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Currently lacking research to explore the correlation between inflammatory markers and the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy in the treatment of advanced gastric cancer. This study is a retrospective study and included patients with advanced gastric cancer who receiving ICIs combined with chemotherapy from January 2020 to December 2022. We analysed the relationship between systemic inflammatory markers and the efficacy of ICIs combined chemotherapy and constructed a clinical prediction model. A nomogram was constructed based on the results of the bidirectional stepwise regression model. A total of 197 patients were enrolled in the training group, with a median follow-up period of time 26 months. Kaplan Meier analysis showed that the median OS of patients with low systemic immune-inflammatory index (SII) and low platelet to lymphocyte ratio (PLR) was superior to those with high SII and PLR. Univariate and multivariate Cox regression analysis showed that SII, NLR, PLR, and N stage as independent prognostic factors for OS. Adding SII to the conventional model improved the predictive ability of the 12-month OS. A total of 95 patients were included in the validation group, and external validation of the SII-based nomogram showed favourable predictive performance. Baseline SII, PLR, and N stage may serve as independent predictive factors for survival outcomes in advanced gastric cancer patients undergoing ICIs combined with chemotherapy. The SII-based nomogram can provide intuitive and accurate prognosis prediction of individual patients.
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Neoplasias Gástricas , Humanos , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Estudos Retrospectivos , Modelos Estatísticos , NeutrófilosRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a life-threatening subtype of breast cancer with limited treatment options. Therefore, this network meta-analysis (NMA) aimed to evaluate and compare the effect of various neoadjuvant chemotherapy (NCT) options on the long-term survival of patients with TNBC. METHODS: PubMed, Embase, Medline, Cochrane Library, Web of Science, and major international conference databases were systematically searched for randomized controlled trials (RCTs) on the efficacy of various NCT options in patients with TNBC. Searches were performed from January 2000 to June 2023. Study heterogeneity was assessed using the I2 statistic. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate disease-free survival (DFS) and overall survival (OS). Odds ratios (ORs) and 95% CIs were used to evaluate the pathologic complete response (pCR). The primary outcome was DFS. RESULTS: We conducted an NMA of 21 RCTs involving 8873 patients with TNBC. Our study defined the combination of anthracyclines and taxanes as the preferred treatment option. On this basis, the addition of any of the following new drugs is considered a new treatment option: bevacizumab (B), platinum (P), poly-ADP-ribose polymerase inhibitors (PARPi), and immune checkpoint inhibitor (ICI). Based on the surface under the cumulative ranking curve (SUCRA) values, the top three SUCRA area values of DFS were taxanes, anthracycline, and cyclophosphamide (TAC; 89.23%); CT (84.53%); and B (81.06%). The top three SUCRA area values of OS were CT (83.70%), TAC (62.02%), and B-containing regimens (60.06%). The top three SUCRA area values of pCR were B + P-containing regimens (82.7%), ICI + P-containing regimens (80.2%), and ICI-containing regimens (61.8%). CONCLUSIONS: This NMA showed that standard chemotherapy is a good choice with respect to long-term survival. Moreover, B associated with P-containing regimens is likely to be the optimal treatment option for neoadjuvant TNBC in terms of pCR.
