Search Results (66)

Background: Ionizing radiation (IR) induces profound bone marrow (BM) injury by disrupting hematopoietic stem cell (HSC) homeostasis, leading to acute myelosuppression and long-term hematopoietic dysfunction. Although transcriptome-wide analyses have advanced our understanding of radiation responses, the key molecular networks and hub genes governing post-irradiation BM injury remain incompletely defined. Methods: This study aimed to systematically identify radiation-responsive pathways and central genes in BM after irradiation through an integrative bioinformatics approach based on RNA sequencing (RNA-seq). Public RNA-seq data from mouse BM HSCs collected 3 days after whole-body irradiation were analyzed. Differentially expressed genes (DEGs) were identified using two independent statistical frameworks to improve the robustness of the results. Functional analysis was performed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Protein–protein interaction (PPI) networks were constructed using STRING, and hub genes were identified using network topology parameters. Results: Both analysis pathways consistently demonstrated extensive transcriptome reprogramming after irradiation. DEGs were primarily enriched in processes related to cytokine signaling, hematopoietic lineage regulation, immune response, and extracellular matrix remodeling. KEGG analysis highlighted cytokine–cytokine receptor interaction, hematopoietic cell lineage, JAK-STAT signaling, and PI3K-Akt signaling as key molecular axes. GSEA further supported coordinated changes in pathways related to inflammatory response, stress response, and metabolic reprogramming. PPI network analysis identified four consensus hub genes, namely Il6, Cd34, Gypa, and Pdgfrb, which are related to inflammatory signaling, hematopoietic regulation, erythroid dynamics, and microenvironmental remodeling, respectively. Conclusion: This integrative bioinformatics study demonstrates that radiation-induced BM injury is associated with coordinated activation of inflammatory cytokine networks, alterations in the hematopoietic program, and microenvironmental restructuring. The hub genes identified in this study may represent candidate regulatory genes or molecular indicators potentially involved in the response to radiation-induced hematopoietic damage. Full article

Myeloid/lymphoid neoplasms with tyrosine kinase rearrangements (MLN-TKs) are rare clonal eosinophilias driven by PDGFRA, PDGFRB and other kinase fusions, highly sensitive to tyrosine kinase inhibitors. Their detection remains challenging, particularly for cryptic PDGFRA rearrangements. We performed a large multicenter real-world validation of the generic quantitative RT-PCR assay (gPDGFR), which detects 3′ PDGFRA/PDGFRB overexpression independently of fusion partner. A total of 231 consecutive patients with hypereosinophilia from 12 French centers were analyzed, and assay robustness was further assessed in an independent heterogeneous cohort of 102 tyrosine kinase inhibitor (TKI)-treated patients. Twenty-two PDGFR-rearranged cases (14 PDGFRA-r, 8 PDGFRB-r) were identified. The assay demonstrated 100% sensitivity and 100% negative predictive value. For PDGFRA, positive predictive value and specificity reached 100%. In contrast, PDGFRB overexpression showed lower specificity due to borderline false-positive cases, underscoring the need for confirmatory testing. In selected patients, longitudinal gPDGFR kinetics paralleled fusion-specific RT-qPCR, supporting its use for molecular follow-up when dedicated assays are unavailable, although it does not provide quantitative measurable residual disease assessment. Overall, gPDGFR represents a robust, partner-independent first-line screening strategy that can be readily integrated into routine diagnostic workflows to enable timely identification of patients eligible for targeted therapy. Full article

