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关键词： lung transplantation   ex vivo lung perfusion   cell-free DNA   primary graft dysfunction   MOLECULAR-PATTERNS   DAMAGE  

摘要： Background: Cell-free DNA (cfDNA), such as mitochondrial DNA (mtDNA) and nuclear DNA (nuDNA), are known to be released from injured cells and as such have been explored as biomarkers for tissue injury in different clinical settings. Ex vivo lung perfusion (EVLP) has been developed as an effective technique for marginal donor lung functional assessment. We hypothesized that the level of cfDNA in EVLP perfusate may reflect tissue injury and thus can be developed as a biomarker to quantify the degree of donor lung injury or predict the development of primary graft dysfunction (PGD) after lung transplantation (LTx). Methods: The perfusate from 62 donor lungs transplanted at our institution between May 2010 and December 2015 was sampled for cfDNA at 1 and 4 hours of perfusion. Sequences of genes encoding nicotinamide adenine dinucleotide dehydrogenase 1 (NADH-1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were used to represent mtDNA and nuDNA, respectively. Levels were quantified by real-time polymerase chain reaction and correlated with clinical outcome after LTx. Results: In our entire cohort, 14 patients developed PGD grade 3 (PGD3) within 72 hours after LTx. The non-PGD group included 48 patients (PGD0-1). Concentrations of mtDNA in the perfusate of the PGD3 group were significantly higher than those in non-PGD group at 1 hour of EVLP (1874 +/- 844 vs 1259 +/- 885 copies/mu L; P = .011). The perfusate of the PGD3 group had significantly higher levels of nuDNA compared with the non-PGD group at both 1 hour (1498 +/- 1895 vs 675 +/- 391 copies/mu L; P = .008) and 4 hours (4521 +/- 5810 vs 1764 +/- 1494 copies/mu L; P = .001). In donation after cardiac death (DCD) cases, mtDNA levels were significantly higher in the PGD3 group compared with the non-PGD group at 1 hour of EVLP (2060 +/- 997 vs 1184 +/- 782 copies/mu L; P = .040), and the levels of nuDNA were significantly higher in the PGD3 group compared with the non-PGD group at both 1 hour (1021 +/- 495 vs 6

关键词： Sinonasal   Lymphoma   Squamous cell carcinoma   Magnetic resonance imaging   Radiomics   APPARENT DIFFUSION-COEFFICIENTS   MALIGNANT-LYMPHOMA   TEXTURE ANALYSIS   NECK-CANCER   HEAD   PARAMETERS   DIAGNOSIS   CT  

摘要： Purpose To develop and validate an MRI-based radiomics model in differentiation between sinonasal primary lymphomas and squamous cell carcinomas (SCCs). Materials and methods One-hundred-and-fifty-four patients were enrolled (74 individuals with SCCs and 80 with lymphomas). After feature analysis and feature selection with variance threshold and least absolute shrinkage and selection operator (LASSO) methods, an MRI-based radiomics model with the support vector machine (SVM) classifier was constructed in differentiation between lymphomas and SCCs. Areas under the receiver operating characteristic curves (AUCs) of the MRI-based radiomics model were compared with those of radiologists using Delong test. Results Five features (T1 original shape Compactness2, T1 wavelet-HHH first-order Total Energy, T2 wavelet-HLH GLCM Informational Measure of Correlation1, T1 wavelet-LHL GLCM Inverse Variance and T1 square GLRLM Long Run Low Gray Level Emphasis) were finally selected in the radiomics model. The AUC values in differentiation between lymphomas and SCCs were 0.94 for the training dataset and 0.85 for the validation dataset, respectively. For all the patient datasets, the AUC values of radiomics model, readers 1, 2 and 3 were 0.92, 0.76, 0.77 and 0.80, respectively. For the validation datasets, no significant difference was found between the AUCs of the radiomics model and those of the three radiologist (P = 0.459, 0.469, 0.738 for radiologist 1, 2 and 3, respectively). Conclusion An MRI-based radiomics model can help to differentiate sinonasal lymphomas from SCCs with high accuracy.