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Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadjuvante , Metanálise em Rede , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/patologia , Terapia Neoadjuvante/métodos , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antraciclinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Intervalo Livre de Doença , Taxoides/uso terapêutico , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagemRESUMO
Primary sclerosing cholangitis (PSC), a chronic cholestatic liver condition, is frequently associated with inflammatory bowel disease. Specific immune cells have been implicated in PSC pathogenesis with the emergence of the "microbiota" and "gut lymphocyte homing" hypotheses, albeit their identities remain controversial. The first genome-wide association analysis leveraged nonoverlapping data from 3757 Europeans to evaluate 731 immunophenotypes. A genome-wide association analysis comprising 2871 cases and 12,019 controls yielded summary statistics for PSC. An inverse-variance weighted (IVW) analysis was performed to identify immunophenotypes causally related to PSC, and the results were validated using weighted mode, MR-Egger, and weighted median methods. Comprehensive sensitivity analyses were performed to verify the robustness, heterogeneity, and horizontal pleiotropy of the results. IVW analysis revealed 26 immune traits exhibiting causal associations with PSC. CD3 on HLA-DR+ CD4+ (IVW odds ratio [OR]: 0.904; 95% confidence interval [CI]: 0.828-0.986, Pâ =â .023) and CD3 on secreting Treg (IVW OR: 0.893; 95% CI: 0.823-0.969, Pâ =â .007) were negatively associated with PSC susceptibility and demonstrated high consistency across the 3 validation methods. Moreover, 7 other immune traits, including CD39+ resting Treg absolute cell (IVW ORâ =â 1.083, 95% CI: 1.013-1.157, Pâ =â .019), CD39+ secreting Treg absolute cell (IVW ORâ =â 1.063, 95% CI: 1.012-1.118, Pâ =â .015), CD3 on naive CD8br (IVW ORâ =â 0.907, 95% CI: 0.835-0.986, Pâ =â .022), CD3 on CD39+ activated Treg (IVW ORâ =â 0.927, 95% CI: 0.864-0.994, Pâ =â .034), CD28 on resting Treg (IVW ORâ =â 0.724, 95% CI: 0.630-0.833, Pâ =â 5.95E-06), and CD39 on CD39+ CD4+ (IVW ORâ =â 1.055, 95% CI: 1.001-1.112, Pâ =â .044) exhibited consistent results in the Weighted Median and Weighted Mode validation methods. Moreover, no significant heterogeneity or horizontal pleiotropy was observed across the single nucleotide polymorphisms. The leave-one-out results revealed that sequentially eliminating each single nucleotide polymorphism had no significant influence on model effect estimates or qualitative inference. This study evaluated potential causal links between 731 immune traits and PSC susceptibility. Twenty-six immune traits were identified using the IVW method. Verification across multiple methods revealed 9 immune traits with a plausible causal connection to PSC. These findings may uncover mechanistic pathways and novel therapeutic approaches.
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Colangite Esclerosante , Estudo de Associação Genômica Ampla , Imunofenotipagem , Análise da Randomização Mendeliana , Colangite Esclerosante/genética , Colangite Esclerosante/imunologia , Humanos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Background: No intervention definitively extends transplant-free survival in primary sclerosing cholangitis (PSC). Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), may enhance PSC prognosis, but their efficacy is debated. Methods: We analyzed HMGCR single-nucleotide polymorphisms from published genome-wide association studies using Mendelian randomization to assess the causal relationship between HMGCR and PSC risk. Effects of HMGCR were compared with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, common lipid-lowering drugs, using coronary heart disease risk as a positive control. The inverse-variance weighted (IVW) method was the primary analysis, complemented by the weighted median method. Heterogeneity analysis, examination of horizontal pleiotropy, and leave-one-out sensitivity analysis were conducted for result robustness. Results: Genetically predicted HMGCR exhibited a pronounced detrimental effect on PSC in both the IVW method (odds ratio [OR] [95%] = 2.43 [1.23-4.78], P = 0.010) and the weighted median method (OR [95%] = 2.36 [1.02-5.45], P = 0.044). However, PCSK9 did not reach statistical significance. Moreover, all analyses passed through heterogeneity analysis, horizontal pleiotropy analysis, and leave-one-out sensitivity analysis. Conclusion: This study has confirmed a causal relationship between HMGCR and PSC risk, suggesting statins targeting HMGCR could enhance PSC patient outcomes.
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The path-following problem of unmanned surface vessels (USVs) is solved in this paper, considering unknown interference, energy-saving strategy, input constraints, and input rate of change constraints. Firstly, the USV model considering lumped interference is given, while an interference observer based on finite-time theory is used for interference estimation where the convergence time is specified. Then, to accelerate the USV convergence to a given path, a novel improved adaptive finite-time line-of-sight (IAFTLOS) scheme is developed. The proposed IAFTLOS scheme makes the cross-path error with finite-time convergence. At the same time, an adaptive time-varying looking distance law is designed to improve the convergence performance further. Next, nonlinear model predictive control is introduced to deal with rates of change and input constraints. In addition, an energy-saving strategy is incorporated into the design of the controller. Finally, stable control of the whole cascade system is achieved, and comparative simulation cases verify the feasibility and robustness of the entire system.
