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"Organoids", three-dimensional self-organized organ-like miniature tissues, are proposed as intermediary models that bridge the gap between animal and human studies in drug development. Despite recent advancements in organoid model development, studies on toxicity using these models are limited. Therefore, in this study, we aimed to analyze the functionality and gene expression of pre- and post-differentiated human hepatic organoids derived from induced pluripotent stem cells and utilize them for toxicity assessment. First, we confirmed the functional similarity of this hepatic organoid model to the human liver through various functional assessments, such as glycogen storage, albumin and bile acid secretion, and cytochrome P450 (CYP) activity. Subsequently, utilizing these functionally validated hepatic organoids, we conducted toxicity evaluations with three hepatotoxic substances (ketoconazole, troglitazone, and tolcapone), which are well known for causing drug-induced liver injury, and three non-hepatotoxic substances (sucrose, ascorbic acid, and biotin). The organoids effectively distinguished between the toxicity levels of substances with and without hepatic toxicity. We demonstrated the potential of hepatic organoids with validated functionalities and genetic characteristics as promising models for toxicity evaluation by analyzing toxicological changes occurring in hepatoxic drug-treated organoids.
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Despite its potential for clean hydrogen harvesting, photoelectrochemical (PEC) water-splitting cells face challenges in commercialization, particularly related its harvesting performance and productivity at an industrial scale. Herein, a facile fabrication method of flexible thin-film photoanode for PEC water-splitting to overcome these limitations, based on laser processing technologies, is proposed. Laser-induced graphene, a carbon structure produced through direct laser writing carbonization (DLWC), plays a dual role: a flexible and stable current collector and a substrate for the hydrothermal synthesis of tungsten trioxide (WO3) nanorods (NRs). To facilitate water-splitting, a femtosecond-pulsed laser (fs laser) is focused on the WO3 NRs, converting their crystalline phase from pristine orthorhombic to monoclinic structure without thermal damage. With NiFe layered double hydroxide (LDH) catalyst, the flexible thin-film photoanode exhibits good PEC performance (1.46 mA cm-2 at 1.23 VRHE) and retains ≈90% of its performance after 3000 bending cycles. With its excellent mechanical properties, the flexible photoanode can be operated in various shapes with different curvatures, enabling space-efficient PEC water-splitting by loading larger photoanode within a given space. This study is expected to contribute to the advancement of large-scale solar water-splitting cells, introducing a new approach to enhance H2/O2 production and expand its application range.
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An organoid is a self-organized three-dimensional structure derived from stem cells that mimics the structure, cell composition, and functional characteristics of specific organs and tissues and is used for evaluating the safety and effectiveness of drugs and the toxicity of industrial chemicals. Organoid technology is a new methodology that could replace testing on animals testing and accelerate development of precision and regenerative medicine. However, large variations in production can occur between laboratories with low reproducibility of the production process and no internationally agreed standards for quality evaluation factors at endpoints. To overcome these barriers that hinder the regulatory acceptance and commercialization of organoids, Korea established the Organoid Standards Initiative in September 2023 with various stakeholders, including industry, academia, regulatory agencies, and standard development experts, through public and private partnerships. This developed general guidelines for organoid manufacturing and quality evaluation and for quality evaluation guidelines for organoid-specific manufacturing for the liver, intestines, and heart through extensive evidence analysis and consensus among experts. This report is based on the common standard guideline v1.0, which is a general organoid manufacturing and quality evaluation to promote the practical use of organoids. This guideline does not focus on specific organoids or specific contexts of use but provides guidance to organoid makers and users on materials, procedures, and essential quality assessment methods at end points that are essential for organoid production applicable at the current technology level.
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This paper presents guidelines for the systematic management of packaging, storage, transportation, and traceability of source cells used for organoid research. Given the important role of source cells in organoid studies, it is important to ensure the preservation of their quality and integrity throughout transportation and distribution processes. The proposed guidelines, therefore, call for a cohesive strategy through these stages to minimize the risks of contamination, deterioration, and loss-threats that significantly compromise the safety, efficacy, and efficiency of source cells. Central to these guidelines is the quality control measures that include roles and responsibilities across the entire supply chain, with recommendations specific to packaging materials, transportation facilities, and storage management. Furthermore, the need for an integrated management system is emphasized, spanning from source cell collection to the final application. This system is crucial for maintaining the traceability and accountability of source cells, facilitating the sharing, distribution, and utilization on a global scale, and supporting to advance organoid research and development.
