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Intestinal stem cells (ISCs) are maintained by stemness signaling for precise modulation of self-renewal and differentiation under homeostasis. However, the way in which intestinal immune cells regulate the self-renewal of ISCs remains elusive. Here we found that mouse and human Lgr5+ ISCs showed high expression of the immune cell-associated circular RNA circPan3 (originating from the Pan3 gene transcript). Deletion of circPan3 in Lgr5+ ISCs impaired their self-renewal capacity and the regeneration of gut epithelium in a manner dependent on immune cells. circPan3 bound mRNA encoding the cytokine IL-13 receptor subunit IL-13Rα1 (Il13ra1) in ISCs to increase its stability, which led to the expression of IL-13Rα1 in ISCs. IL-13 produced by group 2 innate lymphoid cells in the crypt niche engaged IL-13Rα1 on crypt ISCs and activated signaling mediated by IL-13âIL-13R, which in turn initiated expression of the transcription factor Foxp1. Foxp1 is associated with ß-catenin in rendering its nuclear translocation, which caused activation of the ß-catenin pathway and the maintenance of Lgr5+ ISCs.
Assuntos
Autorrenovação Celular/imunologia , Interleucina-13/metabolismo , Mucosa Intestinal/imunologia , RNA/metabolismo , Células-Tronco/fisiologia , Animais , Proteínas de Transporte/genética , Diferenciação Celular/imunologia , Autorrenovação Celular/genética , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , RNA/genética , RNA/imunologia , RNA Circular , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regeneração/genética , Regeneração/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , beta Catenina/imunologia , beta Catenina/metabolismoRESUMO
Innate lymphoid cells (ILCs) communicate with other hematopoietic and nonhematopoietic cells to regulate immunity, inflammation and tissue homeostasis. How ILC lineages develop and are maintained remains largely unknown. In this study we observed that a divergent long noncoding RNA (lncRNA), lncKdm2b, was expressed at high levels in intestinal group 3 ILCs (ILC3s). LncKdm2b deficiency in the hematopoietic system led to reductions in the number and effector functions of ILC3s. LncKdm2b expression sustained the maintenance of ILC3s by promoting their proliferation through activation of the transcription factor Zfp292. Mechanistically, lncKdm2b recruited the chromatin organizer Satb1 and the nuclear remodeling factor (NURF) complex onto the Zfp292 promoter to initiate its transcription. Deletion of Zfp292 or Bptf also abrogated the maintenance of ILC3s, leading to susceptibility to bacterial infection. Therefore, our findings reveal that lncRNAs may represent an additional layer of regulation of ILC development and function.
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Infecções Bacterianas/genética , Proteínas F-Box/genética , Imunidade Inata , Histona Desmetilases com o Domínio Jumonji/genética , Linfócitos/fisiologia , RNA Longo não Codificante/genética , Animais , Antígenos Nucleares/genética , Diferenciação Celular/genética , Linhagem da Célula/genética , Proliferação de Células/genética , Montagem e Desmontagem da Cromatina , Proteínas de Ligação a DNA/genética , Suscetibilidade a Doenças , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Ativação TranscricionalRESUMO
Evolution in time-varying environments naturally leads to adaptable biological systems that can easily switch functionalities. Advances in the synthesis of environmentally responsive materials therefore open up the possibility of creating a wide range of synthetic materials which can also be trained for adaptability. We consider high-dimensional inverse problems for materials where any particular functionality can be realized by numerous equivalent choices of design parameters. By periodically switching targets in a given design algorithm, we can teach a material to perform incompatible functionalities with minimal changes in design parameters. We exhibit this learning strategy for adaptability in two simulated settings: elastic networks that are designed to switch deformation modes with minimal bond changes and heteropolymers whose folding pathway selections are controlled by a minimal set of monomer affinities. The resulting designs can reveal physical principles, such as nucleation-controlled folding, that enable such adaptability.