Background: Acute myeloid leukemia (AML) with CBFB::MYH11 fusion and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) are genetically defined and typically mutually exclusive entities. Case Presentation: We report a unique case of de novo AML harboring two clonal, transcriptionally active class-defining fusions: CBFB::MYH11 and GOLGA4::PDGFRB. A 61-year-old woman presented with leukocytosis with neutrophilia, eosinophilia, and monocytosis; circulating blasts; and a markedly hypercellular marrow. Cytogenetic analysis revealed inv(16)(p13.1q22) and t(3;5)(p21;q32) in all 20 metaphases, and RNA sequencing confirmed expression of both CBFB::MYH11 and GOLGA4::PDGFRB fusions. In addition, an oncogenic WT1 frameshift variant was identified. Hematopathologic findings were largely consistent with AML with CBFB::MYH11 fusion but exhibited features reminiscent of PDGFRB-rearranged MLN-TK. The patient achieved complete remission following the standard 7 + 3 induction chemotherapy regimen for AML with gemtuzumab ozogamicin. Conclusions: This case illustrates the diagnostic challenges posed by concomitant class-defining alterations in hematologic neoplasms and underscores the importance of integrated genomic assessment. Full article

H3K4me3, a well-established histone modification associated with active promoters, plays a critical role in orchestrating gene expression programs that govern mammary gland development and lactation. In this study, we present the first comprehensive epigenomic profiling of H3K4me3 modifications during mammary gland development in Yili horses using Cleavage Under Targets and Tagmentation (CUT&Tag) and RNA sequencing. Mammary gland tissues were collected from two developmental stages—early lactation and peak lactation. A total of 393 differentially expressed genes (DEGs) were identified between two groups, among which 72 DEGs (54 upregulated H3K4me3 targets and 18 downregulated targets) were directly regulated by H3K4me3. KEGG enrichment analyses revealed that these DEGs were involved in ECM–receptor interaction, focal adhesion, the PI3K-Akt signaling pathway, and the calcium signaling pathway. In these pathways, five genes were identified as potential regulators of mammary gland development. Among these, PTGES, COL1A1, PDGFRB, and RYR1 exhibited consistent upregulation at both the transcriptomic and chromatin levels, whereas PRKAG3 showed significant downregulation. These findings offer novel insights into the epigenetic regulation of lactation in horses and lay a theoretical foundation for improving milk production traits through targeted molecular breeding strategies. Full article

We studied the expression of connexin 43 (Cx43) and pannexin 1 (PANX1) in different cellular populations of the kidneys of diabetic mice and diabetic and non-diabetic patients, to evaluate their role as potential therapeutic targets in diabetic kidney disease (DKD). A combination of a low dose of streptozotocin and a high-fat diet (HFD) was used to induce a type 2 diabetes model (DM2) in mice. Kidney tissues from diabetic (n = 9) and control patients (n = 11) who underwent nephrectomy were collected. Tissues from mice and humans were processed for double immunofluorescence, using antibodies against Cx43, phosphorylated Cx43 (pCx43) or PANX1 and markers for specific cell populations: endothelium (CD31/PECAM1); pericytes/mesangium (PDGFRB); podocytes (nephrin/synaptopodin); proximal tubules and collecting ducts (aquaporin 2). The results showed a significant decrease in the expression of pCx43 in PDGFRB-immunoreactive mesangium in diabetic patients compared to the control group (p < 0.0001). This contrasted with an increase in pCx43 in pericytes of diabetic mice (p = 0.1). However, we found a general decrease in Cx43 protein expression in diabetic mouse kidneys (p < 0.05). We also found a decrease in the expression of PANX1 in endothelial cells of diabetic patients (p < 0.05) and a significant increase in PANX1 expression in cells expressing PDGFRB (p < 0.05). Expression of PANX1 in endothelium (r = −0.50; p < 0.05) and pCx43 in the mesangium (r = −0.65; p < 0.01) correlated negatively with the percentage of sclerotic glomeruli. The expression and activation of Cx43 and the expression of PANX1 are altered in distinct populations of renal cells during long-term type 2 diabetes mellitus, especially cells of the vascular wall. This may indicate their role in the pathophysiological processes of DKD. Therefore, connexin and pannexin channels could be considered as possible therapeutic targets in the prevention and treatment of diabetic kidney disease. Full article