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In patients with autoimmune disorders such as rheumatoid arthritis (RA), delayed wound healing is often observed. Timely and effective wound healing is a crucial determinant of a patient's quality of life, and novel materials for skin wound repair, such as bioactive peptides, are continuously being studied and developed. One such bioactive peptide, AESIS-1, has been studied for its well-established anti-rheumatoid arthritis properties. In this study, we attempted to use the anti-RA material AESIS-1 as a therapeutic wound-healing agent based on disease-modifying antirheumatic drugs (DMARDs), which can help restore prompt wound healing. The efficacy of AESIS-1 in wound healing was assessed using a full-thickness excision model in diabetic mice; this is a well-established model for studying chronic wound repair. Initial observations revealed that mice treated with AESIS-1 exhibited significantly advanced wound repair compared with the control group. In vitro studies revealed that AESIS-1 increased the migration activity of human dermal fibroblasts (HDFs) without affecting proliferative activity. Moreover, increased HDF cell migration is mediated by upregulating chemokine receptor expression, such as that of CXC chemokine receptor 2 (CXCR2). The upregulation of CXCR2 through AESIS-1 treatment enhanced the chemotactic reactivity to CXCR2 ligands, including CXC motif ligand 8 (CXCL8). AESIS-1 directly activates the ERK and p38 mitogen-activated protein kinase (MAPK) signaling cascades, which regulate the migration and expression of CXCR2 in fibroblasts. Our results suggest that the AESIS-1 peptide is a strong wound-healing substance that increases the movement of fibroblasts and the expression of CXCR2 by turning on the ERK and p38 MAPK signaling cascades.
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Antirreumáticos , Artrite Reumatoide , Diabetes Mellitus Experimental , Humanos , Animais , Camundongos , Receptores de Interleucina-8B , Qualidade de Vida , Movimento Celular , Fibroblastos , Peptídeos , CicatrizaçãoRESUMO
Neutrophils perform essential functions in antimicrobial defense and tissue maintenance at mucosal barriers. However, a dysregulated neutrophil response and, in particular, the excessive release of neutrophil extracellular traps (NETs) are implicated in the pathology of various diseases. In this review, we provide an overview of the basic concepts related to neutrophil functions, including NET formation, and discuss the mechanisms associated with NET activation and function in the context of the prevalent oral disease periodontitis.
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Armadilhas Extracelulares , Neutrófilos , Saúde Bucal , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Humanos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Animais , Periodontite/imunologia , Periodontite/patologia , Periodontite/metabolismoRESUMO
The cut chrysanthemum holds one of the most substantial segments of the global floriculture market, particularly in Korea. We conducted a detailed assessment of the genetic structures across the cut chrysanthemum breeding lines in Korea. Using standard and spray chrysanthemum breeding lines from leading Korean research institutes, we first compared the variability of 12 horticultural traits, revealing a wide range of variation for most traits. We found that the overall flower diameter (OFD) and ray floret length (RFL) showed a solid positive relationship, regardless of the type. From a multivariate approach, OFD, RFL, and ray floret width (RFW) show consistently high association. Genotypic and phenotypic coefficients of variation analyses further indicated the significant genetic control over most traits. However, certain traits, like the volume of flowers (VF) in standard types, are more influenced by environments. Lastly, our analysis demonstrated substantial variability in broad-sense heritability (H); plant height (PH) consistently showed high H in both types. But the number of side branches (NOSB) and VF exhibited inconsistent H scores. These findings highlight the need for type-specific breeding strategies and modulating environmental management to optimize the trait expressions depending on the H scores, which offers significant implications for future breeding strategies.
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HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4+ T cells. We propose that the Vprâ¢VprBPâ¢Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.
