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OBJECTIVES: The purpose of this study is to assess the diagnostic efficacy of contrast-enhanced CT scans for small bowel bleeding. METHODS: This retrospective study evaluated patients diagnosed with non-neoplastic small intestinal bleeding (including duodenum) who underwent abdominal CT at our institution from December 2013 to March 2023. Patients were categorized into diverticulum and non-diverticulum groups based on the cause of bleeding. Active bleeding was defined on the CT images as extravasation of contrast material in the intestinal lumen during the arterial phase and/or progressive accumulation of contrast material during the venous phase. We have documented the original report (extracted from the medical record system and additional consultation opinions from senior radiologists), including the presence of active bleeding and its potential bleeding location. Furthermore, two radiologists reassessed the CT images, seeking consensus on the diagnosis between them. RESULTS: The study included 165 patients, predominantly male, with a median age of 30 years. Active bleeding was identified in 48.3% of patients. Notably, all identified bleeding diverticula in the diverticulum group exhibited cul-de-sac termination. Among the identified causes of bleeding, Crohn's disease was most prevalent (46.7%, N of causes = 64). Significant differences were observed in the diagnostic methods between the diverticulum and non-diverticulum groups, with surgery predominantly applied in the diverticulum group, and endoscopy in the non-diverticulum group (n = 49 vs n = 15, p = 0.001). Contrast agent extravasation was significantly higher in the diverticulum group (n = 54 vs n = 16, p = 0.001), and Meckel's diverticulum cases appearing tubular were significantly higher than in other diverticulum cases (n = 25 vs n = 3, p < 0.001). CONCLUSION: CT allows for a higher detection rate of diverticular bleeding, even if asymptomatic, guiding classification into multiple potentially clinically relevant categories. CRITICAL RELEVANCE STATEMENT: Contrast-enhanced CT imaging is effective in determining the location and cause of non-neoplastic small bowel bleeding, especially diverticular bleeding. Therefore, the use of enhanced CT should be prioritized in the diagnosis and management of small bowel bleeding. KEY POINTS: CT has potential value in the diagnosis of small bowel bleeding. CT imaging suggests possible surgical intervention for active bleeding detection. CT diagnoses and localizes small bowel bleeding, aiding in treatment and prioritizing in guidelines.
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Background: Bladder cancer (BC), as a common type of cancer, has a poor prognosis, also some common invasive prognostic or therapeutic markers are difficult to obtain, which makes further treatment of BC difficult. Glycyl-tRNA synthetase (GARS), as one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids, has been identified as a target in many diseases, including tumors. Methods: Bioassay analysis revealed that GARS was in high expression in most cancer tissues. The expression of GARS gene in BC tissues could assess the prognosis of BC patients, and the expression in urinary extracellular vesicles (uEVs) of patients was positively correlated with the expression in tissues. In addition to this, we analyzed GARS-related differential gene expression, copy number variation (CNV) and mutation profiles, potential biological functions, immune cell infiltration and drug sensitivity. In vivo and vitro tumorigenic experiments were performed to validate the function of GARS. Single-cell data were used to further analyze its role in the microenvironment. Results: In our study, we found that GARS was highly expressed in 30 cancer tissues including BC, and high GARS expression was negatively correlated with the prognosis of BC patients. To address this phenomenon, we analyzed the differential genes between high and low GARS groups by enrichment analysis, and identified the biological signaling pathways that were mainly enriched for their functions, and found that the enrichment was found in immune-related signaling pathways and regulation of cell-cell adhesion. Then we found that GARS was positively associated with immune cell infiltration in BC, and some common immune checkpoints were significantly overexpressed in the GARS-high group. Besides, we found that GARS was enriched in myofibroblasts in the tumor microenvironment, and the enrichment was positively correlated with epithelial-mesenchymal transition (EMT)-related genes. This study also showed a positive correlation between GARS and BC RNA stemness. Patients in the GARS-high group had considerably higher rates of P53 and Titin (TTN) mutations than those in the GARS-low group. Drug Sensitivity analysis screened for drugs that were more sensitive to GARS-high patients. Further, we found that knockdown of GARS significantly inhibited the proliferation, migration and invasion ability both in vivo and in vitro. Finally, we found that in patients with high GARS the expression in uEVs was also at a high level. Conclusions: In summary, this study provided evidence that GARS can be used as a prognostic and therapeutic marker for BC, we can detect GARS in uEVs instead of tissue, to provide a new, simple, noninvasive way to obtain prognostic and therapeutic markers for BC patients.
