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关键词： Prognostic markers   Tumour heterogeneity  

摘要： Intratumor heterogeneity has been recognized in numerous cancers as a major source of metastatic dissemination. In uveal melanomas, the existence and identity of specific subpopulations, their biological function and their contribution to metastasis remain unknown. Here, in multiscale analyses using single-cell RNA sequencing of six different primary uveal melanomas, we uncover an intratumoral heterogeneity at the genomic and transcriptomic level. We identify distinct transcriptional cell states and diverse tumor-associated populations in a subset of the samples. We also decipher a gene regulatory network underlying an invasive and poor prognosis state driven in part by the transcription factor HES6. HES6 heterogenous expression has been validated by RNAscope assays within primary human uveal melanomas, which further unveils the existence of these cells conveying a dismal prognosis in tumors diagnosed with a favorable outcome using bulk analyses. Depletion of HES6 impairs proliferation, migration and metastatic dissemination in vitro and in vivo using the chick chorioallantoic membrane assay, demonstrating the essential role of HES6 in uveal melanomas. Thus, single-cell analysis offers an unprecedented view of primary uveal melanoma heterogeneity, identifies bona fide biomarkers for metastatic cells in the primary tumor, and reveals targetable modules driving growth and metastasis formation. Significantly, our findings demonstrate that HES6 is a valid target to stop uveal melanoma progression.

摘要： 2696

关键词： Mantle cell lymphoma   Blastoid variant   Palatine tonsil lymphoma   Waldeyer’   s ring   Head and neck lymphoma  

摘要： Head and neck lymphomas can present with a wide range of symptoms. Timely and accurate diagnosis is often challenging. The blastoid variant of mantle cell lymphoma (MCL) accounts for less than one-third of all MCL cases. Isolated primary presentation on the palatine tonsils is rare, and prognosis and outcome are seemingly unfavorable. An 81-year-old man presented with persistent odynophagia, dysphagia, and obstructive hypertrophic palatine tonsils with purulent exudate. The signs and symptoms were non-responsive to antibiotic therapy, and the tonsils were biopsied. The cellular morphology, immunophenotype, and genotype supported a diagnosis of the blastoid variant of MCL. After staging, the patient underwent chemotherapy with Rituximab-Bendamustine (R-Benda). The patient is in clinical remission more than two years after therapy. We report an exceedingly rare case of blastoid MCL that is prone to be misdiagnosed as tonsillitis. We review the literature and discuss treatment options of this uncommon malignancy.

摘要： 2836

摘要： 473

关键词： mediastinal tumors   germ cell tumors   thoracic surgery   chemotherapy  

摘要： Objective: Treatment of primary mediastinal nonseminomatous germ cell tumors involves cisplatin-based chemotherapy followed by surgery to remove residual disease. We undertook a study to determine short and long-term outcomes. Methods: A retrospective analysis of patients with primary mediastinal nonseminomatous germ cell tumors who underwent surgery at our institution from 1982 to 2017 was performed. Results: A total of 255 patients (mean age, 29.2 years) were identified. Acute respiratory distress syndrome occurred postoperatively in 27 patients (10.9%), which was responsible for all 11 (4.3%) postoperative deaths. Of patients who developed acute respiratory distress syndrome, more patients received bleomycin-containing chemotherapy (25 out of 169;14.8%) than non-bleomycin regimens (2 out of 77;2.6%) (P = .004). With respect to variables independently predictive of longterm survival, evidence of choriocarcinoma before chemotherapy (n = 12) was determined to be an adverse factor (P = .006). In contrast, biopsy-proven elements of seminoma (n = 34) were predictive of improved survival (P = .04). The worst pathology identified in the residual mediastinal mass after chemotherapy was necrosis in 61 patients (25.0%), teratoma in 84 patients (34.4%), and malignant (persistent germ cell or non-germ cell cancer) in 97 patients (39.8%), which influ-enced overall survival (P <.001). Additionally, teratoma with stromal atypia (n = 18) demonstrated decreased survival compared with teratoma without atypia (n = 66;P = .031). Patients with malignancy involving>50% of the residual mass (n = 47) had a 2.3-fold increased risk of death compared with <= 50% malignancy (n = 45;P = .008). Finally, elevated postoperative serum tumor markers (n = 40) was significantly predictive of adverse survival (P < .001). Conclusions: In the treatment of primary mediastinal nonseminomatous germ cell tumors, avoiding bleomycin-containing chemotherapy is important. Pre-and post chemotherapy pathology an

关键词： Image recognition   Image classification   AutoML   Architecture search  

摘要： In recent years, the neural architecture search has continuously made significant progress in the field of image recognition. Among them, the differentiable method has obvious advantages compared with other search methods in terms of computational cost and accuracy to deal with image classification. However, the differentiable method is usually composed of single cell, which cannot efficiently extract the features of the network. In response to this problem, we propose a multi-level cell progressive differentiable method which allows cells to have different types according to the levels of the network. In differentiable method, the gap between the search network and the evaluation one is large, and the correlation is low. We design an algorithm to improve the distribution of architecture parameters. We also optimize the loss function and use the regularization method of additional action to improve deep network performance. The method achieves good search and classification results on CIFAR10 and ImageNet (mobile setting).

