👤 Dong Lin

Background Myeloid/lymphoid neoplasm with eosinophilia and rearrangement of FGFR1(MLN-FGFR1), also referred to as 8p11 myeloproliferative syndrome (EMS), arises from aberrant FGFR1 gene rearrangement in bone marrow hematopoietic stem cells, resulting in the transformation of myeloid/lymphoid cells into neoplastic growths. The clinical and laboratory features of affected individuals are influenced by the specific partner genes. Purpose This article aims to report a case of MLN-FGFR1 involving a novel CNTRL::FGFR1 splicing variant and to discuss its clinicopathological characteristics and treatment challenges. Methods/Results We report a case of MLN-FGFR1 in a 35-year-old male patient presenting with leukocytosis, lymphadenopathy, hepatosplenomegaly, and a mixed population of B lymphoblasts, T lymphoblasts, and monoblasts in the bone marrow and lymph nodes. Comprehensive molecular profiling, including chromosomal karyotyping, fluorescence in situ hybridization (FISH), targeted transcriptome sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing, identified a novel splicing variant of the CNTRL::FGFR1 fusion, resulting from a t(8;9)(p11;q33) translocation. This novel splicing variant involves an in-frame fusion between exon 38 of CNTRL and exon 11 of FGFR1, retaining the kinase domain of FGFR1 and leading to its constitutive activation. Despite multiple treatment regimens, the patient failed to achieve complete remission (CR). Conclusion The findings highlight the urgent need for targeted therapies, such as FGFR inhibitors, to improve outcomes in patients with FGFR1-rearranged malignancies. Show less

Idiopathic hypogonadotropic hypogonadism (IHH) is a set of rare diseases characterized by abnormal sexual development with clinical heterogeneity and genotypic complexity. This study aims to investigate the phenotypic and genotypic characteristics of male IHH in southern China, and evaluate the therapeutic effects of current treatments. Fifty-one male IHH patients from southern China were enrolled in this study. Their clinical, imaging, hormonal and genetic findings were analyzed retrospectively. In this study, the most common causative gene of IHH was FGFR1 (45.10%), followed by ANOS1 (21.57%) and CHD7 (17.65%). Forty-five different variants, including 22 known and 23 novel variants, were found. The mean age at diagnosis was 7.84 ± 5.89 years, the most common clinical phenotype was micropenis (98.04%), the most frequent imaging feature was abnormal ultrasound of sexual glands (86.84%), and the most representative biochemical manifestations were low basal luteinizing hormone (LH) and testosterone (98.04% and 100.00%, respectively). Age-phenotype and genotype-phenotype correlations were observed in this cohort. The penile length, testicular volume, basal testosterone, and the proportion of patients with low basal inhibin B were associated with age. Most patients with ANOS1 variant had a family history, impaired olfactory function, and much lower basal anti-mullerian hormone (AMH), whereas patients with CHD7 variant were younger, presented CHARGE phenotypes, and had higher basal follicle-stimulating hormone (FSH) and LH. Moreover, 34 patients were treated with different strategies for 2.75 ± 1.82 years. After treatment, the penile length, and the levels of FSH, LH and testosterone increased significantly. Our study adds 51 southern Chinese male patients, and expands the mutational spectrum for IHH. Our cohort suggests that a combination of clinical, biochemical and genetic criteria will facilitate early diagnosis. Our work also highlights the differentially diagnostic values of family history, impaired olfactory function, CHARGE features, and basal AMH, FSH and LH in distinguishing different molecular bases of IHH. Show less

Adult granulosa cell tumors (aGCTs) of the ovary are uniquely characterized by an almost ubiquitous somatic mutation in the FOXL2 gene (p.C134W). We report the first series of 7 aGCTs harboring pathogenic FGFR1 kinase domain mutations, providing a novel alternative oncogenic mechanism in these rare FOXL2 -wildtype tumors. Archival sex cord-stromal tumors that underwent targeted DNA sequencing (MSK-IMPACT, Oncopanel, and Foundation Medicine assays) were reviewed. Histopathologic and immunophenotypic features were reviewed by expert pathologists. Seven cases were identified with FGFR1 hotspot mutations (codons N546, N577, K656, and K687), 6 of which lacked the pathognomonic FOXL2 p.C134W variant. All tumors demonstrated the classic histology of aGCT (microfollicular growth, Call-Exner bodies, "coffee bean" nuclei) with 5/5 showing robust inhibin-α positivity by immunohistochemistry. No distinct morphologic or immunophenotypic differences were found compared with conventional FOXL2 -mutant aGCTs. Clinically, most patients presented at early stage (IA) and underwent surgical management. Four patients experienced recurrent disease involving peritoneal or omental sites, but overall clinical behavior was comparable to typical aGCTs. These findings establish FGFR1 alterations as an alternative oncogenic driver in a subset of FOXL2 -wildtype aGCTs. From a diagnostic standpoint, the absence of FOXL2 p.C134W mutation does not exclude the diagnosis of aGCT when the morphology and immunoprofile are characteristic. Show less

