VISTA (V-domain Immunoglobulin Suppressor of T cell Activation), encoded by VSIR, functions as an inhibitory checkpoint predominantly expressed on myeloid cells. Despite its recognized role in solid tumors, systematic characterization of VSIR regulation and clinical implications in hematological malignancies remains limited. We performed integrative multi-omics analyses of diverse hematological malignancies (> 10,000 transcriptomes) to elucidate VSIR expression patterns, epigenetic regulation, and therapeutic potential. VSIR exhibited preferential upregulation in hematological malignancies, particularly myeloid leukemias. We identified dual epigenetic mechanisms driving VSIR overexpression: promoter hypomethylation progressively intensified from healthy controls through myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML), validated by targeted bisulfite sequencing in 130 clinical samples; chromatin immunoprecipitation sequencing revealed direct transcriptional activation by KMT2A fusion proteins through enrichment of H3K4me3, H3K79me2, and H3K27ac activating marks at the VSIR promoter. Menin inhibitor treatment substantially reduced KMT2A occupancy and histone modifications, confirming Menin-dependent regulation. Similarly, NPM1 mutations promoted VSIR expression through stabilizing Menin-containing chromatin complexes. Functionally, VSIR-high tumors showed enrichment in immune regulatory pathways and predicted favorable immunotherapy responses. Prognostically, elevated VSIR expression conferred adverse outcomes in AML while predicting improved survival in DLBCL and MM. Computationally, VSIR-high patients showed increased likelihood of benefiting from immune checkpoint blockade, validated in real-world immunotherapy cohorts. The elucidated Menin-VSIR regulatory axis suggests potential for combining Menin inhibitors with VISTA checkpoint blockade in KMT2A-rearranged AML. Our findings suggest that VSIR expression is epigenetically dysregulated in hematological malignancies through dual mechanisms, which could inform biomarker-driven patient selection and rational design of combination immunotherapies.

MECOM (the MDS1 and EVI1 complex locus) rearrangements have been identified as an independent high-risk factor in acute myeloid leukemia (AML). The diversity of MECOM rearrangement partner genes significantly influences disease mechanisms and prognosis. The majority of atypical MECOM rearrangements result in EVI1 overexpression through translocation into super-enhancer-containing regions. This report describes a rare, recurrent MBNL1::MECOM rearrangement identified in a myelodysplastic neoplasm (MDS) patient with a concurrent SF3B1 mutation. Although conventional cytogenetics showed a normal karyotype, the rearrangement was confirmed by next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH). Concurrently, the patient exhibited high EVI1 expression, consistent with the common mechanism observed in atypical MECOM rearrangements. Given the well-documented association between SF3B1 mutations and MECOM rearrangements, analysis of MECOM expression and RNA sequencing (RNA-seq) is crucial for SF3B1-mutated patients, even in the absence of elevated blast counts. Furthermore, this case underscores the need for further research into the synergistic biological role of spliceosome mutations and MECOM rearrangements in driving leukemia.

Gastric cancer (GC) is a malignancy with high global incidence and mortality, and its poor prognosis and therapeutic failure are largely attributable to a complex tumor microenvironment. Extracellular vesicles (EVs) mediate intercellular molecular communication and are deeply involved in the initiation and progression of GC. Here, we focus on exosomes, the most thoroughly studied EV subtype (30–150 nm), and examine their biological roles in GC and their potential for clinical translation. We construct an exosome-derived molecular network of GC progression across six dimensions: promoting tumor cell proliferation, orchestrating an immunosuppressive microenvironment, inducing tumor angiogenesis, remodeling the extracellular matrix, guiding metastasis, and mediating drug resistance. In this review, we systematically summarize exosome-derived non-coding RNAs and proteins as biomarkers for early detection and prognosis of GC. Moreover, emerging strategies targeting exosomes or employing exosomes as delivery vehicles are discussed. Finally, we address current challenges in exosome research and propose future directions. This review aims to serve as a reference for basic research and clinical translation in GC, emphasizing that deciphering exosome-mediated intercellular dialogue is essential for understanding the molecular underpinnings of tumor progression and developing novel intervention strategies.