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ABSTRACT: Introduction: Previous studies have manifested that those sedatives acting on γ-aminobutyric acid A (GABAa) receptor could produce effective brain protection against regional and global ischemic stimulation. The present study was designed to investigate the effect of a novel GABAa receptor agonist, remimazolam postconditioning (RP) on cerebral outcome after global ischemic stimulation induced by cardiac arrest and resuscitation in swine. Methods: A total of 24 swine were used in this study, in which the animals were randomly divided into the following three groups: sham group (n = 6), cardiopulmonary resuscitation (CPR) group (n = 9), and CPR + RP group (n = 9). The experimental model was established by the procedure of 10 min of cardiac arrest and 5 min of CPR. Those resuscitated swine in the CPR + RP group received an intravenous infusion of 2.5 mg/kg of remimazolam within 60 min. Postresuscitation cerebral injury biomarkers and neurological function were evaluated for a total of 24 h. At 24 h after resuscitation, brain cortex was harvested to evaluate the severity of pathologic damage, including tissue inflammation, oxidative stress, apoptosis, and necroptosis. Results: Baseline characteristics and CPR outcomes were not significantly different between the CPR and CPR + RP groups. After resuscitation, significantly greater cerebral injury and neurological dysfunction were observed in the CPR and CPR + RP groups than in the sham group. However, remimazolam postconditioning significantly alleviated cerebral injury and improved neurological dysfunction after resuscitation when compared with the CPR group. At 24 h after resuscitation, tissue inflammation, oxidative stress, and cell apoptosis and necroptosis were significantly increased in the CPR and CPR + RP groups when compared with the sham group. Nevertheless, the severity of pathologic damage mentioned previously were significantly milder in those swine treated with the remimazolam when compared with the CPR group. Conclusions: In a swine model of cardiac arrest and resuscitation, the remimazolam administered after resuscitation significantly improved the markers of postresuscitation cerebral injury and therefore protected the brain against global ischemic stimulation.
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Benzodiazepinas , Reanimação Cardiopulmonar , Modelos Animais de Doenças , Parada Cardíaca , Animais , Suínos , Parada Cardíaca/terapia , Benzodiazepinas/uso terapêutico , Benzodiazepinas/farmacologia , Biomarcadores/metabolismo , Lesões Encefálicas , Masculino , Feminino , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Objective: Chondrocyte death is the hallmark of cartilage degeneration during osteoarthritis (OA). However, the specific pathogenesis of cell death in OA chondrocytes has not been elucidated. This study aims to validate the role of CDKN1A, a key programmed cell death (PCD)-related gene, in chondrogenic differentiation using a combination of single-cell and bulk sequencing approaches. Design: OA-related RNA-seq data (GSE114007, GSE55235, GSE152805) were downloaded from Gene Expression Omnibus database. PCD-related genes were obtained from GeneCards database. RNA-seq was performed to annotate the cell types in OA and control samples. Differentially expressed genes (DEGs) among those cell types (scRNA-DEGs) were screened. A nomogram of OA was constructed based on the featured genes, and potential drugs targeting the featured genes were predicted. The presence of key genes was confirmed using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), Western blot (WB), and immunohistochemistry (IHC). Micromass culture and Alcian blue staining were used to determine the effect of CDKN1A on chondrogenesis. Results: Six cell types, namely HomC, HTC, RepC, preFC, FC, and RegC, were annotated in scRNA-seq data. Five featured genes (JUN, CDKN1A, HMGB2, DDIT3, and DDIT4) were screened by multiple biological information analysis methods. TAXOTERE had the highest ability to dock with DDIT3. Functional analysis indicated that CDKN1A was enriched in processes related to collagen catabolism and acts as a positive regulator of autophagy. Additionally, CDKN1A was found to be associated with several KEGG pathways, including those involved in acute myeloid leukemia and autoimmune thyroid disease. CDKN1A was confirmed down-regulated in the joint tissues of OA mouse model and OA model cell. Inhibiting the expression of CDKN1A can significantly suppress the differentiation of OA chondrocytes. Conclusion: Our findings highlight the critical role of CDKN1A in promoting cartilage formation in both in vivo and in vitro and suggest its potential as a therapeutic target for OA treatment.
