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Rationale: MG53's known function in facilitating tissue repair and anti-inflammation has broad applications to regenerative medicine. There is controversy regarding MG53's role in the development of type 2 diabetes mellitus. Objective: This study aims to address this controversy - whether MG53's myokine function contributes to inhibition of insulin signaling in muscle, heart, and liver tissues. Study design: We determined the binding affinity of the recombinant human MG53 (rhMG53) to the insulin receptor extracellular domain (IR-ECD) and found low affinity of interaction with Kd (>480 nM). Using cultured C2C12 myotubes and HepG2 cells, we found no effect of rhMG53 on insulin-stimulated Akt phosphorylation (p-Akt). We performed in vivo assay with C57BL/6J mice subjected to insulin stimulation (1 U/kg, intraperitoneal injection) and observed no effect of rhMG53 on insulin-stimulated p-Akt in muscle, heart and liver tissues. Conclusion: Overall, our data suggest that rhMG53 can bind to the IR-ECD, however has a low likelihood of a physiologic role, as the Kd for binding is ~10,000 higher than the physiologic level of MG53 present in the serum of rodents and humans (~10 pM). Our findings question the notion proposed by Xiao and colleagues - whether targeting circulating MG53 opens a new therapeutic avenue for type 2 diabetes mellitus and its complications.
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Insulina , Fígado , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt , Receptor de Insulina , Animais , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , Receptor de Insulina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Insulina/metabolismo , Insulina/farmacologia , Miocárdio/metabolismo , Células Hep G2 , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Masculino , Transdução de Sinais/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Citocinas/metabolismo , Proteínas de MembranaRESUMO
Histone deacetylases (HDACs) are important epigenetic regulators of gene expression and various cellular processes, and are potential targets for anticancer therapy. In particular, HDAC8 is a promising therapeutic target for childhood neuroblastoma. To date, five HDAC inhibitors have been approved as anticancer drugs; however, all are non-selective HDAC inhibitors with various side effects. Furthermore, many promising HDAC inhibitors incorporate hydroxamic acid as a zinc binding group (ZBG), which may be associated with toxicity. Therefore, identification of isoform-selective HDAC inhibitors with novel ZBG is crucial. Here, a series of sulfur-based selective HDAC8 inhibitors featuring a novel ZBG were identified by modifying the early hit, ajoene, a component of garlic. Structure-activity relationship studies uncovered potent and selective HDAC8 inhibitors, and docking studies provided a structural rationale for HDAC8 inhibitory activity. One of the potent compounds, (Z)-1-phenyl-7-(4-methoxyphenyl)-2,3,7-trithiahepta-4-ene-7-oxide (15c), exhibited antiproliferative activity, with a GI50 of 2 µM, against neuroblastoma cell lines. 15c also showed significant in vivo efficacy in a neuroblastoma BE(2)-C xenograft model.
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ABSTRACT: Hemorrhagic transformation is a serious complication of ischemic stroke, which occurs at a rate of between 18% and 42%. 68Ga-FAPI PET can visualize acute cerebral infarction at risk of hemorrhagic transformation in the brain. We report a case of 68Ga-FAPI PET imaging in a patient with recurrent ischemic stroke. 68Ga-FAPI PET imaging revealed FAPI uptake in acute ischemic stroke with hemorrhagic transformation, but did not in some acute infarction and chronic infarction without hemorrhagic transformation. These findings suggest potential role of 68Ga-FAPI PET in the evaluation of acute ischemic stroke with the risk of hemorrhagic transformation.
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In the field of molecular diagnostics, the demand for multiplex detection, aimed at reducing overall analysis costs and streamlining procedures, is on the rise, prompting ongoing developments in various technologies. In this study, we developed a novel system, the split T7 promoter-based three-way junction-transcription, coupled with Cas12a/Blocker DNA (T3-CaB), for the multiplex detection of target nucleic acids. The T3-CaB system builds upon the foundation of the T3 system, generating numerous RNA transcripts upon encountering target nucleic acids. Subsequently, these RNA transcripts displace the blocker DNA from reporter DNA, allowing active Cas12a to engage in efficient trans-cleavage reaction on the reporter DNA, resulting in a strong fluorescence signal. Importantly, the proposed system operates at the isothermal condition (37 °C), with the entire analysis completed within 90 min. Further, the detection performance of the proposed system surpasses that of the preceding Cas12a/Blocker DNA system. Model targets, namely the 16S rRNA of Staphylococcus aureus and Escherichia coli, were selected, and a successful demonstration of multiplex detection was achieved. This technology holds promise for broadening the applicability of CRISPR/Cas-based diagnostics, especially in settings necessitating multiplex detection capabilities.
