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Objective: This study aimed to identify plasma biomarkers that are significantly altered in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and are closely associated with AAV disease activity, as well as to explore their role in the pathogenesis of AAV. Methods: Cytokines were measured using Human Immune Response Panel 80-Plex in plasma from 59 patients with AAV and 20 healthy controls (HCs). The differentially expressed cytokines between the two groups and the possible signaling pathway involved in the pathogenesis of AAV were analyzed by bioinformatics. Relationship analysis was performed between these cytokines and clinical parameters to identify the biomarkers that can effectively indicate disease activity. Results: We identified 65 differentially expressed cytokines between the two groups. Among them, 43 cytokines significantly affected the risk of AAV. Bioinformatic analysis showed that the 43 cytokines were primarily enriched in signaling pathways such as cytokine-cytokine receptor interaction, viral protein interaction with cytokine and cytokine receptor, chemokine signaling pathway, and IL-17 signaling pathway. The levels of 25 cytokines were significantly positively correlated with Birmingham Vasculitis Activity Score (BVAS), and the levels of 2 cytokines were significantly negatively correlated with BVAS. Receiver operating characteristic analysis showed that 9 cytokines can distinguish between disease relapse and remission (PTX3: area under curve (AUC)=0.932, IL34: AUC=0.856, IL2RA: AUC=0.833, CCL23: AUC=0.826, VEGFA: AUC=0.811, TNFSF13: AUC=0.795, Granzyme A: AUC=0.788, CSF3: AUC=0.773 and IL1A: AUC=0.765). The elevated levels of these 9 cytokines suggested a risk of disease relapse. The AUC of CCL11 in disease relapse and remission was 0.811 (p=0.0116). Unlike the other 9 cytokines, a negatively association existed between CCL11 level and the risk of disease relapse. Conclusion: A group of cytokines that may be involved in AAV pathogenesis was identified. Increased PTX3, IL34, IL2RA, CCL23, and VEGFA levels correlate with active disease in AAV and may be used as biomarkers to identify the disease relapse of AAV.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Biomarcadores , Citocinas , Humanos , Masculino , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Feminino , Citocinas/sangue , Pessoa de Meia-Idade , Biomarcadores/sangue , Idoso , Adulto , Estudos de Casos e Controles , Transdução de SinaisRESUMO
BACKGROUND: The aim of this prospective observational cohort study was to unveil the predictors of treatment response to tocilizumab (TCZ) therapy in rheumatoid arthritis (RA) patients, in terms of clinical characteristics and serum proinflammatory cytokines, especially to explore the predictive value of granulocyte macrophage-colony stimulating factor (GM-CSF). METHODS: Active adult RA patients with inadequate response to MTX intending to receive TCZ therapy were recruited prospectively in the study. A total of 174 severe RA patients were included for the identification of the associations between treatment response and the following characteristic features: demographics, medications, disease activity, serum proinflammatory cytokines and so on. RESULTS: Disease duration (OR = 0.996), tender joint count (TJC)/68 (OR = 0.943), neutrophil ratio (W4/baseline) (OR = 0.224), the high level of GM-CSF > 5 ng/ml (OR = 0.414) at baseline were the independent adverse predictors of good response assessed by clinical disease activity index (CDAI) at week 24 (W24) for TCZ therapy in RA patients. Moreover, DAS28-ESR (OR = 2.951, P = 0.002) and the high level of GM-CSF > 10 ng/ml at baseline (OR = 5.419, P = 0.002) were independent predictors of poor response, but not the high level of GM-CSF > 5 ng/ml (OR = 2.713, P = 0.054). The patients in the high GM-CSF group had significantly higher DAS28-ESR and serum levels of cytokines (IL-17A, IL-1ß, IL-6, TNF-α) at baseline, as well as significantly higher rate of non-good response (62.8% vs. 39.4%, P = 0.010) and poor response (27.9% vs. 9.1%, P = 0.004) than the low GM-CSF group at W24. In addition, poor responders had significantly higher levels of GM-CSF with concomitant increase in the serum levels of IL-17A and IL-1ß at baseline than those in moderate and good response groups, while serum levels of IL-6 and TNF-α at baseline were not significantly different in three response groups. CONCLUSION: The high levels of GM-CSF (> 5 ng/ml and > 10 ng/ml) at baseline were the independent predictors of non-good response and poor response to TCZ at W24 respectively. The high level of GM-CSF at baseline is a marker of high disease activity and a predictor of poor response to TCZ in severe RA patients, which may facilitate the development of individualized treatment strategies for refractory RA.
