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BACKGROUND: This was a single-arm, phase 2 clinical trial of Bavarian Nordic (BN)-Brachyury vaccine plus radiotherapy (RT) designed to determine the objective response rate (ORR), progression-free survival (PFS), and safety of the combination in chordoma. METHODS: A total of 29 adult patients with advanced chordoma were treated with two subcutaneous priming vaccine doses of modified vaccinia Ankara-Bavarian Nordic (MVA-BN)-Brachyury and one vaccine dose of fowlpox virus (FPV)-Brachyury before RT. After RT, booster vaccinations were given with FPV-Brachyury every 4 weeks for 4 doses, then every 12 weeks (week 110). A minimum RT dose of >8 Gy in one fraction for each target was required. Response was evaluated by modified Response Evaluation Criteria in Solid Tumors 1.1 (mRECIST), where only radiated lesions were considered targets, and by standard RECIST 1.1 in a subset of patients. RESULTS: Two of 26 evaluable patients experienced durable partial response (PR) (ORR of 7.7%; 90% confidence interval [CI], 2.6-20.8]) by mRECIST 1.1. A total of 21 patients (80.8%; 90% CI, 65.4-90.3) had stable disease, and three patients (11.5%; 90% CI, 4.7-25.6) had progressive disease as best response per mRECIST 1.1. Median PFS was not reached during the study. CONCLUSIONS: This trial confirms the safety of BN-Brachyury and RT. Although the study did not meet the predefined study goal of four responses in 29 patients, we did observe two PRs and a PFS of greater than 2 years. For a vaccine-based study in chordoma, an ultra-rare disease where response rates are low, a randomized study or novel trial designs may be required to confirm activity.
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Noninvasive tracking devices are widely used to monitor real-time posture. Yet significant potential exists to enhance postural control quantification through walking videos. This study advances computational science by integrating OpenPose with a Support Vector Machine (SVM) to perform highly accurate and robust postural analysis, marking a substantial improvement over traditional methods which often rely on invasive sensors. Utilizing OpenPose-based deep learning, we generated Dynamic Joint Nodes Plots (DJNP) and iso-block postural identity images for 35 young adults in controlled walking experiments. Through Temporal and Spatial Regression (TSR) models, key features were extracted for SVM classification, enabling the distinction between various walking behaviors. This approach resulted in an overall accuracy of 0.990 and a Kappa index of 0.985. Cutting points for the ratio of top angles (TAR) and the ratio of bottom angles (BAR) effectively differentiated between left and right skews with AUC values of 0.772 and 0.775, respectively. These results demonstrate the efficacy of integrating OpenPose with SVM, providing more precise, real-time analysis without invasive sensors. Future work will focus on expanding this method to a broader demographic, including individuals with gait abnormalities, to validate its effectiveness across diverse clinical conditions. Furthermore, we plan to explore the integration of alternative machine learning models, such as deep neural networks, enhancing the system's robustness and adaptability for complex dynamic environments. This research opens new avenues for clinical applications, particularly in rehabilitation and sports science, promising to revolutionize noninvasive postural analysis.
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Objective.A major challenge in treatment of tumors near skeletal muscle is defining the target volume for suspected tumor invasion into the muscle. This study develops a framework that generates radiation target volumes with muscle fiber orientation directly integrated into their definition. The framework is applied to nineteen sacral tumor patients with suspected infiltration into surrounding muscles.Approach.To compensate for the poor soft-tissue contrast of CT images, muscle fiber orientation is derived from cryo-images of two cadavers from the human visible project (VHP). The approach consists of (a) detecting image gradients in the cadaver images representative of muscle fibers, (b) mapping this information onto the patient image, and (c) embedding the muscle fiber orientation into an expansion method to generate patient-specific clinical target volumes (CTV). The validation tested the consistency of image gradient orientation across VHP subjects for the piriformis, gluteus maximus, paraspinal, gluteus medius, and gluteus minimus muscles. The model robustness was analyzed by comparing CTVs generated using different VHP subjects. The difference in shape between the new CTVs and standard CTV was analyzed for clinical impact.Main results.Good agreement was found between the image gradient orientation across VHP subjects, as the voxel-wise median cosine similarity was at least 0.86 (for the gluteus minimus) and up to 0.98 for the piriformis. The volume and surface similarity between the CTVs generating from different VHP subjects was on average at least 0.95 and 5.13 mm for the Dice Similarity Coefficient and the Hausdorff 95% Percentile Index, showing excellent robustness. Finally, compared to the standard CTV with different margins in muscle and non-muscle tissue, the new CTV margins are reduced in muscle tissue depending on the chosen clinical margins.Significance.This study implements a method to integrate muscle fiber orientation into the target volume without the need for additional imaging.
