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关键词： Aging   Age-related diseases   Senescence   Senolytic   Senomorphic  

摘要： The review aims to summarize and discuss the current knowledge on targeting senescent cells to reduce the risk of age-related diseases in animal models and human studies. The role of cellular senescence in aging and the major age-related diseases -including Alzheimer's disease, atherosclerosis, and type 2 diabetes- as well as the use of senotherapeutic strategies in both experimental and preclinical studies, will be described. A large number of molecules, including synthetic agents and natural compounds, have been proposed for anti-senescence activities. Research on senotherapeutics, which includes senolytic and senomorphic, has a growing interest, and their safety and reliability as anti-aging drugs have been tested in clinical trials. Initial findings suggest that the senotherapeutic approach may be translatable to humans. Due to the lack of evidence, caution must be used against senolytic agents due to their potential side-effects. In this context, natural senolytic compounds should have the advantage of low toxicity and potentially more useful in humans, although the mechanisms of action need to be defined.

关键词： recurrent glioblastoma   GBM relapse   HSV-thymidine kinase (HSVTK)   ganciclovir (GCV)   tumor associated myeloid cells (TAM)   monocyte-derived macrophages (MDM)   microglia   tumor cell invasion  

摘要： Simple Summary We established a new minimally invasive mouse model for GBM relapse. For this, we utilized orthotopical implantation of HSVTK-transduced GBM cells and pharmacological treatment with GCV. In addition, we implanted patient-derived GBM cells of primary or recurrent tumors. We found that recurrent GBM were more aggressively invasive than primary GBM. Moreover, the recurring tumors had a higher ratio of monocyte-derived macrophages among the entire population of tumor associated myeloid cells. This shift in the composition of tumor-associated immune cells appeared to be independent from cell-death signaling or surgical intervention. This model provides the means to investigate the entire process of tumor relapse and test standard as well as experimental therapeutic strategies for relapsing GBM under defined conditions. Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be combined with conventional therapeutic approaches. Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism. This is followed by GBM re-growth over a predictable timeframe. Pharmacological de-bulking followed by tumor relapse was accomplished with an orthotopic mouse glioma model. Relapsing experimental tumors recapitulated pathological features often observed in recurrent human GBM, like increased invasiveness or altered immune cell composition. Orthotopic implantation of GBM cells originating from biopsies of one patient at initial or follow-up treatment reproduced these findings. Interestingly, relapsing GBM of both models contained a much higher ratio of monocyte-derived macrophages (MDM) versus microglia than primary GBM. This was not altered when combining pharmacological de-bulking with

关键词： database research   glycaemic control   insulin therapy   type 2 diabetes  

摘要： Aims To investigate the interrelations between glycaemic metrics of fasting plasma glucose (FPG), postprandial glucose (PPG), glycated haemoglobin (HbA1c), and percentage of time in target range 3.9 to 10.0 mmol/L (%TIR) in patients on insulin therapy. Materials and methods A pooled analysis was conducted using datasets extracted from an integrated database of insulin lispro clinical trials (Eli Lilly and Company). Studies in patients with type 2 diabetes on basal-bolus or basal-plus insulin therapy, and with >= 7-point self-monitored blood glucose profiles were included in the analysis. A multivariate regression model was used to quantify the contribution of FPG and PPG change to the change in HbA1c and %TIR. In addition, a linear regression model was used to describe the relationship between %TIR and HbA1c. Results Five studies encompassing 1572 patients met the criteria for inclusion. On average, a 1-mmol/L change in FPG was associated with 2.7 mmol/mol (0.25%) change in HbA1c (range 2.0 to 2.8 mmol/mol [0.18%-0.26%];all P <0.0001), and a 1-mmol/L change in PPG with 1.8 mmol/mol (0.16%) change in HbA1c (range 1.2 to 2.1 mmol/mol [0.11%-0.19%];all P <0.01). Furthermore, a 1-mmol/L reduction in FPG and PPG was associated with an increase in TIR of 6.5% (range 5.8%-9.2%) and 5.3% (range 4.1%-8.7%), respectively, all P <0.0001. A decrease in HbA1c of 10.9 mmol/mol (1%) corresponded with an increase in TIR of 8.3%, on average. Conclusions In patients with type 2 diabetes on basal-bolus or basal-plus insulin therapy, management of both FPG and PPG is important for achievement of HbA1c and TIR goals.