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Hepatic fibrosis is a compensatory response to chronic liver injury and inflammation, and dietary intervention is recommended as one of the fundamental prevention strategies. Raspberry ketone (RK) is an aromatic compound first isolated from raspberry and widely used to prepare food flavors. The current study investigated the hepatoprotection and potential mechanism of RK against hepatic fibrosis. In vitro, hepatic stellate cell (HSC) activation was stimulated with TGF-ß and cultured with RK, farnesoid X receptor (FXR), or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) agonist or inhibitor, respectively. In vivo, C57BL/6 mice were injected intraperitoneally with thioacetamide (TAA) at 100/200 mg/kg from the first to the fifth week. Mice were intragastrically administrated with RK or Cur once a day from the second to the fifth week. In activated HSCs, RK inhibited extracellular matrix (ECM) accumulation, inflammation, and epithelial-mesenchymal transition (EMT) process. RK both activated FXR/PGC-1α and regulated their crosstalk, which were verified by their inhibitors and agonists. Deficiency of FXR or PGC-1α also attenuated the effect of RK on the reverse of activated HSCs. RK also decreased serum ALT/AST levels, liver histopathological change, ECM accumulation, inflammation, and EMT in mice caused by TAA. Double activation of FXR/PGC-1α might be the key targets for RK against hepatic fibrosis. Above all, these discoveries supported the potential of RK as a novel candidate for the dietary intervention of hepatic fibrosis.
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Butanonas , Células Estreladas do Fígado , Cirrose Hepática , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptores Citoplasmáticos e Nucleares , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Butanonas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Cirrose Hepática/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/tratamento farmacológico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Rubus/química , Transdução de Sinais/efeitos dos fármacos , RatosRESUMO
Background: Osteosarcoma primarily affects children and adolescents, with current clinical treatments often resulting in poor prognosis. There has been growing evidence linking programmed cell death (PCD) to the occurrence and progression of tumors. This study aims to enhance the accuracy of OS prognosis assessment by identifying PCD-related prognostic risk genes, constructing a PCD-based OS prognostic risk model, and characterizing the function of genes within this model. Method: We retrieved osteosarcoma patient samples from TARGET and GEO databases, and manually curated literature to summarize 15 forms of programmed cell death. We collated 1621 PCD genes from literature sources as well as databases such as KEGG and GSEA. To construct our model, we integrated ten machine learning methods including Enet, Ridge, RSF, CoxBoost, plsRcox, survivalSVM, Lasso, SuperPC, StepCox, and GBM. The optimal model was chosen based on the average C-index, and named Osteosarcoma Programmed Cell Death Score (OS-PCDS). To validate the predictive performance of our model across different datasets, we employed three independent GEO validation sets. Moreover, we assessed mRNA and protein expression levels of the genes included in our model, and investigated their impact on proliferation, migration, and apoptosis of osteosarcoma cells by gene knockdown experiments. Result: In our extensive analysis, we identified 30 prognostic risk genes associated with programmed cell death (PCD) in osteosarcoma (OS). To assess the predictive power of these genes, we computed the C-index for various combinations. The model that employed the random survival forest (RSF) algorithm demonstrated superior predictive performance, significantly outperforming traditional approaches. This optimal model included five key genes: MTM1, MLH1, CLTCL1, EDIL3, and SQLE. To validate the relevance of these genes, we analyzed their mRNA and protein expression levels, revealing significant disparities between osteosarcoma cells and normal tissue cells. Specifically, the expression levels of these genes were markedly altered in OS cells, suggesting their critical role in tumor progression. Further functional validation was performed through gene knockdown experiments in U2OS cells. Knockdown of three of these genes-CLTCL1, EDIL3, and SQLE-resulted in substantial changes in proliferation rate, migration capacity, and apoptosis rate of osteosarcoma cells. These findings underscore the pivotal roles of these genes in the pathophysiology of osteosarcoma and highlight their potential as therapeutic targets. Conclusion: The five genes constituting the OS-PCDS model-CLTCL1, MTM1, MLH1, EDIL3, and SQLE-were found to significantly impact the proliferation, migration, and apoptosis of osteosarcoma cells, highlighting their potential as key prognostic markers and therapeutic targets. OS-PCDS enables accurate evaluation of the prognosis in patients with osteosarcoma.