Marrow-isolated adult multilineage inducible (MIAMI) cells are a subpopulation of mesenchymal stem/stromal cells (MSC) with enhanced self-renewal, multilineage plasticity, and anti-inflammatory properties, suggesting that their extracellular vesicles (MIA-EVs) may confer advantages over conventional MSC-EVs. MIAMI cells were transcriptionally profiled and expressed regenerative markers, including PDGFRB, CDX2, and TERT. We report the first successful isolation and characterization of MIA-EVs. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, transmission electron microscopy, flow cytometry, and surface markers. Cargo analysis identified growth factors (IGFBP-1, HGF, VEGF-D) and 19 highly expressed miRNA targeting survival, regenerative, and immune regulatory pathways. MIA-EVs were efficiently internalized, enhanced keratinocyte wound closure and suppressed osteosarcoma proliferation in vitro. Conditioned MIA-EVs reshaped pathway weighting without altering core regulatory identity, as a conserved 15-miRNA backbone persisted across naïve, irradiated, and cytokine-primed states. In contrast, a 9-miRNA core shared with MSC-EVs defined a basal mesenchymal framework, while MIA-EVs expanded regenerative, survival, and immune network connectivity. Similar to embryonic stem cell (ESC)-EVs, both MIA- and cytokine-primed EVs promoted M2 macrophage polarization, selectively upregulating IL1R2 and PPARG/STAT1, respectively. Meanwhile, MSC-EVs induced heterogeneous responses. These findings establish MIA-EVs as a conditioning-resistant, systems-regulated, cell-free platform with regenerative, immunomodulatory, and cytoprotective potential under hostile microenvironments. Full article

Small bowel obstruction (SBO) in dogs is most commonly caused by foreign bodies or neoplasia; however, SBO secondary to transmural fibroplasia remains a rare clinical complication of canine chronic enteropathy. This report describes the complex case of mechanical SBO caused by transmural ileal fibroplasia and inflammation at the ileocolic junction in a 9-year-old mixed-breed dog with concomitant hyperadrenocorticism (HAC). The primary presentation involved chronic severe weight loss and intermittent anorexia, contrasting with the acute presentation typical of most SBO cases. Imaging studies revealed severe, circumferential thickening up to 10 mm of the small intestine wall at the ileocolic junction (ICJ), resulting in complete luminal stricture and marked proximal dilation. Surgical intestinal resection and anastomosis were performed for alleviation of the obstruction, and histopathology confirmed severe mural and serosal enteritis with extensive fibroplasia extending into the adjacent mesentery, thereby excluding neoplastic processes. Quantitative PCR analysis demonstrated a significant upregulation of mRNA expression for PDGFRB and FGFR compared to normal tissue. Postoperative recovery was rapid; although soft feces persisted for one month, normal stool consistency was subsequently restored, and the patient achieved significant weight gain. This case underscores the diagnostic and therapeutic challenges associated with non-neoplastic, inflammation-driven SBO and suggests that activation of the PDGFR-β/FGFR pathways may play a key role in fibroplasia-related intestinal strictures, offering a novel molecular perspective beyond conventional SBO etiologies. Full article

