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Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.
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Proteínas Adaptadoras de Sinalização CARD , Humanos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/deficiência , Feminino , Adulto Jovem , Mutação , Neutrófilos/imunologia , Células Th17/imunologia , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Monócitos/imunologia , CitocinasRESUMO
BACKGROUND: Dihydromyricetin (DHM), a flavonoid compound of natural origin, has been identified in high concentrations in ampelopsis grossedentata and has a broad spectrum of biological and pharmacological functions, particularly in regulating glucose and lipid metabolism. The objective of this research was to examine how DHM affected nonalcoholic fatty liver disease (NAFLD) and its underlying mechanisms involved in the progression of NAFLD in a rat model subjected to a high-fat diet (HFD). Additionally, the study examines the underlying mechanisms in a cellular model of steatohepatitis using palmitic acid (PA)-treated HepG2 cells, with a focus on the potential correlation between autophagy and hepatic insulin resistance (IR) in the progress of NAFLD. METHODS: SD rats were exposed to a HFD for a period of eight weeks, followed by a treatment with DHM (at doses of 50, 100, and 200 mg·kg-1·d-1) for additional six weeks. The HepG2 cells received a 0.5 mM PA treatment for 24 h, either alone or in conjunction with DHM (10 µM). The histopathological alterations were assessed by the use of Hematoxylin-eosin (H&E) staining. The quantification of glycogen content and lipid buildup in the liver was conducted by the use of PAS and Oil Red O staining techniques. Serum lipid and liver enzyme levels were also measured. Autophagic vesicle and autolysosome morphology was studied using electron microscopy. RT-qPCR and/or western blotting techniques were used to measure IR- and autophagy-related factors levels. RESULTS: The administration of DHM demonstrated efficacy in ameliorating hepatic steatosis, as seen in both in vivo and in vitro experimental models. Moreover, DHM administration significantly increased GLUT2 expression, decreased G6Pase and PEPCK expression, and improved IR in the hepatic tissue of rats fed a HFD and in cells exhibiting steatosis. DHM treatment elevated Beclin 1, ATG 5, and LC3-II levels in hepatic steatosis models, correlating with autolysosome formation. The expression of AMPK levels and its downstream target PGC-1α, and PPARα were decreased in HFD-fed rats and PA-treated hepatocytes, which were reversed through DHM treatment. AMPK/ PGC-1α and PPARα knockdown reduced the impact of DHM on hepatic autophagy, IR and accumulation of hepatic lipid. CONCLUSIONS: Our findings revealed that AMPK/ PGC-1α, PPARα-dependent autophagy pathways in the pathophysiology of IR and hepatic steatosis has been shown, suggesting that DHM might potentially serve as a promising treatment option for addressing this disease.
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Flavonóis , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Camundongos , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Resistência à Insulina/fisiologia , Ratos Sprague-Dawley , Fígado/patologia , Metabolismo dos Lipídeos , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Ácido Palmítico/uso terapêutico , Autofagia , Dieta Hiperlipídica , Camundongos Endogâmicos C57BLRESUMO
The medical community acknowledges the presence of thyroid disorders and nonalcoholic fatty liver disease (NAFLD). Nevertheless, the interconnection between these two circumstances is complex. Thyroid hormones (THs), including triiodothyronine (T3) and thyroxine (T4), and thyroid-stimulating hormone (TSH), are essential for maintaining metabolic balance and controlling the metabolism of lipids and carbohydrates. The therapeutic potential of THs, especially those that target the TRß receptor isoform, is generating increasing interest. The review explores the pathophysiology of these disorders, specifically examining the impact of THs on the metabolism of lipids in the liver. The purpose of this review is to offer a thorough analysis of the correlation between thyroid disorders and NAFLD, as well as suggest potential therapeutic approaches for the future.