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Apoptose , Neoplasias Ósseas , Osteossarcoma , Osteossarcoma/genética , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Humanos , Apoptose/genética , Prognóstico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/mortalidade , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Aprendizado de Máquina , Perfilação da Expressão Gênica , Transcriptoma , Proliferação de Células/genética , Bases de Dados Genéticas , Biologia Computacional/métodosRESUMO
Three previously undescribed and sixteen known alkaloids were bioguidedly isolated from the bulbs of Narcissus tazetta subsp. chinensis (M.Roem.) Masamura & Yanagih. The structures were elucidated by spectroscopic data, including HRESIMS, NMR, and ECD. Eleven of the isolated alkaloids exhibited immunosuppressive activity on the proliferation of human T cells. (+)-Narciclasine (18) showed the most significantly suppressive activity with an IC50 value of 14 ± 5 nM. In vitro, (+)-narciclasine (18) blocked NF-κB signal transduction, but did not affect PI3K/AKT signal transduction. What was more, (+)-narciclasine significantly reduced ALT and AST levels and alleviated liver damage induced by ConA in AIH mouse model.
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Alcaloides , Proliferação de Células , Imunossupressores , Narcissus , Narcissus/química , Humanos , Animais , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Imunossupressores/farmacologia , Imunossupressores/química , Imunossupressores/isolamento & purificação , Camundongos , Proliferação de Células/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Estrutura Molecular , NF-kappa B/metabolismo , NF-kappa B/antagonistas & inibidores , Benzofenantridinas/farmacologia , Benzofenantridinas/química , Benzofenantridinas/isolamento & purificação , Relação Estrutura-Atividade , Relação Dose-Resposta a Droga , Estereoisomerismo , Transdução de Sinais/efeitos dos fármacos , Fenantridinas , Alcaloides de AmaryllidaceaeRESUMO
Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A2A receptor (A2AR) on trigeminal ganglia. Antagonism of trigeminal A2AR with a selective A2AR inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A2AR overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A2AR. Therefore, we established trigeminal A2AR-mediated CGRP release as a promising druggable circuit in OSCC treatment.
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Peptídeo Relacionado com Gene de Calcitonina , Carcinoma de Células Escamosas , Progressão da Doença , Neoplasias Bucais , Receptor A2A de Adenosina , Animais , Humanos , Camundongos , Antagonistas do Receptor A2 de Adenosina/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Neoplasias Bucais/metabolismo , Pirimidinas/farmacologia , Receptor A2A de Adenosina/metabolismo , Triazóis , Nervo Trigêmeo/metabolismoRESUMO
Epimedium, a traditional Chinese medicine commonly used as a dietary supplement, contains polysaccharides and flavonoids as its main bioactive ingredients. In this study, a neutral homogeneous polysaccharide (EPSN-1) was isolated from Epimedium brevicornu Maxim. EPSN-1 was identified as a glucan with a backbone of â4)-α-D-Glcp-(1â, branched units comprised α-D-Glcp-(1â6)-α-D-Glcp-(1â, ß-D-Glcp-(1â6)-ß-D-Glcp-(1â and α-D-Glcp-(1â connected to the C6 position of backbone. The conformation of EPSN-1 in aqueous solution indicated its potential to form nanoparticles. This paper aims to investigate the carrier and pharmacodynamic activity of EPSN-1. The findings demonstrated that, on the one hand, EPSN-1, as a functional ingredient, may load Icariin (ICA) through non-covalent interactions, improving its biopharmaceutical properties such as solubility and stability, thereby improving its intestinal absorption. Additionally, as an effective ingredient, EPSN-1 could help maintain the balance of the intestinal environment by increasing the abundance of Parabacteroides, Lachnospiraceae UGG-001, Anaeroplasma, and Eubacterium xylanophilum group, while decreasing the abundance of Allobaculum, Blautia, and Adlercreutzia. Overall, this dual action of EPSN-1 sheds light on the potential applications of natural polysaccharides, highlighting their dual role as carriers and contributors to biological activity.