关键词： NSCLC   relapse   recurrence   survival   utilization  

摘要： Aims Adjuvant chemotherapy has been shown to improve survival in patients with completely resected early-stage non-small cell lung cancer (NSCLC). This study evaluated real-world relapse rates and healthcare resource utilization in patients with stage II-IIIB NSCLC receiving adjuvant therapy in a community oncology setting after complete resection. Patients and Methods The study included patients with stage II-IIIB NSCLC and complete resection receiving any adjuvant therapy during 06/2008-04/2017 at US Oncology Network clinics, with follow-up through 04/2019. Primary endpoints were rate of relapse, time to relapse (TTR), disease-free survival (DFS), overall survival (OS), and monthly emergency department (ED) visits and hospitalizations before and after relapse. Results The study identified 456 patients;median age was 66 years, 50% were male. In patients with relapse (45.2%), median follow-up was 31.7 months and median TTR was 13.7 months. Median DFS in the overall population was 42.9 months. Median OS was 82.4 months in the overall population and shorter in patients with relapse than without relapse (41.6 months vs. not reached, p < 0.0001). Patients with relapse had significantly more monthly ED visits (mean [SD] 0.10 [0.24] vs. 0.03 [0.08], p < 0.0001) and hospitalizations (mean [SD] 0.20 [0.43] vs. 0.05 [0.10], p < 0.0001) following relapse than before relapse. Conclusions Patients with stage II-IIIB NSCLC treated with adjuvant therapy after complete resection had high relapse rates, reduced survival, and significantly increased healthcare resource use when relapse occurred. New therapeutic options to reduce relapse rates in patients with early-stage NSCLC could reduce healthcare utilization and costs.

关键词： Diabetic retinopathy   Maximum principal curvature   Hessian matrix   Squeeze-excitation   Bottleneck   Convolutional neural network  

摘要： Diabetic retinopathy is ophthalmological distress, diabetic patients suffer due to clots, lesions, or haemorrhage formation in the light-sensitive region of the retina. Blocking of vessels leads, due to the increase of blood sugar leads to the formation of new vessel growth, which gives rise to mesh-like structures. Assessing the branching retinal vasculature is an important aspect for ophthalmologists for efficient diagnosis. The fundus scans of the eye are first subjected to pre-processing, followed by segmentation. To extract the branching blood vessels, the technique of maximal principal curvature has been applied, which utilizes the maximum Eigenvalues of the Hessian matrix. Adaptive histogram equalization and the morphological opening, are performed post to that, to enhance and eliminate falsely segmented regions. The proliferation of optical nerves was observed much greater in diabetic or affected patients than in healthy ones. We have used a convolution neural network (CNN) to train the classifier for performing classification. The CNN, constructed for classification, comprises a combination of squeeze and excitation and bottleneck layers, one for each class, and a convolution and pooling layer architecture for classification between the two classes. For the performance evaluation of the proposed algorithm, we use the dataset DIARETDB1 (standard Diabetic Retinopathy Dataset) and the dataset provided by a medical institution, comprised of fundus scans of both affected and normal retinas. Experimental results show that the proposed algorithm provides improved results, when compared to traditional schemes. The model yielded an accuracy of 98.7 % and a precision of 97.2 % while evaluated on the DIARETDB1 dataset.

关键词： apoptosis   deoxynivalenol   human brain endothelial cells   oxidative stress   vitamin E  