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HIV-1 , Linfócitos T , Humanos , Centrossomo , Carcinogênese , Transformação Celular Neoplásica , Aneuploidia , Linfócitos T CD4-PositivosRESUMO
At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.
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Interleucina-23 , Periodontite , Humanos , Células Epiteliais , Inflamação , Receptor 5 Toll-Like/metabolismoRESUMO
BACKGROUND: The recurrence of thyroid cancer poses challenges compounded by postoperative fibrosis and anatomic changes. By overcoming the limitations of current localizing dye techniques, indocyanine green-macroaggregated albumin-hyaluronic acid (ICG-MAA-HA) mixture dye promises improved localization. This study aimed to evaluate the efficacy and safety of the dye for recurrent thyroid cancer. METHODS: The nine patients in this study underwent surgery and postoperative ultrasonography. The dye was injected into recurrent lesions in all the patients preoperatively. During surgery, the lesions were confirmed with an imaging system before and after excision. If the lesion was unidentifiable with the naked eye, surgical excision was performed under the corresponding fluorescent guide. Side effects related to the dye injection and completeness of the surgery were evaluated. RESULTS: No side effects such as bleeding, skin tattooing, or pain during or after the dye injection were reported, and no discoloration occurred that interfered with the surgical field of view during surgery. In three cases (33.3 %), because it was difficult to localize metastatic lesions with the naked eye, the operation was successfully completed using an imaging system. The completeness of the surgical resection was confirmed by ultrasonography after an average of 5 months postoperatively. CONCLUSION: The study found that ICG-MAA-HA dye effectively located metastatic and recurrent thyroid cancer and had favorable results in terms of minimal procedural side effects and potential for assisting the surgeon. A large-scale multi-institutional study is necessary to prove the clinical significance regarding patient survival and disease control.
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Verde de Indocianina , Neoplasias da Glândula Tireoide , Humanos , Ácido Hialurônico , Corantes , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Albuminas , Biópsia de Linfonodo Sentinela/métodosRESUMO
Single-cell RNA sequencing and flow cytometry approaches have been instrumental in understanding cellular states within various tissues and organs. However, tissue dissociation methods can potentially alter results and create bias due to preferential recovery of particular cell types. Here we present efforts to optimize methods for dissociation of murine oral mucosal tissues and provide three different protocols that can be utilized to isolate major cell populations in the oral mucosa. These methods can be used both in health and in states of inflammation, such as periodontitis. The optimized protocols use different enzymatic approaches (collagenase II, collagenase IV and the Miltenyi whole skin dissociation kit) and yield preferential recovery of immune, stromal and epithelial cells, respectively. We suggest choosing the dissociation method based on the cell population of interest to study, while understanding the limitations of each approach.
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Mucosa Bucal , Periodontite , Animais , Camundongos , Citometria de Fluxo/métodos , Colagenases/metabolismo , InflamaçãoRESUMO
HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observed that approximately 1-5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cell biology analyses, we discovered that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr formed a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhanced Plk4's functionality by promoting its relocalization to the procentriole assembly and induced centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogated Vpr's capacity to induce all these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induced multiple centrosomes and aneuploidy in primary CD4+ T cells. We propose that the Vprâ¢VprBPâ¢Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.
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Neutrophil infiltration is a hallmark of periodontitis, a prevalent oral inflammatory condition in which Th17-driven mucosal inflammation leads to destruction of tooth-supporting bone. Herein, we document that neutrophil extracellular traps (NETs) are early triggers of pathogenic inflammation in periodontitis. In an established animal model, we demonstrate that neutrophils infiltrate the gingival oral mucosa at early time points after disease induction and expel NETs to trigger mucosal inflammation and bone destruction in vivo. Investigating mechanisms by which NETs drive inflammatory bone loss, we find that extracellular histones, a major component of NETs, trigger upregulation of IL-17/Th17 responses, and bone destruction. Importantly, human findings corroborate our experimental work. We document significantly increased levels of NET complexes and extracellular histones bearing classic NET-associated posttranslational modifications, in blood and local lesions of severe periodontitis patients, in the absence of confounding disease. Our findings suggest a feed-forward loop in which NETs trigger IL-17 immunity to promote immunopathology in a prevalent human inflammatory disease.