Tongue squamous cell carcinoma, the most aggressive subtype of oral squamous cell carcinoma, which is associated with high mortality, frequent recurrence, and early lymph-node metastasis. Triptolide, a bioactive diterpenoid from Tripterygium wilfordii, exhibits broad anticancer activity. Although its inhibitory action on OSCC has been established, its specific molecular regulatory mechanisms in TSCC, a distinct and aggressive subtype, remain largely underexplored. The present study investigates the regulatory role of triptolide in the PI3K-AKT signaling pathway, which is a critical axis intimately linked to tumor survival and metastasis. A network-pharmacology workflow was used to intersect triptolide putative targets with TSCC-related genes. Core hubs were identified with Cytoscape; KEGG and GO analyses highlighted the PI3K-AKT axis as the top enriched pathway. Binding kinetics were quantified by molecular docking and surface plasmon resonance (SPR). Cellular assays (CCK-8, Transwell, wound-healing, Western blot and immunofluorescence) validated the predictions. We retrieved 389 common targets and shortlisted eight key nodes (JUN, MAPK1, MAPK3, AKT1, TP53, BCL2, STAT3, MYC). SPR revealed high-affinity binding of triptolide to AKT1 and PI3K. Functionally, triptolide dose-dependently suppressed TSCC cell proliferation, invasion, and migration, downregulated PI3K-AKT signaling proteins, and reduced the colocalization and phosphorylation levels of p-PI3K and p-AKT. This study is the first to demonstrate the pivotal role of the PI3K-AKT signaling pathway in mediating the antitumor effects of triptolide in tongue squamous cell carcinoma. Our findings thereby provide a novel theoretical foundation for the development of traditional Chinese medicine-based therapeutic strategies targeting this malignancy.

ObjectiveTo investigate the role of the iron-sulfur cluster assembly factor SFU1 in the virulence-related traits of Candida albicans, particularly its function within the cariogenic cross-kingdom biofilm formed with Streptococcus mutans.MethodsThe SFU1 deletion and complemented strains were constructed. Their effects on growth, acid production, morphogenesis, metabolic activity, ROS accumulation, and biofilm formation of C. albicans were evaluated. The roles of SFU1 in the development, architecture, and spatial distribution of the C. albicans-S. mutans dual-species biofilm were further analyzed. The cariogenic metabolite profile and matrix synthesis were assessed by measuring lactic acid production, lactate dehydrogenase activity, extracellular polysaccharide content, and expression levels of related genes.ResultsThe SFU1 deletion strain exhibited inhibited hyphal formation, reduced metabolic activity, elevated intracellular ROS levels, impaired biofilm formation, and downregulated expression of hyphal and adhesion-related genes (ALS3, EFG1, UME6). In the cross-kingdom biofilm, the sfu1/sfu1 mutant failed to form hyphal networks, resulting in loose biofilm architecture, reduced biomass, and poor integration of S. mutans. Furthermore, the dual-species biofilm showed significantly decreased lactic acid and EPS production. Co-cultured S. mutans exhibited downregulated expression of EPS synthesis genes (gtfB/C) and upregulated expression of EPS degradation genes (dexA/B).ConclusionSFU1 modulates hyphal development, redox homeostasis, and biofilm formation in C. albicans, thereby profoundly affecting its pathogenic synergy with S. mutans. SFU1 deletion leads to disrupted architecture and attenuated cariogenic virulence of the dual-species biofilm. This study reveals the potential value of targeting fundamental metabolic pathways in C. albicans to interfere with the cariogenicity of cross-kingdom biofilms, and provides a novel perspective for the prevention and therapy of dental caries.