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Anticorpos Monoclonais Humanizados , Antirreumáticos , Artrite Reumatoide , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Feminino , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Antirreumáticos/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento , Adulto , Estudos de Coortes , Idoso , Biomarcadores/sangue , Valor Preditivo dos TestesRESUMO
Rheumatoid arthritis (RA) is a common autoimmune rheumatic disease that causes chronic synovitis, bone erosion, and joint destruction. The autoantigens in RA include a wide array of posttranslational modified proteins, such as citrullinated proteins catalyzed by peptidyl arginine deiminase4a. Pathogenic anti-citrullinated protein antibodies (ACPAs) directed against a variety of citrullinated epitopes are abundant both in plasma and synovial fluid of RA patients. ACPAs play an important role in the onset and progression of RA. Intensive and extensive studies are being conducted to unveil the mechanisms of RA pathogenesis and evaluate the efficacy of some investigative drugs. In this review, we focus on the formation and pathogenic function of ACPAs.
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Anticorpos Antiproteína Citrulinada , Artrite Reumatoide , Humanos , Artrite Reumatoide/imunologia , Anticorpos Antiproteína Citrulinada/imunologia , Autoantígenos/imunologia , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismoRESUMO
Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by dryness of the eyes and mouth. The histological feature is mononuclear cell infiltration in exocrine glands, primarily salivary and lachrymal glands. As the disease progresses, some other tissues and organs may be involved and extraglandular manifestations ensue. The major current treatments are palliative and empirical, and in most cases the outcomes are not satisfactory. Emerging data indicate a critical role of lymphocytes in its development and progression. While pioneering work targeting B cells has demonstrated some encouraging results, more trials are warranted to validate the safety and efficacy. In addition, modulation of T cell function with abatacept ameliorates the severity of pSS. Furthermore, clinical trials to inhibit important cytokines involved in its formation have been carried out. In this article, we summarize and compare current biological therapies in order to find new and effective treatments for pSS.
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OBJECTIVE: To investigate the metabolic changes during therapy of tocilizumab (TCZ) and methotrexate (MTX) in non-diabetic rheumatoid arthritis (RA) patients and for the first time explore the associations between metabolic parameters and serum YKL-40 (sYKL-40) levels. METHODS: We enrolled active non-diabetic RA patients who were refractory to MTX. Patients received intravenous TCZ (8 mg/kg) once every 4 weeks combined with MTX for 24 weeks. Metabolic parameters and sYKL-40 levels were measured before TCZ infusion at baseline, week 4, week 12, and week 24. Correlations were assessed by the Spearman's rank correlation analysis. RESULTS: A total of 91 non-diabetic RA patients were enrolled in this study. At week 24, we observed a significant elevation in body mass index (BMI), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels. In contrast, there was a significant decrease in TC/HDLC ratio. No apparent changes in insulin resistance were found. Additionally, we detected a significant reduction in sYKL-40 levels during the study. At week 24, changes in sYKL-40 levels showed a significant negative correlation (r = -0.334, p = 0.002) with changes in TC levels. CONCLUSION: The combined therapy of TCZ and MTX resulted in a significant increase in BMI and lipid levels, while an evident decrease in the TC/HDLC ratio and sYKL-40 levels in RA patients. Additionally, there was a significant correlation between the decrease in sYKL-40 levels and the increase in TC levels during treatment with TCZ and MTX. Key Points ⢠Lipid levels elevated significantly and sYKL-40 levels decreased obviously after therapy of TCZ combined with MTX in Chinese RA patients. ⢠There was a significant correlation between the increase in TC levels and the decrease in sYKL-40 levels during treatment with TCZ and MTX in RA patients.
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Anticorpos Monoclonais Humanizados , Antirreumáticos , Artrite Reumatoide , Proteína 1 Semelhante à Quitinase-3 , Metotrexato , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Proteína 1 Semelhante à Quitinase-3/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Metotrexato/uso terapêutico , Antirreumáticos/uso terapêutico , Adulto , Quimioterapia Combinada , Triglicerídeos/sangue , Índice de Massa Corporal , HDL-Colesterol/sangue , Idoso , Colesterol/sangue , China , População do Leste AsiáticoRESUMO
BACKGROUND: In radiotherapy, real-time tumor tracking can verify tumor position during beam delivery, guide the radiation beam to target the tumor, and reduce the chance of a geometric miss. Markerless kV x-ray image-based tumor tracking is challenging due to the low tumor visibility caused by tumor-obscuring structures. Developing a new method to enhance tumor visibility for real-time tumor tracking is essential. PURPOSE: To introduce a novel method for markerless kV image-based tracking of lung tumors via deep learning-based target decomposition. METHODS: We utilized a conditional Generative Adversarial Network (cGAN), known as Pix2Pix, to build a patient-specific model and generate the synthetic decomposed target image (sDTI) to enhance tumor visibility on the real-time kV projection images acquired by the onboard kV imager equipped on modern linear accelerators. We used 4DCT simulation images to generate the digitally reconstructed radiograph (DRR) and DTI image pairs for model training. We augmented the training dataset by randomly shifting the 4DCT in the superior-inferior, anterior-posterior, and left-right directions during the DRR and DTI generation process. We performed real-time 2D tumor tracking via template matching between the DTI generated from the CT simulation and the sDTI generated from the real-time kV projection images. We validated the proposed method using nine patients' datasets with implanted beacons near the tumor. RESULTS: The sDTI can effectively improve the image contrast around the lung tumors on the kV projection images for the nine patients. With the beacon motion as ground truth, the tracking errors were on average 0.8 ± 0.7 mm in the superior-inferior (SI) direction and 0.9 ± 0.8 mm in the in-plane left-right (IPLR) direction. The percentage of successful tracking, defined as a tracking error less than 2 mm in the SI direction, is 92.2% on the 4312 tested images. The patient-specific model took approximately 12 h to train. During testing, it took approximately 35 ms to generate one sDTI, and 13 ms to perform the tumor tracking using template matching. CONCLUSIONS: Our method offers the potential solution for nearly real-time markerless lung tumor tracking. It achieved a high level of accuracy and an impressive tracking rate. Further development of 3D lung tumor tracking is warranted.
