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关键词： Tumor microenvironment   MHCII   Cancer cell-specific MHCII expression   NSCLC   Multispectral tissue imaging   LUNG-CANCER   THERAPY   ACTIVATION   EPITHELIUM  

摘要： Introduction: In patients with NSCLC, the prognostic significance of the tumor microenvironment (TME) immune composition has been revealed using single-or dual-marker staining on sequential tissue sections. Although these studies reveal that relative abundance and localization of immune cells are important parameters, deeper analyses of the NSCLC TME are necessary to refine the potential application of these findings to clinical care. Currently, the complex spatial relationships between cells of the NSCLC TME and potential drivers contributing to its immunologic composition remain unknown. Methods: We used multispectral quantitative imaging on the lung adenocarcinoma TME in 153 patients with resected tumors. On a single slide per patient, we evaluated the TME with markers for CD3, CD8, CD14, CD19, major histocompatibility complex II (MHCII), cytokeratin, and 4',6-diamidino-2-phenylindole (DAPI). Image analysis, including tissue segmentation, phenotyping, and spatial localization, was performed. Results: Specimens wherein greater than or equal to 5% of lung cancer cells expressed MHCII (MHCIIhi TME) had increased levels of CD4(+) and CD8(+) T cells and CD14(+) cell infiltration. In the MHCIIhi TME, the immune infil-trate was closer to cancer cells and expressed an activated phenotype. Morphologic image analysis revealed cancer cells in the MHCIIhi TME more frequently interfaced with CD4(+) and CD8(+) T cells. Patients with an MHCIIhi TME experienced improved overall survival (p = 0.046). Conclusions: Lung cancer cell-specific expression of MHCII associates with levels of immune cell infiltration, spatial localization, and activation status within the TME. This suggests that cancer cell-specific expression of MHCII may represent a biomarker for the immune system's recognition and activation against the tumor. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

关键词： Alzheimer disease   MAPK signaling pathway   Amyloid-beta   P38   ERK   JNK   PROTEIN-KINASE PATHWAYS   JNK INHIBITOR SP600125   ALZHEIMERS-DISEASE   MOUSE MODEL   P38   ERK   ACTIVATION   RECEPTOR   PHOSPHORYLATION   SB203580  

摘要： Alzheimer's disease (AD) is characterized with increased formation of amyloid-beta (A beta) in the brain. A beta peptide toxicity is associated with disturbances of several intracellular signaling pathways such as mitogen activated protein kinases (MAPKs). The aim of this study was to investigate the role of MAPKs and their interactions in A beta-induced neurotoxicity using isolated hippocampal neurons from the rat. Primary hippocampal cells were cultured in neurobasal medium for 4 days. Cells were treated with A beta 25-35 and/or MAPKs inhibitors for 24 h. Cell viability was determined by an MTT assay and phosphorylated levels of P38, JNK, and ERK were measured by Western blots. A beta treatment (10-40 mu M) significantly decreased hippocampal cell viability in a dose-dependent manner. Inhibition of P38 and ERK did not restore cell viability, while JNK inhibition potentiated the A beta-induced neurotoxicity. Compared to the controls, A beta treatment increased levels of phosphorylated JNK, ERK, and c-Jun, while it had no effect on levels of phosphorylated P38. In addition, P38 inhibition led to decreased expression levels of phosphorylated ERK; inhibition of JNK resulted in decreased expression of c-Jun; and inhibition of ERK, decreased phosphorylated levels of JNK. These results strongly suggest that P38, ERK, and JNK are not independently involved in A beta-induced toxicity in the hippocampal cells. In AD, which is a multifactorial disease, inhibiting a single member of the MAPK signaling pathway, does not seem to be sufficient to mitigate A beta-induced toxicity and thus their interactions with each other or potentially with different signaling pathways should be taken into account.

关键词： Single-cell RNA sequencing   mycosis fungoides   alpha beta TCR   gamma delta TCR   lesion progression  

摘要： Background:In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20–30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. Methods:In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, in order to characterize markers of lesion progression. Results:Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of a combination of tissue residency markers, heat shock proteins, tumor suppressor genes and chemokine receptors in the malignant clone. By contrast, collateral benign infiltrating immune cells within the lesions did not show consistent changes at the mRNA level. This phenomenon was not only found in conventional TCR-αβ MF, but also in a case of TCR-γδ MF, suggesting a mechanism across MF subtypes. Markers of disease progression were reverted upon successful topical treatment with chlormethine. Conclusions:Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.