Tongue squamous cell carcinoma (TSCC) often develops therapeutic resistance. Metabolic reprogramming, particularly the glycolysis/lactate/histone lactylation axis, is a critical driver of tumor progression and therapy resistance. This study investigated the anti-tumor mechanism of Rhaponticin (Rha), focusing on the metabolic/epigenetic axis involving hypoxia-inducible factor 1α (HIF-1α), glycolysis, and histone H3K18 lactylation (H3K18la). SCC9 and SCC9-CisR cells were treated with Rha alone or in combination with 2-deoxy-D-glucose (2-DG) or sodium lactate (LacNa). The effects of Rha on glycolysis and H3K18la were evaluated by extracellular acidification rate assays, glucose/lactate quantification, and western blotting. Gain- and loss-of-function studies targeting HIF-1α were conducted to determine the mechanistic dependency of Rha-mediated effects. Subcutaneous and liver metastasis xenograft models were established for in vivo validation. Rha significantly suppressed glycolysis, glucose consumption, and lactate production, concomitant with the downregulation of HK2, LDHA, GLUT1, and H3K18la levels. Rha not only mimicked the effects of 2-DG by inhibiting clonogenicity, migration, and invasion and decreasing cisplatin resistance in SCC9 or SCC9-CisR cells but also reversed LacNa-mediated promotion of these parameters, indicating that Rha acts through the glycolysis/lactate pathway. Rha inhibited tumor growth and liver metastasis, enhanced cisplatin sensitivity, and decreased H3K18la levels in mouse models. Mechanistically, Rha inhibited HIF-1α, thereby attenuating glycolytic flux and decreasing lactate-driven H3K18la. Rha inhibits TSCC progression and enhances cisplatin sensitivity by targeting HIF-1α and repressing the glycolysis/lactate/H3K18la axis, suggesting that Rha is a promising candidate for disrupting metabolic/epigenetic crosstalk in TSCC.

ABSTRACT Conjugated polymer‐based phototheranostics have attracted considerable attention for cancer treatment owing to their excellent photothermal properties and biocompatibility. However, integrating efficient photodynamic activity into conjugated polymer systems without compromising their intrinsic photothermal performance remains a major challenge. Here, we report structurally engineered selenophene‐doped polypyrrole nanoplatforms (Ppy‐PSe NPs) for imaging‐guided synergistic phototherapy. Incorporation of selenium‐containing heterocycles into the conjugated polypyrrole framework introduces a pronounced heavy‐atom effect, which promotes intersystem crossing and substantially enhances reactive oxygen species (ROS) generation while preserving broadband near‐infrared (NIR) absorption and efficient photothermal conversion. Upon NIR laser irradiation, Ppy‐PSe induces severe oxidative stress, lysosomal disruption, cytoskeletal collapse, and apoptotic cell death. Mechanistically, ROS‐mediated suppression of HSP90 disrupts the oncogenic JAK2/STAT3 signaling axis, thereby reprogramming tumor thermotolerance and sensitizing malignant cells to photothermal injury. In vivo, Ppy‐PSe exhibits favorable biosafety, efficient tumor accumulation, and robust photoacoustic imaging capability for real‐time therapeutic guidance. Notably, NIR‐triggered treatment achieves complete tumor eradication in a lymphoma xenograft model, particularly under NIR‐II irradiation. This work establishes a multifunctional conjugated polymer nanoplatform that integrates ROS amplification, thermo‐sensitization reprogramming, and imaging‐guided synergistic phototherapy for precision cancer treatment.

OBJECTIVE:Tongue squamous cell carcinoma (TSCC) is characterized by high invasiveness and early lymph node metastasis, leading to a poor prognosis.Current surgical and chemoradiotherapy regimens often cause functional impairment, drug resistance, and other drawbacks. Thus, developing highly effective, lowtoxicity treatments is a key research priority. Traditional Chinese medicine (TCM) offers unique advantages via multitarget synergistic effects, enabling innovative therapeutic approaches. METHOD:In this study, we developed Astragaloside IV-Brucea javanica oil nanoemulsion (AS/BJO-NEs) and characterized its stability, polydispersity, and pharmacokinetic profile. The effects of AS/BJO-NEs on TSCC cells were evaluated through a series of functional assays, including CCK-8 (viability), colony formation (proliferation), and scratch wound healing (migration). Both in vitro and in vivo experiments were performed to investigate whether its mechanism involves regulation of the MTFR2-HIF-1α-EZH2/FoxM1 signaling axis. RESULTS:The optimized AS/BJONEs exhibited uniform spherical morphology at the nanoscale and demonstrated favorable stability. In both in vitro and in vivo models, AS/BJONEs significantly suppressed the malignant phenotype of TSCC cells. Mechanistic investigation further revealed that the anti-tumor effects of AS/BJONEs are mediated, at least in part, through targeting the MTFR2-HIF-1α-EZH2/FoxM1 signaling axis, as confirmed by establishing stable MTFR2/HIF-1α knockdown and overexpression cell models. CONCLUSION:This study demonstrates that AS/BJONEs inhibit TSCC progression by targeting the MTFR2-HIF-1α-EZH2/FoxM1 signaling axis. Our findings provide experimental evidence supporting the development of multi-target therapeutic strategies derived from traditional Chinese medicine for the treatment of TSCC.