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Recurrent spontaneous abortion (RSA) is a common pregnancy-related disorder. Cbl proto-oncogene like 1 (CBLL1) is an E3 ubiquitin ligase, which has been reported to vary with the menstrual cycle in the endometrium. However, whether CBLL1 is involved in the occurrence and development of RSA remains unclear. This study aimed to investigate the effects of CBLL1 on RSA. We analyzed the expression of CBLL1 in the decidua of RSA patients, as well as its functional effects on cellular senescence, oxidative stress, and proliferation of human endometrial stromal cells (HESCs). RNA sequencing was employed to identify a key downstream target gene regulated by CBLL1. We found that CBLL1 was upregulated in the decidua of RSA patients. Additionally, overexpression of CBLL1 promoted HESC senescence, increased oxidative stress levels, and inhibited proliferation. Phosphatase and tensin homolog located on chromosome 10 (PTEN) was identified as one of the important downstream target genes of CBLL1. In vivo experiments demonstrated that CBLL1 overexpression in the endometrium caused higher embryo absorption rate in mice. Consequently, elevated CBLL1 expression is a potential cause of RSA, representing a novel therapeutic target for RSA.
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Aborto Habitual , Senescência Celular , Endométrio , PTEN Fosfo-Hidrolase , Células Estromais , Adulto , Animais , Feminino , Humanos , Camundongos , Gravidez , Aborto Habitual/metabolismo , Aborto Habitual/genética , Aborto Habitual/patologia , Proliferação de Células , Decídua/metabolismo , Decídua/patologia , Endométrio/metabolismo , Endométrio/patologia , Estresse Oxidativo , Proto-Oncogene Mas , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Células Estromais/metabolismoRESUMO
The proteasome holoenzyme is activated by its regulatory particle (RP) consisting of two subcomplexes, the lid and the base. A key event in base assembly is the formation of a heterohexameric ring of AAA-ATPases, which is guided by at least four RP assembly chaperones in mammals: PAAF1, p28/gankyrin, p27/PSMD9, and S5b. Using cryogenic electron microscopy, we analyzed the non-AAA structure of the p28-bound human RP at 4.5 Å resolution and determined seven distinct conformations of the Rpn1-p28-AAA subcomplex within the p28-bound RP at subnanometer resolutions. Remarkably, the p28-bound AAA ring does not form a channel in the free RP and spontaneously samples multiple "open" and "closed" topologies at the Rpt2-Rpt6 and Rpt3-Rpt4 interfaces. Our analysis suggests that p28 assists the proteolytic core particle to select a specific conformation of the ATPase ring for RP engagement and is released in a shoehorn-like fashion in the last step of the chaperone-mediated proteasome assembly.
Assuntos
Chaperonas Moleculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Microscopia Crioeletrônica , Células HEK293 , Humanos , Proteínas com Domínio LIM/metabolismo , Proteínas com Domínio LIM/ultraestrutura , Modelos Moleculares , Chaperonas Moleculares/ultraestrutura , Complexo de Endopeptidases do Proteassoma/ultraestrutura , Ligação Proteica , Estrutura Quaternária de Proteína , Subunidades Proteicas , Proteínas Proto-Oncogênicas/ultraestrutura , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Fatores de Transcrição/ultraestrutura , TransfecçãoRESUMO
Aprotic lithium-oxygen (Li-O2) batteries are considered to be a promising alternative option to lithium-ion batteries for high gravimetric energy storage devices. However, the sluggish electrochemical kinetics, the passivation, and the structural damage to the cathode caused by the solid discharge products have greatly hindered the practical application of Li-O2 batteries. Herein, the nonsolid-state discharge products of the off-stoichiometric Li1-xO2 in the electrolyte solutions are achieved by iridium (Ir) single-atom-based porous organic polymers (termed as Ir/AP-POP) as a homogeneous, soluble electrocatalyst for Li-O2 batteries. In particular, the numerous atomic active sites act as the main nucleation sites of O2-related discharge reactions, which are favorable to interacting with O2-/LiO2 intermediates in the electrolyte solutions, owing to the highly similar lattice-matching effect between the in situ-formed Ir3Li and LiO2, achieving a nonsolid LiO2 as the final discharge product in the electrolyte solutions for Li-O2 batteries. Consequently, the Li-O2 battery with a soluble Ir/AP-POP electrocatalyst exhibits an ultrahigh discharge capacity of 12.8 mAh, an ultralow overpotential of 0.03 V, and a long cyclic life of 700 h with the carbon cloth cathode. The manipulation of nonsolid discharge products in aprotic Li-O2 batteries breaks the traditional growth mode of Li2O2, bringing Li-O2 batteries closer to being a viable technology.