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OBJECTIVES: This study aims to compare the efficacy of peripheral add multifocal soft contact lenses (SCLs) (excluding bifocal SCLs) with single vision contact lenses or spectacles in controlling myopia progression. METHOD: A comprehensive literature search was conducted in the Pubmed, EMBASE, Web of Science, and Cochrane Library databases until October 2023. The literature was thoroughly screened based on predetermined eligibility criteria. Pooled odds ratios (ORs) were calculated for dichotomous data and weighted mean differences (WMD) for continuous data. RESULTS: A total of 11 articles comprising 787 participants were included in this meta-analysis. Our pooled results demonstrated that the peripheral add multifocal SCLs groups exhibited significantly reduced refraction progression (MD = 0.20; 95%CI, 0.14 â¼ 0.27; P<0.001) and less axial length elongation (MD=-0.08; 95%CI, -0.09â¼-0.08; P<0.001) compared to the control group. There was no significant difference in high-contrast logMAR distance visual acuity between the two groups (MD = 0.01; 95%CI, -0.00 â¼ 0.02; P = 0.19). However, the group using single-vision lenses had better low-contrast logMAR distance visual acuity compared to those using peripheral add multifocal SCLs (MD = 0.06; 95%CI, 0.02 â¼ 0.10; P = 0.004). Data synthesis using a random-effects model indicated an incidence of contact lens-related adverse events of 0.065 (95%CI, 0.048 â¼ 0.083). CONCLUSIONS: The present meta-analysis signifies that peripheral defocus modifying contact lenses are effective in slowing down the progression of myopia and reducing axial elongation.
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Lentes de Contato Hidrofílicas , Miopia , Refração Ocular , Acuidade Visual , Humanos , Acuidade Visual/fisiologia , Criança , Refração Ocular/fisiologia , Miopia/fisiopatologia , Miopia/terapia , Progressão da DoençaRESUMO
This study aimed to investigate ultrasound features of arteriovenous fistula stenosis and their relationship with primary patency after percutaneous transluminal angioplasty (post-intervention primary patency) and compare this classification with that using lesion location. Hemodialysis patients who underwent ultrasound-guided percutaneous transluminal angioplasty for arteriovenous fistula stenosis from July 2020 to December 2021 were retrospectively evaluated. Lesions (excluding inflow arteries) were categorized into five groups based on ultrasound features, and the clinical characteristics and risk factors affecting the post-intervention primary patency of the arteriovenous fistula were analyzed. Among 185 patients, 100 (54.05%), 36 (19.46%), 22 (11.89%), 11 (5.95%), and 16 (8.65%) were classified into the intima-dominant, non-intima-dominant, valve obstruction, vascular calcification, and mixed groups, respectively. The dialysis duration and arteriovenous fistula use time were the highest in the vascular calcification group at 86 (interquartile range: 49-140) and 77 (interquartile range: 49-110) months, respectively. Diabetes mellitus was most common in the intima-dominant group (42.0%). In Kaplan-Meier and univariate Cox analysis, type III lesion location (stenosis in the venous confluence site) was associated with the lower post-intervention primary patency. In the multivariate Cox analysis, percutaneous transluminal angioplasty times (the number of times patients were treated with percutaneous transluminal angioplasty for arteriovenous fistula stenosis dysfunction), vascular calcification, calcification at the lesion site requiring percutaneous transluminal angioplasty, and serum parathyroid hormone levels were independent risk factors for post-intervention primary patency. Ultrasound features showed that calcification of the arteriovenous fistula was detrimental to the post-intervention primary patency of arteriovenous fistula.
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Fístula Arteriovenosa , Calcificação Vascular , Humanos , Constrição Patológica , Estudos Retrospectivos , Ultrassonografia , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/terapia , Fístula Arteriovenosa/diagnóstico por imagem , Fístula Arteriovenosa/terapiaRESUMO
Sinopodophylli Fructus is a traditional medicine used by the Tibetan people. It is known for its ability to regulate menstruation and promote blood circulation. Presently, bioactive constituents that have been isolated and identified from Sinopodophylli Fructus mainly include 15 lignans(e.g., podophyllotoxin, deoxypodophyllotoxin, and 4'-demethylpodophyllotoxin) and 20 flavonoids(e.g., quercetin, kaempferol, and rutin). These components exhibit pharmacological effects such as anticancer, antibacterial, and lipid-lowering activities. Additionally, Sinopodophylli Fructus contains other components such as proteins, fatty acids, polysaccharides, vitamins, amino acids, and trace elements. According to the relevant literature reports in China and abroad, this article reviewed the chemical constituents and pharmacological effects of Sinopodophylli Fructus, aiming to provide references for the development and rational clinical application of this medicinal resource.