Aberrant activation of fibroblast growth factor receptors (FGFRs) plays a critical role in tumorigenesis across multiple cancer types, driving the development of various FGFR inhibitors. Despite clinical advances, therapeutic efficacy remains limited by the emergence of drug resistance, primarily mediated by gatekeeper mutations in FGFRs. To overcome this challenge, we designed and synthesized a novel series of 7-(1-methyl-1 Show less

Fibroblast growth factor receptor (FGFR) alterations are established therapeutic targets in cholangiocarcinoma and urothelial carcinoma but remain understudied in colorectal cancer (CRC). This study investigates the prevalence, clinicopathological correlates, and prognostic impact of FGFR alterations in CRC. We analyzed 608 stage I-IV CRC samples (2014-2024) through next-generation sequencing (NGS) and immunohistochemistry (IHC). FGFR genomic status was correlated with survival outcomes using Kaplan-Meier and Cox regression analyses. External validation of FGFR genomic alterations was carried out using the 19 datasets (n = 6998) with prognostic impact validated through The Cancer Genome Atlas Colon and Rectum Adenocarcinoma (COREAD) dataset (Firehose Legacy, n = 640), both accessed via cBioPortal database. Large-scale genomic profiling of CRC [n = 7606 (608 in-house + 6998 public cohorts)] identified FGFR1 amplification (3.8% prevalence) as the predominant FGFR alteration subtype. Multivariable analysis confirmed FGFR alterations as independent predictors of poor disease-free survival [DFS; hazard ratio (HR) 2.58, P = 0.0002] and progression-free survival (PFS; HR 2.17, P = 0.0011), with FGFR1 amplification showing strongest prognostic impact (DFS HR 2.91, PFS HR 2.52, P < 0.01). Notably, the prognostic magnitude of FGFR alterations was comparable to KRAS/BRAF mutations in both localized and metastatic CRC. In addition, we established a semiquantitative immunoreactive score (IRS) system achieving 95.2% concordance with NGS (κ = 0.901), enabling reliable FGFR1 screening in routine pathology workflows. This study provides the first comprehensive characterization of FGFR genomic alterations in CRC through large-scale profiling (n = 7606), establishing FGFR1 amplification as the predominant alteration. Unlike FGFR2/3-driven malignancies, FGFR1-amplified CRC exhibited aggressive clinical behavior and inferior survival outcomes across disease stages. To address the diagnostic challenges in routine practice, we further developed a validated immunohistochemical scoring system (IRS), establishing a cost-effective and clinically feasible alternative to molecular assays for identifying FGFR1-driven CRC subsets. Show less

Fibroblast growth factor receptors (FGFRs) are well-established oncology targets, with aberrant FGFR2 and FGFR3 activation implicated in multiple tumor types, including cholangiocarcinoma and urothelial carcinoma. Currently approved FGFR2/3-targeted therapies rely on pan-FGFR small-molecule kinase inhibitors, which often lead to off-target toxicities due to unintended inhibition of FGFR1 and FGFR4, as well as acquired resistance driven by gatekeeper mutations. Herein, we report the discovery of INCB126503, a highly potent, orally bioavailable FGFR2/3 inhibitor with excellent isoform selectivity and equipotent activity against gatekeeper mutants. INCB126503 effectively suppresses FGFR signaling in vivo without inducing hyperphosphatemia and demonstrates significant antitumor efficacy in xenograft models harboring FGFR3 genetic alterations. Show less