Objective This study aimed to investigate whether Astragaloside-Brucea javanica oil nanoemulsion (AS/BJO-NEs) inhibits the malignant progression of oral squamous cell carcinoma (OSCC) and to further explore its potential regulatory mechanisms. Methods Immunohistochemistry (IHC) was used to evaluate the expression of related pathway proteins in human OSCC and adjacent normal tissues. Stable OSCC cell lines with knockdown or overexpression of CDK1/HOXC10 were established. The effects of AS/BJO-NEs and the underlying mechanisms were assessed in vitro through colony formation, wound healing, and Transwell invasion assays, as well as RT-qPCR, western blot, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. An OSCC subcutaneous xenograft model in nude mice was constructed for in vivo validation using RT-qPCR, western blot, hematoxylin and eosin (H&E) staining, and IHC. Results Analysis of clinical samples revealed upregulated expression of CDK1, P-EZH2, HOXC10, MTFR2, and N-cadherin, alongside downregulated expression of H3K27me3 and E-cadherin in OSCC tissues. In vitro experiments confirmed that AS/BJO-NEs downregulated CDK1 in a concentration-dependent manner, subsequently reducing the expression of P-EZH2, HOXC10, and MTFR2, increasing H3K27me3 levels, and inhibiting cell proliferation, migration, and invasion. H3K27me3 was enriched in the HOXC10 promoter region, and HOXC10 directly bound to and activated MTFR2 transcription. In vivo experiments demonstrated that AS/BJO-NEs effectively inhibited tumor growth, regulated molecules within this pathway and epithelial-mesenchymal transition (EMT) markers, whereas CDK1 overexpression counteracted these effects Conclusion This study demonstrates that AS/BJO-NEs exert anti-OSCC effects by inhibiting CDK1, downregulating HOXC10, thereby reducing MTFR2 expression, and suppressing cell proliferation, migration, invasion, and the EMT process.

Objective:To investigate the expression and methylation alterations of ARHGAP10 in AML and to further explore its clinical significance.Methods:ARHGAP10 expression was measured by RT-qPCR in 18 controls and 68 AML patients.ARHGAP10 methylation was assessed using targeted sulfite sequencing in 25 controls and 102 AML patients.The clinical significance of ARHGAP10 expression and methylation changes in AML was further analyzed.Results:Analysis of publicly available datasets identified increased expression of ARHGAP10 in AML patients,which was further validated in our hospital cohort.Among the FAB subtypes,ARHGAP10 expression was significantly higher in the M2 and M5 subgroups compared to the control group.ROC curve analysis indicated that ARHGAP10 expression could be a potential diagnostic biomarker for AML.Kaplan-Meier analysis showed that high ARHGAP10 expression and ARHGAP10 hypomethylation were associated with shorter overall survival.Furthermore,ARHGAP10 hypomethylation was observed in AML patients,and further analysis revealed a negative correlation between ARHGAP10 methylation level and expression level.Conclusion:ARHGAP10 exhibits high expression and hypomethylation changes in AML,and these alterations may serve as potential indicators of poor prognosis in AML patients.