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Medicamentos de Ervas Chinesas , Medicina Tradicional Tibetana , Humanos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Animais , Flavonoides/química , Flavonoides/farmacologia , Frutas/químicaRESUMO
Chitosan is a promising adsorbent for removing a wide range of pollutants from wastewater. However, its practical application is hindered by instability in acidic environments, which significantly impairs its adsorption capacity and limits its utilization in water purification. While cross-linking can enhance the acid stability of chitosan, current solvent-based methods are often costly and environmentally unfriendly. In this study, a solvent-free mechanochemical process was developed using high-energy ball milling to cross-link chitosan with various polyanionic linkers, including dextran sulfate (DS), poly[4-styrenesulfonic acid-co-maleic acid] (PSSM), and tripolyphosphate (TPP). The mechanochemically cross-linked (MCCL) chitosan products exhibited superior adsorption capacity and stability in acidic solutions compared to pristine chitosan. Chitosan cross-linked with DS (Cht-DS) showed the highest Reactive Red 2 (RR2) adsorption capacity, reaching 1559 mg·g-1 at pH 3, followed by Cht-PSSM (1352 mg·g-1) and Cht-TPP (1074 mg·g-1). The stability of MCCL chitosan was visually confirmed by the negligible mass loss of Cht-DS and Cht-PSSM tablets in pH 3 solution, unlike the complete dissolution of the pristine chitosan tablet. The MCCL significantly increased the microhardness of chitosan, with the order Cht-DS > Cht-PSSM > Cht-TPP, consistent with the RR2 adsorption capacity. When tested on simulated rinsing wastewater from chromium electroplating, Cht-DS effectively removed Cr(VI) (98.75% removal) and three per- and polyfluoroalkyl substances (87.40-95.87% removal), following pseudo-second-order adsorption kinetics. This study demonstrates the potential of the cost-effective and scalable MCCL approach to produce chitosan-based adsorbents with enhanced stability, mechanical strength, and adsorption performance for treating highly acidic industrial wastewater containing a mixture of toxic pollutants.
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Introduction: Prone positioning in critical care units may reduce mortality in specific patients who have been admitted with severe conditions. Aim: The current meta-analysis aims to assess the impact of prone compared to supine position besides the safety and tolerability of different enteral feeding techniques in critically ill patients regarding mortality, pneumonia, aspiration, and vomiting. Material and methods: A systematic literature search found 25 relevant trials involving 1984 participants at the start of the study. Statistical analysis using the dichotomous analysis methods was used within the fixed model to calculate the odds ratio (OR) with 95% confidence intervals (CIs). Results: In comparison with the post-pyloric nutrition group, gastric feeding had no significant impact on the mortality rate (OR = 1; 95% CI: 0.76-1.32). While the findings showed a significantly higher incidence of pneumonia with gastric feeding compared with post-pyloric nutrition (OR = 1.92; 95% CI: 1.43--2.57), there was no significant difference regarding pulmonary aspiration and vomiting (OR = 1.41; 95% CI: 0.75-2.65 and OR = 0.92; 95% CI:, 0.66-1.27, respectively). Reflux gastric content was significantly higher with gastric nutrition (OR = 8.23; 95% CI: 2.43-27.89). Conclusions: From reduced gastrointestinal events to significantly higher vomiting rates, prone position during enteral feeding showed mixed effects. Post-pyloric feeding is more tolerated and safer compared with gastric feeding. The mortality rate is not significantly different between techniques.
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Herein, we detail a multidisciplinary approach and sequential treatment for two infants with congenital granular cell epulis (CGCE). Ultrasonic examinations at 34 weeks of gestation revealed prominent oral masses in both fetuses. To devise a carefully considered treatment strategy, a comprehensive multidisciplinary consultation including oral and maxillofacial surgeons, pediatricians, obstetricians, and anesthesiologists was convened. Following cesarean sections, the lesions were successfully removed, measuring approximately 30 × 15 mm and 30 × 20 mm in size, respectively. Immunohistochemical analysis showed that vimentin was positive, S-100 protein was negative, and NSE protein and CD68 protein were negative. These findings underscore the importance of prenatal diagnosis of congenital granular cell epulis for the effective management of these rare benign conditions.