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Aprendizado Profundo , Tomografia Computadorizada Quadridimensional , Processamento de Imagem Assistida por Computador , Neoplasias Pulmonares , Radioterapia Guiada por Imagem , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/diagnóstico por imagem , Humanos , Radioterapia Guiada por Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Tomografia Computadorizada Quadridimensional/métodosRESUMO
Objective.We report on paraspinal motion and the clinical implementation of our proprietary software that leverages Varian's intrafraction motion review (IMR) capability for quantitative tracking of the spine during paraspinal SBRT. The work is based on our prior development and analysis on phantoms.Approach.To address complexities in patient anatomy, digitally reconstructed radiographs (DRR's) that highlight only the spine or hardware were constructed as tracking reference. Moreover, a high-pass filter and first-pass coarse search were implemented to enhance registration accuracy and stability. For evaluation, 84 paraspinal SBRT patients with sites spanning across the entire vertebral column were enrolled with prescriptions ranging from 24 to 40 Gy in one to five fractions. Treatments were planned and delivered with 9 IMRT beams roughly equally distributed posteriorly. IMR was triggered every 200 or 500 MU for each beam. During treatment, the software grabbed the IMR image, registered it with the corresponding DRR, and displayed the motion result in near real-time on auto-pilot mode. Four independent experts completed offline manual registrations as ground truth for tracking accuracy evaluation.Main results.Our software detected ≥1.5 mm and ≥2 mm motions among 17.1% and 6.6% of 1371 patient images, respectively, in either lateral or longitudinal direction. In the validation set of 637 patient images, 91.9% of the tracking errors compared to manual registration fell within ±0.5 mm in either direction. Given a motion threshold of 2 mm, the software accomplished a 98.7% specificity and a 93.9% sensitivity in deciding whether to interrupt treatment for patient re-setup.Significance.Significant intrafractional motion exists in certain paraspinal SBRT patients, supporting the need for quantitative motion monitoring during treatment. Our improved software achieves high motion tracking accuracy clinically and provides reliable guidance for treatment intervention. It offers a practical solution to ensure accurate delivery of paraspinal SBRT on a conventional Linac platform.
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Radiocirurgia , Humanos , Radiocirurgia/métodos , Software , Movimento (Física) , Planejamento da Radioterapia Assistida por ComputadorRESUMO
OBJECTIVES: To explore the risk factors of early death in dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 antibody (anti-MDA5-DM). To explore the optimal treatment regimen for patients with anti-MDA5-DM. METHODS: Patients with newly onset anti-MDA5-DM from June 2018 to October 2021 in our centre were retrospectively reviewed for 6 months. Patients were divided into five groups based on initial treatments. The major outcome was mortality in 6 months. Secondary outcomes included remission and severe infection. RESULTS: A total of 214 patients were included in the study. During 6 month follow-up, 63 patients (30.14%) died, 112 patients (53.59%) achieved remission, 52 patients (24.88%) experienced serious infection and 5 patients (2.34%) were lost. Independent risk factors of mortality in the first 6 months after diagnosis were as follows: age> 53 years, skin ulcer, peripheral blood lymphocyte count (LYMP)≤ 0.6×109/L, lactate dehydrogenase (LDH) > 500 U/L, C reactive protein (CRP) > 5mg/L, anti-Ro52 antibody and ground-glass opacity (GGO) score> 2. On the contrary, prophylactic use of the compound sulfamethoxazole (SMZ Co) was independent protective factor. The five-category treatment was not an independent influencing factor of early death, but subgroup analysis found that patients with rapidly progressive interstitial lung disease (RPILD) responded better to a triple combination of high-dose glucocorticoids (GC), calcineurin inhibitors (CNI) and cyclophosphamide (CYC) or a triple combibation of GC, CNI and tofacitinib (TOF). CONCLUSIONS: Advanced age, skin ulcer, lymphopenia, anti-Ro52 antibody and higher levels of LDH, CRP and GGO score increase the risk of early death for MDA5-DM, while prophylactic use of SMZ Co is protective. Aggressive therapy with combined immunosuppressants may improve the short-term prognosis of anti-MDA5-DM with RPILD.