Premature ovarian insufficiency (POI) profoundly compromises female reproductive health through accelerated follicle depletion and endocrine disruption. Emerging evidence highlights the therapeutic potential of mesenchymal stem cell-derived exosomes (MSC-Exs), particularly when their function is enhanced by hypoxic preconditioning. In this study, the ability of hypoxia-preconditioned MSC-Exs (H-Exs) to ameliorate oxidative damage to granulosa cells (GCs) and restore ovarian function, was systematically evaluated, and a POI rat model was used to investigate the underlying mechanism. CircRNAs specifically expressed in H-Exs were identified and validated. The ability of H-Exs and their corresponding circPTP4A2 to repair oxidative damage and restore mitochondrial function were evaluated by antioxidant enzyme assays, reactive oxygen species (ROS) assays, JC-1 staining, ATP level assays, oxygen consumption rate (OCR) measurements and TEM. The interaction between circPTP4A2 and YBX1 was analysed by molecular dynamics simulations, RIP, CHX assays, and MG132 assays, and the restorative effect of the circPTP4A2/YBX1 axis on ovarian function was verified. Our findings revealed that compared with normoxic MSC-Exs (N-Exs), H-Exs exerted superior protective effects, significantly attenuating oxidative stress and restoring mitochondrial bioenergetics in KGN cells. Mechanistically, circPTP4A2 was identified as a hypoxia-responsive cargo selectively enriched in H-Exs. This circular RNA stabilized Y-box binding protein 1 (YBX1) through direct interaction, increasing its antioxidative capacity and mitochondrial regulatory functions. Hypoxia-inducible factor 1-alpha (HIF-1α) was further shown to transcriptionally upregulate circPTP4A2 via direct binding to the promoter region of its host gene PTP4A2. These results establish the circPTP4A2/YBX1 axis as a critical mediator of the therapeutic efficacy of H-Exs for POI, providing both mechanistic insights and a translational framework for exosome-based regenerative strategies.

PURPOSE:This study was designed to investigate the relationship between peripheral blood inflammatory markers and prognosis in MDS patients. METHODS:We conducted a study involving 183 MDS patients who were diagnosed at Taizhou Hospital of Zhejiang Province and Enze Hospital between January 2015 and December 2019. The end point of follow-up was September 2022. To minimize the impact of other confounding factors among the 110 included MDS patients, X-tile software was used to determine the optimal cutoff points for peripheral blood inflammation markers. Based on these cutoff points, the cohort of patients was divided into a high-risk group and a low-risk group. The OS in each group was analyzed by the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were employed. RESULTS:The MDS patients included 73 men and 37 women with a median age of 72 years (32-92 years). The median OS was 28 months (1-83 months), 17 patients (15.45%) experienced conversion to AML, and 94 patients (85.45%) died during the follow-up period. The optimal cutoff points were ALC (1.2 × 109/L), AMC (0 × 109/L), CRP (6.1 mg/L), MLR (0.125), NLR (2.25) and PLR (71.4). Patients in the ALC (≤1.2 × 109/L, P = 0.017), MLR (>0.125, P = 0.01), PLR (>71.43, P = 0.044), and CRP (>6.1 mg/L, P < 0.0001) groups had shorter overall survival. The MLR (>0.125, P = 0.011) and CRP (>6.1 mg/L, P = 0.017) levels were related to poor prognosis. CONCLUSIONS:Elevated MLR and CRP levels may be independent indicators of poor prognosis in newly diagnosed MDS patients.

Receptor-interacting protein kinase 3 (RIPK3) has been implicated in the pathogenesis of diverse human cancers. However, the role of RIPK3 in acute myeloid leukemia (AML) is not fully understood, which needs further research and clarification. We first identified the expression and clinical prognostic value of RIPK3 in AML through a public database and further validated in our research cohort. In addition, the biological function of RIPK3 in leukemic development was further verified through in vitro experiments. Based on the GEPIA database, we screened that RIPK3 overexpression among RIPK family was associated with poor prognosis in AML. Afterwards, another independent cohort from our research center further confirmed the expression pattern of RIPK3 in AML patients. Clinically, increased RIPK3 expression was closely related to specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation. The significant association of RIPK3 overexpression with FAB-M4/M5 was further validated in AML cell lines. Notably, AML patients with RIPK3 overexpression received transplantation presented a markedly longer survival than those just receiving chemotherapy, whereas those with RIPK3 underexpression showed similar survival between transplantation and chemotherapy group. Bioinformatics analysis showed the significant association of RIPK3 expression with diverse oncogenes/tumor suppressor genes and tumor-related biological processes in AML. Subsequently, we further performed functional experiments in vitro confirmed the potential oncogenic role of RIPK3 in AML. Overexpression of RIPK3 was associated with specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation, and may facilitate the leukemic development. Moreover, RIPK3 overexpression was associated poor prognosis, and may guide treatment choice in AML.