Inflammatory breast cancer (IBC) is a rare and clinically distinct form of breast cancer associated with poor outcomes. The biological mechanisms driving IBC remain poorly understood, partly due to limited large-scale genomic studies that directly compare IBC with non-IBC cases. We conducted a retrospective analysis of 140 patients with IBC (68 primary tumors and 72 metastatic tumors) and 2,317 patients with non-IBC (700 primary tumors, 65 local recurrences, and 1,552 metastases). We compared clinicopathologic features, single-nucleotide variants, copy-number variants, tumor mutational burden, and exploratory survival outcomes between IBC and non-IBC tumors. The most frequent somatic alterations in IBC were detected in TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%), and GATA3 (8%). Multivariate logistic regression revealed a significant enrichment of TP53 single-nucleotide variants in IBC, particularly in HER2+ and hormone receptor-positive disease. Tumor mutational burden did not differ between IBC and non-IBC cases. In HER2+ disease, a pathway analysis revealed an enrichment of NOTCH pathway alterations. TP53, CCND1, and RB1 alterations were associated with poor outcomes in IBC. This study provides a comprehensive resource of somatic alterations in a large cohort of patients with metastatic IBC and non-IBC, highlighting genomic features associated with worse outcomes. Our findings reveal a significant enrichment of TP53 mutations, reinforcing its critical role in IBC pathogenesis. Few other distinct differences in IBC were observed, suggesting further investigations-beyond bulk sequencing of the somatic genome-are required to better understand the biology driving this aggressive disease. Show less

The angiogenesis phenomenon is crucial for the formation of new blood vessels in cancer cells. The cancerous cells' progress hampers other healthy cells. The main objective of this study is to explore and decipher multimodal natural compounds against VEGFR2, EphB4, FGFR-1, and TIE-2 drug targets to arrest angiogenesis and progression. The receptor-based pharmacophore modeling of VEGFR2, EphB4, FGFR-1, and TIE-2 was developed and validated through enrichment parameters. Further, the validated hypothesis allowed for screening druglike natural product databases such as SuperNatural 3.0, COCONUT, and LOTUS. The common pharmacophoric featured natural compounds were assessed for binding affinities using absolute end-point methods. Finally, density functional theory has been studied to understand the chemical reactivity and stability of the protein complexes. Among all of the screened natural compounds, 17 natural compounds were found to align accurately against validated pharmacophore models having higher fitness scores and align scores. Taking reference drugs sorafenib (VEGFR2), NVP-BHG712 (EphB4), pemiganitib (FGFR-1), and DP1919 (TIE-2), three promising natural compounds CNP0003920, CNP0243075, and CNP0211397 were concluded based on their end-point binding energies, binding interactions, molecular dynamics, and optimal pharmacokinetic and toxicity profiles. The density functional theory (DFT) results suggested that the identified compounds bound with protein complexes are stable. Our findings can represent a promising starting point for developing multimodal analogues VEGFR2, EphB4, FGFR-1, and TIE-2 proteins. Show less

β-Sitosterol (BS), is a significant bioactive component of phytosterols found in plants, foods, and dietary supplements. Its nutritional benefits include lowering of cholesterol levels, boost immune system as well as reduce inflammation. Previous studies have demonstrated its significant anticancer effects across various human cancers. However, the specific mechanisms of action of BS in lung cancer remain unclear. This study aimed to investigate the mechanisms through which BS exerts its anticancer properties in human lung cancer cells, focusing on its anti-proliferative, apoptotic, cytotoxic, and anti-migratory effects. We conducted an in vitro study to assess the effects of BS on lung cancer cell lines A549 and H1975. We used a range of assays, including MTT, western blot, wound healing, transwell migration, immunofluorescence, TUNEL, and cell survival assays, to evaluate the impact of BS on cell proliferation, apoptosis, cytotoxicity, and migration. Our findings indicate that BS inhibits the proliferation of lung cancer cells in a time- and dose-dependent manner. It significantly promotes apoptosis and impairs both cancer cell migration and survival. Additionally, BS suppresses the expression of both fibroblast growth factor receptor-1 (FGFR1) and epidermal growth factor (EGFR), leading to the downregulation of the PI3K/AKT/mTOR/CD1 signaling pathway. BS demonstrates significant anticancer potential in lung cancer cells by inhibiting proliferation, inducing apoptosis, and reducing cell migration. These effects are likely mediated by the concurrent downregulation of FGFR1 and EGFR, leading to the inhibition of the PI3K/AKT/mTOR/CD1 signaling pathway, thereby warranting further investigation of BS as a potential therapeutic agent for lung cancer. Show less

FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1 Show less

Time-restricted feeding (TRF) is a dietary intervention that has been shown to have numerous health benefits. However, it is important to further investigate the potential effectiveness of TRF in addressing sarcopenic obesity (SO), which is characterized by a combination of age-related obesity and sarcopenia. In this study, 14-month-old C57BL/6J male mice were fed either regular chow diet or high-fat diet (HFD), and had either ad libitum or restricted access to food for 8 hours daily (Intervention for 7 months). For the human trial (ChiCTR2100052876), obese individuals (n=21) with a Body Mass Index ≥28 were recruited and instructed to adopt an 8-hour eating window and a 16-hour fasting period. Here, we found that the TRF intervention significantly reduced global fat mass (P < .001) and volume (P < .05), and increase lean mass compared to mice fed with HFD. Furthermore, TRF improved overall metabolic mobility (8h TRF+HFD vs. AL+HFD). This intervention also enhanced liver FGF21 protein levels (P < .01) and the expression of FGFR1 and FGF21 target genes in adipose and muscle tissues, thus improving mitochondrial quality control in these tissues. Notably, TRF interventions led to a significant decrease in serum FGF21 levels (P < .05). In the human trial, TRF intervention resulted in a significant reduction in weight (P < .001) and body fat levels (P < .001) among obese individuals, as well as a decrease in serum GLU (P < .001), insulin (P < .001), and TC levels (P < .05). Overall, the findings indicate that TRF intervention improves SO by regulating liver FGF21 expression, thereby enhancing FGF21 sensitivity in adipose and muscle tissues. Show less

Deep brain stimulation (DBS) has emerged as a prospective treatment for psychiatric disorders; for example, DBS targeting the nucleus accumbens (NAc) abolishes addictive behaviors. However, neither the core pathway nor the cellular mechanisms underlying these therapeutic effects are known. Here, morphine-induced conditioned place preference (CPP) in mice as an addiction model and NAc-DBS combined with adeno-associated virus gene delivery for activity-dependent tagging, transgenic and chemogenetic manipulation of recruited neuronal networks are used. It is reported that a cortical-accumbal pathway and local fibroblast growth factor 1 (FGF1) signaling in the medial prefrontal cortex (mPFC) are critical for NAc-DBS to be effective in altering morphine CPP. It is shown that NAc-DBS retrogradely activates mPFC neurons projecting to the NAc, and chemogenetic activation/inhibition of these DBS-activated neuron ensembles in the mPFC reproduces the NAc-DBS effects on CPP. Sustained therapeutic effects accompany reductions in local FGF1 binding to fibroblast growth factor receptor 1 (FGFR1) in these neurons. Additionally, overexpressing FGF1 in the mPFC-NAc pathway abolishes the therapeutic effects of NAc-DBS. These results demonstrate that the mPFC-NAc pathway forms a top-down motif to regulate the therapeutic effects of subcortical DBS on addiction. These results support the potential for addiction treatments involving FGF1 signaling and highlight the mPFC as a target for noninvasive brain stimulation. Show less

Studying the molecular properties of drugs and their interactions with human targets aids in better understanding the clinical performance of drugs and guides drug development. In computer-aided drug discovery, it is crucial to utilize effective molecular feature representations for predicting molecular properties and designing ligands with high binding affinity to targets. However, designing an effective multi-task and self-supervised strategy remains a significant challenge for the pretraining framework. In this study, a multi-task self-supervised deep learning framework is proposed, MTSSMol, which utilizes ≈10 million unlabeled drug-like molecules for pretraining to identify potential inhibitors of fibroblast growth factor receptor 1 (FGFR1). During the pretraining of MTSSMol, molecular representations are learned through a graph neural networks (GNNs) encoder. A multi-task self-supervised pretraining strategy is proposed to fully capture the structural and chemical knowledge of molecules. Extensive computational tests on 27 datasets demonstrate that MTSSMol exhibits exceptional performance in predicting molecular properties across different domains. Moreover, MTSSMol's capability is validated to identify potential inhibitors of FGFR1 through molecular docking using RoseTTAFold All-Atom (RFAA) and molecular dynamics simulations. Overall, MTSSMol provides an effective algorithmic framework for enhancing molecular representation learning and identifying potential drug candidates, offering a valuable tool to accelerate drug discovery processes. All of the codes are freely available online at https:// github.com/zhaoqi106/MTSSMol. Show less