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Importance: Although optic disc hemorrhage (DH) is widely recognized as a glaucoma risk factor, its clinical relevance in relation to proximity has not been investigated. Objective: To determine the association of the proximal location of DH with glaucoma progression. Design, Setting, and Participants: In this longitudinal observational cohort study, 146 eyes of 146 patients at Seoul National University Hospital who had had 1 or more DH with at least 5 years of follow-up and had at least 5 reliable visual field examinations were included. These data were analyzed January 10, 2010, through June 27, 2017. Exposures: Laminar, marginal, rim, and parapapillary subtypes of DH were identified based on their respective proximal locations. The laminar and marginal subtypes were classified into the cup-type group, while the rim and parapapillary subtypes were classified into the peripapillary-type group. Kaplan-Meier survival analysis was used to compare survival experiences and multivariate analysis with the Cox proportional hazard model to identify risk factors for glaucoma progression. Regression analyses, both univariate and multivariate, were used to discover significant indicators of mean deviation (MD) loss. Main Outcome and Measure: The primary outcome was glaucoma progression. Glaucoma progression was defined either as structural or functional deterioration. Results: For all of the eyes, the mean follow-up period was 10.9 (3.7) years (range, 5.1-17.8 years), the mean age at which DH was first detected was 55.1 (11.3) years (range, 21-77 years), and 94 participants were female (64.1%). Over the mean follow-up period of 10.9 years, glaucoma progression was detected in 94 eyes (61.4%) with an MD change of -0.48 dB per year. The cup-type group showed a faster rate of MD change relative to the peripapillary-type group (-0.56 vs -0.32 dB per year; difference = -0.24; 95% CI, -0.37 to -0.11; P = .01). The cup group showed a higher cumulative probability of progression of glaucoma (80.4%) relative to the peripapillary group (54.4%; difference = 26.0%; 95% CI, 11.4%-40.6%; P < .001) in a life table analysis. The presence of cup hemorrhage was associated with an increased risk of glaucoma progression (hazard ratio, 3.28; 95% CI, 2.12-5.07; P < .001) in the multivariate Cox proportional hazard model. Cup-type DH was associated to MD loss rate in regression analysis. Conclusions And Relevance: This study showed glaucoma progression was higher in cases of DH classified as the cup type. These findings support the potential utility of assessing the proximal location of DH to predict how glaucoma might progress.
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This study reports the effects of changes in the waveform and frequency of radio frequency (RF) energy on the tissue ablation range. We developed a 70-watt RFA generator that provides sine and square waves and allows frequency control between 10 Hz and 500 kHz. The changes in the ablation range according to the waveform and frequency were observed using the developed generator. In the waveform variation test, the distance between the electrodes and the electrode type were changed for both waveforms with the frequency set to 500 kHz. In the frequency variation test, the waveform and electrode type were changed with the frequency set to 10, 100, and 500 kHz, while the distance between the electrodes was set to 20 mm. A fixed 45 voltage was applied using the bipolar method. RF energy was applied for 90 s in vitro. The temperature was regulated to not exceed 70°C. The ablation range was calculated using ImageJ software. The analysis results showed that the ablation range was larger with the square wave than with the sine wave and at 10 kHz than at 500 kHz. The developed generator can advance research on ablation area and depth in RF ablation.
