ABSTRACT
Ionogels are promising material candidates for ionotronics due to their excellent ionic conductivity, stretchability, and thermal stability. However, it is challenging to develop 3D printable ionogels with both excellent electrical and mechanical properties. Here, we report a highly conductive and stretchable nanostructured (CSN) ionogel for 3D printing ionotronic sensors. We propose the photopolymerization-induced microphase separation strategy to prepare the CSN ionogels comprising continuous conducting nanochannels intertwined with cross-linked polymeric framework. The resultant CSN ionogels simultaneously achieves high ionic conductivity (over 3 S m-1), high stretchability (over 1500%), low degree of hysteresis (0.4% at 50% strain), wide-temperature-range thermostability (-72 to 250 °C). Moreover, its high compatible with DLP 3D printing enables the fabrication of complex ionogel micro-architectures with high resolution (up to 5 µm), which allows us to manufacture capacitive sensors with superior sensing performances. The proposed CSN ionogel paves an efficient way to manufacture the next-generation capacitive sensors with enhanced performance.
ABSTRACT
Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21 deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.
ABSTRACT
Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4+ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4+ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4+IL4+ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.
Subject(s)
Cell Differentiation , Disease Models, Animal , Receptor, Cannabinoid, CB2 , Scleroderma, Systemic , Signal Transduction , Suppressor of Cytokine Signaling 3 Protein , Th2 Cells , Animals , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/pathology , Th2 Cells/immunology , Mice , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Cell Differentiation/drug effects , Signal Transduction/drug effects , Humans , Suppressor of Cytokine Signaling 3 Protein/metabolism , Female , Janus Kinases/metabolism , Male , Mice, Knockout , Cannabinoids/pharmacology , Cannabinoids/therapeutic use , Bleomycin , Cannabinoid Receptor Agonists/pharmacology , Cannabinoid Receptor Agonists/therapeutic use , Middle AgedSubject(s)
Abscess , Pyoderma Gangrenosum , Humans , Pyoderma Gangrenosum/diagnosis , Male , Adult , Face , Abscess/diagnosis , RecurrenceABSTRACT
BACKGROUND: The role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC. METHODS: This study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status. RESULTS: We observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules. CONCLUSION: CD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , CD8-Positive T-Lymphocytes , CA-19-9 Antigen , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/pathology , PrognosisABSTRACT
Therapeutic approaches for cancer have become increasingly diverse in recent times. A comprehensive understanding of the tumor microenvironment (TME) holds great potential for enhancing the precision of tumor therapies. Neoadjuvant therapy offers the possibility of alleviating patient symptoms and improving overall quality of life. Additionally, it may facilitate the reduction of inoperable tumors and prevent potential preoperative micrometastases. Within the TME, cancer-associated fibroblasts (CAFs) play a prominent role as they generate various elements that contribute to tumor progression. Particularly, extracellular matrix (ECM) produced by CAFs prevents immune cell infiltration into the TME, hampers drug penetration, and diminishes therapeutic efficacy. Therefore, this review provides a summary of the heterogeneity and interactions of CAFs within the TME, with a specific focus on the influence of neoadjuvant therapy on the microenvironment, particularly CAFs. Finally, we propose several potential and promising therapeutic strategies targeting CAFs, which may efficiently eliminate CAFs to decrease stroma density and impair their functions.
Subject(s)
Cancer-Associated Fibroblasts , Neoplasms , Humans , Neoadjuvant Therapy , Quality of Life , Neoplasms/drug therapy , Tumor Microenvironment , FibroblastsABSTRACT
OBJECTIVE: Interferon (IFN)-1 signatures are a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood. METHODS: For hypothesis generation, we performed single-cell RNA sequencing (scRNA-seq) on skin biopsies (four patients with SSc and two controls) using the BD Rhapsody platform. Two publicly available data sets of skin scRNA-seq were used for validation (GSE138669: 12 patients with diffuse cutaneous SSc [dcSSc] and 10 controls; GSE195452: 52 patients with dcSSc and 41 patients with limited cutaneous SSc [lcSSc] and 54 controls). The IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNα-2 adenovirus-associated virus (AAV)-induced model and verified in an SSc cohort (n = 61). RESULTS: The discovery and validation data sets showed similar findings. Endothelial cells (ECs) had the most prominent IFN-1 signature among dermal nonimmune cells. The EC IFN-1 signature was increased both in patients with SSc versus controls and in patients with dcSSc versus those with lcSSc. Among EC subclusters, the IFN-1 signature was statistically higher in the capillary ECs of patients with dcSSc, which was higher than those in patients with lcSSc, which in turn was higher than those in healthy controls (HCs). Endothelial-to-mesenchymal transition (EndoMT) scores increased in parallel. Deteriorated bleomycin-induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular myxovirus resistance (MX) 1, an IFN-1 response protein, was significantly increased both in total SSc versus HC skin and in dcSSc versus lcSSc skin. Baseline vascular MX1 performed similarly to skin score in predicting disease progression over 6 to 34 months in total SSc and was superior in the dcSSc subpopulation. CONCLUSION: The EC IFN-1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis.