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Armadilhas Extracelulares , Periodontite , Animais , Humanos , Histonas , Interleucina-17 , Inflamação/patologia , Periodontite/patologia , Neutrófilos/patologiaRESUMO
BACKGROUND: Prediction models for mediastinal metastasis and its detection by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been developed using a prospective cohort of potentially operable patients with non-small cell lung cancer (NSCLC). RESEARCH QUESTION: Can mediastinal metastasis and its detection by EBUS-TBNA be predicted with prediction models in NSCLC? STUDY DESIGN AND METHODS: For the prospective development cohort, 589 potentially operable patients with NSCLC were evaluated (July 2016-June 2019) from five Korean teaching hospitals. Mediastinal staging was performed using EBUS-TBNA (with or without the transesophageal approach). Surgery was performed for patients without clinical N (cN) 2-3 disease by endoscopic staging. The prediction model for lung cancer staging-mediastinal metastasis (PLUS-M) and a model for mediastinal metastasis detection by EBUS-TBNA (PLUS-E) were developed using multivariable logistic regression analyses. Validation was performed using a retrospective cohort (n = 309) from a different period (June 2019-August 2021). RESULTS: The prevalence of mediastinal metastasis diagnosed by EBUS-TBNA or surgery and the sensitivity of EBUS-TBNA in the development cohort were 35.3% and 87.0%, respectively. In PLUS-M, younger age (< 60 years and 60-70 years compared with ≥ 70 years), nonsquamous histology (adenocarcinoma and others), central tumor location, tumor size (> 3-5 cm), cN1 or cN2-3 stage by CT, and cN1 or cN2-3 stage by PET-CT were significant risk factors for N2-3 disease. Areas under the receiver operating characteristic curve (AUCs) for PLUS-M and PLUS-E were 0.876 (95% CI, 0.845-0.906) and 0.889 (95% CI, 0.859-0.918), respectively. Model fit was good (PLUS-M: Hosmer-Lemeshow P = .658, Brier score = 0.129; PLUS-E: Hosmer-Lemeshow P = .569, Brier score = 0.118). In the validation cohort, PLUS-M (AUC, 0.859 [95% CI, 0.817-0.902], Hosmer-Lemeshow P = .609, Brier score = 0.144) and PLUS-E (AUC, 0.900 [95% CI, 0.865-0.936], Hosmer-Lemeshow P = .361, Brier score = 0.112) showed good discrimination ability and calibration. INTERPRETATION: PLUS-M and PLUS-E can be used effectively for decision-making for invasive mediastinal staging in NSCLC. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02991924; URL: www. CLINICALTRIALS: gov.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias do Mediastino , Humanos , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática/patologia , Neoplasias do Mediastino/patologia , Mediastino/patologia , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , IdosoRESUMO
Lyn, a tyrosine kinase that is activated by double-stranded DNAdamaging agents, is involved in various signaling pathways, such as proliferation, apoptosis, and DNA repair. Ribosomal protein S3 (RpS3) is involved in protein biosynthesis as a component of the ribosome complex and possesses endonuclease activity to repair damaged DNA. Herein, we demonstrated that rpS3 and Lyn interact with each other, and the phosphorylation of rpS3 by Lyn, causing ribosome heterogeneity, upregulates the translation of p-glycoprotein, which is a gene product of multidrug resistance gene 1. In addition, we found that two different regions of the rpS3 protein are associated with the SH1 and SH3 domains of Lyn. An in vitro immunocomplex kinase assay indicated that the rpS3 protein acts as a substrate for Lyn, which phosphorylates the Y167 residue of rpS3. Furthermore, by adding various kinase inhibitors, we confirmed that the phosphorylation status of rpS3 was regulated by both Lyn and doxorubicin, and the phosphorylation of rpS3 by Lyn increased drug resistance in cells by upregulating p-glycoprotein translation. [BMB Reports 2023; 56(5): 302-307].