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Ondas de Rádio , Eletrodos , Ablação por Cateter/métodos , Ablação por Radiofrequência/métodos , Animais , TemperaturaRESUMO
The rapid advancements in natural language processing, particularly with the development of Generative Pre-trained Transformer (GPT) models, have opened up new avenues for researchers across various domains. This review article explores the potential of GPT as a research tool, focusing on the core functionalities, key features, and real-world applications of the GPT-4 model. We delve into the concept of prompt engineering, a crucial technique for effectively utilizing GPT, and provide guidelines for designing optimal prompts. Through case studies, we demonstrate how GPT can be applied at various stages of the research process, including literature review, data analysis, and manuscript preparation. The utilization of GPT is expected to enhance research efficiency, stimulate creative thinking, facilitate interdisciplinary collaboration, and increase the impact of research findings. However, it is essential to view GPT as a complementary tool rather than a substitute for human expertise, keeping in mind its limitations and ethical considerations. As GPT continues to evolve, researchers must develop a deep understanding of this technology and leverage its potential to advance their research endeavors while being mindful of its implications.
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Background: Although radiology reports are commonly used for lung cancer staging, this task can be challenging given radiologists' variable reporting styles as well as reports' potentially ambiguous and/or incomplete staging-related information. Objective: To compare performance of ChatGPT large-language models (LLMs) and human readers of varying experience in lung cancer staging using chest CT and FDG PET/CT free-text reports. Methods: This retrospective study included 700 patients (mean age, 73.8±29.5 years; 509 male, 191 female) from four institutions in Korea who underwent chest CT or FDG PET/CT for non-small cell lung cancer initial staging from January, 2020 to December, 2023. Examinations' reports used a free-text format, written exclusively in English or in mixed English and Korean. Two thoracic radiologists in consensus determined the overall stage group (IA, IB, IIA, IIB, IIIA, IIIB, IIIC, IVA, IVB) for each report using the AJCC 8th-edition staging system, establishing the reference standard. Three ChatGPT models (GPT-4o, GPT-4, GPT-3.5) determined an overall stage group for each report using a script-based application programming interface, zero-shot learning, and prompt incorporating a staging system summary. Six human readers (two fellowship-trained radiologists with lesser experience than the radiologists who determined the reference standard, two fellows, two residents) also independently determined overall stage groups. GPT-4o's overall accuracy for determining the correct stage among the nine groups was compared with that of the other LLMs and human readers using McNemar tests. Results: GPT-4o had an overall staging accuracy of 74.1%, significantly better than the accuracy of GPT-4 (70.1%, p=.02), GPT-3.5 (57.4%, p<.001), and resident 2 (65.7%, p<.001); significantly worse than the accuracy of fellowship-trained radiologist 1 (82.3%, p<.001) and fellowship-trained radiologist 2 (85.4%, p<.001); and not significantly different from the accuracy of fellow 1 (77.7%, p=.09), fellow 2 (75.6%, p=.53), and resident 1 (72.3%, p=.42). Conclusions: The best-performing model, GPT-4o, showed no significant difference in staging accuracy versus fellows, but significantly worse performance versus fellowship-trained radiologists. The findings do not support use of LLMs for lung cancer staging in place of expert healthcare professionals. Clinical Impact: The findings indicate the importance of domain expertise for performing complex specialized tasks such as cancer staging.
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Body odor is considered a diagnostic indicator of various infectious and chronic diseases. But, few studies have examined the odor markers for various toxic effects in the mammalian system. This study attempted to identify the novel diagnostic odor biomarkers for chemical-induced hepatotoxicity in animals. The changes in the concentration of odors were analyzed in the urine of Sprague Dawley (SD) rats treated with two dosages (100 or 200 mg/kg) of 1,2,3-trichloropropane (TCP) using gas chromatography-mass spectrometry (GC-MS). The TCP treatment induced significant toxicity, including a decrease in body weight, an increase in serum biochemical factors, and histopathological changes in the liver of SD rats. During this hepatotoxicity, the concentrations of six odors (ethyl alcohol, acrolein (2-propenal), methanesulfonyl chloride, methyl ethyl ketone, cyclotrisiloxane, and 2-heptanone) in urine changed significantly after the TCP treatment. Among them, acrolein, an acrid and pungent compound, showed the highest rate of increase in the TCP-treated group compared to the Vehicle-treated group. In addition, this increase in acrolein was accompanied by enhanced spermine oxidase (SMOX) expression, an acrolein metabolic enzyme, and the increased level of IL-6 transcription as a regulator factor that induces SMOX production. The correlation between acrolein and other parameters was conformed using correlagram analyses. These results provide scientific evidence that acrolein have potential as a novel diagnostic odor biomarker for TCP-induced hepatotoxicity. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-024-00253-0.