Subject(s)
Muscle Fibers, Skeletal , Humans , Radiotherapy Planning, Computer-Assisted/methods , Visible Human Projects , Tomography, X-Ray Computed , Male , Female , Image Processing, Computer-Assisted/methodsABSTRACT
Automatic classification of colon and lung cancer images is crucial for early detection and accurate diagnostics. However, there is room for improvement to enhance accuracy, ensuring better diagnostic precision. This study introduces two novel dense architectures (D1 and D2) and emphasizes their effectiveness in classifying colon and lung cancer from diverse images. It also highlights their resilience, efficiency, and superior performance across multiple datasets. These architectures were tested on various types of datasets, including NCT-CRC-HE-100K (set of 100,000 non-overlapping image patches from hematoxylin and eosin (H&E) stained histological images of human colorectal cancer (CRC) and normal tissue), CRC-VAL-HE-7K (set of 7180 image patches from N = 50 patients with colorectal adenocarcinoma, no overlap with patients in NCT-CRC-HE-100K), LC25000 (Lung and Colon Cancer Histopathological Image), and IQ-OTHNCCD (Iraq-Oncology Teaching Hospital/National Center for Cancer Diseases), showcasing their effectiveness in classifying colon and lung cancers from histopathological and Computed Tomography (CT) scan images. This underscores the multi-modal image classification capability of the proposed models. Moreover, the study addresses imbalanced datasets, particularly in CRC-VAL-HE-7K and IQ-OTHNCCD, with a specific focus on model resilience and robustness. To assess overall performance, the study conducted experiments in different scenarios. The D1 model achieved an impressive 99.80 % accuracy on the NCT-CRC-HE-100K dataset, with a Jaccard Index (J) of 0.8371, a Matthew's Correlation Coefficient (MCC) of 0.9073, a Cohen's Kappa (Kp) of 0.9057, and a Critical Success Index (CSI) of 0.8213. When subjected to 10-fold cross-validation on LC25000, the D1 model averaged (avg) 99.96 % accuracy (avg J, MCC, Kp, and CSI of 0.9993, 0.9987, 0.9853, and 0.9990), surpassing recent reported performances. Furthermore, the ensemble of D1 and D2 reached 93 % accuracy (J, MCC, Kp, and CSI of 0.7556, 0.8839, 0.8796, and 0.7140) on the IQ-OTHNCCD dataset, exceeding recent benchmarks and aligning with other reported results. Efficiency evaluations were conducted in various scenarios. For instance, training on only 10 % of LC25000 resulted in high accuracy rates of 99.19 % (J, MCC, Kp, and CSI of 0.9840, 0.9898, 0.9898, and 0.9837) (D1) and 99.30 % (J, MCC, Kp, and CSI of 0.9863, 0.9913, 0.9913, and 0.9861) (D2). In NCT-CRC-HE-100K, D2 achieved an impressive 99.53 % accuracy (J, MCC, Kp, and CSI of 0.9906, 0.9946, 0.9946, and 0.9906) with training on only 30 % of the dataset and testing on the remaining 70 %. When tested on CRC-VAL-HE-7K, D1 and D2 achieved 95 % accuracy (J, MCC, Kp, and CSI of 0.8845, 0.9455, 0.9452, and 0.8745) and 96 % accuracy (J, MCC, Kp, and CSI of 0.8926, 0.9504, 0.9503, and 0.8798), respectively, outperforming previously reported results and aligning closely with others. Lastly, training D2 on just 10 % of NCT-CRC-HE-100K and testing on CRC-VAL-HE-7K resulted in significant outperformance of InceptionV3, Xception, and DenseNet201 benchmarks, achieving an accuracy rate of 82.98 % (J, MCC, Kp, and CSI of 0.7227, 0.8095, 0.8081, and 0.6671). Finally, using explainable AI algorithms such as Grad-CAM, Grad-CAM++, Score-CAM, and Faster Score-CAM, along with their emphasized versions, we visualized the features from the last layer of DenseNet201 for histopathological as well as CT-scan image samples. The proposed dense models, with their multi-modality, robustness, and efficiency in cancer image classification, hold the promise of significant advancements in medical diagnostics. They have the potential to revolutionize early cancer detection and improve healthcare accessibility worldwide.