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BACKGROUND: Clinical studies on programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors for treating triple-negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor-infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin-dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies. METHODS: The authors tested three CDK inhibitors on the TNBC cell lines MDA-MB-231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune-related mechanisms of different combination therapy experiments in a 4T1 cell-transplanted BALB/c mouse model. RESULTS: Treatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell-cycle arrest and induced apoptosis in human breast cancer MDA-MB-231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD-L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels. CONCLUSIONS: Combination therapy with CDK and PD-L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.
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Neoplasias de Mama Triplo Negativas , Animais , Humanos , Camundongos , Antígeno B7-H1 , Quinases Ciclina-Dependentes , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Lgr5+ intestinal stem cells (ISCs) exhibit self-renewal and differentiation features under homeostatic conditions, but the mechanisms controlling Lgr5 + ISC self-renewal remain elusive. Here, we show that the chromatin remodeler SRCAP is highly expressed in mouse intestinal epithelium and ISCs. Srcap deletion impairs both self-renewal of ISCs and intestinal epithelial regeneration. Mechanistically, SRCAP recruits the transcriptional regulator REST to the Prdm16 promoter and induces expression of this transcription factor. By activating PPARδ expression, Prdm16 in turn initiates PPARδ signaling, which sustains ISC stemness. Rest or Prdm16 deficiency abrogates the self-renewal capacity of ISCs as well as intestinal epithelial regeneration. Collectively, these data show that the SRCAP-REST-Prdm16-PPARδ axis is required for self-renewal maintenance of Lgr5 + ISCs.
Assuntos
Adenosina Trifosfatases/metabolismo , Mucosa Intestinal/enzimologia , Transdução de Sinais , Células-Tronco/enzimologia , Adenosina Trifosfatases/genética , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Mucosa Intestinal/citologia , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Células-Tronco/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (Pâ =â .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Inibidores de Proteínas Quinases , Terapia de Salvação , Humanos , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/complicações , Masculino , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/complicações , Feminino , Terapia de Salvação/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Veia Porta/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Adulto , Trombose VenosaRESUMO
BACKGROUND: Abnormal placental development is a significant factor contributing to perinatal morbidity and mortality, affecting approximately 5-7% of pregnant women. Trophoblast syncytialization plays a pivotal role in the establishment and maturation of the placenta, and its dysregulation is closely associated with several pregnancy-related disorders, including preeclampsia and intrauterine growth restriction. However, the underlying mechanisms and genetic determinants of syncytialization are largely unknown. METHODS: We conducted a systematic drug screen using an epigenetic compound library to systematically investigate the epigenetic mechanism essential for syncytialization, and identified mixed lineage leukemia 1 (MLL1), a histone 3 lysine 4 methyltransferase, as a crucial regulator of trophoblast syncytialization. BeWo cells were utilized to investigate the role of MLL1 during trophoblast syncytialization. RNA sequencing and CUT&Tag were further performed to search for potential target genes and the molecular pathways involved. Human placenta tissue was used to investigate the role of MLL1 in TEA domain transcription factor 4 (TEAD4) expression and the upstream signaling during syncytialization. A mouse model was used to examine whether inhibition of MLL1-mediated H3K4me3 regulated placental TEAD4 expression and fetoplacental growth. RESULTS: Genetic knockdown of MLL1 or pharmacological inhibition of the MLL1 methyltransferase complex (by MI-3454) markedly enhanced syncytialization, while overexpression of MLL1 inhibited forskolin (FSK)-induced syncytiotrophoblast formation. In human placental villous tissue, MLL1 was predominantly localized in the nuclei of cytotrophoblasts. Moreover, a notable upregulation in MLL1 expression was observed in the villus tissue of patients with preeclampsia compared with that in the control group. Based on RNA sequencing and CUT&Tag analyses, depletion of MLL1 inhibited the Hippo signaling pathway by suppressing TEAD4 expression by modulating H3K4me3 levels on the TEAD4 promoter region. TEAD4 overexpression significantly reversed the FSK-induced or MLL1 silencing-mediated trophoblast syncytialization. Additionally, decreased hypoxia-inducible factor 1A (HIF1A) enrichment at the MLL1 promoter was observed during syncytialization. Under hypoxic conditions, HIF1A could bind to and upregulate MLL1, leading to the activation of the MLL1/TEAD4 axis. In vivo studies demonstrated that the administration of MI-3454 significantly enhanced fetal vessel development and increased the thickness of the syncytial layer, thereby supporting fetoplacental growth. CONCLUSIONS: These results revealed a novel epigenetic mechanism underlying the progression of syncytialization with MLL1, and suggest potential avenues for identifying new therapeutic targets for pregnancy-related disorders.