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Tumor de Células Granulares , Diagnóstico Pré-Natal , Humanos , Feminino , Gravidez , Tumor de Células Granulares/cirurgia , Tumor de Células Granulares/patologia , Tumor de Células Granulares/congênito , Diagnóstico Pré-Natal/métodos , Recém-Nascido , Neoplasias Gengivais/cirurgia , Neoplasias Gengivais/patologia , Neoplasias Gengivais/congênito , Adulto , Masculino , Ultrassonografia Pré-NatalRESUMO
The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer (NSCLC). Although researchers have disclosed that interleukin 17 (IL-17) can increase matrix metalloproteinases (MMPs) induction causing NSCLC cell metastasis, the underlying mechanism remains unclear. In the study, we found that IL-17 receptor A (IL-17RA), p300, p-STAT3, Ack-STAT3, and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17. p300, STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3, Ack-STAT3 and MMP19 level as well as the cell migration and invasion. Mechanism investigation revealed that STAT3 and p300 bound to the same region (-544 to -389 nt) of MMP19 promoter, and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity, p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17. Meanwhile, p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact, synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion. Besides, the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300, STAT3 or MMP19 gene plus IL-17 treatment, the nodule number, and MMP19, Ack-STAT3, or p-STAT3 production in the lung metastatic nodules were all alleviated. Collectively, these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation, which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos , Animais , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Interleucina-17/genética , Interleucina-17/metabolismo , Fosforilação , Neoplasias Pulmonares/patologia , Acetilação , Camundongos Nus , Transcrição Gênica , Movimento Celular/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão GênicaRESUMO
Background: There is growing evidence of associations between the gut microbiota and anxiety disorders, where changes in gut microbiotas may affect brain function and behavior via the microbiota-gut-brain axis. However, population-level studies offering a higher level of evidence for causality are lacking. Our aim was to investigate the specific gut microbiota and associated metabolites that are closely related to anxiety disorders to provide mechanistic insights and novel management perspectives for anxiety disorders. Method: This study used summary-level data from publicly available Genome-Wide Association Studies (GWAS) for 119 bacterial genera and the phenotype "All anxiety disorders" to reveal the causal effects of gut microbiota on anxiety disorders and identify specific bacterial genera associated with anxiety disorders. A two-sample, bidirectional Mendelian randomization (MR) design was deployed, followed by comprehensive sensitivity analyses to validate the robustness of results. We further conducted multivariable MR (MVMR) analysis to investigate the potential impact of neurotransmitter-associated metabolites, bacteria-associated dietary patterns, drug use or alcohol consumption, and lifestyle factors such as smoking and physical activity on the observed associations. Results: Bidirectional MR analysis identified three bacterial genera causally related to anxiety disorders: the genus Eubacterium nodatum group and genus Ruminococcaceae UCG011 were protective, while the genus Ruminococcaceae UCG011 was associated with an increased risk of anxiety disorders. Further MVMR suggested that a metabolite-dependent mechanism, primarily driven by tryptophan, tyrosine, phenylalanine, glycine and cortisol, which is consistent with previous research findings, probably played a significant role in mediating the effects of these bacterial genera to anxiety disorders. Furthermore, modifying dietary pattern such as salt, sugar and processed meat intake, and adjusting smoking state and physical activity levels, appears to be the effective approaches for targeting specific gut microbiota to manage anxiety disorders. Conclusion: Our findings offer potential avenues for developing precise and effective management approaches for anxiety disorders by targeting specific gut microbiota and associated metabolites.
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A series of heterocyclic ring-fused derivatives of bisnoralcohol (BA) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Most of these derivatives possessed potent antiosteoporosis activities in a dose-dependent manner. Among these compounds, 31 (SH442, IC50 = 0.052 µM) exhibited the highest potency, displaying 100% inhibition at 1.0 µM and 82.8% inhibition at an even lower concentration of 0.1 µM, which was much more potent than the lead compound BA (IC50 = 2.325 µM). Cytotoxicity tests suggested that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation did not result from their cytotoxicity. Mechanistic studies revealed that SH442 inhibited the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, TRAF6, c-Fos, CTSK, and MMP9. Especially, SH442 could significantly attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as promising leads for the development of a new type of antiosteoporosis agent.