关键词： SARS-CoV-2   Antivirals   Primary human airway epithelial cells   Remdesivir   GS-441524   EIDD-1931   COMMON   VIRUS   DRUGS  

摘要： There are, besides remdesivir, no approved antivirals for the treatment of SARS-CoV-2 infections. To aid in the search for antivirals against this virus, we explored the use of human tracheal airway epithelial cells (HtAEC) and human small airway epithelial cells (HsAEC) grown at the air-liquid interface (ALI). These cultures were infected at the apical side with one of two different SARS-CoV-2 isolates. Each virus was shown to replicate to high titers for extended periods of time (at least 8 days) and, in particular an isolate with the D614G in the spike (S) protein did so more efficiently at 35 degrees C than 37 degrees C. The effect of a selected panel of reference drugs that were added to the culture medium at the basolateral side of the system was explored. Remdesivir, GS-441524 (the parent nucleoside of remdesivir), EIDD-1931 (the parent nucleoside of molnupiravir) and IFN (beta 1 and lambda 1) all resulted in dose-dependent inhibition of viral RNA and infectious virus titers collected at the apical side. However, AT-511 (the free base form of AT-527 currently in clinical testing) failed to inhibit viral replication in these in vitro primary cell models. Together, these results provide a reference for further studies aimed at selecting SARS-CoV-2 inhibitors for further preclinical and clinical development.

关键词： Prebiotics   Crohn's disease   Microbiota   Pre-disease   First-degree relative   Prevention   GASTROINTESTINAL PH PROFILES   INTESTINAL BARRIER FUNCTION   BUTYRATE-PRODUCING BACTERIA   INTRALUMINAL PH   RISK   OLIGOFRUCTOSE   BIFIDOBACTERIA   PERMEABILITY   PATHOGENESIS   METAANALYSIS  

摘要： Background & aims: Siblings of people with Crohn's disease (CD) share aspects of the disease phenotype (raised faecal calprotectin, altered microbiota), which are markers of risk for their own development of CD. The aim was to determine whether supplementation with prebiotic oligofructose/inulin induces a prebiotic response and impacts the risk phenotype in CD patients and siblings. Methods: Patients with inactive CD (n = 19, CD activity index <150) and 12 of their unaffected siblings (with calprotectin >50 mg/g) ingested oligofructose/inulin (15 g/day) for three weeks. Faecal microbiota (qPCR), intestinal permeability (lactulose-rhamnose test), blood T cells (flow-cytometry) and calprotectin (ELISA) were measured at baseline and follow-up. Results: Following oligofructose/inulin, calprotectin did not significantly change in patients (baseline mean 537 SD 535 mg/g; follow-up mean 974 SD 1318 mg/g, p = 0.08) or siblings (baseline mean 73 SD 90 mg/g: follow up mean 58 SD 72 mg/g, p = 0.62). Faecal Bifidobacteria and Bifidobacterium longum increased in patients and siblings; Bifidobacterium adolescentis and Roseburia spp. increased only in siblings. Compared with patients, siblings had a greater magnitude change in Bifidobacteria (+14.6% vs +0.4%, p = 0.028), B. adolescentis (+1.1% vs 0.0% p = 0.006) and Roseburia spp. (+1.5% vs -0.1% p = 0.004). Intestinal permeability decreased significantly in patients after oligofructose/inulin to a level that was similar to siblings. Blood T cell abundance reduced in siblings but not patients following oligofructose/inulin. Conclusions: Oligofructose/inulin supplementation did not significantly impact calprotectin, but the prebiotic effect was more marked in healthy siblings compared with patients with inactive CD and was associated with alterations in other CD risk markers. Future research should focus on dietary intervention, including with prebiotics, in the primary prevention of CD. (c) 2021 Elsevier Ltd and European Society f