Assuntos
Histona-Lisina N-Metiltransferase , Proteína de Leucina Linfoide-Mieloide , Placenta , Pré-Eclâmpsia , Animais , Feminino , Humanos , Camundongos , Gravidez , Epigênese Genética , Placenta/metabolismo , Fatores de Transcrição de Domínio TEA , Trofoblastos/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismoRESUMO
Developing cost-effective, durable bifunctional electrocatalysts is crucial but remains challenging due to slow hydrogen/oxygen evolution reaction (HER/OER) kinetics in water electrolysis. Herein, a combined engineering strategy of phosphorous vacancy (Vp) and spontaneous built-in electric field (BIEF) is proposed to design novel highly-conductive Co-doped MoP@MXene heterostructures with phosphorous vacancy (Vp-Co-MoP@MXene). Wherein, Co doping regulates the surface electronic structure and charge re-distribution of MoP, Vp induces more defects and active sites, while BIEF accelerates the interfacial charge transfer rate between Vp-Co-MoP and MXene. Therefore, the synergistic integration of Vp-Co-MoP/MXene efficiently decreases activation energy and kinetic barrier, thus promoting its intrinsically catalytic activity and structural stability. Consequently, the Vp-Co-MoP@MXene catalyst displays low overpotentials of 102.3/196.5 and 265.0/320.0 mV at 10/50 mA cm-2 for HER and OER, respectively. Notably, two-electrode electrolyzers with the Vp-Co-MoP@MXene bifunctional catalysts to achieve 10/50 mA cm-2, only need low-cell voltages of 1.57/1.64 V in alkaline media. Besides, experimental and theoretical results confirm that the hetero-structure effectively reduces hydrogen adsorption free energy and rate-determining-step energy barrier of OER intermediates, thereby greatly boosting its intrinsically catalytic activity. This work verifies an effective strategy to fabricate efficient non-precious bifunctional electro-catalysts for water splitting via combination engineering of phosphorous vacancy, cation doping, and BIEF.
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Vertically-ordered mesoporous silica films (VMSF, also named as silica isoporous membranes) have shown tremendous potential in the field of electroanalytical sensors due to their unique features in terms of controllable and ultrasmall nanopores, high molecular selectivity and permeability, and mechanical stability. This review will present the recent progress on the biomedical analytical applications of VMSF, focusing on the small biomolecules, diseases-related biomarkers, drugs and cancer cells. Finally, conclusions with recent developments and future perspective of VMSF in the relevant fields will be envisioned.
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Inappropriate endometrial stromal decidualization has been implied as an important reason of many pregnancy-related complications, such as unexplained recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction. Here, we observed that thrombospondin-1, an adhesive glycoprotein, was significantly downregulated in endometrial decidual cells from patients with unexplained recurrent spontaneous abortion. The immortalized human endometrial stromal cell line was used to investigate the possible THBS1-mediated regulation of decidualization. In vitro experiments found that the expression level of THBS1 increased with the normal decidualization process. Knockdown of THBS1 could decrease the expression levels of prolactin and insulin-like growth factor binding protein-1, two acknowledged human decidualization markers, whereas THBS1 overexpression could reverse these effects. The RNA sequencing results demonstrated that the extracellular regulated protein kinases signaling pathway was potentially affected by the knockdown of THBS1. We further confirmed that the regulation of THBS1 on decidualization was achieved through the ERK signaling pathway by the treatment of inhibitors. Moreover, knockdown of THBS1 in pregnant mice could impair decidualization and result in an increased fetus resorption rate. Altogether, our study demonstrated a crucial role of THBS1 in the pathophysiological process of unexplained recurrent spontaneous abortion and provided some new insights into the research of pregnancy-related complications.