关键词： PROTEIN-KINASE-A   CYCLIC-AMP   COMPLEXES   CAMP   TRANSITION   PURINOSOME   COMPARTMENTATION   GRANULES   DYNAMICS   DISEASE  

摘要： Numerous processes occur simultaneously in the cell both for normal function and in response to changes in the environment. The ability of cells to segregate biochemical reactions into separate compartments is essential to ensure specificity and efficiency in cellular processes. The discovery of liquid-liquid phase separation as a mechanism of compartmentalization has revised our thinking regarding the intracellular organization of molecular pathways such as signal transduction. Here, we highlight recent studies that advance our understanding of how phase separation impacts the organization of biochemical processes, with a particular focus on the tools used to study the functional impact of phase separation. In addition, we offer some of our perspectives on the pathological consequences of dysregulated phase separation in biochemical pathways.

关键词： Immune cell isolation   Mucosa   Fibrosis   ENDOTHELIAL-CELLS   T-CELLS   DISEASE   LIGHT   LUNG  

摘要： Understanding the interplay between immune and structural cells is important for studying fibrosis and inflammation; however, primary immune cell isolation from organs that are typically enriched in stromal cells, like the lung, esophagus, or gut, proves to be an ongoing challenge. In fibrotic conditions, this challenge becomes even greater as infiltrating cells become trapped in the robust extracellular matrix (ECM). This protocol details a method to isolate cells at high yield from stroma-rich organs that can be used for further analyses via flow cytometry, stimulation, or culturing. Validation of this method is confirmed by flow cytometry data assessing immune cell populations of interest. This protocol can be completed in approximately 5-6 h.

关键词： Cytotoxic cutaneous T cell lymphoma   primary cutaneous CD8+aggressive epidermotropic cytotoxic T cell lymphoma   JAK-STAT  

摘要： Background:Primary cytotoxic T cell lymphomas are a heterogenous collection of ill-defined diseases with aggressive disease course and poor response to conventional therapy. Of these, primary cutaneous CD8+ aggressive epidermotropic T cell lymphoma and cutaneous T cell lymphoma, not otherwise specified, have undergone few to no systematic analyses of its genetic landscape. In this study, we classify these lymphomas based on their histological and clinical features and perform systematic genomic analyses to find novel therapeutic targets. Methods:We clinically characterize 35 patients from 10 institutions with cytotoxic T cell lymphoma and performed integrative clinical, pathological, and genetic analyses. We perform Archer™ Heme Fusion on an initial 24 FFPE samples. In addition, we perform DNA and/or RNA sequencing on 11 cases. We functionally validate our genetic findings by transducing alterations into Ba/F3 cells and subsequently performing biochemical assays. In this setting, we assess sensitivity to FDA-approved small molecule inhibitors. We provide orthogonal evidence of transcriptional upregulation by geneset enrichment analysis. Results:We find kinase fusions impacting JAK-STAT signaling in all primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our cohort. Three of these fusions have not previously been described in cancer. Known fusions have been shown to upregulate JAK-STAT signaling. Upon each transduction, CAPRIN1-JAK2 and SELENOI-ABL1 cause increased phosphorylation and display IL-3-independent growth compared to control. Upon treatments to small molecule inhibitors, ruxolitinib and imatinib respectively, CAPRIN1-JAK2 and SELENOI-ABL1 expressing cells exhibit sensitivity. Cutaneous T cell lymphoma, not otherwise specified, harbor JAK-STAT hotspot mutations but not kinase fusions. Conclusions:All 9 primary cutaneous CD8+ aggressive epidermotropic T cell lymphomas in our series harbor kinase fusions, while the majority of the cutaneous T

关键词： Hexapod robot   Staircase climbing   Robot design   Leg mechanism   Dimension design   REACHABLE WORKSPACE   WAIST   GAIT  