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Background/purpose: Local anesthesia (LA) training is an essential clinical skill in dental education. However, the traditional teaching method of student-to-student injection has ethical concerns. This study investigated whether a flipped classroom (FC) teaching model with instructional videos improves students' skills in administering LA. Materials and methods: Fourth-year dental students in 2017 (traditional teaching, n = 70) and 2018 (FC model, n = 79) were assessed for their ability to perform an inferior alveolar nerve block and lingual nerve block. The FC group watched pre-recorded videos prior to a hands-on training session. Skills were evaluated using a 24-item checklist converted to letter grades. Perceptions of the FC approach were also surveyed. Results: The FC group showed statistically significantly higher final grades than the traditional teaching group (P < 0.05). Most FC students agreed that the videos improved clarity and learning objectives. Conclusion: The FC teaching model with procedural video instruction improved skills and confidence in administering LA over traditional teaching methods. Videos can be a beneficial supplement in pre-clinical dental training.
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Osteoarthritis (OA) is a persistent inflammatory disease, and long-term clinical treatment often leads to side effects. In this study, we evaluated pterostilbene (PT), a natural anti-inflammatory substance, for its protective effects and safety during prolonged use on OA. Results showed that PT alleviated the loss of chondrocytes and widened the narrow joint space in an octacalcium phosphate (OCP)-induced OA mouse model (n = 3). In vitro experiments demonstrate that PT reduced NLRP3 inflammation activation (relative protein expression: C: 1 ± 0.09, lipopolysaccharide (LPS): 1.14 ± 0.07, PT: 0.91 ± 0.07, LPS + PT: 0.68 ± 0.04) and the release of inflammatory cytokines through NF-κB signaling inactivation (relative protein expression: C: 1 ± 0.03, LPS: 3.49 ± 0.02, PT: 0.66 ± 0.08, LPS + PT: 2.78 ± 0.05), ultimately preventing cartilage catabolism. Interestingly, PT also altered gut microbiota by reducing inflammation-associated flora and increasing the abundance of healthy bacteria in OA groups. Collectively, these results suggest that the PT can be considered as a protective strategy for OA.
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The unique physical and biological characteristics of proton and carbon ions allow for improved sparing of normal tissues, decreased integral dose to the body, and increased biological effect through high linear energy transfer. These properties are particularly useful for sarcomas given their histology, wide array of locations, and age of diagnosis. This review summarizes the literature and describes the clinical situations in which these heavy particles have advantages for treating sarcomas.
Subject(s)
Heavy Ion Radiotherapy , Proton Therapy , Sarcoma , Humans , Protons , Sarcoma/radiotherapyABSTRACT
BACKGROUND: Accurate gross tumor volume (GTV) delineation is a critical step in radiation therapy treatment planning. However, it is reader dependent and thus susceptible to intra- and inter-reader variability. GTV delineation of soft tissue sarcoma (STS) often relies on CT and MR images. PURPOSE: This study investigates the potential role of 18F-FDG PET in reducing intra- and inter-reader variability thereby improving reproducibility of GTV delineation in STS, without incurring additional costs or radiation exposure. MATERIALS AND METHODS: Three readers performed independent GTV delineation of 61 patients with STS using first CT and MR followed by CT, MR, and 18F-FDG PET images. Each reader performed a total of six delineation trials, three trials per imaging modality group. Dice Similarity Coefficient (DSC) score and Hausdorff distance (HD) were used to assess both intra- and inter-reader variability using generated simultaneous truth and performance level estimation (STAPLE) GTVs as ground truth. Statistical analysis was performed using a Wilcoxon signed-ranked test. RESULTS: There was a statistically significant decrease in both intra- and inter-reader variability in GTV delineation using CT, MR 18F-FDG PET images vs. CT and MR images. This was translated by an increase in the DSC score and a decrease in the HD for GTVs drawn from CT, MR and 18F-FDG PET images vs. GTVs drawn from CT and MR for all readers and across all three trials. CONCLUSION: Incorporation of 18F-FDG PET into CT and MR images decreased intra- and inter-reader variability and subsequently increased reproducibility of GTV delineation in STS.