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Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally. Synovial macrophages, as immune cells, play an essential role in cartilage damage in OA. Therefore, regulating macrophages is crucial for controlling the pathological changes in OA. Triggering receptor expressed on myeloid cells 2 (TREM2), as expressed on immune cell surfaces, such as macrophages and dendritic cells, has suppressed inflammation and regulated M2 macrophage polarization but demonstrated an unknown role in synovial macrophage polarization in OA. This study aimed to investigate TREM2 expression downregulation in OA mice macrophages. Furthermore, the expression trend of TREM2 was associated with polarization-related molecule expression in macrophages of OA mice. Results: We used TREM2 knockout (TREM2-KO) mice to observe that TREM2 deficiency significantly exacerbated the joint inflammation response in OA mice, thereby accelerating disease progression. Separating macrophages and chondrocytes from TREM2-KO mice and co-cultivating them significantly increased chondrocyte apoptosis and inhibited chondrocyte proliferation. Further, TREM2 deficiency also significantly enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 3 (CXCL3) expression. Furthermore, NF-κB signaling pathway inhibition significantly suppressed arthritis inflammation in OA mice, thereby effectively alleviating TREM2 deficiency-related adverse effects on chondrocytes. Notably, knocking down CXCL3 of TREM2-KO mice macrophages significantly inhibits inflammatory response and promotes chondrocyte proliferation. Intravenous recombinant TREM2 protein (soluble TREM2, sTREM2) injection markedly promotes macrophage polarization from M1 to M2 and improves the joint tissue pathology and inflammatory response of OA. Conclusion: Our study reveals that TREM2 promotes macrophage polarization from M1 to M2 during OA by NF-κB/CXCL3 axis regulation, thereby improving the pathological state of OA.
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NF-kappa B , Osteoartrite , Animais , Camundongos , Quimiocinas CXC , Inflamação , Glicoproteínas de Membrana/genética , Osteoartrite/genética , Fosfatidilinositol 3-Quinases , Receptores Imunológicos/genética , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Numerous studies have reported the efficacy of antibody-drug conjugates (ADCs) for treating breast cancer. However, during cytotoxic drug treatment, long-term disabling fatigue is common. Moreover, studies in the relevant literature have indicated that fatigue can significantly increase the incidence of depression and sleep disorders. Therefore, this meta-analysis aims to evaluate the incidence of fatigue in breast cancer survivors treated with ADCs. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library databases were systematically searched for articles and conference abstracts published before March 16, 2023. Further, two authors independently extracted data from the included studies. The primary outcome of this study was the incidence of all-grade fatigue caused by the use of ADCs in patients with breast cancer. Finally, a random-effects model was used to calculate the incidence and 95% confidence intervals (CIs) of the outcome. RESULTS: Overall, 7963 patients from 31 studies were included in this meta-analysis to assess the incidence of fatigue caused by the use of approved and marketed ADCs in patients with breast cancer. Notably, the incidence of all-grade fatigue during ADC monotherapy was 39.84% (95% CI, 35.09%-44.69%). In subgroup analyses, among ADCs, the incidence of trastuzumab deruxtecan-induced fatigue was the highest, with an all-grade fatigue incidence of 47.05% (95% CI, 42.38%-51.75%). Meanwhile, the incidence of trastuzumab emtansine (T-DM1)-induced all-grade fatigue was 35.17% (95% CI, 28.87%-41.74%), which was the lowest among ADCs. Further, the incidence of all-grade fatigue due to sacituzumab govitecan was 42.82% (95% CI, 34.54%-51.32%), which was higher than that due to T-DM1. Moreover, the incidence of fatigue was higher with T-DM1 combination therapy than with monotherapy. CONCLUSIONS: Clinicians have highlighted the high incidence of ADC-related fatigue and its negative impact on patients' physical and mental health, making fatigue an important research variable. The results of this study will further contribute to a comprehensive understanding of ADCs, which have some clinical importance and are of great benefit to patients with breast cancer.