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Epimedium , Flavonoides , Glucanos , Hiperplasia Prostática , Epimedium/química , Masculino , Glucanos/química , Glucanos/farmacologia , Glucanos/isolamento & purificação , Hiperplasia Prostática/tratamento farmacológico , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Animais , Portadores de Fármacos/química , Humanos , Microbioma Gastrointestinal/efeitos dos fármacosRESUMO
Multilineage-differentiating stress-enduring (Muse) cells are a type of pluripotent cell with unique characteristics such as non-tumorigenic and pluripotent differentiation ability. After homing, Muse cells spontaneously differentiate into tissue component cells and supplement damaged/lost cells to participate in tissue repair. Importantly, Muse cells can survive in injured tissue for an extended period, stabilizing and promoting tissue repair. In addition, it has been confirmed that injection of exogenous Muse cells exerts anti-inflammatory, anti-apoptosis, anti-fibrosis, immunomodulatory, and paracrine protective effects in vivo. The discovery of Muse cells is an important breakthrough in the field of regenerative medicine. The article provides a comprehensive review of the characteristics, sources, and potential mechanisms of Muse cells for tissue repair and regeneration. This review serves as a foundation for the further utilization of Muse cells as a key clinical tool in regenerative medicine.
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PURPOSE: To evaluate the efficacy of Mohs micrographic surgery (MMS) combined with photodynamic therapy (PDT) in treating non-invasive extramammary Paget's disease (EMPD). MATERIALS AND METHODS: A 77-year-old male patient with non-invasive EMPD was treated with MMS followed by PDT. Preoperative fluorescence localization using 5-aminolevulinic acid (ALA) was performed to determine the surgical scope. MMS was conducted under lumbar anesthesia with intraoperative frozen-section pathology. Postoperative PDT was administered weekly for three sessions. RESULTS: The patient achieved negative surgical margins after two rounds of intraoperative pathology. Postoperative follow-up over two years showed no recurrence, and the patient did not experience significant adverse reactions. CONCLUSION: The combination of MMS and PDT was effective in treating non-invasive EMPD, demonstrating favorable clinical outcomes and no recurrence over the two-year follow-up period.
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Ácido Aminolevulínico , Cirurgia de Mohs , Doença de Paget Extramamária , Fotoquimioterapia , Fármacos Fotossensibilizantes , Neoplasias Cutâneas , Humanos , Masculino , Idoso , Doença de Paget Extramamária/patologia , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/cirurgia , Ácido Aminolevulínico/uso terapêutico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/terapia , Fármacos Fotossensibilizantes/uso terapêutico , Resultado do Tratamento , Terapia Combinada , Margens de ExcisãoRESUMO
Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers. Chemotherapy remains one dominant therapeutic strategy, while a substantial proportion of patients may develop chemotherapeutic resistance; therefore, it is particularly significant to identify the patients who could achieve maximum benefits from chemotherapy. Presently, four pyroptosis genes are reported to correlate with the chemotherapeutic response or prognosis of HNSCC, while no study has assessed the combinatorial predicting efficacy of these four genes. Hence, this study aims to evaluate the predictive value of a multi-gene pyroptosis model regarding the prognosis and chemotherapeutic responsiveness in HNSCC. Methods: By utilizing RNA-sequencing data from The Cancer Genome Atlas database and the Gene Expression Omnibus database, the pyroptosis-related gene score (PRGscore) was computed for each HNSCC sample by performing a Gene Set Variation Analysis (GSVA) based on four genes (Caspase-1, Caspase-3, Gasdermin D, Gasdermin E). The prognostic significance of the PRGscore was assessed through Cox regression and Kaplan-Meier survival analyses. Additionally, chemotherapy sensitivity stratified by high and low PRGscore was examined to determine the potential association between pyroptosis activity and chemosensitivity. Furthermore, chemotherapy sensitivity assays were conducted in HNSCC cell lines in vitro. Results: As a result, our study successfully formulated a PRGscore reflective of pyroptotic activity in HNSCC. Higher PRGscore correlates with worse prognosis. However, patients with higher PRGscore were remarkably more responsive to chemotherapy. In agreement, chemotherapy sensitivity tests on HNSCC cell lines indicated a positive association between overall pyroptosis levels and chemosensitivity to cisplatin and 5-fluorouracil; in addition, patients with higher PRGscore may benefit from the immunotherapy. Overall, our study suggests that HNSCC patients with higher PRGscore, though may have a less favorable prognosis, chemotherapy and immunotherapy may exhibit better benefits in this population.