关键词： Synchronous   Metachronous   Lung cancer   Follow-up   Surgery   Guidelines   PULMONARY RADIOFREQUENCY ABLATION   FORTHCOMING 8TH EDITION   DOSE COMPUTED-TOMOGRAPHY   PROJECT BACKGROUND DATA   LYMPH-NODE DISSECTION   LEFT UPPER LOBECTOMY   LONG-TERM OUTCOMES   SURGICAL-TREATMENT   COMPLETION PNEUMONECTOMY   FOLLOW-UP  

摘要： Multiple lung cancers can be found simultaneously, with incidence ranging from 1% to 8%. Documentation of more than 1 pulmonary lesion can be challenging, because these solid, ground-glass, or mixed-density tumors may represent multicentric malignant disease or intrapulmonary metastases. If mediastinal nodal and distant deposits are excluded, surgery should be contemplated. After surgical treatment of lung cancer, patients should be followed closely for an undetermined period of time. Good clinical judgment is of outmost importance in deciding which individuals will benefit from those surgical interventions and which are candidates for alternate therapies. Every case should be discussed in a multidisciplinary meeting.

关键词： Endothelial-to-mesenchymal transition   Endothelial cells   Bone morphogenic protein-7   Transforming growth factor beta   Systemic sclerosis   PULMONARY-FIBROSIS   COLLAGEN-SYNTHESIS   SIGNALING PATHWAY   IN-VIVO   PATHOGENESIS   ACTIVATION   PHENOTYPE   ENDOMT  

摘要： Background: Systemic sclerosis (SSc) is an autoimmune inflammatory and vascular disorder that causes tissue fibrosis of the skin and internal organs. Endothelial-to-mesenchymal transition (EndoMT) has been considered an important mechanism in the pathogenesis of vascular remodeling in SSc. Recent studies suggested that bone morphogenic protein 7 (BMP-7) has anti-fibrotic effects in several fibrotic diseases. Objectives: To investigate the mechanism of BMP-7 in inhibiting TGF-beta-induced EndoMT in systemic sclerosis (SSc). Methods: Skin tissues of both healthy controls and SSc patients were detected the distribution of BMP-7. TGF-beta was applied to induce the EndoMT model of human umbilical vein endothelial cells (HUVECs), and bleomycin was used to established the SSc mouse model. After treatment of BMP-7, the protein levels of endothelial specific markers, mesenchymal cell products, transcription factors and Akt signal pathway were examined by western blotting, immunofluorescence or immunohistochemistry both in vivo and in vitro. Results: The expression of BMP-7 was decreased in the basal layer of epidermis and dermis of SSc patients. EndoMT in TGF-beta-treated HUVECs and skins of SSc mouse model were markedly attenuated after treatment with rh-BMP-7. Moreover, Akt/mTOR/p70S6K phosphorylation was involved in EndoMT and BMP-7 suppressed TGF-beta- or bleomycin-induced theses phosphorylation in HUVECs or SSc mouse model. Conclusion: BMP-7 reduced the production of TGF-beta-induced EndoMT in HUVECs and SSc mouse model through Akt/mTOR/p70S6K signaling pathway. These findings suggested that BMP-7 could be employed as a promising antifibrotic therapy for SSc. (c) 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

关键词： SPIKE GLYCOPROTEIN   PHYLOGENETIC ANALYSIS   RESPIRATORY-TRACT   IMMUNE-RESPONSES   CORONAVIRUS   PROTECTION   CYTOKINE   PATHOGENICITY   INNATE   RECEPTORS  

摘要： Infectious bronchitis virus (IBV), an avian coronavirus, is highly contagious. Chickens with IBV infection develop acute pathogenesis in multiple organs, including the respiratory and urogenital tracts. Frequent recombination in the spike (S) glycoprotein gene has made vaccine strategies ineffective. To understand IBV pathogenesis, we analyzed the genetic distance between Korean IBV isolates and other coronaviruses, including SARS-CoV-2. To obtain comprehensive information about early immune responses such as innate cytokine production and associated immune regulation during IBV infection, we infected primary chicken embryonic kidney cells and performed transcriptome analysis. We observed that the functional pathways of innate immunity are regulated and confirmed expression of genes that coordinate early immune responses. Understanding the immune profile of the host cell may assist in vaccine development.