Background: Colorectal cancer (CRC) demonstrates substantial clinical and biological diversity across age groups, ancestral backgrounds, and treatment settings, alongside a rising incidence of early-onset disease (EOCRC). The mitogen-activated protein kinase (MAPK) pathway is a major driver of CRC development and therapy response; however, the distribution and prognostic value of MAPK alterations across distinct patient subgroups remain unclear. Methods: We analyzed 2515 CRC tumors with harmonized demographic, clinical, genomic, and treatment metadata. Patients were stratified by ancestry (Hispanic/Latino [H/L] vs. non-Hispanic White [NHW]), age at diagnosis (early-onset [EO] vs. late-onset [LO]), and FOLFOX chemotherapy exposure. MAPK pathway alterations were identified using a curated gene set encompassing canonical EGFR-RAS-RAF-MEK-ERK signaling components and regulatory nodes. Conversational artificial intelligence (AI-HOPE and AI-HOPE-MAPK) enabled natural language-driven cohort construction and exploratory analytics; findings were validated using Fisher’s exact testing, chi-square analyses, and Kaplan–Meier survival estimates. Results: MAPK pathway disruption demonstrated marked heterogeneity across ancestry and treatment contexts. Among EO H/L patients, FGFR3, NF1, and RPS6KA6 mutations were significantly enriched in tumors not receiving FOLFOX, whereas PDGFRB alterations were more frequent in FOLFOX-treated EO H/L tumors relative to EO NHW counterparts. In late-onset H/L disease, NTRK2 and PDGFRB mutations were more common in non-FOLFOX tumors. Distinct MAPK-associated alterations were also observed among NHW patients, particularly in non-FOLFOX settings, including AKT3, FGF4, RRAS2, CRKL, DUSP4, JUN, MAPK1, RRAS, and SOS1. Survival analyses provided borderline evidence that MAPK alterations may be linked to improved overall survival in treated EO NHW patients. Conversational AI markedly accelerated analytic throughput and multi-parameter discovery. Conclusions: Although MAPK alterations are pervasive in CRC, their distribution varies meaningfully by ancestry, age, and treatment exposure. These findings highlight NF1, MAPK3, RPS6KA4, and PDGFRB as potential biomarkers in EOCRC and H/L patients, supporting the need for ancestry-aware precision oncology approaches. Full article

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases originating from hematopoietic stem cell transformation, characterized by the clonal proliferation of hematopoietic progenitors. A specific subset includes myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions, particularly involving PDGFR A or B, which are sensitive to TK inhibitor treatment. We report a case of a 21-year-old patient with a myeloproliferative/myelodysplastic neoplasm, presenting with hyperleukocytosis, anemia, thrombocytopenia, and elevated LDH. The peripheral blood smear showed hypogranular neutrophils, eosinophils, basophils, and myeloid precursors. The absence of BCR::ABL1 and mutations in JAK2, CALR, and MPL excluded common MPNs. Cytogenetic analysis revealed a rearrangement between chromosomes 5 and 14. FISH analysis confirmed an inverted insertion from chromosome 5 to chromosome 14, involving the PDGFRB gene. WGS and RNAseq identified a fusion between PDGFRB and CCDC88C, causing the constitutive activation of PDGFRB. The fusion gene was confirmed by sequencing. This allowed for targeted therapy with a tyrosine kinase inhibitor (TKI), leading to molecular remission monitored by RT-qPCR. This case highlights how a multidisciplinary approach can identify atypical transcripts in MPN, guiding targeted therapy with TK inhibitors, thus resulting in effective treatment and molecular remission. Full article

Primary Brain Calcification (PBC) is a neurodegenerative disorder of unknown etiology that results in bilateral calcifications within the brain. PBC symptoms vary, including Parkinsonian symptoms and psychiatric symptoms. Abnormalities in phosphate metabolism within the brain are hypothesized to be a mechanism underlying the onset of PBC, but the precise pathophysiological mechanism remains unclear. Furthermore, no fundamental treatment or therapeutic agent for PBC has been established. Previous studies have reported SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, JAM2, CMPK2, and NAA60 as causative genes for familial PBC. Elucidating the pathophysiological mechanisms of PBC and developing treatments and therapeutic agents requires appropriate experimental disease models. Knockout mice and mutant mice targeting familial causative genes have been reported to be useful as in vivo models of PBC. Furthermore, several disease-specific iPS cells for PBC have been reported, suggesting their potential utility as PBC models. This paper reviews each familial causative gene and current PBC models, including genetically modified animals and disease-specific iPS cells, and examines their usefulness for understanding disease mechanisms and advancing therapeutic research. Full article