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Neoplasias de Cabeça e Pescoço , Piroptose , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Piroptose/efeitos dos fármacos , Piroptose/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Prognóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Caspase 1/genética , Caspase 1/metabolismo , Masculino , Feminino , Caspase 3/genética , Caspase 3/metabolismo , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Pessoa de Meia-Idade , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Estimativa de Kaplan-Meier , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Idoso , GasderminasRESUMO
Chimeric antigen receptor T (CAR-T) cells therapy is a milestone achievement in the immunotherapy of relapsed and refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). However, some patients treated with CAR-T cells do not achieve complete remission, the mechanisms of which have not been elucidated. In the present study, we report a 9-year-old pediatric patient with refractory B-ALL received a triple infusion of autologous CD19 CAR-T cells therapy after the second relapse. CAR-T cells expanded in the peripheral blood and bone marrow. However, the patient did not achieve complete remission, indicating a lack of response to CAR-T cells therapy. Analysis of etiological factors revealed that the number of CD4 and CD8 double-negative T (DNT) cells was significantly upregulated in the peripheral blood, bone marrow, and autologous CAR-T cells products. In conclusiont, these findings indicate that DNT cells mediated resistance to CAR-T cells therapy in this pediatric patient with R/R B-ALL.
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Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Antígenos CD19/imunologia , Receptores de Antígenos Quiméricos/imunologia , Masculino , Recidiva , Resistencia a Medicamentos Antineoplásicos , FemininoRESUMO
A high concentration gel polymer electrolyte (GPE) was prepared by simply using LiFSI-LiNO3 dissolved in 1,3-dioxolane. The LiâLi cell achieves stable battery cycling for over 3200 h. Furthermore, the LiâCu cell demonstrates a high CE of 99.2%. Even at a high current density of 8 mA cm-2, a high CE of 98.5% was still achieved. Notably, in a LiâLiFePO4 cell, this electrolyte enables high capacity retention of 94.5% and an average CE of 99.8% over 500 cycles, showing promising prospects for high-performance lithium metal batteries.
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Chronic inflammation is a significant contributor to hypertensive heart failure. Carnosol (Car), primarily derived from the sage plant (Salvia carnosa), exhibits anti-inflammatory properties in a range of systems. Nevertheless, the influence of angiotensin II (Ang II) on cardiac remodeling remains uncharted. Car was shown to protect mice's hearts against Ang II-induced heart damage at dosages of 20 and 40 mg/kg/d. This protection was evident in a concentration-related decrease in the remodeling of the heart and dysfunction. Examination of the transcriptome revealed that the pivotal roles in mediating the protective effects of Car involved inhibiting Ang II-induced inflammation and the activation of the mitogen-activated protein kinase (MAPK) pathway. Furthermore, Car was found to inhibit p38 phosphorylation, therefore reducing the level of inflammation in cultured cardiomyocytes and mouse hearts. This effect was attributed to the direct binding to p38 and inhibition of p38 protein phosphorylation by Car both in vitro and in vivo. In addition, the effects of Car on inflammation were neutralized when p38 was blocked in cardiomyocytes.
