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关键词： Intensity-modulated radiotherapy   locally advanced   outcomes   sinonasal squamous cell carcinoma  

摘要： Aims: Sinonasal malignancies are rare;the most common histological subtype is squamous cell carcinoma (SCC). No randomised trial data exist to guide treatment decisions, with options including surgery, radiotherapy and chemotherapy. The role and sequence of a primary non-surgical approach in this disease remains uncertain. The aim of this study was to present treatment outcomes for a multicentre population of patients with locally advanced, stage IVa/b sinonasal SCC treated with radical-intent intensity-modulated radiotherapy, either definitively or postoperatively. Materials and methods: Consecutively treated patients with locally advanced, stage IVa/b sinonasal SCC at four UK oncology centres between January 2012 and December 2017 were retrospectively identified. Descriptive statistics and survival analyses were carried out. Univariable Cox regression analysis was carried out to evaluate the relationship between patient, disease and treatment factors and survival outcomes. Results: In total, 56 patients with sinonasal SCC were included (70% maxillary sinus, 21% nasal cavity, 9% ethmoid/frontal sinus). Forty-one patients (73%) were treated by surgery/adjuvant (chemo)radiotherapy and 15 (27%) by definitive (chemo)radiotherapy. The median duration of follow-up was 3.8 years (interquartile range 2.0-4.7 years). Estimates for 5-year overall survival and progression-free survival were 30.2% and 24.2%, respectively. Local, regional and distant treatment failures were seen in 33%, 33% and 16% of patients, respectively. Univariable analysis revealed inferior progression-free survival for patients treated with neck dissection (hazard ratio 2.6, 95% confidence interval 1.2-6.1, P = 0.022) but no other significant association between the studied factors and survival outcomes. Conclusion: We show poor survival outcomes and high rates of locoregional treatment failure for patients with locally advanced stage IVa/b sinonasal SCC. There is a need to investigate improved treatment

关键词： deep learning   diabetic retinopathy   grading   retinal   fundus images  

摘要： Diabetic retinopathy (DR) is a diabetes disorder that disturbs human vision. It starts due to the damage in the light-sensitive tissues of blood vessels at the retina. In the beginning, DR may show no symptoms or only slight vision issues, but in the long run, it could be a permanent source of impaired vision, simply known as blindness in the advanced as well as in developing nations. This could be prevented if DR is identified early enough, but it can be challenging as we know the disease frequently shows rare signs until it is too late to deliver an effective cure. In our work, we recommend a framework for severity grading and early DR detection through hybrid deep learning Inception-ResNet architecture with smart data preprocessing. Our proposed method is composed of three steps. Firstly, the retinal images are preprocessed with the help of augmentation and intensity normalization. Secondly, the preprocessed images are given to the hybrid Inception-ResNet architecture to extract the vector image features for the categorization of different stages. Lastly, to identify DR and decide its stage (e.g., mild DR, moderate DR, severe DR, or proliferative DR), a classification step is used. The studies and trials have to reveal suitable outcomes when equated with some other previously deployed approaches. However, there are specific constraints in our study that are also discussed and we suggest methods to enhance further research in this field.

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： cell isolation   fluorescence-activated cell sorting   liver   non-alcoholic steatohepatitis  

摘要： NASH is a chronic liver disease that affects 3%-6% of individuals and requires urgent therapeutic developments. Isolating the key cell types in the liver is a necessary step towards understanding their function and roles in disease pathogenesis. However, traditional isolation methods through gradient centrifugation can only collect one or a few cell types simultaneously and pose technical difficulties when applied to NASH livers. Taking advantage of identified cell surface markers from liver single-cell RNAseq, here we established the combination of gradient centrifugation and antibody-based cell sorting techniques to isolate five key liver cell types (hepatocytes, endothelial cells, stellate cells, macrophages and other immune cells) from a single mouse liver. This method yielded high purity of each cell type from healthy and NASH livers. Our five-in-one protocol simultaneously isolates key liver cell types with high purity under normal and NASH conditions, enabling for systematic and accurate exploratory experiments such as RNA sequencing.