摘要： Robot dimension design based on staircase-climbing is essential but seldom studied for legged robots. Incorporating the staircase-climbing in design is novel and relevant. The robot dimension, including the leg dimension and the body dimension, affects the staircase-climbing capability. This paper studies the dimension design for a novel hexapod robot. In dimension design for the leg mechanisms, the critical problem is to handle the interferences between the leg mechanism and staircase. Firstly, all interferences in climbing a staircase are classified into three cases. The corresponding three conditions to avoid the three interference cases are originally proposed. Secondly, the dimension of a single leg mechanism is derived analytically according to the staircase size under the premise of avoiding the three interference cases. The robot body coordinates the leg mechanisms and affects the ability to adjust the tilting angle in climbing a staircase. The body dimension is derived analytically with the constraints of leg workspace, leg-staircase interferences, and the static stability margin. The design example of a hexapod robot climbing 35-degree and 45-degree staircases is given and verified by simulations and experiments. (c) 2021 Elsevier Ltd. All rights reserved.

关键词： Primary cutaneous B-cell lymphomas   epidemiology   pediatric dermatology  

摘要： Background:The incidence of primary cutaneous B-cell lymphomas (PCBCL) in the pediatric population is unknown, and the information on pediatric PCBCL has mostly been gathered from individual case reports or series from single centers. Objective:To assess the incidence of PCBCL in the pediatric population (<20 years) compared with adult patients (≥20 years) and delineate its demographic and clinicopathologic characteristics. Methods:This was a population-based, retrospective cohort study of patients in 18 cancer registries in the United States diagnosed between 2000 to 2016 through the Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted incidence rates were calculated for PCBCL in pediatric and adult populations. Demographic, clinical, and pathological characteristics were compared between the two groups. Results:5,128 adult and 48 pediatric PCBCL cases were included. The median age at diagnosis in the pediatric group was 16.5 years. The major histologic subtypes of pediatric cases were marginal zone lymphoma (77.1%), diffuse large B-cell lymphoma (12.5%) and follicle center lymphoma (10.4%), which significantly differed from the distribution in the adult group (p<0.001) where subtypes were equally distributed. The age-adjusted pediatric PCBCL incidence rate (per 1,000,000 person‐years) was 0.12 (95% CI 0.09-0.16) and incidence in the adult population was approximately 40-fold higher (IRR 41.4, 95% CI 31.2-56.2, P<0.001). All 48 pediatric cases were alive during a median follow-up time of 48 months. Conclusions:Pediatric PCBCL is a rare and indolent disease, which affects mostly adolescents of both sexes. Clinical presentation is similar to adults, but marginal zone subtype is significantly over-represented.

关键词： Pharmacology/Toxicology   Neurosciences  

关键词： LONG-TERM   CANCER   IMPACT  

摘要： Purpose: The survival benefit of postoperative adjuvant treatment (POAT) for stage II oral tongue squamous cell carcinoma (OTSCC) remains controversial. This large SEER-based study aims to establish a prognostic nomogram to visualize the overall survival of these patients and to aid in POAT decision making. Patients and Methods: The cut-off points of age at diagnosis and examined lymph node number (ELN) were determined using the population-based data from the SEER database. Univariate and multivariate Cox hazards regression models were utilized to identify prognostic factors that were integrated into the establishment of the prognostic nomogram. Patients with stage II OTSCC were then stratified into 3 cohorts based on this nomogram. The survival benefit of POAT was evaluated in these cohorts. Results: Age at diagnosis (with cutoff points of 50 and 75 years) and ELN (with cutoff points of 0 and 22) was significantly associated with the survival outcomes in patients with stage II OTSCC. After the multivariate analysis, 4 factors, including age at diagnosis, sex, ELN, and differentiation grade, were identified as independent prognostic factors. Additionally, a prognostic nomogram with these factors was constructed to predict overall survival and to stratify these patients. Only patients in the high-risk cohort could significantly benefit from postoperative adjuvant treatment. Conclusions: This prognostic nomogram could accurately predict the overall survival of stage II OTSCC patients after curative surgery. Notably, this model could also assist the decision-making of postoperative adjuvant treatment for patients with stage II OTSCC. (C) 2021 The American Association of Oral and Maxillofacial Surgeons.