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Abietanos , Angiotensina II , Anti-Inflamatórios , Camundongos Endogâmicos C57BL , Miócitos Cardíacos , Remodelação Ventricular , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Angiotensina II/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Masculino , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Camundongos , Abietanos/farmacologia , Abietanos/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Remodelação Ventricular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/induzido quimicamente , Fosforilação/efeitos dos fármacos , Células CultivadasRESUMO
OBJECTIVES: This study aims to investigate the effects of type 17 immune response on the proliferation of oral epithelial cells in periodontitis. DESIGN: A time-dependent ligature induced periodontitis mouse model was utilized to explore gingival hyperplasia and the infiltration of interleukin 17A (IL-17A) positive cells. Immunohistochemistry and flow cytometry were employed to determine the localization and expression of IL-17A in the ligature induced periodontitis model. A pre-existing single-cell RNA sequencing dataset, comparing individuals affected by periodontitis with healthy counterparts, was reanalyzed to evaluate IL-17A expression levels. We examined proliferation markers, including proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription (STAT3), Yes-associated protein (YAP), and c-JUN, in the gingival and tongue epithelium of the periodontitis model. An anti-IL-17A agent was administered daily to observe proliferative changes in the oral mucosa within the periodontitis model. Cell number quantification, immunofluorescence, and western blot analyses were performed to assess the proliferative responses of human normal oral keratinocytes to IL-17A treatment in vitro. RESULTS: The ligature induced periodontitis model exhibited a marked infiltration of IL-17A-positive cells, alongside significant increase in thickness of the gingival and tongue epithelium. IL-17A triggers the proliferation of human normal oral keratinocytes, accompanied by upregulation of PCNA, STAT3, YAP, and c-JUN. The administration of an anti-IL-17A agent attenuated the proliferation in oral mucosa. CONCLUSIONS: These findings indicate that type 17 immune response, in response to periodontitis, facilitates the proliferation of oral epithelial cells, thus highlighting its crucial role in maintaining the oral epithelial barrier.
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Imunidade Adaptativa , Proliferação de Células , Células Epiteliais , Interleucina-17 , Periodontite , Periodontite/imunologia , Células Epiteliais/citologia , Células Epiteliais/imunologia , Proliferação de Células/genética , Animais , Camundongos , Modelos Animais de Doenças , Interleucina-17/genética , Interleucina-17/imunologia , Transporte Proteico/imunologia , Queratinócitos/citologia , Queratinócitos/imunologia , Humanos , Linhagem Celular , Perda do Osso Alveolar/imunologia , Imunidade Adaptativa/imunologiaRESUMO
PURPOSE: Establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) is involved in the mitotic S-phase adhesins acetylation and is responsible for bridging two sister chromatids. However, present ESCO2 cancer research is limited to a few cancers. No systematic pan-cancer analysis has been conducted to investigate its role in diagnosis, prognosis, and effector function. METHODS: We thoroughly examined the ESCO2 carcinogenesis in pan-cancer by combining public databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), UALCAN and Tumor Immune Single-cell Hub (TISCH). The analysis includes differential expression analysis, survival analysis, cellular effector function, gene mutation, single cell analysis, and tumor immune cell infiltration. Furthermore, we confirmed ESCO2's impacts on clear cell renal cell carcinoma (ccRCC) cells' proliferative and invasive capacities in vitro. RESULTS: In our study, 30 of 33 cancer types exhibited considerably greater levels of ESCO2 expression in tumor tissue using TCGA and GTEx databases, whereas acute myeloid leukemia (LAML) exhibited significantly lower levels. Kaplan-Meier survival analyses in adrenocortical carcinoma (ACC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), mesothelioma (MESO), and pancreatic adenocarcinoma (PAAD) demonstrated that tumor patients with high ESCO2 expression have short survival periods. However, in thymoma (THYM), colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ), ESCO2 was a favorable prognostic factor. Moreover, ESCO2 expression positively correlates with tumor stage and tumor size in several cancers, including LIHC, KIRC, KIRP and LUAD. Function analysis revealed that ESCO2 participates in mitosis, cell cycle, DNA damage repair, and other processes. CDK1 was identified as a downstream gene regulated by ESCO2. Furthermore, ESCO2 might also be implicated in immune cell infiltration. Finally, ESCO2'S knockdown significantly inhibited the A498 and T24 cells' proliferation, invasion, and migration. CONCLUSIONS: In conclusion, ESCO2 is a possible pan-cancer biomarker and oncogene that can reliably predict the prognosis of cancer patients. ESCO2 was also implicated in the cell cycle and proliferation regulation. In a nutshell, ESCO2 is a therapeutically viable and dependable target.