Subject(s)
Fluorodeoxyglucose F18 , Magnetic Resonance Imaging , Positron-Emission Tomography , Sarcoma , Tumor Burden , Humans , Sarcoma/diagnostic imaging , Sarcoma/pathology , Sarcoma/radiotherapy , Positron-Emission Tomography/methods , Female , Male , Magnetic Resonance Imaging/methods , Middle Aged , Radiopharmaceuticals , Observer Variation , Adult , Aged , Reproducibility of Results , Tomography, X-Ray Computed/methods , Soft Tissue Neoplasms/diagnostic imaging , Soft Tissue Neoplasms/pathology , Soft Tissue Neoplasms/radiotherapy , Radiotherapy Planning, Computer-Assisted/methodsABSTRACT
Background/purpose: Though the gold standard method for mandible reconstruction of the defect from segmental mandibulectomy is by osseous flap or graft, using reconstruction plates is still indicated in some cases. Traditionally, the plate is bended immediately after the segmental mandibulectomy by freehand. However, it's difficult to fit well to the original position of mandible, which may result in more complications. This study therefore aimed to investigate whether using prebent plates on computer-aided 3D printing models could reduce the complication rate. Materials and methods: Patients who received mandible reconstruction by reconstruction plate from 2018 to 2022 were enrolled and evaluated in this study. The data, including demographics, indications for surgery, pre-existed preoperative and postoperative therapies, classification of defects, and postoperative outcomes were collected and analyzed. Results: A total of 52 patients were enrolled in our study. The prebent group exhibited a significantly lower complication rate than that of the immediately bent group (P = 0.012). Other risk factors of plate complications included postoperative adjuvant radiotherapy (P = 0.017) and previous surgery (P = 0.047). The complication-free survival rate was also better in the prebent group in a 3-year follow-up period (P = 0.012). Conclusion: Prebent plates on computer-aided printing models proved to be an effective approach to reduce the complications for mandibular reconstruction in segmental mandibulectomy.
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Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell-specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca2+ handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. Panx3 deficiency was associated with increased expression of the gene encoding the H2O2-producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H2O2-induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and in blood pressure seen in mice with endothelial Panx3 deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.
Subject(s)
Hypertension , Transcription Factors , Animals , Humans , Mice , Cell Differentiation , Cell Proliferation/physiology , Connexins/metabolism , Hydrogen Peroxide/pharmacology , Obesity , Oxidative Stress , Proto-Oncogene Proteins c-bcl-6/metabolism , Transcription Factors/metabolismABSTRACT
Crosslinking plays an important role in collagen-based tissues since it affects mechanical behavior and tissue metabolism. Aging and diabetes affect the type and density of crosslinking, effectively altering tissue properties. However, most studies focus on these effects under large stress rather than daily activities. We focus on the deformation mechanisms and structural change at the binding sites for integrins, proteoglycans, and collagenase in collagen fibrils using a fully atomistic model. We show that high-connectivity enzymatic crosslinking (our "HC" model, representing normal tissues) and advanced-glycation end-products (our "Glucosepane" model, which increase in diabetes) result in uniform deformation under daily activity, but low-connectivity enzymatic crosslinking (our "LC" model, representing aging tissues) does not. In particular, the HC model displays more sliding, which may explain the ability of healthy tissues to absorb more strain energy. In contrast, AGEs induce instability in the structures near the binding sites, which would affect the tissue metabolism of the collagen molecule. Our results provide important insights into the molecular mechanisms of collagen and a possible explanation for the role of crosslinking in tissues undergoing daily activity.