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Osteoclastos , Osteoporose , Animais , Feminino , Camundongos , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Ovariectomia , Ligante RANK/metabolismo , Ligante RANK/antagonistas & inibidores , Células RAW 264.7 , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Cigarette smoking during pregnancy is known to be associated with the incidence of attention-deficit/hyperactive disorder (ADHD). Recent developments in deep learning algorithms enable us to assess the behavioral phenotypes of animal models without cognitive bias during manual analysis. In this study, we established prenatal nicotine exposure (PNE) mice and evaluated their behavioral phenotypes using DeepLabCut and SimBA. We optimized the training parameters of DeepLabCut for pose estimation and succeeded in labeling a single-mouse or two-mouse model with high fidelity during free-moving behavior. We applied the trained network to analyze the behavior of the mice and found that PNE mice exhibited impulsivity and a lessened working memory, which are characteristics of ADHD. PNE mice also showed elevated anxiety and deficits in social interaction, reminiscent of autism spectrum disorder (ASD). We further examined PNE mice by evaluating adult neurogenesis in the hippocampus, which is a pathological hallmark of ASD, and demonstrated that newborn neurons were decreased, specifically in the ventral part of the hippocampus, which is reported to be related to emotional and social behaviors. These results support the hypothesis that PNE is a risk factor for comorbidity with ADHD and ASD in mice.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Aprendizado Profundo , Gravidez , Feminino , Animais , Camundongos , Nicotina/efeitos adversos , Comportamento SocialRESUMO
Mesangial proliferative glomerulonephritis (MsPGN) and its related rat model Thy-1 nephritis (Thy-1N) are associated with C5b-9 deposition and are characterized by proliferation of glomerular mesangial cell (GMC) and expansion of extracellular matrix (ECM) expansion, alongside overexpression of multiple growth factors. Although fibroblast growth factor 1 (FGF1), platelet-derived growth factor alpha (PDGFα), and transforming growth factor beta 1 (TGF-ß1) are well known for their proproliferative and profibrotic roles, the molecular mechanisms responsible for regulating the expression of these growth factors have not been thoroughly elucidated. In this study, we found that sublytic C5b-9 induction of sex-determining region Y-box 9 (SOX9) transactivated FGF1, PDGFα, and TGF-ß1 genes in GMCs, resulting in a significant increase in their mRNA and protein levels. Besides, sublytic C5b-9 induction of activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylated SOX9 at serine 181 and serine 64, which enhanced SOX9's ability to transactivate FGF1, PDGFα, and TGF-ß1 genes in GMCs. Furthermore, we demonstrated that inhibiting ERK1/2 activation or silencing either ERK1/2 or SOX9 gene led to reduced SOX9 phosphorylation, decreased generation of FGF1, PDGFα, and TGF-ß1, and ameliorated glomerular injury in rat Thy-1N. Overall, these findings suggest that expression of FGF1, PDGFα, and TGF-ß1 is promoted by ERK1/2-mediated phosphorylation of SOX9, which may provide a valuable insight into the pathogenesis of MsPGN and offer a potential target for the development of novel treatment strategies for MsPGN.
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Fator 1 de Crescimento de Fibroblastos , Nefrite , Ratos , Animais , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fosforilação , Ratos Sprague-Dawley , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Sistema de Sinalização das MAP Quinases , Nefrite/metabolismo , Serina/metabolismoRESUMO
Metastasis is the major cause of cancer-related death, and lymph node is the most common site of metastasis in breast cancer. However, the alterations that happen in tumor-draining lymph nodes (TDLNs) to form a premetastatic microenvironment are largely unknown. Here, we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer. With the progression of tumor, the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis. The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized. Mechanistically, B and follicular helper T (Tfh) cells parallelly expand and contract to determine the size of TDLN. The activation status and specific antitumor immunity of CD8+ T cells in the TDLN are determined by interleukin-21 (IL-21) produced by Tfh cells, thus showing parallel changes. The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells. On the basis of the B-Tfh-IL-21-CD8+ T cell axis, we prove that targeting the axis could activate TDLNs to resist metastasis. Together, our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.