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Acetiltransferases , Adenocarcinoma , Proteínas Cromossômicas não Histona , Neoplasias do Colo , Humanos , Adenocarcinoma de Pulmão , Neoplasias do Córtex Suprarrenal , Carcinoma Hepatocelular , Carcinoma de Células Renais/genética , Neoplasias Renais , Neoplasias Hepáticas , Neoplasias Pulmonares , Neoplasias Pancreáticas , Neoplasias do TimoRESUMO
The emergence of multidrug-resistant bacteria along with their resilient biofilms necessitates the development of creative antimicrobial remedies. We designed versatile fluorinated polymer micelles with surface-charge-switchable properties, demonstrating enhanced efficacy against Methicillin-Resistant Staphylococcus Aureus (MRSA) in planktonic and biofilm states. Polymethacrylate diblock copolymers with pendant fluorocarbon chains and carboxyl betaine groups were prepared using reversible addition-fragmentation chain transfer polymerization. Amphiphilic fluorinated copolymers self-assembled into micelles, encapsulating ciprofloxacin in their cores (CIP@FCBMs) for antibacterial and antibiofilm applications. As a control, fluorine-free copolymer micelles loaded with ciprofloxacin (CIP@BCBMs) were prepared. Although both CIP@FCBMs and CIP@BCBMs exhibited pH-responsive surface charges and lipase-triggered drug release, CIP@FCBMs exhibited powerful antimicrobial and antibiofilm activities in vitro and in vivo, attributed to superior serum stability, higher drug loading, enhanced fluorination-facilitated cellular uptake, and lipase-triggered drug release. Collectively, reversing surface charge, on-demand antibiotic release, and fluorination-mediated nanoparticles hold promise for treating bacterial infections and biofilms.
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Antibacterianos , Betaína , Biofilmes , Ciprofloxacina , Lipase , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Lipase/metabolismo , Concentração de Íons de Hidrogênio , Animais , Betaína/química , Betaína/administração & dosagem , Betaína/análogos & derivados , Infecções Estafilocócicas/tratamento farmacológico , Ciprofloxacina/farmacologia , Ciprofloxacina/administração & dosagem , Ciprofloxacina/química , Fluorocarbonos/química , Fluorocarbonos/farmacologia , Micelas , Liberação Controlada de Fármacos , Polímeros/química , Humanos , Ácidos Polimetacrílicos/químicaRESUMO
Layered manganese-based cathode materials are considered as one of the promising cathodes benefit from inherent low manufacturing cost, non-toxic and high safety in aqueous zinc-ion batteries (AZIBs). However, the sluggish reaction kinetics within layered cathodes is inevitable due to the poor electrical/ionic conductivity. Herein, MnTiO3 is reported as a new cathode material for AZIBs and in-situ induced Mn-defect within MnTiO3 during the first charging is desirable to improve the reaction kinetics to a great extent. Additionally, DFT calculations further demonstrate that MnTiO3 with manganese defects exhibits a uniform charge distribution at the defect sites, enhancing the attraction towards H+ and Zn2+ ions. Furthermore, it performs good cycling stability which can obtain 115 mA h g-1 even at 400 mA g-1 after 450 cycles and the discharge capacity reaches up to 233.8 mAh/g at 100 mA g-1 when Mn-defect MnTiO3 was employed as the cathode. This research could provide a new method for the development and mechanism research of cathode materials for AZIBs.
RESUMO
Scene Graph Generation (SGG) aims to detect all objects and identify their pairwise relationships in the scene. Recently, tremendous progress has been made in exploring better context relationship representations. Previous work mainly focuses on contextual information aggregation and uses de-biasing strategies on samples to eliminate the preference for head predicates. However, there remain challenges caused by indeterminate feature training. Overlooking the label confusion problem in feature training easily results in a messy feature distribution among the confused categories, thereby affecting the prediction of predicates. To alleviate the aforementioned problem, in this paper, we focus on enhancing predicate representation learning. Firstly, we propose a novel Adaptive Message Passing (AMP) network to dynamically conduct information propagation among neighbors. AMP provides discriminating representations for neighbor nodes under the view of de-noising and adaptive aggregation. Furthermore, we construct a feature-assisted training paradigm alongside the predicate classification branch, guiding predicate feature learning to the corresponding feature space. Moreover, to alleviate biased prediction caused by the long-tailed class distribution and the interference of confused labels, we design a Bi-level Curriculum learning scheme (BiC). The BiC separately considers the training from the feature learning and de-biasing levels, preserving discriminating representations of different predicates while resisting biased predictions. Results on multiple SGG datasets show that our proposed method AMP-BiC has superior comprehensive performance, demonstrating its effectiveness.