This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance in hepatocellular carcinoma. Bioinformatics tools and drug sensitivity assays were used to investigate the association between Aurora-A expression level and lenvatinib resistance in hepatocellular carcinoma cell lines. Cell function experiments had performed after treatment with lenvatinib and/or a selective Aurora-A inhibitor (MLN-8237). CircRNA microarray, RIP, RNA pull-down, and dual-luciferace reporter assay were performed to identify the downstream molecular mechanism of Aurora-A dysregulation. Aurora-A expression was positively correlated with lenvatinib resistance in hepatocellular carcinoma cells. The Aurora-A selective inhibitor MLN-8237, in combination with lenvatinib, synergistically inhibited hepatocellular carcinoma cell proliferation in vitro and vivo, suggesting the Aurora-A might be a potential therapeutic target for lenvatinib resistance. Mechanistically, Aurora-A induced FGFR1 expression through the hsa-circ-0058046/miR-424-5p/FGFR1 axis. Aurora-A promotes lenvatinib resistance through hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma cells. The simultaneous inhibition of FGFR1 by the Aurora-A inhibitor MLN-8237 and lenvatinib overcame lenvatinib resistance in hepatocellular carcinoma cells. Collectively, our findings indicate that Aurora-A promotes lenvatinib resistance through the hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma (HCC) cells. These results suggest that Aurora-A may serve as a therapeutic target for HCC patients exhibiting lenvatinib resistance. Furthermore, the combination of lenvatinib and MLN-8237 shows potential for clinical trials aimed at overcoming lenvatinib resistance. Show less

Chemoresistance is one ofthe main challenges for advanced NPCtreatment.We previouslyproved LHX2 transcriptionally regulates FGF1 and promotes cancer progression through activating FGF1/FGFR axis,which prompted us toexplore the potential inhibitors for FGFR to improve the therapy response. RT-qPCR, immunohistochemistry, western blot assayand immunofluorescencewere applied to verify the gene expression levels. Xenograftmodel as well as lung metastasis model was performed forin vitroassays. Flow cytometry and Tunel stainingwere used to determine the apoptosis of NPC cells.The interaction between β-eudesmol and FGFR1/2 was analyzed by Autodock software. β-eudesmol inhibited the growth and metastasisof NPCin vivoandin vitro.In addition,β-eudesmol treatment promoted NPC apoptosis and sensitized NPC to cisplatin. β-eudesmol putatively bound to FGFR and blocked the Akt signaling, STAT3 signalingandERKsignaling,which in turn restrainedABCC1 transcription. β-eudesmol suppressed cell growth, metastasis and chemoresistance in NPC through targetingFGF1/FGFR signaling, thereby blocking the Akt signaling, STAT3 signaling andERKsignaling, as well as down-regulating ABCC1 expression. Our findings provided a novel potential drug for NPC treatment. Show less

Good skin quality not only improved carcass quality but also increased consumer demand for fresh poultry meat. This study aimed to investigate the developmental changes in skin growth and quality of Pekin ducks during 1-6 weeks of age. The skin samples were collected from the breast, back, and thigh tissues of six male ducks at the end of each week. The skin strength, skin thickness, and collagen content as well as the related gene expressions were determined for the evaluation of skin quality. The results showed that the body weight, absolute skin weight, areas, and density, epidermal and dermal thickness (breast and thigh), shearing force, piercing force (back and thigh), and collagen content in Pekin ducks increased linearly and quadratically with age, reaching a plateau at 5-6 weeks of age (P < 0.05). The mRNA expressions of IGF-1 and FGFR1 related to cell proliferation were highest in breast, back, and thigh of ducks at 3 weeks of age, while the mRNA expression of FGF14 and EGF associated with collagen synthesis reached maximum values at 5 weeks of age. Additionally, the mRNA expressions of IGF1R and FGFR2 were upregulated in breast and thigh skins of ducks at 1 week old and in back skin of ducks at 3 weeks old compared with birds at other weeks old (P < 0.05). In conclusion, the developmental pattern of skin growth and structure of Pekin ducks in a linear manner with increased age. The skin quality was increased in a quadratic manner, which was associated with the changes in mRNA expression of target genes related to cell proliferation and collagen synthesis. Show less

