Abstract
Tumor-draining lymph nodes are critical sites for generating tumor antigen-specific T cells and are associated with durable immune responses. However, lymph nodes are often the first site of ...metastasis and lymph node metastases portend worse outcomes. Through cross species single cell gene expression analysis of breast cancer progression and metastasis to lymph nodes, we uncovered features that define the heterogeneity, plasticity, and immune evasion of cancer cells. Notably, a subpopulation of metastatic cancer cells in the lymph node were marked by high levels of MHC class II (MHC-II) gene expression both in mice and humans. Mechanistically, the IFN-γ and JAK/STAT signaling pathways mediate MHC-II expression in cancer cells. Ablation of IFNGR1/2 or CIITA, the transactivator of MHC-II, in cancer cells prevented tumor progression. Interestingly, MHC-II+ cancer cells lacked co-stimulatory molecule expression, engendered the expansion of regulatory T cells and blunted CD4+ effector T cells in the tumor draining lymph nodes and favor tumor progression. Overall, our data suggests that cancer cell plasticity during breast cancer progression and metastasis to lymph nodes endows metastatic cells with the ability to avoid immune surveillance. These data provide the basis for new opportunities to therapeutically stimulate anti-cancer immune responses against local and systemic metastases.
Citation Format: Pin-Ji Lei, Ethel Pereira, Patrik Andersson, Zohreh Amoozgar, Jan Willem Van Wijnbergen, Meghan J. O'Melia, Hengbo Zhou, Sampurna Chatterjee, William Wee Ho, Jessica M. Posada, Ashwin Srinivasan Kumar, Satoru Morita, Charlie Chuang, Ilgin Ergin, Dennis Jones, Peigen Huang, Semir Beyaz, Timothy P. Padera. Single cell analysis of breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1298.
Transcription regulation emerged to be one of the key mechanisms in regulating autophagy. Inhibitors of H3K9 methylation activates the expression of LC3B, as well as other autophagy-related genes, ...and promotes autophagy process. However, the detailed mechanisms of autophagy regulated by nuclear factors remain elusive. In this study, we performed a drug screen of SMYD2-/- cells and discovered that SMYD2 deficiency enhanced the cell death induced by BIX01294, an inhibitor of histone H3K9 methylation. BIX-01294 induces accumulation of LC3 II and autophagy-related cell death, but not caspase-dependent apoptosis. We profiled the global gene expression pattern after treatment with BIX-01294, in comparison with rapamycin. BIX-01294 selectively activates the downstream genes of p53 signaling, such as p21 and DOR, but not PUMA, a typical p53 target gene inducing apoptosis. BIX-01294 also induces other autophagy-related genes, such as ATG4A and ATG9A. SMYD2 is a methyltransferase for p53 and regulates its transcription activity. Its deficiency enhances the BIX-01294-induced autophagy-related cell death through transcriptionally promoting the expression of p53 target genes. Taken together, our data suggest BIX-01294 induces autophagy-related cell death and selectively activates p53 target genes, which is repressed by SMYD2 methyltransferase.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUNDAlthough the overall incidence of tuberculosis in underdeveloped areas has increased in recent years, esophageal tuberculosis (ET) is still rare. Intestinal tuberculosis (ITB) is relatively ...more common, but there are few reports of ET complicated with ITB. We report a case of secondary ET complicated with ITB in a previously healthy patient. CASE SUMMARYA 27-year-old female was hospitalized for progressive dysphagia, retrosternal pain, acid regurgitation, belching, heartburn, and nausea. Upper gastrointestinal endoscopy showed a mid-esophageal ulcerative hyperplastic lesion. Endoscopic ultrasonography showed a homogeneous hypoechoic lesion, with adjacent enlarged lymph nodes. Biopsy histopathology showed inflammatory exudation, exfoliated epithelial cells and interstitial granulation tissue proliferation. Colonoscopy revealed a rat-bite ulcer in the terminal ileum and a superficial ulcer in the ascending colon, near the ileocecal region. The ileum lesion biopsy showed focal granulomas with caseous necrosis. Polymerase chain reaction for Mycobacterium tuberculosis was positive in the esophageal and ileum lesion biopsies. The T-cell spot tuberculosis test was also positive. The patient was diagnosed with secondary ET infiltrated by mediastinal lymphadenopathy and complicated with ITB, possibly from the Mycobacterium tuberculosis-infected esophageal lesion. After 2 mo of anti-tuberculosis therapy, her symptoms improved significantly, and upper gastrointestinal endoscopy showed healing ulcers. CONCLUSIONWhen dysphagia or odynophagia occurs in patients at high-risk for tuberculosis, ET should be considered.