Subject(s)
Diabetes Mellitus , Humans , Diabetes Mellitus/metabolism , Glycation End Products, Advanced/metabolism , Extracellular Matrix/metabolism , Collagen/chemistry , Collagenases/metabolismABSTRACT
PURPOSE: This study investigated the impact of different levels of COVID-19 social restrictions (social distancing in 2020, large-scale home confinement in 2021) on myopia prevalence and behaviours in a preschool population with school-based eyecare programme. METHODS: Repeated cross-sectional surveys were conducted between August and December in 2019, 2020 and 2021. Children aged 5-6 years received ocular examinations, and questionnaires were answered by caregivers before the day of the examination. The main outcome measures were the changes in after-school time spent on homework, screen-based devices and outdoors. Secondary outcome was the change in myopia prevalence (spherical equivalent [SE] ≤ -0.5 D in either eye after cycloplegia). RESULTS: A total of 9997 preschoolers were included in the analysis. Under tighter restrictions, more preschoolers spent ≥1 h/day on screen-based devices (42.8% in 2019, 45.2% in 2020, 48.9% in 2021, p < 0.001), and fewer preschoolers spent ≥30 min/day on after-school outdoor activities (49.5% in 2019, 46.0% in 2020, 41.0% in 2021, p < 0.001) on weekdays. A similar trend was found on weekends. While more preschoolers spent ≥2 h/day on screen-based devices (35.3% in 2019, 38.5% in 2020, 43.0% in 2021, p < 0.001), fewer preschoolers spent ≥2 h/day on outdoor activities (41.7% in 2019, 41.7% in 2020, 34.0% in 2021, p < 0.001). The mean SE and myopia prevalence were stable (9.1% in 2019, 10.3% in 2020, 9.4% in 2021, p = 0.707). CONCLUSION: Our study showed dose-dependent effect of social restrictions on near-work and outdoor behaviours at home. The prevalence of myopia did not increase significantly with short-term cessation of school-based eyecare programmes.
Subject(s)
COVID-19 , Myopia , Child, Preschool , Child , Humans , Prevalence , Cross-Sectional Studies , COVID-19/epidemiology , COVID-19/prevention & control , Refraction, Ocular , Myopia/epidemiology , Surveys and QuestionnairesABSTRACT
Muscular dystrophy (MD) is a genetic disorder that causes progressive muscle weakness and degeneration. Limb-girdle muscular dystrophy (LGMD) is a type of MD that mainly causes muscle atrophy within the shoulder and pelvic girdles. LGMD is classified into autosomal dominant (LGMD-D) and autosomal recessive (LGMD-R) inheritance patterns. Mutations in the Dysferlin gene (DYSF) are common causes of LGMD-R. However, genetic screening of DYSF mutations is rare in Taiwan. Herein, we identified a novel c.2867_2871del ACCAG deletion and a previously reported c.937+1G>A mutation in DYSF from a Taiwanese family with LGMD. The primary symptoms of both siblings were difficulty climbing stairs, walking on the toes, and gradually worsening weakness in the proximal muscles and increased creatine kinase level. Through pedigree analysis and sequencing, two siblings from this family were found to have compound heterozygous DYSF mutations (c. 937+1G>A and c. 2867_2871del ACCAG) within the separated alleles. These mutations induced early stop codons; if translated, truncated DYSF proteins will be expressed. Or, the mRNA products of these two mutations will merit the nonsense-mediated decay, might result in no dysferlin protein expressed. To our knowledge, this is the first report of a novel c.2867_2871del ACCAG deletion in DYSF. Further research is required to examine the effects of the novel DYSF mutation in Taiwanese patients with LGMD.
Subject(s)
Muscular Dystrophies, Limb-Girdle , Humans , Dysferlin/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Mutation , Muscular Atrophy , Inheritance PatternsABSTRACT
Nasopharyngeal carcinoma (NPC) is an epithelial cancer originating in the nasopharynx epithelium. Nevertheless, annotating pathology slides remains a bottleneck in the development of AI-driven pathology models and applications. In the present study, we aim to demonstrate the feasibility of using immunohistochemistry (IHC) for annotation by non-pathologists and to develop an efficient model for distinguishing NPC without the time-consuming involvement of pathologists. For this study, we gathered NPC slides from 251 different patients, comprising hematoxylin and eosin (H&E) slides, pan-cytokeratin (Pan-CK) IHC slides, and Epstein-Barr virus-encoded small RNA (EBER) slides. The annotation of NPC regions in the H&E slides was carried out by a non-pathologist trainee who had access to corresponding Pan-CK IHC slides, both with and without EBER slides. The training process utilized ResNeXt, a deep neural network featuring a residual and inception architecture. In the validation set, NPC exhibited an AUC of 0.896, with a sensitivity of 0.919 and a specificity of 0.878. This study represents a significant breakthrough: the successful application of deep convolutional neural networks to identify NPC without the need for expert pathologist annotations. Our results underscore the potential of laboratory techniques to substantially reduce the workload of pathologists.