Assuntos
Aborto Habitual , Decídua , Endométrio , Células Estromais , Trombospondina 1 , Adulto , Animais , Feminino , Humanos , Camundongos , Gravidez , Aborto Habitual/genética , Aborto Habitual/metabolismo , Decídua/metabolismo , Endométrio/metabolismo , Endométrio/patologia , Células Estromais/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , MasculinoRESUMO
Pulmonary sarcoidosis is an immune-mediated disorder closely related to Th17/Treg cell imbalance. Dexamethasone has been shown to regulate inflammation and immune responses in sarcoidosis patients. However, the underlying mechanisms of dexamethasone regulating Th17/Treg balance in sarcoidosis remain elusive. Herein, we elucidated the function role of TGF-ß/Smad3 signaling in pulmonary sarcoidosis development and explored the underlying mechanism of dexamethasone in treating pulmonary sarcoidosis. We found that the TGF-ß/Smad3 pathway was inactivated in pulmonary sarcoidosis patients. Propionibacterium acnes (PA) induced mouse model was generated to investigate the function of TGF-ß/Smad3 signaling in vivo. Data indicated that IL17A inhibition with neutralizing antibody and activation of TGF-ß/Smad3 signaling with SRI-011381 alleviated granuloma formation in the sarcoidosis mouse model. Moreover, we revealed that the Th17/Treg cell ratio was increased with PA treatment in mouse bronchoalveolar lavage fluid (BALF) and peripheral blood. The concentration of cytokines produced by Th17 cells (IL-17A, IL-23) was up-regulated in the BALF of PA-treated mice, while those produced by Tregs (IL-10, TGF-ß1) presented significant reduction. The treatment of IL-17A neutralizing antibody or SRI-011381 was demonstrated to rescue the PA-induced changes in the concentration of IL-17A, IL-23, IL-10, and TGF-ß1. Additionally, we demonstrated that dexamethasone treatment activated the TGF-ß/Smad3 signaling in the lung tissues of pulmonary sarcoidosis mice. Dexamethasone was also revealed to promote the rebalancing of the Th17/Treg ratio and attenuated the granuloma formation in pulmonary sarcoidosis. In conclusion, dexamethasone activates the TGF-ß/Smad3 signaling and induces Th17/Treg rebalance, alleviating pulmonary sarcoidosis, which suggests the potential of dexamethasone in treating pulmonary sarcoidosis.
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Dexametasona , Sarcoidose Pulmonar , Animais , Humanos , Camundongos , Anticorpos Neutralizantes/farmacologia , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Granuloma/prevenção & controle , Interleucina-10/metabolismo , Interleucina-17 , Interleucina-23/metabolismo , Sarcoidose Pulmonar/tratamento farmacológico , Linfócitos T Reguladores , Células Th17 , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1RESUMO
BACKGROUND: Combination treatment with transcatheter arterial chemoembolization (TACE), lenvatinib, and anti-programmed death-1 (anti-PD-1) antibodies (triple therapy) has a high rate of tumor response and converted resection for initially unresectable hepatocellular carcinoma (uHCC) patients. This study aimed to assess the outcomes of salvage surgery in uHCC patients after conversion therapy with triple therapy. METHODS: uHCC patients who met the criteria for hepatectomy after receiving triple therapy as first-line treatment were eligible for inclusion in this study. The overall survival (OS) and progression-free survival (PFS) rates in patients who received salvage surgery (SR group) and those who did not (non-SR group) were compared. RESULTS: Of the 144 patients assessed, 91 patients underwent salvage surgery and 53 did not. The OS rates in the SR group were significantly better than those in the non-SR group. The 1- and 2-year OS rates in the SR group were 92.0% and 79.9%, respectively, whereas those in the non-SR group were 85.5% and 39.6 %, respectively (p = 0.007); however, there was no significant difference in the PFS rates. Upon further stratification, OS and PFS were significantly better in the SR group than in the non-SR group in patients who were assessed as partial responses (PR), while there was no significant difference in patients who were assessed as complete response (CR). CONCLUSIONS: Salvage surgery is recommended and is associated with a favorable prognosis for uHCC patients who were assessed as PR after conversion therapy, however it may not be necessary for uHCC if CR was achieved.