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Dermatomiosite , Úlcera Cutânea , Humanos , Pessoa de Meia-Idade , Dermatomiosite/complicações , Estudos Retrospectivos , Autoanticorpos , Helicase IFIH1 Induzida por Interferon , Prognóstico , Glucocorticoides/uso terapêutico , Úlcera Cutânea/complicaçõesRESUMO
Cancer has keeping the main threat to the health of human being. Its overall survival rate has shown rare substantial progress in spite of the improving diagnostic and treatment techniques for cancer in recent years. Indeed, such classic strategies for malignant tumor as surgery, radiation and chemotherapy have been developed and bring more hope to the patients, but still been accompanied by certain limitations, which include the challenge of managing large wound sizes, systemic toxic side effects, and harmful to the healthy tissues caused by imprecise alignment with tumors in radiotherapy. Furthermore, immunotherapy exhibits a limited therapeutic effect in advanced tumors which is reported only up to 25%-30%. The combination of nanomaterials and cancer treatment offers new hope for cancer patients, demonstrating strong potential in the field of medical research. Among the extensively utilized nanomaterials, calcium carbonate nanomaterials (CCNM) exhibit a broad spectrum of biomedical applications due to their abundant availability, cost-effectiveness, and exceptional safety profile. CCNM have the potential to elevate intracellular Ca2+ levels in tumor cells, trigger the mitochondrial damage and ultimately lead to tumor cell death. Moreover, compared with other types of nanomaterials, CCNM exhibit remarkable advantages as delivery systems owing to their high loading capacity, biocompatibility and biodegradability. The purpose of this review is to provide an overview of CCNM synthesis, focusing on summarizing its diverse roles in cancer treatment and the benefits and challenges associated with CCNM in cancer therapy. Hoping to present the significance of CCNM as for the clinical application, and summarize information for the design of CCNM and other types of nanomaterials in the future.
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BACKGROUND: X-ray image quality is critical for accurate intrafraction motion tracking in radiation therapy. PURPOSE: This study aims to develop a deep-learning algorithm to improve kV image contrast by decomposing the image into bony and soft tissue components. In particular, we designed a priori attention mechanism in the neural network framework for optimal decomposition. We show that a patient-specific prior cross-attention (PCAT) mechanism can boost the performance of kV image decomposition. We demonstrate its use in paraspinal SBRT motion tracking with online kV imaging. METHODS: Online 2D kV projections were acquired during paraspinal SBRT for patient motion monitoring. The patient-specific prior images were generated by randomly shifting and rotating spine-only DRR created from the setup CBCT, simulating potential motions. The latent features of the prior images were incorporated into the PCAT using multi-head cross attention. The neural network aimed to learn to selectively amplify the transmission of the projection image features that correlate with features of the priori. The PCAT network structure consisted of (1) a dual-branch generator that separates the spine and soft tissue component of the kV projection image and (2) a dual-function discriminator (DFD) that provides the realness score of the predicted images. For supervision, we used a loss combining mean absolute error loss, discriminator loss, perceptual loss, total variation, and mean squared error loss for soft tissues. The proposed PCAT approach was benchmarked against previous work using the ResNet generative adversarial network (ResNetGAN) without prior information. RESULTS: The trained PCAT had improved performance in effectively retaining and preserving the spine structure and texture information while suppressing the soft tissues from the kV projection images. The decomposed spine-only x-ray images had the submillimeter matching accuracy at all beam angles. The decomposed spine-only x-ray significantly reduced the maximum errors to 0.44 mm (<2 pixels) in comparison to 0.92 mm (â¼4 pixels) of ResNetGAN. The PCAT decomposed spine images also had higher PSNR and SSIM (p-value < 0.001). CONCLUSION: The PCAT selectively learned the important latent features by incorporating the patient-specific prior knowledge into the deep learning algorithm, significantly improving the robustness of the kV projection image decomposition, and leading to improved motion tracking accuracy in paraspinal SBRT.