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Neoplasias da Mama , Imunoconjugados , Feminino , Humanos , Ado-Trastuzumab Emtansina/farmacologia , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/psicologia , Fadiga/induzido quimicamente , Fadiga/epidemiologia , Imunoconjugados/efeitos adversos , IncidênciaRESUMO
BACKGROUND: Granzyme K (GZMK) is a crucial mediator released by immune cells to eliminate tumor cells, playing significant roles in inflammation and tumorigenesis. Despite its importance, the specific role of GZMK in breast cancer and its mechanisms are not well understood. METHODS: We utilized data from the TCGA and GEO databases and employed a range of analytical methods including GO, KEGG, GSEA, ssGSEA, and PPI to investigate the impact of GZMK on breast cancer. In vitro studies, including RT-qPCR, CCK-8 assay, cell cycle experiments, apoptosis assays, Celigo scratch assays, Transwell assays, and immunohistochemical methods, were conducted to validate the effects of GZMK on breast cancer cells. Additionally, Cox regression analysis integrating TCGA and our clinical data was used to develop an overall survival (OS) prediction model. RESULTS: Analysis of clinical pathological features revealed significant correlations between GZMK expression and lymph node staging, differentiation grade, and molecular breast cancer subtypes. High GZMK expression was associated with improved OS, progression-free survival (PFS), and recurrence-free survival (RFS), as confirmed by multifactorial Cox regression analysis. Functional and pathway enrichment analyses of genes positively correlated with GZMK highlighted involvement in lymphocyte differentiation, T cell differentiation, and T cell receptor signaling pathways. A robust association between GZMK expression and T cell presence was noted in the breast cancer tumor microenvironment (TME), with strong correlations with ESTIMATEScore (Cor = 0.743, P < 0.001), ImmuneScore (Cor = 0.802, P < 0.001), and StromalScore (Cor = 0.516, P < 0.001). GZMK also showed significant correlations with immune checkpoint molecules, including CTLA4 (Cor = 0.856, P < 0.001), PD-1 (Cor = 0.82, P < 0.001), PD-L1 (Cor = 0.56, P < 0.001), CD48 (Cor = 0.75, P < 0.001), and CCR7 (Cor = 0.856, P < 0.001). Studies indicated that high GZMK expression enhances patient responsiveness to immunotherapy, with higher levels observed in responsive patients compared to non-responsive ones. In vitro experiments confirmed that GZMK promotes cell proliferation, cell division, apoptosis, cell migration, and invasiveness (P < 0.05). CONCLUSION: Our study provides insights into the differential expression of GZMK in breast cancer and its potential mechanisms in breast cancer pathogenesis. Elevated GZMK expression is associated with improved OS and RFS, suggesting its potential as a prognostic marker for breast cancer survival and as a predictor of the efficacy of immunotherapy.
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Biomarcadores Tumorais , Neoplasias da Mama , Granzimas , Imunoterapia , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Neoplasias da Mama/mortalidade , Feminino , Prognóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Imunoterapia/métodos , Granzimas/metabolismo , Granzimas/genética , Resultado do Tratamento , Pessoa de Meia-Idade , Microambiente Tumoral/imunologiaRESUMO
As an autoimmune-mediated inflammatory demyelinating disease of the central nervous system, multiple sclerosis (MS) is often confused with cerebral small vessel disease (cSVD), which is a regional pathological change in brain tissue with unknown pathogenesis. This is due to their similar clinical presentations and imaging manifestations. That misdiagnosis can significantly increase the occurrence of adverse events. Delayed or incorrect treatment is one of the most important causes of MS progression. Therefore, the development of a practical diagnostic imaging aid could significantly reduce the risk of misdiagnosis and improve patient prognosis. We propose an interpretable deep learning (DL) model that differentiates MS and cSVD using T2-weighted fluid-attenuated inversion recovery (FLAIR) images. Transfer learning (TL) was utilized to extract features from the ImageNet dataset. This pioneering model marks the first of its kind in neuroimaging, showing great potential in enhancing differential diagnostic capabilities within the field of neurological disorders. Our model extracts the texture features of the images and achieves more robust feature learning through two attention modules. The attention maps provided by the attention modules provide model interpretation to validate model learning and reveal more information to physicians. Finally, the proposed model is trained end-to-end using focal loss to reduce the influence of class imbalance. The model was validated using clinically diagnosed MS (n=112) and cSVD (n=321) patients from the Beijing Tiantan Hospital. The performance of the proposed model was better than that of two commonly used DL approaches, with a mean balanced accuracy of 86.06 % and a mean area under the receiver operating characteristic curve of 98.78 %. Moreover, the generated attention heat maps showed that the proposed model could focus on the lesion signatures in the image. The proposed model provides a practical diagnostic imaging aid for the use of routinely available imaging techniques such as magnetic resonance imaging to classify MS and cSVD by linking DL to human brain disease. We anticipate a substantial improvement in accurately distinguishing between various neurological conditions through this novel model.