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BACKGROUND: Immune checkpoint blockade has shown low response rates for advanced breast cancer, and combination strategies are needed. Microwave ablation (MWA) may be a trigger of antitumor immunity. This window-of-opportunity trial (ClinicalTrials.gov: NCT04805736) was conducted to determine the safety and feasibility of preoperative camrelizumab (an anti-PD-1 antibody) combined with MWA in the treatment of early-stage breast cancer. METHODS: Sixty participants were randomized to preoperatively receive single-dose camrelizumab alone (n = 20), MWA alone (n = 20), or camrelizumab+MWA (n = 20). A random number table was used to allocate interventions. The primary outcome was the safety and feasibility of MWA combined with camrelizumab. FINDINGS: Camrelizumab and MWA were well tolerated alone and in combination without delays in prescheduled surgery. No treatment-related grade III/IV adverse events were observed. Different from in the single-dose camrelizumab or MWA group, participants showed stable counts of blood cells after combination therapy. After combination therapy, peripheral CD8+ T cells showed enhanced cytotoxic and effect-memory functions. Clonal expansional CD8+ T cells showed higher cytotoxic activity and effector memory- and tumor-specific signatures than emergent clones after combination therapy. Enhanced interactions between clonal expansional CD8+ T cells and monocytes were observed, suggesting that monocytes contributed to the enhanced functions of clonal expansional CD8+ T cells. Major histocompatibility complex (MHC) class I-related pathways and interferon signaling pathways were activated in monocytes by combination therapy. CONCLUSIONS: Camrelizumab combined with MWA was feasible for early-stage breast cancer. Peripheral CD8+ T cells were activated after combination therapy, dependent on monocytes with activated MHC class I pathways. FUNDING: This study was supported by the Natural Science Foundation of Jiangsu Province (BK20230017).
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/induzido quimicamente , Linfócitos T CD8-Positivos/metabolismo , Micro-Ondas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversosRESUMO
This study aimed to characterize the composition of intestinal and nasal microbiota in septic patients and identify potential microbial biomarkers for diagnosis. A total of 157 subjects, including 89 with sepsis, were enrolled from the affiliated hospital. Nasal swabs and fecal specimens were collected from septic and non-septic patients in the intensive care unit (ICU) and Department of Respiratory and Critical Care Medicine. DNA was extracted, and the V4 region of the 16S rRNA gene was amplified and sequenced using Illumina technology. Bioinformatics analysis, statistical processing, and machine learning techniques were employed to differentiate between septic and non-septic patients. The nasal microbiota of septic patients exhibited significantly lower community richness (P = 0.002) and distinct compositions (P = 0.001) compared to non-septic patients. Corynebacterium, Staphylococcus, Acinetobacter, and Pseudomonas were identified as enriched genera in the nasal microbiota of septic patients. The constructed machine learning model achieved an area under the curve (AUC) of 89.08, indicating its efficacy in differentiating septic and non-septic patients. Importantly, model validation demonstrated the effectiveness of the nasal microecological diagnosis prediction model with an AUC of 84.79, while the gut microecological diagnosis prediction model had poor predictive performance (AUC = 49.24). The nasal microbiota of ICU patients effectively distinguishes sepsis from non-septic cases and outperforms the gut microbiota. These findings have implications for the development of diagnostic strategies and advancements in critical care medicine.IMPORTANCEThe important clinical significance of this study is that it compared the intestinal and nasal microbiota of sepsis with non-sepsis patients and determined that the nasal microbiota is more effective than the intestinal microbiota in distinguishing patients with sepsis from those without sepsis, based on the difference in the lines of nasal specimens collected.