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Algoritmos , Redes Neurais de Computação , Humanos , Movimento (Física)RESUMO
OBJECTIVE: Dermatomyositis (DM) positive with anti-melanoma differentiation-associated gene 5 (anti-MDA5-DM) is a systemic autoimmune disease with high mortality. This study aimed to explore the risk factors of death in anti-MDA5-DM and validate a prediction model for all-cause mortality in anti-MDA5-DM. METHOD: We conducted a retrospective study using a single-centre cohort of patients with newly onset anti-MDA5-DM from June 1, 2018 to August 31, 2021. Patients were divided into four groups according to baseline ground-glass opacity (GGO) score: Group A, GGO ≤ 1; Group B, 1 < GGO ≤ 2; Group C, 2 < GGO ≤ 3; Group D, GGO > 3. The primary outcome was death during the follow-up. Secondary outcomes included death within 3, 6, 12 months, severe infection, and remission during the first 12 months. RESULTS: A total of 200 patients were included in the study. Based on multivariable Cox regression, the prognostic factors at baseline were identified as CRP > 5 mg/L, serum ferritin (SF) > 600ng/ml, positive anti-Ro52 antibody, prophylactic use of compound sulfamethoxazole (SMZ Co), four-category GGO score: GGO ≤ 1, 1 < GGO ≤ 2, 2 < GGO ≤ 3, GGO > 3. The final mortality of four groups was 16.4, 22.2, 48.5, 92.0%, respectively. Compared with Group A, the Hazards Ratio (HR) of Group B was 1.408, (p = 0.408), HR of Group C was 3.433 (p = 0.005), HR of Group D was 4.376 (p = 0.001). CONCLUSIONS: GGO score is a reliable predictor for risk stratification in anti-MDA5-DM and may provide guidance for individualized managements of patients.
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Dermatomiosite , Doenças Pulmonares Intersticiais , Humanos , Dermatomiosite/tratamento farmacológico , Dermatomiosite/complicações , Estudos Retrospectivos , Estudos de Coortes , Autoanticorpos , Helicase IFIH1 Induzida por Interferon , PrognósticoRESUMO
BACKGROUND: Intrafraction motion monitoring in External Beam Radiation Therapy (EBRT) is usually accomplished by establishing a correlation between the tumor and the surrogates such as an external infrared reflector, implanted fiducial markers, or patient skin surface. These techniques either have unstable surrogate-tumor correlation or are invasive. Markerless real-time onboard imaging is a noninvasive alternative that directly images the target motion. However, the low target visibility due to overlapping tissues along the X-ray projection path makes tumor tracking challenging. PURPOSE: To enhance the target visibility in projection images, a patient-specific model was trained to synthesize the Target Specific Digitally Reconstructed Radiograph (TS-DRR). METHODS: Patient-specific models were built using a conditional Generative Adversarial Network (cGAN) to map the onboard projection images to TS-DRR. The standard Pix2Pix network was adopted as our cGAN model. We synthesized the TS-DRR based on the onboard projection images using phantom and patient studies for spine tumors and lung tumors. Using previously acquired CT images, we generated DRR and its corresponding TS-DRR to train the network. For data augmentation, random translations were applied to the CT volume when generating the training images. For the spine, separate models were trained for an anthropomorphic phantom and a patient treated with paraspinal stereotactic body radiation therapy (SBRT). For lung, separate models were trained for a phantom with a spherical tumor insert and a patient treated with free-breathing SBRT. The models were tested using Intrafraction Review Images (IMR) for the spine and CBCT projection images for the lung. The performance of the models was validated using phantom studies with known couch shifts for the spine and known tumor deformation for the lung. RESULTS: Both the patient and phantom studies showed that the proposed method can effectively enhance the target visibility of the projection images by mapping them into synthetic TS-DRR (sTS-DRR). For the spine phantom with known shifts of 1 mm, 2 mm, 3 mm, and 4 mm, the absolute mean errors for tumor tracking were 0.11 ± 0.05 mm in the x direction and 0.25 ± 0.08 mm in the y direction. For the lung phantom with known tumor motion of 1.8 mm, 5.8 mm, and 9 mm superiorly, the absolute mean errors for the registration between the sTS-DRR and ground truth are 0.1 ± 0.3 mm in both the x and y directions. Compared to the projection images, the sTS-DRR has increased the image correlation with the ground truth by around 83% and increased the structural similarity index measure with the ground truth by around 75% for the lung phantom. CONCLUSIONS: The sTS-DRR can greatly enhance the target visibility in the onboard projection images for both the spine and lung tumors. The proposed method could be used to improve the markerless tumor tracking accuracy for EBRT.