Cancer exhibits diverse and complex phenotypes driven by multifaceted molecular interactions. Recent biomedical research has emphasized the comprehensive study of such diseases by integrating multi-omics datasets (genome, proteome, transcriptome, epigenome). This approach provides an efficient method for identifying genetic variants associated with cancer and offers a deeper understanding of how the disease develops and spreads. However, it is challenging to comprehend complex interactions among the features of multi-omics datasets compared to single omics. This study investigates multi-omics lung cancer data obtained from The Cancer Genome Atlas (TCGA) repository. Differentially expressed genes were identified using four statistical approaches: LIMMA, T-test, Canonical Correlation Analysis (CCA), and the Wilcoxon test applied across gene expression (GE), DNA methylation, and microRNA (miRNA) datasets. Kernel Machine Regression (KMR) was subsequently employed to perform data fusion across the multi-modal datasets. The empirical results highlight notable interactions among GE, miRNA expression, and DNA methylation in lung cancer. Our analysis identified 38 genes that show significant associations with lung cancer. Among these, 8 genes of highest ranking (PDGFRB, PDGFRA, SNAI1, ID1, FGF11, TNXB, ITGB1, and ZIC1) were highlighted by rigorous statistical analysis. Furthermore, in silico studies identified three top-ranked potential candidate drugs (Selinexor, Orapred, and Capmatinib) that may offer promising therapeutic potential against lung cancer. The effectiveness of these candidate drugs is further reinforced by evidence from independent research studies, which emphasize their potential in lung cancer treatment. Full article

Objectives: Bisphenol A (BPA), a prototypical environmental endocrine-disrupting chemical (EDC), is ubiquitously present in environmental matrices and biological fluids. Dietary ingestion and inhalation exposure to BPA can induce testicular oxidative stress and apoptosis. This study aimed to investigate the protective effects and underlying mechanisms of Pfaffia glomerata (Pg), a perennial herb of the Amaranthaceae family, against BPA-induced reproductive system injury. Methods: Potential targets and molecular mechanisms were predicted through network pharmacology. Physiological indicators, histopathological changes, serum biochemical parameters, and Western blot analysis were used to systematically evaluate the ameliorative effects of Pg and elucidate its mechanisms. Results: Our network pharmacology analysis identified core targets of Pg in attenuating reproductive system injury, including PTPN11, PIK3CA, JAK2, PIK3R1, PDGFRB, and others. GO enrichment and KEGG pathway analysis indicated that these key targets primarily regulate steroid metabolism, enhance antioxidant capacity, and modulate signaling pathways such as PI3K-AKT, Fc epsilon RI, and cAMP. In vivo studies demonstrated that all Pg dose groups showed significant improvement in BPA-induced histopathological injury to testicular tissues. BPA exposure increased serum levels of follicle-stimulating hormone (FSH) while decreasing testosterone (T), estradiol (E2), and progesterone (PROG) levels. Furthermore, BPA elevated serum levels of the testicular marker enzymes acid phosphatase (ACP) and lactate dehydrogenase (LDH) but reduced alkaline phosphatase (ALP) levels; all these effects were significantly reversed with Pg treatment. Western blot results showed that compared with the model group, high-dose Pg significantly upregulated the expression of phosphorylated AKT (p-AKT), phosphorylated PI3K (p-PI3K), and Bcl-2, while downregulating Cleaved Caspase-3 and Bax. Conclusions: Our findings indicate that Pg may attenuate BPA-induced reproductive system injury by activating the PI3K/AKT signaling pathway, upregulating the anti-apoptotic protein Bcl-2, and inhibiting the activation of the apoptotic effector Caspase-3. The study provides a new theoretical basis for the development of novel natural drugs or health products. Full article