摘要： Fusarium mycotoxins are one of the largest families of mycotoxins. Among these mycotoxins, deoxynivalenol is the most widespread pollutant of grains. However, the mechanism underlying the effect of deoxynivalenol on cytotoxicity in human brain endothelial cells was still unclear. This study examined whether deoxynivalenol induced oxidative stress-associated cytotoxicity in primary human brain endothelial cells (HBEC-5i), and explored whether Vitamin E (VE), a selective antioxidant, had protective effects on deoxynivalenol-treated cells. Deoxynivalenol (10-50 mu M) concentration-dependently induced cytotoxicity in HBEC-5i cells. Deoxynivalenol (IC50 = 20 mu M) activated mitochondrial apoptotic pathway by modulating antioxidant protein expressions (Nrf2, HO-1 and NQO1). More significantly, pre-treatment with VE (20 mu M) attenuated the deoxynivalenol-induced cytotoxicity in this cell model. Together, VE significantly alleviated the apoptotic effects of deoxynivalenol in HBEC-5i cells suggesting that it protected the cells against deoxynivalenol-induced oxidative damage. Our findings provided new insight that VE had the potential to ameliorate neurotoxicity of deoxynivalenol.

关键词： Primary immunodeficiency disease   severe combined immunodeficiency   reduced intensity conditioning   fludarabine   busulfan   therapeutic drug monitoring  

摘要： Purpose The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). Methods We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. Results The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. Conclusions RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are requ

关键词： atherosclerosis   cardiovascular diseases   endothelial cells   gene expression   macrophages   microRNA  

摘要： Objective: Atherosclerosis is the underlying cause of most cardiovascular diseases. The main cell types associated with disease progression in the vascular wall are endothelial cells, smooth muscle cells, and macrophages. Although their role in atherogenesis has been extensively described, molecular mechanisms underlying gene expression changes remain unknown. The objective of this study was to characterize microRNA (miRNA)-related regulatory mechanisms taking place in the aorta during atherosclerosis. Approach and Results: We analyzed the miRNA expression changes in primary human aortic endothelial cells and human umbilical vein endothelial cells, human aortic smooth muscle cells, and macrophages (CD14+) under various proatherogenic stimuli by integrating GRO-seq, miRNA-seq, and RNA-seq data. Despite the highly cell-type-specific expression of multi-variant primary miRNAs, the majority of mature miRNAs were found to be common to all cell types and dominated by 2 to 5 abundant miRNA species. We demonstrate that transcription contributes significantly to the mature miRNA levels although this is dependent on miRNA stability. An analysis of miRNA effects in relation to target mRNA pools highlighted pathways and targets through which miRNAs could affect atherogenesis in a cell-type-dependent manner. Finally, we validate miR-100-5p as a cell-type specific regulator of inflammatory and HIPPO-YAP/TAZ-pathways. Conclusions: This integrative approach allowed us to characterize miRNA dynamics in response to a proatherogenic stimulus and identify potential mechanisms by which miRNAs affect atherogenesis in a cell-type-specific manner.

关键词： Alien invasive species   Cryptic invasion   Distribution   Eragrostis albensis var   scholziana   Integrative taxonomy   Lovegrasses  

摘要： The Eragrostis pilosa complex (Poaceae) comprises five widely distributed and regionally invasive species-E. albensis, E. amurensis, E. imberbis, E. multicaulis, and E. pilosa, distinguished by tiny and variable morphological characters and with so far unknown phylogenetic relationships. Recently, some doubts have been raised about the status of an invasive glandular morphotype occurring in Central Europe assigned either to E. amurensis or to E. albensis. Here, we addressed this issue by analysing morphology, internal transcribed spacers of nuclear ribosomal DNA, and five inter-simple sequence repeat markers. The genetic evidence supported closer relationship of this glandular morphotype to eglandular E. albensis, widely established in Central Europe, than to glandular E. amurensis described from Asia. We propose to adopt a new taxonomic treatment that E. albensis includes both eglandular and glandular individuals, and to classify the glandular ones as E. albensis var. scholziana M. Nobis & A. Wrobel var. nova. Currently this new taxon is known from a dozen of localities in Central Europe and is invasive in the lower section of the Oder River valley, whereas Eragrostis albensis var. albensis has already spread widely across Europe in riparian phytocenoses and anthropogenic habitats. Since probably the first registered records in 1940s, it has been observed in European part of Russia, Belarus, Ukraine, Poland, Slovakia, Czech Republic, Germany, Austria, the Netherlands, and its further invasion is likely to proceed. We provided distribution maps concerning spread dynamics of E. albensis in Europe from 1947 to 2020. In total, the species has been observed on over 1300 localities so far, most of which were found after 2000.