关键词： balcony   ethnography   gender   liminal   mobilities   more-than-human   space  

摘要： Balconies, windows and terraces have come to be identified as spaces with newfound meaning over the past year due to the Covid-19 pandemic and concomitant lockdowns. There was not only a marked increase in the use of these spaces, but more importantly a difference in the very nature of this use since March 2020. It is keeping this latter point in mind, that I make an attempt to understand the spatial mobilities afforded by the balcony in the area of ethnographic research. The street overlooking my balcony, situated amidst an urban village in the city of Delhi - one of my field sites, is composed of middle and lower-middle class residents, dairy farms and farmers, bovines and other nonhumans. In this note, through ethnographic observations, I reflect upon the balcony as constituting that liminal space between 'field' and 'home', as well as, as a spatial framing device which conditions and affects our observations and interactions. This is explored by examining two elements - the gendered nature of the space, and the notion of 'distance and proximity', through personal narratives of engaging-with the field, and subjects-objects of study in the city.

关键词： Activation mapping   Catheter ablation   Pacemapping   Premature ventricular complexes   Radiofrequency ablation  

摘要： BACKGROUND Pacemapping (PM) is a useful maneuver for aiding premature ventricular complex (PVC) ablation. Its standalone clinical value is still to be defined. OBJECTIVES The purpose of this study was to analyze the efficacy of a predefined PM protocol for low-burden PVC ablation, regardless of their site of origin (SOO) and the presence of structural heart disease. METHODS This was a prospective, nonrandomized, multicenter study. The PM protocol was performed when,1 PVC/min was found. The "target area" was delimited by the 3 best matching points.94% correlation, and 3 radiofreqency (RF) applications were delivered. RESULTS Of 185 patients, 105 (57%) underwent activation mapping, 60 (32%) were PM-guided, and 20 (11%) were canceled due to absence of PVCs. Baseline QRS, PVC burden, and outflow tract origin were independent predictors of PM-guided ablation. A higher proportion of right ventricular outflow tract SOO in the PM group (52% vs 40%;P =.03) was observed. Mean target area was 0.6 +/- 0.9 cm(2). Mean 10-ms isochronal area in local activation time (LAT)-guided procedures was higher (1.7 +/- 2.3 cm(2);P <.001). Mean number of PM matching points acquired was 39 +/- 21 (range 6-98). Mean mapping and RF times were similar in both groups. However, significantly shorter procedural (53 +/- 24 vs 61 +/- 26 minutes;P =.04) as well as RF times (111 6 51 vs 149 6 149 seconds;P 5.05) were needed in the PM group using the proposed protocol. Global clinical success reached 87% for the PM group and 90% (P 5.58) the for LAT mapping group. CONCLUSION When LAT mapping is precluded, application of a PMguided ablation protocol directed to.94% matching correlation target area is a more efficient alternative with comparable clinical results.

关键词： Alzheimer disease   MAPK signaling pathway   Amyloid-beta   P38   ERK   JNK  

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： Bone   Metabolism   Bioenergetics   ATP   Metabolomics   LC-MS   MS  

摘要： Introduction Skeletal homeostasis is an exquisitely regulated process most directly influenced by bone resorbing osteoclasts, bone forming osteoblasts, and the mechano-sensing osteocytes. These cells work together to constantly remodel bone as a mechanism to prevent from skeletal fragility. As such, when an individual experiences a disconnect in these tightly coupled processes, fracture incidence increases, such as during ageing, gonadal hormone deficiency, weightlessness, and diabetes. While therapeutic options have significantly aided in the treatment of low bone mineral density (BMD) or osteoporosis, limited options remain for anabolic or bone forming agents. Therefore, it is of interest to continue to understand how osteoblasts regulate their metabolism to support the energy expensive process of bone formation. Objective The current project sought to rigorously characterize the distinct metabolic processes and intracellular metabolite profiles in stromal cells throughout osteoblast differentiation using untargeted metabolomics. Methods Primary, murine bone marrow stromal cells (BMSCs) were characterized throughout osteoblast differentiation using standard staining protocols, Seahorse XFe metabolic flux analyses, and untargeted metabolomics. Results We demonstrate here that the metabolic footprint of stromal cells undergoing osteoblast differentiation are distinct, and while oxidative phosphorylation drives adenosine triphosphate (ATP) generation early in the differentiation process, mature osteoblasts depend on glycolysis. Importantly, the intracellular metabolite profile supports these findings while also suggesting additional pathways critical for proper osteoblast function. Conclusion These data are the first of their kind to characterize these metabolites in conjunction with the bioenergetic profile in primary, murine stromal cells throughout osteoblast differentiation and provide provocative targets for future investigation.