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Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Humanos , Carcinoma Hepatocelular/terapia , Estudos Retrospectivos , Neoplasias Hepáticas/terapia , Resposta Patológica CompletaRESUMO
In brief: The proliferation of the endometrium is regulated by histone methylation. This study shows that decreased NSD2 impairs proliferative-phase endometrial stromal cell proliferation in patients with recurrent implantation failure via epigenetic reprogramming of H3K36me2 methylation on the promoter region of MCM7. Abstract: Recurrent implantation failure (RIF) is a formidable challenge in assisted reproductive technology because of its unclear molecular mechanism. Impaired human endometrial stromal cell (HESC) proliferation disrupts the rhythm of the menstrual cycle, resulting in devastating disorders between the embryo and the endometrium. The molecular function of histone methylation enzymes in modulating HESC proliferation remains largely uncharacterized. Herein, we found that the levels of histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2) and the dimethylation of lysine 36 on histone H3 are decreased significantly in the proliferative-phase endometrium of patients with RIF. Knockdown of NSD2 in an HESC cell line markedly impaired cell proliferation and globally reduced H3K36me2 binding to chromatin, leading to altered expression of many genes. Transcriptomic analyses revealed that cell cycle-related gene sets were downregulated in the endometrium of patients with RIF and in NSD2knockdown HESCs. Furthermore, RNA-sequencing and CUT&Tag sequencing analysis suggested that NSD2 knockdown reduced the binding of H3K36me2 to the promoter region of cell cycle marker gene MCM7 (encoding minichromosome maintenance complex component 7) and downregulated its expression. The interaction of H3K36me2 with the MCM7 promoter was verified using chromatin immunoprecipitation-quantitative real-time PCR. Our results demonstrated a unifying epigenome-scale mechanism by which decreased NSD2 impairs endometrial stromal cell proliferation in the proliferative-phase endometrium of patients with RIF.
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Endométrio , Histonas , Feminino , Humanos , Proliferação de Células , Cromatina/metabolismo , Endométrio/metabolismo , Histonas/metabolismo , Células Estromais/metabolismoRESUMO
Gaucher disease (GD) is an autosomal recessive ailment resulting from glucocerebrosidase deficiency caused by a mutation in the GBA1 gene, leading to multi-organ problems in the liver, spleen, and bone marrow. In China, GD is extremely uncommon and has a lower incidence rate than worldwide. In this study, we report the case of an adult male with an enlarged spleen for 13 years who presented with abdominal distension, severe loss of appetite and weight, reduction of the three-line due to hypersplenism, frequent nosebleeds, and bloody stools. Regrettably, the unexpected discovery of splenic pathology suggestive of splenic Gaucher disease was only made after a splenectomy due to a lack of knowledge about rare disorders. Our patient's delayed diagnosis may have been due to the department where he was originally treated, but it highlights the need for multidisciplinary consultation in splenomegaly of unknown etiology. We then investigated the patient's clinical phenotypes and gene mutation features using genetically phenotypical analysis. The analysis of the GBA1 gene sequence indicated that the patient carried a compound heterozygous mutation consisting of two potentially disease-causing mutations: c.907C > A (p. Leu303Ile) and c.1448 T > C (p. Leu483Pro). While previous research has linked the p. Leu483Pro mutation site to neurologic GD phenotypes (GD2 and GD3), the patients in this investigation were identified as having non-neuronopathic GD1. The other mutation, p. Leu303Ile, is a new GD-related mutation not indexed in PubMed that enriches the GBA1 gene mutation spectrum. Biosignature analysis has shown that both mutations alter the protein's three-dimensional structure, which may be a pathogenic mechanism for GD1 in this patient.