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Tomografia Computadorizada de Feixe Cônico , Neoplasias Pulmonares , Humanos , Tomografia Computadorizada de Feixe Cônico/métodos , Movimento (Física) , Pulmão , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Radiografia , Imagens de FantasmasRESUMO
OBJECTIVE: To investigate the immune response-related protein profiling in plasma of patients with idiopathic inflammatory myopathies (IIMs), especially in anti-MDA5+ dermatomyositis (DM). METHODS: A total of 166 IIM patients and 107 healthy controls (HCs) were enrolled in our study. Ninety-two plasma immune response-related proteins were detected by Olink proteomics in 36 IIM patients and 25 HCs. The expression of plasma KRT19 was validated in another 130 IIM patients, 82 HCs, and 55 other rheumatic diseases. RESULTS: A total of 46 differentially expressed proteins were detected, including 12 upregulated proteins and 34 downregulated proteins in IIM patients compared with HCs. Pathway analysis revealed lactoferrin danger signal response pathway, TLR4 signaling and tolerance, infection, and IL-10 signaling pathway were activated. The immune response-related protein profiling significantly altered in anti-MDA5+ DM patients, with LAMP3, HSD11B1, and KRT19 significantly increased, while SH2D1A, ITGA11, TRIM21, CD28, ITGB6, and HEXIM1 tremendously decreased. In addition, KRT19 was significantly increased in IIM patients, especially in anti-MDA5+ DM patients with the diagnostic value of a significant area under the ROC curve of 0.881. CONCLUSION: Immune response-related proteins are significantly altered in patients with anti-MDA5+ DM patients. KRT19 could be a potential biomarker for anti-MDA5+ DM patients. Key Points ⢠What is already known on this topic? Anti-MDA5+ DM is a distinctive subtype of IIM. Plasma immune response-related proteins panel needs to be investigated. ⢠What this study adds? Plasma protein profiling of immune response-related proteins significantly altered in patients with idiopathic inflammatory myopathies (IIM), especially in anti-MDA5+ DM patients. ⢠How this study might affect research, practice, or policy? KRT19 could be a potential biomarker in patients with anti-MDA5+ dermatomyositis.
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Dermatomiosite , Miosite , Humanos , Proteômica , Autoanticorpos , Biomarcadores , Helicase IFIH1 Induzida por Interferon , Estudos Retrospectivos , Fatores de Transcrição , Proteínas de Ligação a RNARESUMO
BACKGROUND: Alterations in oral microbiota in patients with systemic lupus erythematosus (SLE) is less evaluated. The aim of this study was to compare the characteristics of the oral microbiome in SLE patients and healthy controls, and construct an SLE classifier based on the oral microbiota. METHODS: We sequenced tongue-coating samples of individuals in treatment-naïve SLE (n = 182) and matched healthy controls (n = 280). We characterized the oral microbiome and constructed a microbial classifier in the derivation cohort and validated the results in the validation cohorts. Furthermore, the oral microbiome of posttreatment SLE (n = 73) was characterized. RESULTS: The oral microbial diversity of SLE was increased, and the microbial community was different between SLE and healthy controls. The genera Prevotella and Veillonella were enriched, while Streptococcus and Porphyromonas were reduced in SLE. In addition, an increase was noted in 27 predicted microbial functions, while a decrease was noted in 34 other functions. Thirty-nine operational taxonomy units (OTUs) were identified to be related with seven clinical indicators. Two OTUs were identified to construct a classifier, which yielded area under the curve values of 0.9166 (95% CI 0.8848-0.9483, p < 0.0001), 0.8422 (95% CI 0.7687-0.9157, p < 0.0001), and 0.8406 (95% CI 0.7677-0.9135, p < 0.0001) in the derivation, validation, and cross-regional validation groups, respectively. Moreover, as disease activity increased, Abiotrophia and Lactobacillales increased, while Phyllobacterium and unclassified Micrococcusaceae decreased. Finally, nine OTUs were selected to construct a classifier distinguishing posttreatment SLE patients from healthy controls, which achieved a diagnostic efficacy of 0.9942 (95% CI 0.9884-1, p < 0.0001). CONCLUSIONS: Our study comprehensively characterizes the oral microbiome of SLE and shows the potential of the oral microbiota as a non-invasive diagnostic biomarker in SLE.
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Lúpus Eritematoso Sistêmico , Microbiota , HumanosRESUMO
OBJECTIVES: To investigate the correlation of Behçet's disease (BD) with myelodysplastic syndrome (MDS) and identify the predictive risk factors in Chinese patients. METHODS: A retrospective study of BD associated with MDS (BD-MDS) patients from the First Affiliated Hospital of Zhengzhou University was conducted. RESULTS: Among 15 BD-MDS patients, 10 were females and 5 males. While 13 (86.7%) patients had abnormal karyotype, 11 patients with trisomy 8. 10 (66.7%) had gastrointestinal (GI) involvement. Compared with 60 general BD patients without MDS, the BD-MDS patients were significantly older. In addition, fever and GI involvement were more common in BD-MDS patients, whereas these patients had lower levels of leukocyte count, haemoglobin, and platelet count (p<0.05). Logistic regression analysis showed that GI involvement, low haemoglobin, and high ESR level were independently associated with the development of MDS in BD patients. BD-MDS patients with GI involvement (IBD-MDS) were usually much older and have more fever than IBD patients without MDS, as well as lower leukocyte count, haemoglobin level, platelet count, and higher erythrocyte sedimentation rate (ESR) and C-reactive protein levels (p<0.05). By comparison with 60 primary MDS patients without BD, the BD-MDS patients had more abnormal karyotypes and more trisomy 8 (p<0.05), while the distribution of 2016 WHO subtypes of MDS and IPSS-R categories were similar. CONCLUSIONS: Our findings suggest that cytogenetic abnormalities, especially trisomy 8, may play a role in the association of GI involvement, BD, and MDS. GI involvement, low haemoglobin, and high ESR level were independent predictors for MDS development in BD patients.