Background: Cancer-associated fibroblasts (CAFs) are a key component of the prostate cancer (PCa) microenvironment, the abundance of which is often linked to poor prognosis. The surface markers for CAFs are mostly established, yet our current knowledge of epigenetic alterations in them remains limited. The aim of this study was to evaluate the relationship between CAF-specific DNA methylation, their abundance and the PCa prognosis. Methods: The study included 88 PCa patients with known presence or absence of a biochemical recurrence within a 6-year period. Resected PCa tissue was assessed for the surface expression of FAP, PDGFRb, CD90, and POST, and for the methylation of EDARADD, GATA6, and PITX2 genes using qPCR and ddPCR. Results: The surface expression of FAP, PDGFRb and CD90 was associated with a higher Gleason score (p < 0.05). The analytical sensitivity of ddPCR was superior to qPCR; results obtained using ddPCR demonstrated a more significant association with clinical features of PCa. EDARADD methylation and PDGFRb expression were associated with a risk of biochemical recurrence (HR–0.961 [95% CI: 0.931–0.991] and HR–2.313 [95% CI: 1.054–5.088]; p < 0.05, respectively). Conclusions: Upon further validation, the abundance of CAFs and their specific methylation might become a promising tool for the assessment of prognosis in PCa after radical treatment. Full article

Gestational diabetes mellitus (GDM) and iron deficiency anemia (IDA) are the most common pregnancy-related conditions resulting in adverse maternal and fetal complications. MicroRNAs (miRNAs), particularly miR-182-3p and miR-24-3p, are promising biomarkers as they act as regulatory elements in various diseases; however, their roles in GDM and IDA are unclear. The present study aimed to analyze the expression and functional relevance of miR-182-3p and miR-24-3p in GDM and IDA. Experimental validation via RT-PCR revealed significant upregulation of both miRNAs in GDM and IDA samples. We identified common target genes and signaling pathways associated with these miRNAs, using a combination of data mining, bioinformatic tools (miRDB, TargetScan, miRTarBase, and miRWalk), and differentially expressed gene (DEGs) analysis using the GEO, OMIM, MalaCards, and GeneCards datasets. GO and KEGG pathway analyses revealed that the shared miRNA–mRNA in target genes were enriched in insulin signaling, apoptosis, and inflammatory pathways—key mechanisms implicated in GDM and IDA. Furthermore, hub genes such as IRS1, PIK3CA, CASP3, MAPK7, and PDGFRB were identified, supporting their central role in metabolic dysregulation during pregnancy. These findings demonstrate the potential of miR-182-3p and miR-24-3p as diagnostic biomarkers and therapeutic targets in managing GDM and IDA, offering new insights into the molecular interplay underlying pregnancy complications. Full article

The brain actively obtains nutrients through various transporters on brain microvessel endothelial cells (BMECs). Major facilitator superfamily domain–containing protein 2a (MFSD2A) serves as a key transporter of docosahexaenoic acid (DHA) at the blood–brain barrier (BBB) and is exclusively expressed in BMECs. Although brain pericytes (PCs) regulate MFSD2A expression in BMECs, the underlying mechanism remains unclear. To determine whether PDGF-BB/PDGFRβ signaling between endothelial cells (ECs) and PCs affects MFSD2A protein expression and plasma membrane localization in ECs, we examined the impact of AG1296 (a PDGF receptor inhibitor) and Pdgfrb-knockdown PCs on a non-contact coculture BBB model comprising the primary cultures of rat brain ECs and PCs. The effects of PCs on MFSD2A expression, localization, and brain endothelial DHA uptake was assessed using Western blot, immunofluorescence staining, and [¹⁴C]DHA uptake by ECs, respectively. In ECs cocultured with PCs, MFSD2A expression and plasma membrane localization were significantly higher than in EC monolayers. Moreover, conditioned medium derived from PCs failed to enhance MFSD2A expression. The increased expression and membrane localization of MFSD2A were inhibited by AG1296 and Pdgfrb-knockdown PCs. Furthermore, PCs significantly increased [¹⁴C]DHA uptake by ECs. These findings suggest that PCs enhance MFSD2A expression and plasma membrane localization in ECs through PDGF-BB/PDGFRβ signaling. Full article