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关键词： Depression   Biomarker   CHL1   B cells   CUMS  

摘要： Depression is a common serious mental disorder with unclear pathogenesis. Currently, specific diagnostic biomarkers are yet to be characterized. The close homolog of L1 (CHL1) is a L1 family cell adhesion molecule involved in the regulation of neuronal survival and growth. Although genome-wide expression profiling of human lymphoblastoid cell lines (LCLs) reported neural cell adhesion molecule (NCAM) L1 as a tentative biomarker for selective serotonin reuptake inhibitor (SSRI) antidepressant response, the involvement of CHL1 in depression is unclear. In this study, using a well-established chronic unpredictable mild stress (CUMS) depression mouse model, we examined the mRNA and protein expression of CHL1 in normal control, CUMS, vehicle (VEH), fluoxetine (FLU), and clozapine (CLO) groups. We found that in the CUMS group, both mRNA and protein expression of CHL1 were downregulated in both the hippocampus and the cortex. Treatment of CUMS mice with FLU and CLO reversed CHL1 mRNA and protein expression. In the human study, we showed that CHL1 expression was significantly downregulated in monocytes of unipolar and bipolar depressive patients compared with healthy donors (HD) at both mRNA and protein levels. Consistently, ELISA showed that CHL1 levels in the serum of patients with depression were reduced and negatively correlated with their HRSD-21 scores. Further flow cytometry studies showed that the reduced number of CHL1 positive CD19(+)and CD20(+)B cells of patients with depression was subsequently reversed with antidepressant treatment. Our findings suggested that downregulation of CHL1 from both immune cells and the brain may be linked to the immunopathogenesis of depression. In conclusion, CHL1 may be an important predictive marker for both diagnosis and treatment outcome of depression.

关键词： TriMixDC-MEL   Melanoma   Adjuvant therapy   Dendritic vaccine  

摘要： Background Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients. Materials and methods Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). "Cross-over" was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining. Results Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3-67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel armn = 9 and control armn = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1-6) vs. not reached;log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade >= 3 AE's occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers. Conclusion TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.

关键词： Analytical ultracentrifugation   Circular dichroism spectroscopy   I kappa B kinase   Multi-angle light scattering   NEMO   NF-kappa B   Size-exclusion chromatography  

摘要： The human I kappa B Kinase (IKK) is a multisubunit protein complex of two kinases and one scaffolding subunit that controls induction of transcription factor NF-kappa B activity. IKK behaves as an entity of aberrantly high apparent molecular weight in solution. Recent X-ray crystallographic and cryo-electron microscopy structures of individual catalytic subunits (IKK1/IKK alpha and IKK2/IKK beta) reveal that they are both stably folded dimeric proteins that engage in extensive homo-oligomerization through unique surfaces that are required for activation of their respective catalytic activities. The NEMO/IKK gamma subunit is a predominantly coiled coil protein that is required for activation of IKK through the canonical NF-kappa B signaling pathway. Here we report size-exclusion chromatography, multi-angle light scattering, analytical centrifugation, and thermal denaturation analyses of full-length human recombinant NEMO as well as deletion and disease-linked variants. We observe that NEMO is predominantly a dimer in solution, although by virtue of its modular coiled coil regions NEMO exhibits complicated solution dynamics involving portions that are mutually antagonistic toward homodimerization. This behavior causes NEMO to behave as a significantly larger sized particle in solution. Analyses of NEMO in complex with IKK2 indicate that NEMO preserves this structurally dynamic character within the multisubuit complex and provides the complex-bound IKK2 further propensity toward homo-oligomerization. These observations provide critical information on the structural plasticity of NEMO subunit dimers which helps clarify its role in diseases and in IKK regulation through oligomerization-dependent phosphorylation of catalytic IKK2 subunit dimers.

关键词： Diesel exhaust particle   Human primary nasal epithelial cell   Toxicogenomics   Pathway analysis  

摘要： In this study, we aimed to identify signaling alteration caused by exposure to diesel exhaust particles (DEPs) using primary human nasal epithelial cells (PHNECs). Global gene expression profiles in PHNECs following 50 and 200 mu g/ml of DEP exposure were identified using microarray analysis. To cover the limitation of array-based mRNA expression analysis, text-mining-based software was used to analyze the integrative biological networks and relevant disease-focused functions among identified DEP-responsive genes. The confidence was valued based on the connectivity between the analyzed pathway and marker candidates. Through a literature-based pathway analysis, the stimulation of inflammation- and immune response-related processes mediated by TNF were predicted as major signaling alterations in PHNECs caused by DEP exposure. CSF3, CXCL8, MMP1, and VEGFA were identified as key hub genes in the predicted pathway. Significant expression level changes in the five key genes following DEP exposure were validated in terms of protein and mRNA expression. Although further studies are required, our toxicogenomic investigation provides key clues to the exact mechanism underlying DEP-induced nasal inflammatory damage. It also suggests an efficient approach for other research on adverse effects occurring in the upper respiratory tract following DEP exposure.