RESUMO
Tumor-initiating cells (TICs) resilience and an immunosuppressive microenvironment are aggressive oncogenic phenotypes that contribute to unsatisfactory long-term outcomes in lung adenocarcinoma (LUAD) patients. The molecular mechanisms mediating the interaction between TICs and immune tolerance have not been elucidated. The role of Galectin-9 in oncogenesis and immunosuppressive microenvironment is still unknown. This study explored the potential role of galectin-9 in TIC regulation and immune modulation in LUAD. The results show that galectin-9 supports TIC properties in LUAD. Co-culture of patient-derived organoids and matched peripheral blood mononuclear cells showed that tumor-secreted galectin-9 suppressed T cell cytotoxicity and induced regulatory T cells (Tregs). Clinically, galectin-9 is upregulated in human LUAD. High expression of galectin-9 predicted poor recurrence-free survival and correlated with high levels of Treg infiltration. LGALS9, the gene encoding galectin-9, is found to be transcriptionally regulated by the nuclear factor of activated T cells 2 (NFATc2), a previously reported TIC regulator, via in silico prediction and luciferase reporter assays. Overall, the results suggest that the NFATc2/galectin-9 axis plays a dual role in TIC regulation and immune suppression.
Assuntos
Adenocarcinoma de Pulmão , Galectinas , Neoplasias Pulmonares , Fatores de Transcrição NFATC , Células-Tronco Neoplásicas , Humanos , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Linhagem Celular Tumoral , Galectinas/genética , Galectinas/metabolismo , Galectinas/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/genética , Fenótipo , Microambiente TumoralRESUMO
Importance: Prehypertension increases the risk of developing hypertension and other cardiovascular diseases. Early and effective intervention for patients with prehypertension is highly important. Objective: To assess the efficacy of Tai Chi vs aerobic exercise in patients with prehypertension. Design, Setting, and Participants: This prospective, single-blinded randomized clinical trial was conducted between July 25, 2019, and January 24, 2022, at 2 tertiary public hospitals in China. Participants included 342 adults aged 18 to 65 years with prehypertension, defined as systolic blood pressure (SBP) of 120 to 139 mm Hg and/or diastolic BP (DBP) of 80 to 89 mm Hg. Interventions: Participants were randomized in a 1:1 ratio to a Tai Chi group (n = 173) or an aerobic exercise group (n = 169). Both groups performed four 60-minute supervised sessions per week for 12 months. Main Outcomes and Measures: The primary outcome was SBP at 12 months obtained in the office setting. Secondary outcomes included SBP at 6 months and DBP at 6 and 12 months obtained in the office setting and 24-hour ambulatory BP at 12 months. Results: Of the 1189 patients screened, 342 (mean [SD] age, 49.3 [11.9] years; 166 men [48.5%] and 176 women [51.5%]) were randomized to 1 of 2 intervention groups: 173 to Tai Chi and 169 to aerobic exercise. At 12 months, the change in office SBP was significantly different between groups by -2.40 (95% CI, -4.39 to -0.41) mm Hg (P = .02), with a mean (SD) change of -7.01 (10.12) mm Hg in the Tai Chi group vs -4.61 (8.47) mm Hg in the aerobic exercise group. The analysis of office SBP at 6 months yielded similar results (-2.31 [95% CI, -3.94 to -0.67] mm Hg; P = .006). Additionally, 24-hour ambulatory SBP (-2.16 [95% CI, -3.84 to -0.47] mm Hg; P = .01) and nighttime ambulatory SBP (-4.08 [95% CI, -6.59 to -1.57] mm Hg; P = .002) were significantly reduced in the Tai Chi group compared with the aerobic exercise group. Conclusions and Relevance: In this study including patients with prehypertension, a 12-month Tai Chi intervention was more effective than aerobic exercise in reducing SBP. These findings suggest that Tai Chi may help promote the prevention of cardiovascular disease in populations with prehypertension. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1900024368.