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Bactérias , Biomarcadores , Fezes , Unidades de Terapia Intensiva , Microbiota , RNA Ribossômico 16S , Sepse , Humanos , Sepse/diagnóstico , Sepse/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , RNA Ribossômico 16S/genética , Biomarcadores/análise , Bactérias/isolamento & purificação , Bactérias/genética , Bactérias/classificação , Fezes/microbiologia , Adulto , Aprendizado de Máquina , Microbioma Gastrointestinal , Nariz/microbiologia , Corynebacterium/isolamento & purificação , Corynebacterium/genética , Acinetobacter/isolamento & purificação , Acinetobacter/genética , Idoso de 80 Anos ou mais , Staphylococcus/isolamento & purificação , Staphylococcus/genética , Pseudomonas/isolamento & purificação , Pseudomonas/genéticaRESUMO
Minimally invasive thermal therapy is a successful alternative treatment to surgery in solid tumors with high complete ablation rates, however, tumor recurrence remains a concern. Central memory CD8+ T cells (TCM) play important roles in protection from chronic infection and cancer. Here we find, by single-cell RNA analysis of human breast cancer samples, that although the memory phenotype of peripheral CD8+ T cells increases slightly after microwave ablation (MWA), the metabolism of peripheral CD8+ T cells remains unfavorable for memory phenotype. In mouse models, glycolysis inhibition by 2-deoxy-D-glucose (2DG) in combination with MWA results in long-term anti-tumor effect via enhancing differentiation of tumor-specific CD44hiCD62L+CD8+ TCM cells. Enhancement of CD8+ TCM cell differentiation determined by Stat-1, is dependent on the tumor-draining lymph nodes (TDLN) but takes place in peripheral blood, with metabolic remodeling of CD8+ T cells lasting the entire course of the the combination therapy. Importantly, in-vitro glycolysis inhibition in peripheral CD8+ T cells of patients with breast or liver tumors having been treated with MWA thrice leads to their differentiation into CD8+ TCM cells. Our work thus offers a potential strategy to avoid tumor recurrence following MWA therapy and lays down the proof-of-principle for future clinical trials.
Assuntos
Neoplasias da Mama , Linfócitos T CD8-Positivos , Diferenciação Celular , Glicólise , Memória Imunológica , Micro-Ondas , Glicólise/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Diferenciação Celular/efeitos dos fármacos , Camundongos , Feminino , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Micro-Ondas/uso terapêutico , Desoxiglucose/farmacologia , Desoxiglucose/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Células T de Memória/imunologia , Células T de Memória/metabolismoRESUMO
The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.
Assuntos
Proliferação de Células , Proteínas Hedgehog , Meduloblastoma , Transdução de Sinais , Receptor Smoothened , Esteróis , Receptor Smoothened/antagonistas & inibidores , Receptor Smoothened/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/antagonistas & inibidores , Humanos , Transdução de Sinais/efeitos dos fármacos , Animais , Camundongos , Proliferação de Células/efeitos dos fármacos , Esteróis/química , Esteróis/farmacologia , Esteróis/metabolismo , Meduloblastoma/tratamento farmacológico , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Estrutura Molecular , Colesterol/metabolismoRESUMO
OBJECTIVES: To explore the seroprevalence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in non-HIV cryptococcal meningitis (CM) and assess its predictive value for survival. METHODS: This is a retrospective study of 12 years of non-HIV CM. We detected serum anti-GM-CSF autoantibodies, and evaluated the clinical features and outcomes, together with the exploration of prognostic factors for 2-week and 1-year survival. RESULTS: A total of 584 non-HIV CM cases were included. 301 of 584 patients (51.5%) were phenotypically healthy. 264 Cryptococcus isolates were obtained from cerebrospinal fluid (CSF) culture, of which 251 were identified as C. neoformans species complex and 13 as C. gattii species complex. Thirty-seven of 455 patients (8.1%) tested positive for serum anti-GM-CSF autoantibodies. Patients with anti-GM-CSF autoantibodies were more susceptible to C. gattii species complex infection (66.7% vs. 6.3%; p < 0.001) and more likely to develop pulmonary mass lesions with a diameter >3 centimetres (42.9% vs. 6.5%; p 0.001). Of 584 patients 16 (2.7%) died within 2 weeks, 77 of 563 patients (13.7%) died at 1 year, and 93 of 486 patients (19.1%) lived with disabilities at 1 year. Univariant Cox regression analysis found that anti-GM-CSF autoantibodies were associated with lower 1-year survival (HR, 2.66; 95% CI, 1.34-5.27; p 0.005). Multivariable Cox proportional hazards modelling revealed that CSF cryptococcal antigen titres ≥1:1280 were associated with both, reduced 2-week and 1-year survival rates (HR, 5.44; 95% CI, 1.23-24.10; p 0.026 and HR, 5.09; 95% CI, 1.95-13.26; p 0.001). DISCUSSION: Presence of serum anti-GM-CSF autoantibodies is predictive of poor outcomes, regardless of host immune status and the causative Cryptococcus species complex.