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Síndrome de Behçet , Doenças Inflamatórias Intestinais , Síndromes Mielodisplásicas , Masculino , Feminino , Humanos , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Estudos Retrospectivos , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Doenças Inflamatórias Intestinais/complicaçõesRESUMO
OBJECTIVES: Mortality of dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 antibody (anti-MDA5-DM) is alarming, especially during the first several months. Infection is an important cause of early death. As there are no reports regarding the effect of prophylactic use of compounded sulfamethoxazole (coSMZ; each tablet contains 400 mg of sulfamethoxazole and 80 mg of trimethoprim) in anti-MDA5-DM patients, we conducted this study to evaluate the efficacy of coSMZ in reducing the incidence of Pneumocystis jirovecii pneumonia (PJP). METHODS: Consecutive patients with new-onset anti-MDA5-DM from June 2018 to October 2021 in our centre were retrospectively reviewed for >12 months. They were divided into two groups-coSMZ and non-coSMZ-based on the initial use of prophylactic coSMZ. Mortality and the incidence of severe infection within 12 months were compared between two groups. RESULTS: Compared with the non-coSMZ group (n = 93), the coSMZ group (n = 121) had lower mortality (18.8% vs 51.1%; P < 0.001) and a lower incidence of PJP (6.8% vs 15.2%; P = 0.040) and fatal infection (16.1% vs 3.3%; P = 0.001) during the first 12 months from diagnosis. After adjusting for age, gender, disease duration, peripheral blood lymphocyte count, anti-MDA5 antibody titres, ground-glass opacity scores and treatments, an inverse association was revealed between the prophylactic use of coSMZ and incidence of PJP [adjusted odds ratio 0.299 (95% CI 0.102-0.878), P = 0.028]. CONCLUSION: Prophylactic use of coSMZ is an effective and safe way to improve the prognosis of anti-MDA5-DM patients by preventing the incidence of PJP.
Assuntos
Dermatomiosite , Humanos , Dermatomiosite/complicações , Sulfametoxazol/uso terapêutico , Estudos Retrospectivos , Helicase IFIH1 Induzida por Interferon , PrognósticoRESUMO
Objective. Motion tracking with simultaneous MV-kV imaging has distinct advantages over single kV systems. This research is a feasibility study of utilizing this technique for spine stereotactic body radiotherapy (SBRT) through phantom and patient studies.Approach. A clinical spine SBRT plan was developed using 6xFFF beams and nine sliding-window IMRT fields. The plan was delivered to a chest phantom on a linear accelerator. Simultaneous MV-kV image pairs were acquired during beam delivery. KV images were triggered at predefined intervals, and synthetic MV images showing enlarged MLC apertures were created by combining multiple raw MV frames with corrections for scattering and intensity variation. Digitally reconstructed radiograph (DRR) templates were generated using high-resolution CBCT reconstructions (isotropic voxel size (0.243 mm)3) as the reference for 2D-2D matching. 3D shifts were calculated from triangulation of kV-to-DRR and MV-to-DRR registrations. To evaluate tracking accuracy, detected shifts were compared to known phantom shifts as introduced before treatment. The patient study included a T-spine patient and an L-spine patient. Patient datasets were retrospectively analyzed to demonstrate the performance in clinical settings.Main results. The treatment plan was delivered to the phantom in five scenarios: no shift, 2 mm shift in one of the longitudinal, lateral and vertical directions, and 2 mm shift in all the three directions. The calculated 3D shifts agreed well with the actual couch shifts, and overall, the uncertainty of 3D detection is estimated to be 0.3 mm. The patient study revealed that with clinical patient image quality, the calculated 3D motion agreed with the post-treatment cone beam CT. It is feasible to automate both kV-to-DRR and MV-to-DRR registrations using a mutual information-based method, and the difference from manual registration is generally less than 0.3 mm.Significance. The MV-kV imaging-based markerless motion tracking technique was validated through a feasibility study. It is a step forward toward effective motion tracking and accurate delivery for spinal SBRT.