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OBJECTIVE: Mitotically active cellular fibroma (MACF) of the ovary, characterized by relatively high mitotic activity without severe atypia, was first described in the WHO classification in 2014. However, due to its rarity, the clinicopathological characteristics of ovarian MACF have not been established. This study was performed to describe the clinical, radiological, and pathological features of MACF by analyzing 11 cases of ovarian MACF. MATERIALS AND METHODS: Between 2015 and 2022, 11 patients with ovarian MACFs underwent surgical treatment at our institution. Clinicopathologic data of the patients were retrospectively reviewed from their medical records. RESULTS: Median patient age was 53.7 years (range 21-77 years), and median tumor diameter was 7.8 cm (range 4.3-14.0 cm). Preoperative CA125 was elevated in 4 cases. Four of the eleven patients had abdominal pain, and two presented with vulvar pain or a palpable abdominal mass, respectively. Preoperative radiological impressions included fibroma, fibrothecoma, stromal tumor, and cystadenocarcinoma. A laparoscopic approach was adopted in 7 cases (64%). Intraoperative frozen section was performed in 5 patients, and all demonstrated the presence of a benign, fibromatous stromal tumor. Three patients underwent fertility-sparing surgery, including laparoscopic ovarian cystectomy and unilateral salpingo-oophorectomy. Median follow-up was 37.7 months (range 2-84 months), and no patient experienced disease relapse or died of their disease. CONCLUSION: This study shows that ovarian MACF has a benign clinical course. Fertility-sparing surgery provides a safe therapeutic option for MACF, which can be managed safely by laparoscopy. Imaging findings and final pathological diagnosis were not well matched. Intraoperative frozen section is important for determining surgical extent in mitotically active cellular fibroma of the ovary.
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Fibroma , Neoplasias Ovarianas , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Antígeno Ca-125/sangue , Fibroma/patologia , Fibroma/cirurgia , Fibroma/diagnóstico por imagem , Laparoscopia/métodos , Mitose , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/diagnóstico por imagem , Ovário/patologia , Ovário/cirurgia , Ovário/diagnóstico por imagem , Estudos RetrospectivosRESUMO
Background: Restenosis poses a significant challenge for individuals afflicted with peripheral artery diseases, often leading to considerable morbidity and necessitating repeated interventions. The primary culprit behind the pathogenesis of restenosis is intimal hyperplasia (IH), in which the hyperproliferative and migratory vascular smooth muscle cell (VSMC) accumulate excessively in the tunica intima. 6-Phosphogluconate dehydrogenase (6PGD), sometimes referred to as PGD, is one of the critical enzymes in pentose phosphate pathway (PPP). In this study, we sought to probe whether 6PGD is aberrantly regulated in IH and contributes to VSMC phenotypic switching. Methods: We used clinical specimens of diseased human coronary arteries with IH lesions and observed robust upregulation of 6PGD at protein level in both the medial and intimal layers in comparison with healthy arterial segments. Results: 6PGD activity and protein expression were profoundly stimulated upon platelet-derived growth factor-induced VSMC phenotypic switching. Using gain-of-function (dCas9-mediated transcriptional activation) and loss-of-function (small interfering RNA-mediated) silencing, we were able to demonstrate the pathogenic role of 6PGD in driving VSMC hyperproliferation, migration, dedifferentiation, and inflammation. Finally, we conducted a rat model of balloon angioplasty in the common carotid artery, with Pluronic hydrogel-assisted perivascular delivery of Physcion, a selective 6PGD inhibitor with poor systemic bioavailability, and observed effective mitigation of IH. Conclusions: We contend that aberrant 6PGD expression and activity-indicative of a metabolic shift toward pentose phosphate pathway-could serve as a new disease-driving mechanism and, hence, an actionable target for the development of effective new therapies for IH and restenosis after endovascular interventions.