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Doenças de Pequenos Vasos Cerebrais , Aprendizado Profundo , Esclerose Múltipla , Humanos , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Esclerose Múltipla/diagnóstico por imagem , Masculino , Imageamento por Ressonância Magnética/métodos , Feminino , Redes Neurais de Computação , Interpretação de Imagem Assistida por Computador/métodos , Pessoa de Meia-Idade , Adulto , Neuroimagem/métodosRESUMO
Endoscopic submucosal dissection (ESD) of fibrotic colorectal lesions is difficult and has a high complication rate. There are only a few reports on the utility of orthodontic rubber band (ORB) traction in reducing the difficulty of this procedure. This study aimed to investigate the risk factors for perforation when applying ORB traction during ESD of fibrotic colorectal lesions. We continuously collected the clinical data of 119 patients with fibrotic colorectal lesions who underwent ESD with ORB and clip traction between January 2019 and January 2024. Possible risk factors for perforation were analyzed. The median ORB-ESD operative time was 40 (IQR 28-62) min, and the en bloc and R0 resection rates were 94.1% and 84.0%, respectively. Perforation occurred in 16 of 119 patients (13.4%). The lesion size, lesion at the right half of the colon or across an intestinal plica, the degree of fibrosis, operation time, and the surgeon's experience were associated with perforation during ORB-ESD (P < 0.05). Multivariate logistic regression analysis showed that lesions in the right colon (OR 9.027; 95% CI 1.807-45.098; P = 0.007) and those across an intestinal plica (OR 7.771; 95% CI 1.298-46.536; P = 0.025) were independent risk factors for perforation during ORB-ESD. ORB-ESD is an effective and feasible approach to treat fibrotic colorectal lesions. Adequate preoperative evaluation is required for lesions in the right colon and across intestinal plicas to mitigate the risk of perforation.
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Neoplasias Colorretais , Ressecção Endoscópica de Mucosa , Humanos , Feminino , Masculino , Ressecção Endoscópica de Mucosa/efeitos adversos , Ressecção Endoscópica de Mucosa/métodos , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Fibrose , Perfuração Intestinal/etiologia , Perfuração Intestinal/cirurgia , Colo/cirurgia , Colo/patologia , Colo/lesões , Estudos Retrospectivos , Borracha , Aparelhos Ortodônticos/efeitos adversos , Duração da CirurgiaRESUMO
Interleukin-2 (IL-2) used in multiple sclerosis (MS) therapy modulates the balance between regulatory T (Treg) cells and effector T (Teff) cells. However, the off-target activation of Teff cells by IL-2 limits its clinical application. Therefore, a rapidly prepared immunoswitch nanomodulator termed aT-IL2C NPs was developed, which specifically recognized Treg cells with high TIGIT expression thanks to the presence of an anti-TIGIT and an IL-2/JES6-1 complex (IL2C) being delivered to Treg cells but not to Teff cells with low TIGIT expression. Then, IL2C released IL-2 due to the specific expression of the high-affinity IL-2 receptor on Treg cells, thus enabling the active targeting and selective proliferation of Treg cells. Moreover, the anti-TIGIT of aT-IL2C NPs selectively inhibited the proliferation of Teff cells while leaving the proliferation of Treg cells unaffected. In addition, since the IL-2 receptor on Teff cells had medium-affinity, the IL2C hardly released IL-2 to Teff cells, thus enabling the inhibition of Teff cell proliferation. The treatment of experimental autoimmune encephalomyelitis (EAE) mice with aT-IL2C NPs ameliorated the severity of the EAE and restored white matter integrity. Collectively, this work described a potential promising agent for effective MS therapy.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Camundongos , Animais , Linfócitos T Reguladores , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Interleucina-2/farmacologia , Interleucina-2/uso terapêutico , Interleucina-2/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Proliferação de Células , Camundongos Endogâmicos C57BLRESUMO