Assuntos
Radiocirurgia , Humanos , Radiocirurgia/métodos , Estudos Retrospectivos , Estudos de Viabilidade , Movimento (Física) , Imagens de Fantasmas , Planejamento da Radioterapia Assistida por Computador/métodosRESUMO
Autophagy is closely related to breast cancer and has the dual role of promoting and inhibiting the progression of breast cancer. In this study, we aimed to establish an autophagy-related gene signature for the prognosis of breast cancer. A gene signature composed of the eight most survival-relevant autophagy-associated genes was identified by least absolute shrinkage and selection operator (LASSO) regression analysis. A risk score was calculated based on the gene signature, which divided breast cancer patients into low- or high-risk groups and showed good and poor prognosis, respectively. The risk score displayed good prognostic performance in both the training cohort (TCGA, 1-10-year AUC > 0.63) and the validation cohort (GEO, 1-10-year AUC > 0.66). The multivariate Cox regression and stratified analysis revealed that the risk score was an independent prognostic factor for breast cancer patients. Moreover, the high-risk score was associated with higher infiltration of neutrophils and M2-polarized macrophages, and lower infiltration of resting memory CD4+ T cells, CD8+ T cells, and NK cells. Finally, the high-risk score was associated with myc target, glycolysis, and mTORC1 signaling. The risk score developed based on the autophagy-associated gene signature was an independent prognostic biomarker for breast cancer.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Linfócitos T CD8-Positivos , Prognóstico , Autofagia/genética , GlicóliseRESUMO
AIM: Emerging data have demonstrated that low-grade inflammation in osteoarthritis, a long-held degenerative disease. The inflamed synovium produces various cytokines that induce cartilage destruction and joint pain. A previous study showed that teriparatide, an FDA approved anti-osteoporotic drug, may enhance cartilage repair. Our study focuses on its role in OA synovitis. MATERIALS AND METHODS: Primary mouse articular chondrocytes were used to determine the most potent cytokines involved in OA inflammation and cartilage destruction. A destabilization of the medial meniscus mouse model was established to investigate the effect of teriparatide in OA, particularly, on synovial inflammation and cartilage degradation. RESULTS: In vitro experiments showed that TNF-α was the most potent inducer of cartilage matrix-degrading enzymes, and that teriparatide antagonized the TNF-α of effect. Consistently, articular cartilage samples from TNF-α transgenic mice contained more MMP-13 positive chondrocytes than those from wild type mice. In addition, more type II collagen was cleaved in human OA cartilage than in normal cartilage samples. CONCLUSIONS: Teriparatide can prevent synovitis and cartilage degradation by suppressing TNF-α mediated MMP-13 overexpression. Together with its chondroregenerative capability, teriparatide may be the first effective disease modifying osteoarthritis drug.
Assuntos
Cartilagem Articular , Osteoartrite , Sinovite , Humanos , Camundongos , Animais , Teriparatida/farmacologia , Teriparatida/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Cartilagem/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Condrócitos/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Modelos Animais de Doenças , Sinovite/tratamento farmacológico , Camundongos Transgênicos , Citocinas/metabolismo , Cartilagem Articular/metabolismoRESUMO
BACKGROUND: Lipid and glucose metabolism abnormalities are associated with nonalcoholic fatty liver disease (NAFLD). The triglyceride-glucose (TyG) index is a recently developed indicator that can identify individuals at risk for NAFLD. However, the applicability of the TyG index for identifying NAFLD in patients with type 2 diabetes mellitus (T2DM) is unclear. The aim of this study was to investigate the ability of the TyG index to identify individuals at risk for NAFLD in the T2DM population. METHODS: A total of 2280 participants with T2DM were recruited in this cross-sectional study. The TyG index was calculated, and NAFLD was diagnosed by ultrasonography. Binary logistic regression models were used to evaluate the association of the TyG index, glycemic parameters and lipid parameters with NAFLD. RESULTS: Logistic regression analysis showed that the TyG index was significantly associated with NAFLD in subjects with T2DM, the odds ratio (OR) were 3.27 (95% confidence interval [CI], 2.03-5.27; P < 0.001) for NAFLD in the highest TyG quartile after adjustment for known confounders. In stratified analysis, an elevated TyG index were more remarkably associated with NAFLD in younger patients (< 65 years; OR, 2.35; 95% CI, 1.83-3.02; P < 0.001), females (OR, 2.69; 95% CI, 1.67-4.32; P < 0.001), patients with BMI < 25 kg/m2 (OR, 2.80; 95% CI, 2.01-3.91; P < 0.0001), and with lower high-density lipoprotein cholesterol (< 1 mmol/L; OR, 2.76; 95% CI, 1.98-3.83; P < 0.001). CONCLUSION: The TyG index is significantly associated with NAFLD and shows superior ability for identify NAFLD risk compared with other lipid and glycemic parameters in T2DM.