Phosphorene is a promising candidate for gas sensing materials. This letter describes our study of the adsorption of SF 6 and SF 6 decomposition gases (SO 2 and H 2 S) on phosphorene. We used first ...principles calculations to explore phosphorene's potential applications as gas sensor to diagnose the state of online gas insulated switchgear (GIS). The calculation results showed that only the adsorption of SO 2 induced a moderate adsorption energy and apparent charge transfer. We further investigated the current-voltage (I-V) relationships before and after gas absorption through the non-equilibrium Green's function method. It was found that only SO 2 induced a dramatic change in the I-V relationships. Therefore, phosphorene appears to be a promising candidate for highly sensitive and selective SF 6 decomposition gas sensors for online GIS diagnosis.
Soil respiration (Rs) is a widely monitored parameter in global forest management that results in activities that contribute to ecosystem functions. Rs can vary depending on different disturbance ...levels and ecosystem types as a result of changes in forest management practices. Understanding the mechanisms through which different forest management practices affect Rs can provide a general reference for ecological management and restoration practices. However, the global drivers of Rs across different forest management practices have not been sufficiently studied in the literature. In this study, we investigated the changing trends in Rs based on the relationships evident between biomass and Rs across different forest management practices. We used simple linear models to explore the relationships between biomass (aboveground and belowground biomasses) and Rs at a global scale based on different types of forest management practices and biomes. We observed significant differences in the mean values of Rs among various forest management practices. Furthermore, significant positive relationships between forest biomass and Rs were evident globally. Soil temperature had a significant effect on Rs, but the influences of soil temperature and moisture on Rs changed with the variations in forest management practices. Biome type can regulate the relationships between forest biomass and Rs across different forest management practices. We observed that the relationships between forest biomass and Rs were the strongest for naturally regenerating forests, both with and without signs of management, in tropical and subtropical coniferous and temperate broadleaf and mixed forests. Forest plantations and agroforestry can favor the establishment of similar positive relationships in temperate forest biomes (i.e., temperate conifer forests and boreal forests/taiga). Our results show that aboveground and belowground biomasses can be applied as effective ecological indicators for monitoring Rs levels, depending on different forest management practices and biomes. In this study, we provide evidence for monitoring Rs levels under different forest management practices globally.
In this letter, we took a first principles calculation of five SF 6 decomposition gas molecules (SO 2 , H 2 S, SOF 2 , SO 2 F 2 , and SF 6 ) adsorption on monolayer MoTe 2 . By calculating adsorption ...energy, charge transfer, and work function combined with differential charge density analysis, we predict that MoTe 2 is sensitive and selective to the SO 2 molecule. Furthermore, the total density of states analysis and projected density of states analysis demonstrate that the orbital hybridization is the main reason of the intense charge transfer between the SO 2 molecule and monolayer MoTe 2 . In summary, it can be concluded that MoTe 2 is a promising candidate for SF 6 decomposition gas sensors with high sensitivity and selectivity.
Aims
Microglia‐mediated neuroinflammation plays an important role in the pathological process of ischemic stroke, and the effect of imperatorin on post‐stroke neuroinflammation is not fully ...understood.
Methods
Primary microglia were treated with imperatorin for 2 h followed by LPS (100 ng/ml) for 24 h. The expression of inflammatory cytokines was detected by RT‐PCR, ELISA, and Western blot. The activation of MAPK and NF‐κB signaling pathways were analyzed by Western blot. The ischemic insult was determined using a transient middle cerebral artery occlusion (tMCAO) model in C57BL/6J mice. Behavior tests were used to assess the neurological deficits of MCAO mice. TTC staining was applied to measure infract volume.
Results
Imperatorin suppressed LPS‐induced activation of microglia and pro‐inflammatory cytokines release and attenuated ischemic injury in MCAO mice. The results of transcriptome sequencing and Western blot revealed that downregulation of MAPK and NF‐κB pathways might contribute to the protective effects of imperatorin.
Conclusions
Imperatorin downregulated MAPK and NF‐κB signaling pathways and exerted anti‐inflammatory effects in ischemic stroke, which indicated that imperatorin might be a potential compound for the treatment of stroke.
Imperatorin inhibits MAPKs and NF‐κB signaling pathways and alleviates neuroinflammation in ischemic stroke.
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