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Objective: Chondrocyte apoptosis has been considered a crucial mechanism that is responsible for cartilage destruction in osteoarthritis (OA). The mechanism of interleukin-37 (IL-37) on chondrocyte apoptosis has not been clearly determined in the pathogenesis of OA. Here, we explored the role of IL-37 in the regulation of cellular apoptosis in rat chondrocytes stimulated by IL-1ß. Methods: Rat chondrocytes were used in in vitro study, and were stimulated with IL-1ß (10 ng/mL) and/or recombinant IL-37 (rIL-37; 100 ng/mL) after cytotoxicity assessments using these cytokines were conducted. After rIL-37 treatment of chondrocytes stimulated with IL-1ß, the cell proliferation assay, apoptosis assays, including expression of mitochondrial apoptosis-related markers, flow cytometry analysis of annexin V-FITC/propidium iodide (PI), cell cycle analysis, and Hoechst 33342 staining, and reactive oxygen species (ROS) measurement were used. Results: IL-1ß induced expression of inflammatory cytokines and triggered degradation of the extracellular matrix of rat chondrocytes, but this effect was significantly attenuated by rIL-37 treatment. Enhanced ROS generation following IL-1ß stimulation was reduced in a dose-dependent manner after stimulation with rIL-37. IL-1ß induced pro-apoptotic markers and suppressed anti-apoptotic markers in rat chondrocytes. Flow cytometry using annexin V-FITC/PI revealed that IL-1ß increased the apoptosis rate of rat chondrocytes, and that this effect was markedly reversed by treatment with rIL-37. Conclusions: IL-37 potently attenuated IL-1ß-mediated apoptosis of rat chondrocytes by blocking ROS production. This study suggests that IL-37 can serve as a novel anti-cytokine therapy in OA by blocking chondrocyte apoptosis.
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Natural products with high antioxidant activity are considered as innovative prevention strategies to effectively prevent age-related macular degeneration (AMD) in the early stage because the generation of reactive oxygen species (ROS) leading to the development of drusen is reported as an important cause of this disease. To investigate the prevention effects of the methanol extracts of Euphorbia heterophylla L. (MEE) on AMD, its effects on the antioxidant activity, inflammatory response, apoptosis pathway, neovascularization, and retinal tissue degeneration were analyzed in N-retinylidene-N-retinylethanolamine (A2E)-landed spontaneously arising retinal pigment epithelia (ARPE)-19 cells and BALB/c mice after exposure to blue light (BL). The MEE contained 10 active components and showed high free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and nitric oxide (NO) radicals. The pretreatments of high-dose MEE remarkably suppressed the production of intracellular ROS (88.2%) and NO (25.2%) and enhanced (SOD) activity (84%) and the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) in A2E + BL-treated ARPE-19 cells compared to Vehicle-treated group. The activation of the inducible nitric oxide synthase (iNOS)-induced cyclooxygenase-2 (COX-2) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was significantly inhibited in A2E + BL-treated ARPE-19 cells after the MEE pretreatment. The activation of the apoptosis pathway and increased expression of neovascular proteins (36% for matrix metalloproteinase (MMP)-9) were inhibited in the MEE pretreated groups compared to the Vehicle-treated group. Furthermore, the thickness of the whole retina (31%), outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) were significantly increased by the MEE pretreatment of BALB/c mice with BL-induced retinal degeneration. Therefore, these results suggest that the MEE, with its high antioxidative activity, protects against BL-induced retinal degeneration through the regulation of the antioxidative system, inflammatory response, apoptosis, and neovascularization in the AMD mouse model.
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Colorectal cancer (CRC) remains one of the most formidable challenges in the global health arena. To address this challenge, extensive research has been directed toward developing targeted drug delivery systems (DDS). Cell-derived vesicles (CDV), which mirror the lipid bilayer structure of cell membranes, have garnered tremendous attention as ideal materials for DDS owing to their scalability in production and high biocompatibility. In this study, a novel method, termed colorectal cancer overall Dukes' staging Systematic Evolution of Ligands by Exponential enrichment (CROSS), was developed to identify Toggle Cell 1 (TC1) aptamers with high binding affinity to CRC cells at various Dukes' stages (A-D). Furthermore, a novel DDS was developed by incorporating a cholesterol-modified TC1 aptamer into CDV, which exhibited improved targeting ability and cellular uptake efficiency toward CRC cells compared to CDV alone. The results of this study highlight the potential efficacy of CDV in constructing a targeted DDS while overcoming the current challenges associated with other lipid-based DDS.