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Despite the risk of complications, high dose radiation therapy is increasingly utilized in the management of selected bone malignancies. In this study, we investigate the impact of moderate to high dose radiation (over 50 Gy) on bone metabolism and structure. Between 2015 and 2018, patients with a primary malignant bone tumor of the sacrum that were either treated with high dose definitive radiation only or a combination of moderate to high dose radiation and surgery were prospectively enrolled at a single institution. Quantitative CTs were performed before and after radiation to determine changes in volumetric bone mineral density (BMD) of the irradiated and non-irradiated spine. Bone histomorphometry was performed on biopsies of the irradiated sacrum and the non-irradiated iliac crest of surgical patients using a quadruple tetracycline labeling protocol. In total, 9 patients were enrolled. Two patients received radiation only (median dose 78.3 Gy) and 7 patients received a combination of preoperative radiation (median dose 50.4 Gy), followed by surgery. Volumetric BMD of the non-irradiated lumbar spine did not change significantly after radiation, while the BMD of the irradiated sacrum did (pre-radiation median: 108.0 mg/cm3 (IQR 91.8-167.1); post-radiation median: 75.3 mg/cm3 (IQR 57.1-110.2); p = 0.010). The cancellous bone of the non-irradiated iliac crest had a stable bone formation rate, while the irradiated sacrum showed a significant decrease in bone formation rate [pre-radiation median: 0.005 mm3/mm2/year (IQR 0.003-0.009), post-radiation median: 0.001 mm3/mm2/year (IQR 0.001-0.001); p = 0.043]. Similar effects were seen in the cancellous and endocortical envelopes. This pilot study shows a decrease of volumetric BMD and bone formation rate after high-dose radiation therapy. Further studies with larger cohorts and other endpoints are needed to get more insight into the effect of radiation on bone. Level of evidence: IV.
Subject(s)
Bone Density , Sacrum , Humans , Pilot Projects , Sacrum/surgery , Lumbar Vertebrae , IliumABSTRACT
Lung ischemia-reperfusion injury (IRI), characterized by inflammation, vascular permeability, and lung edema, is the major cause of primary graft dysfunction after lung transplantation. Here, we investigated the cellular mechanisms underlying lung IR-induced activation of endothelial TRPV4 channels, which play a central role in lung edema and dysfunction after IR. In a left lung hilar-ligation model of IRI in mice, we found that lung IRI increased the efflux of ATP through pannexin 1 (Panx1) channels at the endothelial cell (EC) membrane. Elevated extracellular ATP activated Ca2+ influx through endothelial TRPV4 channels downstream of purinergic P2Y2 receptor (P2Y2R) signaling. P2Y2R-dependent activation of TRPV4 channels was also observed in human and mouse pulmonary microvascular endothelium in ex vivo and in vitro models of IR. Endothelium-specific deletion of P2Y2R, TRPV4, or Panx1 in mice substantially prevented lung IRI-induced activation of endothelial TRPV4 channels and lung edema, inflammation, and dysfunction. These results identify endothelial P2Y2R as a mediator of the pathological sequelae of IRI in the lung and show that disruption of the endothelial Panx1-P2Y2R-TRPV4 signaling pathway could be a promising therapeutic strategy for preventing lung IRI after transplantation.
Subject(s)
Reperfusion Injury , TRPV Cation Channels , Humans , Animals , Mice , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism , Receptors, Purinergic P2Y2/genetics , Receptors, Purinergic P2Y2/metabolism , Lung/metabolism , Reperfusion Injury/metabolism , Endothelial Cells/metabolism , Inflammation/metabolism , Adenosine Triphosphate/metabolism , Edema/metabolism , Edema/pathology , Nerve Tissue Proteins/metabolism , Connexins/genetics , Connexins/metabolismABSTRACT
An increase in skin-related autoimmune disorders has been reported as an adverse effect of coronavirus disease 2019 (COVID-19) vaccines. We present the case of a 90-year-old Taiwanese female who was newly diagnosed with anti-transcription intermediary factor 1-gamma (anti-TIF1-γ)-positive dermatomyositis (DM) after receiving a second dose of the AstraZeneca COVID-19 vaccine. Under treatment with prednisolone and monoclonal antibody therapy of abatacept, her skin lesions improved, and her muscle power increased. The serum creatinine phosphokinase level decreased from 4858 to 220 U/L, and the anti-TIF1-γ antibody titer decreased from 202 to 99. Flow cytometry data showed an increase in T cells, while NK cells, B cells (CD19), and plasma blasts all decreased. These findings suggest that standard DM treatment might be beneficial to patients with COVID-19 vaccine-induced DM.