereas CD27dull MBCs accumulate fewer mutations and originate independently from the GC. We conducted a meta-transcriptomic analysis on bulk RNA data from 116 individuals combining four CLL cohorts and healthy B cell subsets (naïve, CD27dull and CD27bright MBCs) to decipher the transcriptional and mechanistic functions of CLL subtypes. CD27bright MBCs showed more transcriptional similarity to M-CLL rather than UM-CLL. Functional enrichment analysis revealed that LPL, ZNF667 and ZNF667-AS1 are potential informative biomarkers for stratification of CLL subtypes. They are part of the mechanistic regulatory pathways of CLL pathology through cholesterol and Epithelial Mesenchymal Transition (EMT) regulation. We applied markers for the GC B-cell substages to map in silico the CLL cohorts to their potential GC B cell counterpart. UM-CLL represented transcriptional mimicry to an early intermediary GC substage whereas M-CLL mimicked later substages in the GC. This could potentially explain the IGHV mutational status of M-CLL as well as hypothesize that CLL subtypes could derive from a GC-dependent pathway. Show less

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs. Show less

Progressive atherosclerotic cardiovascular disease (ASCVD) associated with high Lp(a) (>60 mg/dl) has been approved as indication for regular lipoprotein apheresis (LA) in Germany since 2008. This observational multicenter study enrolled 170 consecutive patients with high Lp(a) and progressive ASCVD despite effective treatment of other ASCVD risk factors as required for approval of reimbursement to analyse the long-term effect of LA on cardiovascular event rates. Additionally cardiovascular event rates were compared to an appropriate UK-Biobank cohort (UKBBC) with established ASCVD and verified impact of elevated Lp(a) on ASCVD risk. Investigations were conducted on patients retrospectively over a 5-year period before the initiation of regular LA, prospectively 5 years after the commencement of LA, and again retrospectively until the completion of 12 years of LA. 154 patients (90.6 %) completed 5 years follow-up, 129 patients (75.9 %) were available in year 12. A decline in the mean annual rate of cardiovascular events per patient was observed from y-5 to y-1 (0.27 ± 0.25) versus y+1 until y+12 (0.06 ± 0.08) (p < 0.001). One year before commencing LA mean event rates per 100 patient years of the primary composite endpoint parameter of major adverse cardiac events (MACE) including nonfatal ischemic stroke (IS) were significantly higher in Pro(a)LiFe patients compared to the UKBBC. Most importantly they were significantly lower one year after commencing LA. Regular LA was associated with a decreased rate of cardiovascular events in patients with high Lp(a) (>60 mg/dl) and progressive ASCVD up to 12 years. Comparison with corresponding incidence rates in the UKBBC supports the clinical efficacy of LA to bring progressive ASCVD associated with high Lp(a) to a halt. However, this comparative analysis cannot replace a true control group or determine the exact effect size. Show less