The global decline in sperm quality in men is closely associated with environmental exposure to the plasticizer Di-(2-ethylhexyl) phthalate (DEHP), but the molecular mechanisms underlying its induction of asthenozoospermia (AZS) remain incompletely understood. By integrating the toxicological targets of DEHP and differential genes in AZS patients, and combining machine learning, molecular docking, and dynamics simulations, this study successfully identified hub genes and signaling pathways induced by DEHP in AZS, aiming to provide new strategies for the prevention and treatment of this disease. A total of 26 toxicological targets were identified, with FGFR1, MMP7, and ST14 clearly defined as playing crucial regulatory roles in DEHP-induced AZS. This study also reveals that DEHP may induce reproductive system inflammation, affecting the proliferation and survival of reproductive cells, and subsequently impacting sperm vitality, possibly through regulating the mTORC1 pathway, TNF-α signaling via the NF-κB pathway, and MYC targets v1 pathway. Furthermore, changes in the immune microenvironment revealed the significant impact of immune status on testicular function. In conclusion, this study provides important scientific evidence for understanding the molecular mechanisms of AZS and developing prevention and treatment strategies based on toxicological targets. Show less

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect in neonates. While there is compelling evidence of genetic contribution to the etiology of TOF, the contribution of noncoding variants to the development of the defect remains unexplored. Potentially damaging noncoding de novo variants (NC DNVs) were detected from 141 Chinese nonsyndromic TOF trios (CHN-TOF) and compared with those detected in the Pediatric Cardiac Genomics Consortium (PCGC). Bioinformatic analyses on noncoding and previously detected coding DNVs were performed to identify developmental pathways affected in TOF. Chinese but not PCGC-TOF patients showed a notably increased burden of putative damaging NC DNVs (n = 249). In Chinese, NC and coding DNVs were predominantly associated with cardiomyocyte differentiation and with chamber/valve/aorta development, respectively, producing a combined enrichment in NOTCH signaling (p = 1.1 × 10 Show less

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. Show less

In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, interleukin (IL)-27 stimulates interferon γ (IFNγ) production by CD4 and CD8 T cells and is essential for disease development. Here, we tested the role of IL-27 in cellular communication. Single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21 Show less

Septic cardiomyopathy (SCM) is a potentially fatal complication of sepsis. In this study, transcriptomic and proteomic analyzes of serum samples from sepsis patients were conducted to uncover the underlying pathological mechanisms and identify potential therapeutic targets for SCM. This retrospective, dual-center study investigated the progression of sepsis to SCM in patients admitted to intensive care units. A total of 50 patients were enrolled and divided into two groups: sepsis with cardiomyopathy (25 cases) and sepsis without cardiomyopathy (25 cases). Co-expression network analysis was employed to elucidate the biological significance of differentially expressed proteins. By integrating proteomic and transcriptomic data, molecular networks were constructed to visualize interactions among key molecules, aiming to enhance data interpretation and support the study's findings. Proteomic analysis identified 216 differentially expressed proteins (Fold change > 1.5, p-value < 0.05) between the two groups. Transcriptomic analysis revealed two proteins, including Interleukin-27 subunit beta (IL-27B) and carbonic anhydrase, co-downregulated in patients with septic cardiomyopathy. IL-27B was associated with the immune response, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated its involvement in the cytokine-cytokine receptor interaction signaling pathway. Comprehensive integrated transcriptomic and proteomic analyzes identified significant changes in protein expression associated with SCM, primarily associated with inflammation-related pathways and amino acid metabolism. These findings provide new insights into the pathological mechanisms of SCM and highlight potential therapeutic targets for its treatment. The Clinical Research Ethics Committee of Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University approved this study, and written informed consent was given by all patients or their legal representatives. (NO.K20201110). Show less