Subject(s)
Interferon Type I , Scleroderma, Systemic , Vascular Diseases , Humans , Endothelial Cells/metabolism , Scleroderma, Systemic/pathology , Fibrosis , Vascular Diseases/pathology , Disease Progression , Skin/pathology , BleomycinABSTRACT
Background: This study aimed to investigate the clinical characteristics of gastric cancer (GC) patients with dermatomyositis (DM) and summarize the perioperative outcomes. Methods: The clinical and pathological data of five patients diagnosed with co-occurring DM and GC (DM-GC group) were retrospectively analyzed, who were admitted to the Department of Gastrointestinal Surgery at Ren ji Hospital, Shanghai Jiao Tong University, between January 2012 and April 2023. Their data were compared with 618 GC patients (GC-1 group) from September 2016 to August 2017 and 35 GC patients who were meticulously screened from 14,580 GC cases from January 2012 and April 2023. The matching criteria included identical gender, age, tumor location, TNM stage, and surgical procedure (7 GC patients were matched for each DM-GC patient). Results: Analysis indicated that the DM-GC group comprised four female and one male patient. The female proportion was significantly higher (P = 0.032) than that of GC-1 group. In DM-GC group, four DM patients were diagnosed as GC within 12 months. One DM patients was diagnosed as GC within 15 months. Among them, four patients presented with varying degrees of skin rashes, muscle weakness while one patient had elevated CK levels as the typical symptom. Similarly, the preoperative tumor markers (CA-199 and CA-125) in the DM-GC group were significantly higher than normal levels (CA-199: 100 vs. 28.6%, P = 0.002; CA-125: 40 vs. 2.9%, P = 0.003) compared to GC-2 group. Moreover, postoperative complication incidence and the length of hospital stay were significantly higher in the DM-GC than GC-2 group [complication rate: 40 vs. 8.6%, P = 0.047; hospital stay: 15 days (range: 9-28) vs. 9 days (range: 8-10), P = 0.021]. Conclusion: GC Patients with dermatomyositis are more prone to experience postoperative complications and longer hospital stay.
ABSTRACT
CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Myeloid-Derived Suppressor Cells , Pancreatic Neoplasms , Mice , Animals , CD8-Positive T-Lymphocytes , Tumor Microenvironment , Pancreatic Neoplasms/drug therapy , Carcinoma, Pancreatic Ductal/drug therapy , Gemcitabine , Pancreatic NeoplasmsSubject(s)
Capillaries , Nails, Malformed , Humans , Veins , Fingers/blood supply , Nails/blood supplyABSTRACT
Neutrophils, the most prevalent innate immune cells in humans, have garnered significant attention in recent years due to their involvement in cancer progression. This comprehensive review aimed to elucidate the important roles and underlying mechanisms of neutrophils in cancer from the perspective of their whole life cycle, tracking them from development in the bone marrow to circulation and finally to the tumor microenvironment (TME). Based on an understanding of their heterogeneity, we described the relationship between abnormal neutrophils and clinical manifestations in cancer. Specifically, we explored the function, origin, and polarization of neutrophils within the TME. Furthermore, we also undertook an extensive analysis of the intricate relationship between neutrophils and clinical management, including neutrophil-based clinical treatment strategies. In conclusion, we firmly assert that directing future research endeavors towards comprehending the remarkable heterogeneity exhibited by neutrophils is of paramount importance.
Subject(s)
Neoplasms , Neutrophils , Humans , Neoplasms/genetics , Tumor MicroenvironmentSubject(s)
Arthritis , Janus Kinase Inhibitors , Humans , Janus Kinase Inhibitors/therapeutic use , PersonalityABSTRACT
In recent years, the incidence of cancers is continuously increasing in young adults. Early-onset cancer (EOC) is usually defined as patients with cancers under the age of 50, and may represent a unique subgroup due to its special disease features. Overall, EOCs often initiate at a young age, present as a better physical performance but high degree of malignancy. EOCs also share common epidemiological and hereditary risk factors. In this review, we discuss several representative EOCs which were well studied previously. By revealing their clinical and molecular similarities and differences, we consider the group of EOCs as a unique subtype compared to ordinary cancers. In consideration of EOC as a rising threat to human health, more researches on molecular mechanisms, and large-scale, prospective clinical trials should be carried out to further translate into improved outcomes.
Subject(s)
Neoplasms , Young Adult , Humans , Prospective Studies , Neoplasms/diagnosis , Neoplasms/epidemiology , Neoplasms/therapy , Risk FactorsABSTRACT
BACKGROUND: The early growth response 1 (EGR1) is a central transcription factor involved in systemic sclerosis (SSc) pathogenesis. Iguratimod is a synthesized anti-rheumatic disease-modifying drug, which shows drastic inhibition to EGR1 expression in B cells. This study is aiming to investigate the anti-fibrotic effect of iguratimod in SSc. METHODS: EGR1 was detected by immunofluorescence staining real-time PCR or western blot. Iguratimod was applied in EGR1 overexpressed or knockdown human dermal fibroblast, bleomycin pre-treated mice, tight skin 1 mice, and SSc skin xenografts. RNA sequencing was performed in cultured fibroblast and xenografts to identify the iguratimod regulated genes. RESULTS: EGR1 overexpressed predominantly in non-immune cells of SSc patients. Iguratimod reduced EGR1 expression in fibroblasts and neutralized changes of EGR1 response genes regulated by TGFß. The extracellular matrix (ECM) production and activation of fibroblasts were attenuated by iguratimod while EGR1 overexpression reversed this effect of iguratimod. Iguratimod ameliorated the skin fibrosis induced by bleomycin and hypodermal fibrosis in TSK-1 mice. Decreasing in the collagen content as well as the density of EGR1 or TGFß positive fibroblasts of skin xenografts from naïve SSc patients was observed after local treatment of iguratimod. CONCLUSION: Targeting EGR1 expression is a probable underlying mechanism for the anti-fibrotic effect of iguratimod.