关键词： SARS-CoV-2   ACE2 receptor   COVID-19  

摘要： Despite the unprecedented effort of the scientific community, the novel SARS-CoV-2 virus has infected more than 46 million people worldwide, killing over one million two hundred thousand. Understanding the mechanisms by which some individuals are more susceptible to SARS-CoV-2 infection and why a subgroup of them are prone to experience severe pneumonia, and death should lead to a better approach and more effective treatments for COVID-19. Here, we focus our attention on ACE2, a primary receptor of SARS-CoV-2. We will discuss its biology, tissue expression, and post-translational regulation that determine its potential to be employed by SARS-CoV-2 for cell entry. Particular attention will be given to how the ACE2 soluble form can have a great impact on disease progression and thus be used in a potential therapeutic strategy. Furthermore, we will discuss repercussions that SARS-CoV-2/ACE2 binding has on the renin-angiotensin system and beyond. Indeed, although mostly neglected, ACE2 can also act on [des-Arg 937]-bradykinin of the kinin-kallikrein system regulating coagulation and inflammation. Thorough comprehension of the role that ACE2 plays in different pathways will be the key to assess the impact that SARS-CoV-2/ACE2 binding has on organismal physiology and will help us to find better therapies and diagnostic tools.

关键词： Adrenal function recovery   Anti-21-hydroxylase antibodies   Hyponatremia   Immunotoxicity   Nivolumab   Primary adrenal insufficiency  

摘要： The immune checkpoint inhibitors (ICPi) revolutionize the cancer therapeutics, though not being devoid of toxicity. The immune-related primary adrenal insufficiency (PAI) is a rare, yet potentially life-threatening, adverse event, posing diagnostic and therapeutic challenges. We report the first case of reversible PAI related to nivolumab (programmed cell-death 1 protein inhibitor) in a 42-year-old male with metastatic rectal adenocarcinoma. PAI manifested as profound fatigue, disorientation, hypotension, hyperpigmentation of palmar creases, and hyponatremia without hyperkalemia 16 weeks after initiation of nivolumab. Due to impending adrenal crisis, intravenous stress doses of hydrocortisone and hydration with normal saline were initiated. When the state of patient was stabilized, PAI was confirmed through 250 mu g Synacthen test 24 h after temporary cessation of hydrocortisone. Hydrocortisone was fixed at maintenance dose, while mineralocorticoid substitution was not required. PAI was ascribed to nivolumab based on history, physical examination, and laboratory workup with emphasis on positivity of anti-21-hydroxylase antibodies and exclusion of other causes of PAI by normal imaging of adrenal glands on computed tomography (CT). Reevaluation of adrenal function during follow up demonstrated complete recovery. A review of literature concerning the immune-related PAI indicated that the complete recovery of adrenal function, the normal CT imaging, and the positivity of anti-21-hydroxylase antibodies observed in our patient are exceptional findings of immune-related PAI. Finally, heightened suspicion of immune-related PAI in case of hyponatremia without hyperkalemia and constant vigilance for diagnosis of rare, but real, reversibility of immune-related PAI are of paramount importance.

关键词： Periosteal cells   Osteogenesis   Chondrogenesis   Orthopedics   Rehabilitation  

摘要： Periosteal cells are the major cell sources of skeletal progenitors for fracture callus. In order to promote bone repair and cartilage formation, besides the application of exogenous growth factors, physical stimulation is an alternative approach to guide cell differentiation. Investigation of appropriate conditions is essential for forming bone and cartilage. In this work, a membrane-type micro-system was developed to provide cell culture environment and cell stretching stimulation during culture course. Circular and oval culture wells were designed to respectively generate uniform and non-uniform 2-axial tensile strain for stretching primary rabbit periosteal cells. Cell orientation and differentiation were studied after cycling stretching for 2 days. The cells aligned to the stretching axis with high tensile strain in the oval culture wells;while the cells expressed random orientation in the circular culture wells. Different responses were significantly shown when the cells were respectively stimulated by uniform and non-uniform 2-axial tensile strains. On the other hand, osteogenic differentiation was shown when the cells were under either uniform or non-uniform 2-axial tensile strain. However, only non-uniform 2-axial tensile strain could induce mature osteoblasts. In addition, the result revealed chondrocytes could be differentiated only under a large and nearly single dimensional tensile strain. In summary, differentiation of the periosteal cells is highly influenced by 2-dimensional distribution of the tensile strain. This work provides some in-sights of the control of axial tensile strain for periosteal cell differentiation.