Neurodevelopmental disorders such as attention deficit and disruptive behaviour disorders (ADHD), autism spectrum disorder (ASD), and schizophrenia have been increasingly prevalent recently. Previous research has demonstrated that inflammatory activity from autoimmune diseases is involved in neurological diseases. However, some studies question the association between inflammatory activities and neurodevelopmental disorders. Herein, we attempt to clarify this relationship using Mendelian randomization (MR) analysis. We used systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes mellitus (T1D) to represent autoimmune diseases. First, we conducted MR analysis to examine associated SNPs between autoimmune and neurodevelopmental disorders. Second, we performed bidirectional MR analysis to identify 429 types of signalling peptides and proteins or relevant receptors with causality reported diseases. Finally, we compared the genes with the gene loci identified in the available TWAS-hub site. The MR results of autoimmune diseases on neurodevelopmental disorders did not present any significant association in all models. However, we identified 20-45 factors in ADHD, ASD, and schizophrenia, including semaphorin 3, IL-27 receptor subunit alpha, and fibroblast growth factor 16, which were considered clinically significant pro-inflammatory mediators. GO and KEGG enrichment analyses revealed unequal integrities among the three neurodevelopmental diseases, and we failed to identify a shared pathway linking autoimmune diseases and neurodevelopmental disorders. TWAS analysis indicated that CHRNA5 potentially mediates inflammatory activities in schizophrenia. According to our data, we failed to identify an association between autoimmune diseases and neurodevelopmental disorders. However, we demonstrated that some pro-inflammatory factors are involved in neurodevelopmental disorders. Show less

Excessive inflammation in sepsis causes microvascular dysfunction associated with organ dysfunction and high mortality. The present studies aimed to examine the therapeutic potential of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor in a clinically relevant polymicrobial sepsis model in mice. Sepsis was induced by cecal ligation and puncture (CLP). Mice were grouped into: Sham control+vehicle; Group 2: CLP+vehicle; Group 3: CLP+dexamethasone (10 mg/kg, s.c.) given 6 h after CLP; Group 4: CLP+linagliptin (1 mg/kg, s.c.) given 6 h after CLP. The experiment was terminated 24 hours after CLP in two experimental sets. Seven-day survival following CLP was determined in a third experimental set. Treatment with linagliptin inhibited DPP-4 activity, increased the levels of active forms of endogenous gastric inhibitory polypeptide and glucagon-like peptide-1, without affecting the blood glucose levels in CLP mice. Compared to vehicle treatment, administration of linagliptin reduced sepsis-induced tissue hyper permeability as evidenced by a reduction in vascular Evans blue leakage, prevented edema formation in the lung, heart, liver and kidney. Furthermore, linagliptin or dexamethasone reduced sepsis-induced proinflammatory cytokine and chemokine production, such as IL-1β, IL-2, IL-10, IL-23, IL-27, VCAM-1, eotaxin, MDC, MCSF1, GCP-2, and NGAL. Importantly, administration of linagliptin improved the 7-day survival rate following CLP in mice. RNA sequencing in lung and heart revealed that linagliptin attenuated key inflammatory pathways including TNF alpha (via NFκB) and IL6/JAK/STAT3 signaling and activated interferon signaling in the heart. Linagliptin treatment can attenuate the inflammatory response, protect against severe sepsis-induced vascular hyperpermeability, reduce multiorgan injury, and most importantly, improve the survival. Show less

TIGIT, a co-inhibitory receptor found on T cells and NK cells, transmits inhibitory signals upon binding to its ligand. This interaction suppresses the activation of various signaling pathways, leading to functional exhaustion of cells, ultimately dampening excessive inflammatory responses or facilitating immune evasion in tumors. Dysregulated TIGIT expression has been noted in T cells across different inflammatory conditions, exhibiting varying effects based on T cell subsets. TIGIT predominantly restrains the effector function of pro-inflammatory T cells, upholds the suppressive function of regulatory T cells, and influences Tfh maturation. Mechanistically, the IL27-induced transcription factors c-Maf and Blimp-1 are believed to be key regulators of TIGIT expression in T cells. Notably, TIGIT expression in T cells is implicated in lung diseases, particularly airway inflammatory conditions such as lung cancer, obstructive pulmonary disease, interstitial lung disease, sarcoidosis, and COVID-19. This review emphasizes the significance of TIGIT in the context of T cell immunity and airway inflammatory diseases. Show less