Global water scarcity and extreme weather intensify drought stress, significantly reducing cotton yield and quality worldwide. Drought treatments are conducted using a population of chromosome segment substitution lines generated from E22 (G. hirsutum) and 3-79 (G. barbadense) as parental lines either show superior yields or fiber quality under both control and drought conditions. Fourteen datasets, covering 4 yields and 4 quality traits, are compiled and assessed for drought resistance using the drought resistance coefficient (DRC) and membership function value of drought resistance (MFVD). Genome-wide association studies, linkage analysis, and bulked segregant analysis are combined to analyze the DR-related QTL. A total of 121 significant QTL are identified by DRC and MFVD of the 8 traits. CRISPR/Cas9 and virus-induced gene silencing techniques verified DRR1 and DRT1 as pivotal genes in regulating drought resistant of cotton, with hap3-79 exhibiting greater drought resistance than hapE22 concerning DRR1 and DRT1. Moreover, 14 markers with superior yield and fiber quality are selected for drought treatment. This study offers valuable insights into yield and fiber quality variations between G. hirsutum and G. barbadense amid drought, providing crucial theoretical and technological backing for developing cotton varieties resilient to drought, with high yield and superior fiber quality.
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Bacillus cereus belongs to Gram-positive bacteria, which is widely distributed in nature and shows certain pathogenicity. Different B. cereus strains carry different subsets of virulence factors, which directly determine the difference in their pathogenicity. It is therefore important to study the distribution of virulence factors and the biological activity of specific toxins for precise prevention and control of B. cereus infection. In this study, the hemolysin BL triayl was expressed, purified, and characterized. The results showed that the bovine pathogenic B. cereus hemolysin BL could be expressed and purified in the prokaryotic expression system, and the bovine pathogenic B. cereus hemolysin BL showed hemolysis, cytotoxicity, good immunogenicity and certain immune protection in mice. In this study, the recombinant expression of hemolysin BL triayl was achieved, and the biological activity of hemolysin BL of bovine pathogenic ceroid spore was investigated. This study may facilitate further investigating the pathogenic mechanism of B. cereus hemolysin BL and developing a detection method for bovine pathogenic B. cereus disease.
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Bacillus cereus , Proteínas de Bactérias , Bovinos , Animais , Camundongos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Bacillus cereus/genética , Bacillus cereus/metabolismo , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Fatores de Virulência/metabolismo , Enterotoxinas/metabolismoRESUMO
This research study measures psychological attraction in relation to food brands by football players advertisements. This research is based on consumer behavior and examines the effect of product choicesand has been conducted in the context of China using primary data analysis techniques. For analysis, the data is generated on the basis of responses to specific questions related to the psychological attraction, food brand advertisement, consumer behavior, and product choice. To measure the data, the smart PLS software ran different results such as statistical ratio analysis, T-test analysis, regression analysis, generalized linear model, and that reliability test analysis. This study aimed to better understand the components of product attributes in the sporting environment in order to better understand what makes a product-athlete endorsement connection more effective. While it is usual for businesses to utilize athletes for advertising and marketing their products or services, only a limited number of studies have looked at the qualities of athletes and the roles these characteristics play in developing an effective advertisement relationship. Analysis of data findings shows that psychological attraction has a positive and significant impact on consumer behavior and product choice. On the other hand, food brand advertisement shows a positive but insignificant effect on product choice.(AU)