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Subfamília B de Transportador de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Proteínas Ribossômicas , Quinases da Família src , Humanos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Reparo do DNA/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistência a Múltiplos Medicamentos/fisiologia , Fosforilação , Quinases da Família src/genética , Quinases da Família src/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismoRESUMO
BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing. METHODS: To overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method. RESULTS: Nintedanib blocked the platelet-derived growth factor receptor ß (PDGFRß) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRß+-CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes. CONCLUSION: Our strategy against PDGFRß+-CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.
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Fibroblastos Associados a Câncer , Neoplasias Pancreáticas , Receptores de Antígenos Quiméricos , Humanos , Interleucina-6 , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Mucosal tissues are constantly exposed to the outside environment. They receive signals from the commensal microbiome and tissue-specific triggers including alimentary and airborne elements and are tasked to maintain balance in the absence of inflammation and infection. Here, we present neutrophils as sentinel cells in mucosal immunity. We discuss the roles of neutrophils in mucosal homeostasis and overview clinical susceptibilities in patients with neutrophil defects. Finally, we present concepts related to specification of neutrophil responses within specific mucosal tissue microenvironments.
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Microbiota , Neutrófilos , Humanos , Imunidade nas Mucosas , Mucosa , InflamaçãoRESUMO
OBJECTIVE: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM). METHODS: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS). RESULTS: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms. CONCLUSIONS: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM. KEY POINTS: ⢠In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. ⢠The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. ⢠The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making.
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Neoplasias Colorretais , Neoplasias Hepáticas , Masculino , Humanos , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/secundário , Estudos Retrospectivos , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologiaRESUMO
Although the typical CT findings of Pneumocystis jiroveci pneumonia (PJP) include diffuse or multifocal areas of ground-glass opacities in both lungs, it can also rarely manifest as multiple pulmonary nodules. We report a rare case of atypical PJP in an immunocompromised patient with multiple myeloma, presenting as widespread ground-glass opacities and multiple necrotic subpleural nodules in both lungs on CT, which proved to be granulomatous PJP on percutaneous transthoracic needle biopsy.
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Activation of microglia, which is the primary immune cell of the central nervous system, plays an important role in neuroinflammation associated with several neuronal diseases. Aminoacyl tRNA synthetase (ARS) complex-interacting multifunctional protein 1 (AIMP1), a structural component of the multienzyme ARS complex, is secreted to trigger a pro-inflammatory function and has been associated with several inflammatory diseases. However, the effect of AIMP1 on microglial activation remains unknown. AIMP1 elevated the expression levels of activation-related cell surface markers and pro-inflammatory cytokines in primary and BV-2 microglial cells. In addition to the AIMP1-mediated increase in the expression levels of M1 markers [interleukin (IL)-6, tumor necrosis factor-α, and IL-1ß], the expression levels of CD68, an M1 cell surface molecule, were also increased in AIMP-1-treated microglial cells, while those of CD206, an M2 cell surface molecule, were not, indicating that AIMP1 triggers the polarization of microglial cells into the M1 state but not the M2 state. AIMP1 treatment induced the phosphorylation of mitogen-activated protein kinases (MAPKs), while MAPK inhibitors suppressed the AIMP1-induced microglial cell activation. AIMP1 also induced the phosphorylation of the nuclear factor-kappa B (NF-κB) components and nuclear translocation of the NF-κB p65 subunit in microglial cells. Furthermore, c-Jun N-terminal kinase (JNK) and p38 inhibitors markedly suppressed the AIMP1-induced phosphorylation of NF-κB components as well as the nuclear translocation of NF-κB p65 subunit, suggesting the involvement of JNK and p38 as upstream regulators of NF-κB in AIMP1-induced microglial cell activation. The NF-κB inhibitor suppressed the AIMP1-induced M1 polarization of the microglial cells. Taken together, AIMP1 effectively induces M1 microglial activation via the JNK and p38/NF-κB-dependent pathways. These results suggest that AIMP1 released under stress conditions may be a pathological factor that induces neuroinflammation.