Although studies have suggested a potential link between the nervous system and prostate cancer, the underlying regulatory mechanisms remain unclear. Therefore, it is crucial to identify the genes involved in regulating prostate cancer within the nervous system. We utilized eQTL data from eight neural cell types as exposure factors and GWAS data for prostate cancer as outcome events. Mendelian randomization (MR) analyses were performed to identify causative genes associated with prostate, bladder, and renal cancers in Astrocytes, Endothelial cells, Excitatory neurons, Inhibitory neurons, Microglia, Oligodendrocytes, OPCs/COPs, and Pericytes. Bladder and renal cancers were used as controls. Sensitivity analyses (heterogeneity, pleiotropy, and leave-one-out tests) were conducted to ensure reliability. In astrocytes, seven positive genes were identified as being causally related to prostate cancer: KANSL1, AC005670.2, ARL17B, LRRC37A2, LRRC37A, MAPT, and LINC02210. In. Endothelial cells, Inhibitory neuron and Microglia, three genes (LRRC37A2, ARL17B, and KANSL1) were identified as risk genes that are associated with prostate cancer. Four protective genes were identified in excitatory neurons, including LRRC37A2, ARL17B, KANSL1 and LINC02210. In oligodendrocytes, eight genes were identified, with LRRC37A2, ARL17B, and KANSL1 acting as protective factors, while OR2L13, OR2L3, OR2L5, OR2L2, and OR2M4 were identified as risk factors. Additionally, sensitivity analyses showed no heterogeneity or horizontal pleiotropy in the MR results, confirming their reliability and stability. In addition, no positive genes were found in bladder cancer and renal cancer. Our study highlights the role of the nervous system, particularly astrocytes, in regulating prostate cancer. We identified three genes, with LRRC37A2, ARL17B, and KANSL1 emerging as key protective factors. These findings provide potential targets for prostate cancer diagnosis and treatment. The online version contains supplementary material available at 10.1007/s12672-025-03711-9. Show less

Bladder cancer (BC) is one of the most common urological malignancies, ranking as the eleventh most common cause of cancer-related deaths worldwide. The lack of specific and sensitive prognostic biomarkers presents a significant challenge in the early diagnosis and treatment of BC. We used the Gene Expression Omnibus (GEO) dataset GSE13507 and the Cancer Genome Atlas (TCGA) database to screen differentially expressed genes related to BC. By using Weighted Gene Co-expression Network Analysis (WGCNA), two modules associated with BC were investigated in GSE13507 and TCGA. Hub genes were identified through Protein-Protein Interaction (PPI) network analysis and their functions were validated through multiple approaches, including Gene Expression Profiling Interactive Analysis (GEPIA), Western Blotting (WB) assay, Human Protein Atlas (HPA), Oncomine analysis, and quantitative Real-Time PCR (qRTPCR) analysis. Additionally, miRNAs associated with hub gene expression were identified using various databases to predict the progression and prognosis of BC. WCGNA and differential gene expression analysis identified 171 common genes as target genes. Ten genes (MYH11, ACTA2, TPM2, ACTG2, CALD1, MYL9, TPM1, MYLK, SORBS1, and LMOD1) were identified using the PPI tool and the CytoHubba plugin of Cytoscape. The CALD1 and MYLK genes showed a significant prognostic value for overall survival and diseasefree survival in patients with BC. According to the HPA and Oncomine databases, CALD1 and MYLK expression levels were significantly lower in BC tissues than in normal tissues. Additionally, qRT-PCR analysis, WB assay, and immunohistochemical analysis confirmed CALD1 and MYLK as tumor suppressor genes in BC. Furthermore, miR-155 showed a significant positive correlation with MYLK. This study established MYLK as a direct target gene of miR-155, functioning as an actionable survival-related gene correlated with BC development. Show less

Gastric cancer (GC) is a common malignant tumor, which originated from the epithelial cells of the stomach. It has the characteristics of high incidence and poor prognosis. Therefore, it is urgent to find new prognostic markers for the diagnosis and treatment of GC. Download gene expression matrix and clinical data from TCGA database and GSE84437 dataset. Through independent prognostic analysis and clinical correlation analysis, 74 prognostic related genes (PRG) were screened out. A PPI network was established for PRG to identify four key genes (KG), namely LMOD1, CRYAB, VCL and MYL9. Survival analysis showed that patients with high expression of KG had poor prognosis. Multivariate Cox regression analysis showed that KG was an independent prognostic factor. TCGA database verifies the importance and significance of KG as a prognostic indicator. Functional enrichment analysis showed that KG was mainly involved in cell adhesion molecules, adhesion spots and PI3K/AKT signaling pathway. KG may be a potential therapeutic target for gastric cancer. Show less

The influence of lactic acid bacteria (LAB) strains of various species isolated from Chinese traditional sourdough on the properties of rice sourdough and the textural and flavor qualities of steamed rice bread (SRB) was investigated. Show less