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Complement component 3 (C3) deficiency has recently been reported as one of the novel causes of constipation. To identify a unique gene specific to constipation caused by C3 deficiency, the total RNA extracted from the mid colon of C3 knockout (C3 KO) mice was hybridized to oligonucleotide microarrays, and the function of the candidate gene was verified in in vitro and in vivo models. C3 KO mice used for microarrays showed definite phenotypes of constipation. Overall, compared to the wild type (WT), 1237 genes were upregulated, and 1292 genes were downregulated in the C3 KO mice. Of these, the major genes included were lysine (K)-specific demethylase 5D (KDM5D), olfactory receptor 870 (Olfr870), pancreatic lipase (PNLIP), and alkaline phosphatase intestinal (ALPI). Specifically, the ALPI gene was selected as a novel gene candidate based on alterations during loperamide (Lop)-induced constipation and intestinal bowel disease (IBD). The upregulation of ALPI expression treated with acetate recovered the expression level of mucin-related genes in primary epithelial cells of C3 KO mice as well as most phenotypes of constipation in C3 KO mice. These results indicate that ALPI plays an important role as the novel gene associated with C3 deficiency-induced constipation.
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Complemento C3 , Constipação Intestinal , Camundongos Knockout , Animais , Constipação Intestinal/genética , Constipação Intestinal/etiologia , Complemento C3/genética , Complemento C3/deficiência , Complemento C3/metabolismo , Camundongos , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Receptores Odorantes/genética , Receptores Odorantes/deficiência , Modelos Animais de Doenças , Loperamida , Colo/metabolismo , Colo/patologia , Perfilação da Expressão GênicaRESUMO
Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS), which leads to demyelination, axonal loss, and neurodegeneration. Increased oxidative stress and neurodegeneration have been implicated in all stages of MS, making neuroprotective therapeutics a promising strategy for its treatment. We previously have reported vinyl sulfones with antioxidative and anti-inflammatory properties that activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces the expression of cytoprotective genes against oxidative stress. In this study, we synthesized vinyl sulfoximine derivatives by modifying the core structure and determined therapeutic potential as Nrf2 activators. Among them, 10v effectively activated Nrf2 (EC50 = 83.5 nM) and exhibited favorable drug-like properties. 10v successfully induced expression of Nrf2-dependent antioxidant enzymes and suppressed lipopolysaccharide (LPS)-induced inflammatory responses in BV-2 microglial cells. We also confirmed that 10v effectively reversed disease progression and attenuated demyelination in an experimental autoimmune encephalitis (EAE) mouse model of MS.
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VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development in mice. Wild-type (WT) and VDUP1 KO mice were used to investigate the role of VDUP1 in the development of azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced CAC. VDUP1 levels significantly decreased in the colonic tumor and adjacent nontumoral tissues of WT mice after AOM/DSS treatment. Moreover, AOM/DSS-treated VDUP1 KO mice exhibited a worse survival rate, disease activity index, and tumor burden than WT mice. VDUP1 deficiency significantly induced cell proliferation and anti-apoptosis in tumor tissues of VDUP1 KO mice compared to WT littermates. Additionally, mRNA levels of interleukin-6 and tumor necrosis factor-alpha and active forms of signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 were significantly increased in the tumor tissues of VDUP1 KO mice. Overall, this study demonstrated that the loss of VDUP1 promoted AOM/DSS-induced colon tumorigenesis in mice, highlighting the potential of VDUP1-targeting strategies for colon cancer prevention and treatment.