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Doença de Gaucher , Esplenopatias , Adulto , Humanos , Masculino , Doença de Gaucher/complicações , Doença de Gaucher/genética , Doença de Gaucher/cirurgia , Esplenectomia , Medula Óssea , Fenótipo , Esplenomegalia/genética , Mutação , Glucosilceramidase/genéticaRESUMO
Danon disease is a rare X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2. We report a case of hypertrophic obstructive cardiomyopathy secondary to a novel mutation in the lysosome-associated membrane protein-2 gene in a 10-year-old male adolescent. We performed a modified extended Morrow procedure to minimise the risk of death and improve the patient's quality of life. The patient did not have exertional dyspnoea, and auscultation did not reveal a cardiac murmur at 1-year follow-up.
Assuntos
Cardiomiopatia Hipertrófica , Doença de Depósito de Glicogênio Tipo IIb , Masculino , Adolescente , Humanos , Criança , Doença de Depósito de Glicogênio Tipo IIb/complicações , Doença de Depósito de Glicogênio Tipo IIb/diagnóstico , Doença de Depósito de Glicogênio Tipo IIb/genética , Qualidade de Vida , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genéticaRESUMO
BACKGROUND: The prognosis of HCC patients without MVI (so called M0) is highly heterogeneous and the need for adjuvant therapy is still controversial. METHODS: Patients with HCC with M0 who underwent liver resection (LR) or liver transplantation (LT) as an initial therapy were included. The Eastern Hepatobiliary Surgery Hospital (EHBH)-M0 score was developed from a retrospective cohort to form the training cohort. The classification which was developed using multivariate cox regression analysis was externally validated. RESULTS: The score was developed using the following factors: α-fetoprotein level, tumour diameter, liver cirrhosis, total bilirubin, albumin and aspartate aminotransferase. The score differentiated two groups of M0 patients (≤3, >3 points) with distinct long-term prognoses outcomes (median overall survival (OS), 98.0 vs. 46.0 months; p < 0.001). The predictive accuracy of the score was greater than the other commonly used staging systems for HCC. And for M0 patients with a higher score underwent LR. Adjuvant transcatheter arterial chemoembolization (TACE) was effective to prolong OS. CONCLUSIONS: The EHBH M0 scoring system was more accurate in predicting the prognosis of HCC patients with M0 after LR or LT. Adjuvant therapy is recommended for HCC patients who have a higher score.
Assuntos
Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Invasividade Neoplásica , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Humanos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Transplante de Fígado , Resultado do Tratamento , Quimioembolização Terapêutica , Técnicas de Apoio para a Decisão , Fatores de Risco , Fatores de Tempo , Adulto , Microvasos/patologia , Medição de RiscoRESUMO
Li-CO2 batteries have received significant attention owing to their advantages of combining greenhouse gas utilization and energy storage. However, the high kinetic barrier between gaseous CO2 and the Li2CO3 product leads to a low operating voltage (<2.5â V) and poor energy efficiency. In addition, the reversibility of Li2CO3 has always been questioned owing to the introduction of more decomposition paths caused by its higher charging plateau. Here, a novel "trinity" Li-CO2 battery system was developed by synergizing CO2, soluble redox mediator (2,2,6,6-tetramethylpiperidoxyl, as TEM RM), and reduced graphene oxide electrode to enable selective conversion of CO2 to Li2C2O4. The designed Li-CO2 battery exhibited an output plateau reaching up to 2.97â V, higher than the equilibrium potential of 2.80â V for Li2CO3, and an ultrahigh round-trip efficiency of 97.1 %. The superior performance of Li-CO2 batteries is attributed to the TEM RM-mediated preferential growth mechanism of Li2C2O4, which enhances the reaction kinetics and rechargeability. Such a unique design enables batteries to cope with sudden CO2-deficient environments, which provides an avenue for the rationally design of CO2 conversion reactions and a feasible guide for next-generation Li-CO2 batteries.