Acute erythroid leukemia (AEL) is a rare acute myeloid leukemia (AML) subtype that is highly aggressive and is associated with a poor prognosis. Notably, the blockage of erythroid differentiation represents a significant factor in the pathogenesis of erythroleukemia. Prior studies indicated that miR-218 inhibited the erythroid differentiation in a chronic myeloid leukemia (CML)-derived erythroleukemia cell line K562. However, functions of miR-218 in primary AEL remains to be elucidated. To address this gap, functions of miR-218 in HEL cells were evaluated through cell differentiation, cell proliferation, colony formation, cell cycle and cell apoptosis experiments. Subsequently, the targeted downstream genes of miR-218 were identified by the transcriptome sequencing and bioinformatic research, of which demonstrated by the dual-luciferase reporter experiment. Finally, the underlying mechanism of miR-218 in leukemogenesis was identified by enrichment analysis and was validated by western blot (WB) assays. Intriguingly, enhanced miR-218 showed no effect on the erythroid differentiation in HEL cells by determination of the expression of erythroid markers including GATA1, KLF1, TFRC and GYPA. However, miR-218 overexpression in HEL cells presented a markedly anti-proliferative and pro-apoptotic effects, inhibited colony formation and G0/G1 arrest. Transcriptome sequencing and bioinformatics analysis revealed that CTNND2 as the candidate gene of miR-218 within its 3'-untranslated region (3'-UTR) could be bonded by it. Reduced expression level of CTNND2 was further demonstrated by quantitative-PCR and WB after miR-218 overexpression in HEL cells. Furthermore, the luciferase report assay revealed that the CTNND2 production was reduced with its 3'-UTR region was bonded by miR-218. In addition, MAPK signaling pathway was identified and validated as the potential functional pathway involved in leukemogenesis caused by miR-218 overexpression in HEL cells. In summary, miR-218 exhibits anti-proliferative and pro-apoptotic functions by targeting CTNND2 and modulating MAPK signaling in HEL cells, yet it has no impact on the erythroid differentiation process.

To elucidate the potential targets and mechanisms of Brucea javanica in the treatment of oral squamous cell carcinoma (OSCC) through network pharmacology and molecular docking, supported by clinical data and in vitro experiments. Potential targets of Brucea javanica and OSCC-related disease targets were identified via the TCMSP, GeneCards, and OMIM databases. A Venn diagram was employed to obtain the intersection targets, which were considered as the potential targets for Brucea javanica in OSCC treatment. The protein–protein interaction (PPI) network was constructed using the STRING database and Cytoscape 3.7.2 to identify core targets. Gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the intersection targets were conducted using the Metascape database. Molecular docking between the main components of Brucea javanica and core targets was performed using AutoDockTools software. The expression of core targets in clinical samples was analyzed via the GEO database. Finally, the effects of Brucea javanica oil (BJO) on OSCC proliferation, invasion, and migration, as well as the expression of the EGFR/PI3K/AKT signaling pathway, were verified in vitro. A total of 60 potential targets of Brucea javanica against OSCC were identified, with β-sitosterol and luteolin selected as the primary active components. The five targets with the highest connectivity, AKT1, CASP3, PTGS2, TP53, and EGFR, were identified as core targets. KEGG pathway analysis indicated that the anti-OSCC effects of Brucea javanica are primarily mediated through the PI3K-AKT signaling pathway, JAK-STAT signaling pathway, etc. Molecular docking studies demonstrated strong binding affinities between the main components of Brucea javanica and its core targets. Analysis of clinical samples revealed elevated expression levels of core targets in OSCC samples compared to normal samples. The CCK-8 assay and colony formation assay indicated that BJO effectively inhibited OSCC cell proliferation. The scratch test and Transwell test showed that BJO could inhibit the invasion and migration of oral squamous cell carcinoma. In addition, Western blot and RT-qPCR showed that BJO could down-regulate the expression of EGFR/PI3K/AKT signaling pathway-related proteins and mRNA. Brucea javanica exhibits multi-target and multi-pathway characteristics in the treatment of oral squamous cell carcinoma, potentially exerting its anti-cancer effects by inhibiting the EGFR/PI3K/AKT signaling pathway.