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The prognosis of early gastric cancer (EGC) patients is associated with lymph node metastasis (LNM). Considering the relatively high rate of LNM in T1b EGC patients, it is crucial to determine the factors associated with LNM. In this study, we constructed and validated predictive models based on machine learning (ML) algorithms for LNM in patients with T1b EGC. Data from patients with T1b gastric cancer were extracted from the Korean Gastric Cancer Association database. ML algorithms such as logistic regression (LR), random forest (RF), extreme gradient boosting (XGBoost), and support vector machine (SVM) were applied for model construction utilizing five-fold cross-validation. The performances of these models were assessed in terms of discrimination, calibration, and clinical applicability. Moreover, external validation of XGBoost models was performed using the T1b gastric cancer database of The Catholic University Medical Center. In total, 3,468 T1b EGC patients were included in the analysis, whom 550 (15.9%) had LNM. Eleven variables were selected to construct the models. The LR, RF, XGBoost, and SVM models were established, revealing area under the receiver operating characteristic curve values of 0.8284, 0.7921, 0.8776, and 0.8323, respectively. Among the models, the XGBoost model exhibited the best predictive performance in terms of discrimination, calibration, and clinical applicability. ML models are reliable for predicting LNM in T1b EGC patients. The XGBoost model exhibited the best predictive performance and can be used by surgeons for the identification of EGC patients with a high-risk of LNM, thereby facilitating treatment selection.
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Objective: Acute respiratory distress syndrome (ARDS) presents a global health challenge, characterized by significant morbidity and mortality. However, the role of natural killer T (NKT) cells in human ARDS remains poorly understood. Therefore, this study explored the numerical and functional status of NKT cells in patients with ARDS, examining their clinical relevance and interactions with macrophages and fibroblasts during various stages of the syndrome. Methods: Peripheral blood from 40 ARDS patients and 30 healthy controls was analyzed, with paired samples of peripheral blood and bronchoalveolar lavage fluid (BALF) from seven ARDS patients. We measured levels of NKT cells, cytokines, CD69, programmed death-1 (PD-1), and annexin-V using flow cytometry, and extracellular matrix (ECM) protein expression using real-time PCR. Results: ARDS patients exhibited decreased circulating NKT cells with elevated CD69 expression and enhanced IL-17 production. The reduction in NKT cells correlated with PaO2/FiO2 ratio, albumin, and C-reactive protein levels. Proliferative responses to α-galactosylceramide (α-GalCer) were impaired, and co-culturing NKT cells with monocytes or T cells from ARDS patients resulted in a reduced α-GalCer response. Increased and activated NKT cells in BALF induced proinflammatory cytokine release by macrophages and ECM protein expression in fibroblasts. Conclusion: ARDS is associated with a numerical deficiency but functional activation of circulating NKT cells, showing impaired responses to α-GalCer and altered interactions with immune cells. The increase in NKT cells within BALF suggests their role in inducing inflammation and remodeling/fibrosis, highlighting the potential of targeting NKT cells as a therapeutic approach for ARDS.
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Células T Matadoras Naturais , Síndrome do Desconforto Respiratório , Humanos , Síndrome do Desconforto Respiratório/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Adulto , Idoso , Macrófagos/imunologia , Macrófagos/metabolismo , Citocinas/metabolismo , Fibroblastos/metabolismo , Fibroblastos/imunologia , Ativação Linfocitária/imunologia , Antígenos de Diferenciação de Linfócitos T , Antígenos CD , Lectinas Tipo CRESUMO
Aerobic granular sludge (AGS) represents an aggregate of sludge formed through the self-immobilization of microorganisms under aerobic conditions. It is currently under scrutiny for its potential as a technology to reduce carbon emissions and promote sustainability. The practicality of AGS stems from its ability to encourage granule formation and enhance structural stability. In this study, a total of five cations (K+, Ca2+, Mg2+, Al3+, Fe3+) were introduced to facilitate stable structuring and the formation of granules for treating high-strength wastewater, such as side-stream treatment. As a result of the experiment, the loosely bound extracellular polymeric substances (LB-EPS) content in the cation-enhanced sludge witnessed a significant increase, leading to elevated total EPS content under all experimental conditions. Furthermore, the protein (PN)/polysaccharide (PS) ratio, a pivotal component of EPS influencing AGS's hydrophobicity and structural stability, exhibited a collective increase, with Mg2+ reaching the highest value of 1.7. The relationship between relative hydrophobicity and the PN/PS ratio was found to strongly impact sludge adhesion, with noteworthy results observed particularly for Mg2+, Al3+, and Fe3+. The viability of attached cells reached 96.8 %, the highest recorded in the case of Mg2+. In the context of treating high-strength wastewater, Mg2+ emerged as the optimal cation for accelerating AGS formation and enhancing structural stability.