关键词： IL-35   Immunosuppression   IL-15R alpha   Neutrophil   Grass carp   INTERLEUKIN-2-RECEPTOR GAMMA-CHAIN   CONTRASTING ROLES   LYMPHOCYTES IMPLICATIONS   EXTRACELLULAR TRAPS   RECEPTOR-ALPHA   BETA-CHAIN   B-CELLS   IL-15   PROLIFERATION   CYTOKINE  

摘要： IL-35 plays a key role in regulatory T (Treg) and regulatory B (Breg) cell functions in mammals. CD25 has been demonstrated as one of the markers of Treg cells, and CD19(+)CD25(hi)CD71(hi) cells have been verified as a type of Breg cells in humans. These results indicate that there is a close relationship between IL-35 and CD25(+) cells. In mammals, CD25 (alias IL-2R alpha) has been identified as having high affinity and specificity for IL-2 binding, and is closely linked and structurally related to IL-15R alpha, which having high affinity for IL-15 binding. In teleost, IL15R alpha can bind to both IL-2 and IL-15, with higher affinity to IL-15 than IL-2, and has been termed a CD25-like molecule in some research studies. To date, no studies of IL-35 and IL-15R alpha have been documented in fish. In this work, five isoforms of IL-15R alpha were cloned from grass carp, and a monoclonal antibody to the protein was developed. The results of flow cytometry and quantitative real-time PCR analyses demonstrated that grass carp IL-35 subunit genes EBI3a and IL-12p35 were mainly expressed in IL-15R alpha(+) cells, while the expression levels of IL-10 and TGF-beta in IL-15R alpha(+) and IL-15R alpha- cells were insignificant. Recombinant grass carp IL-35 (rgcIL-35) could increase the proportion of IL-15R alpha(+) cells in leukocytes, and a certain proportion of IL-15R alpha(+) cells also appeared in myeloid cell subset II after stimulation with rgcIL-35. Meanwhile, the migration, phagocytic ability, and bactericidal ability of grass carp neutrophils were significantly decreased after stimulation with certain concentrations of rgcIL-35. Moreover, neutrophil apoptosis could be significantly inhibited by rgcIL-35.

关键词： I INTERFERONS   RECRUITMENT  

摘要： Dermatomyositis pathogenesis remains incompletely understood; however, recent work suggests a predominant IFN-1 response. We explored dermatomyositis pathogenesis by quantifying the inflammatory cells in the skin, comparing myeloid with plasmacytoid dendritic cell release of IFN-beta, and assessing myeloid dendritic cell (mDC) contribution to hydroxychloroquine refractoriness. Immunohistochemistry was performed to assess cell-type expression in lesional skin biopsies from 12 patients with moderate-to-severe cutaneous dermatomyositis. Immunofluorescence, laser-capture microdissection, and flow cytometry were used to assess mDC release of IFN-beta in lesional skin biopsies and blood of patients with dermatomyositis. Immunohistochemistry was utilized to determine whether myeloid or plasmacytoid dendritic cells were increased in hydroxychloroquine nonresponders. CD4+, CD11c+, and CD69+ cells were more populous in lesional skin of patients with dermatomyositis. mDCs colocalized with IFN-beta by immunofluorescence and laser-capture microdissection revealed increased IFN-beta mRNA expression by mDCs in lesional skin of patients with dermatomyositis. In blood, both mDCs and plasmacytoid dendritic cells were major producers of IFN-beta in patients with dermatomyositis, whereas plasmacytoid dendritic cells predominately released IFN-beta in healthy controls (P < 0.01). mDCs were significantly increased in the skin of hydroxychloroquine nonresponders compared with that in the skin of responders (P < 0.05). mDCs cells appear to play an important role in dermatomyositis pathogenesis and IFN-beta production.

关键词： GATA3   Cutaneous lymphoma   Mycosis fungoides   Anaplastic large cell lymphoma   Primary cutaneous CD30-positive T cell lymphoproliferative disorders   T helper cell  

摘要： Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.