关键词： AscH2   Bactericidal activity   Primary human umbilical vein endothelial cells   HUVEC survival and function   Immunomodulatory effect   S   aureus infection  

摘要： Background: Vitamin C (ascorbic acid, AscH2) has been shown to enhance immunity. Here, we studied its immunomodulatory effect on human endothelial cells (ECs) during S. aureus infection. Materials and methods: The ex vivo effects of AscH2 were performed on primary human umbilical vein endothelial cells (HUVECs) infected or not with S. aureus. Results: AscH2 treatment induced a marked downregulation of nitric oxide (NO) production and a moderate upregulation of arginase activity in S. aureus-infected HUVECs (respectively, p < 0.05 and p > 0.05). Although the upregulated release levels of soluble intercellular adhesion molecular 1 (sICAM-1/sCD54) and sE-selectin (sCD62E) molecules were not significantly different between treated and untreated S. aureus-infected HUVECs, AscH2 treatment induced reversing effect on sICAM-1 release when comparing to uninfected control HUVECs. Moreover, AscH2 treatment appears to have a significant effect on preventing HUVEC necrosis induced by S. aureus infection (p < 0.05). Furthermore, AscH2 treatment induced a significant upregulation of cell protective redox biomarker in S. aureus-infected, as shown by superoxide dismutase (SOD) activity (p < 0.05), but not by catalase activity (p > 0.05). Additionally, S. aureus infection markedly downregulated total bound calcium ions (bCa2+) levels as compared to control HUVECs, whereas, AscH2 treatment induced a slight upregulation of bCa2+ levels in infected HUVECs as compared to infected and untreated HUVECs (p > 0.05). On the other hand, AscH2 treatment downregulated increased total cellular cholesterol content (tccCHOL) levels in HUVECs induced by S. aureus infection (p < 0.05). In addition, AscH2 treatment markedly reversed S. aureus effect on upregulation of intracellular glucose (iGLU) levels within infected HUVECs (p < 0.05). Moreover, AscH2 treatment significantly downregulated S. aureus growth (p < 0.05), and significantly upregulated bacterial internalization and intracellular killing b

关键词： KIT   Lung cancer   Thymic carcinoma   Tuft cells  

摘要： Introduction: In-depth genomic characterization of thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs), failed to identify targetable mutations and suggested unique biology of TETs, including KIT expression in most TCs. Recently, tuft cell-like medullary thymic epithelial cells were identified in the murine thymus, and our reanalysis of the published gene expression data revealed that these cells express KIT. In addition, recently, a minor subset of SCLCs with tuft cell-like features was described. Methods: We interrogated mRNA expression data from our tumor cohorts (N = 60) and publicly available, independent data sets from TETs and NSCLC (N = 1199) for expression of tuft cell genes and KIT. Expression of KIT and of POU2F3 protein, the master regulator of tuft cells, was analyzed in cancer tissue (N = 344) by immunohistochemistry. Results: Normal human thymic tuft cells and most TCs coexpressed KIT and known tuft cell genes, particularly POU2F3 and GFI1B. Unexpectedly, small subsets of tuft cell- like tumors coexpressing POU2F3, GFI1B, and KIT werealso identified among pulmonary squamous cell carcinomas, adenocarcinomas, and large cell neuroendocrine carcinoma and clustered together in each histologic cohort. In addition to the tuft cell-like signature, both thymic and lung tuft cell-like carcinomas had distinct genetic, pathologic, and clinical features in each cohort. Conclusions: We suggest that the tuft cell-like phenotype defines novel subsets of thymic and pulmonary carcinoma. Its high prevalence in thymic squamous cell carcinomas that have no known toxic or viral etiologies suggests a new mechanism of carcinogenesis that may lead to specific drug susceptibilities. (c) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

关键词： HIV cure   HIV latency reversal   BCL2   venetoclax   proteasome inhibitor   ixazomib   human immunodeficiency virus   latency reversal   proteasome  

摘要： The antiapoptotic protein BCL2 inhibits death of HIV-infected cells. Previously, we showed that the BCL2 inhibitor venetoclax selectively kills acutely HIV-infected cells and reduces HIV DNA in latently infected CD4 T cells ex vivo after reactivation with anti-CD3/anti-CD28. However, there is a need to identify a combination therapy with venetoclax and a clinically relevant latency reversal agent. Ixazomib is an oral proteasome inhibitor which we have shown reactivates latent HIV and predisposes reactivated cells to cell death. Here, we determined that the combination of venetoclax and ixazomib kills more latently HIV-infected cells and leads to greater reduction in HIV replication than either treatment alone in vitro in a T cell model. However, combination treatment of ex vivo CD4 T cells from antiretroviral therapy (ART)-suppressed, HIV-positive participants resulted in unanticipated and unacceptable nonspecific toxicity in primary cells. Therefore, while we show proof of concept that multiple agents can enhance selective killing of HIV-infected cells, the combination of venetoclax and ixazomib has unacceptable toxicity in primary cells, and so further investigation is needed to identify a clinically relevant latency reversal agent to combine with venetoclax as a novel strategy to reduce the size of the HIV reservoir. IMPORTANCE A cure for HIV would require eliminating cells that contain the virus in a latent form from the body. Current antiretroviral medications are unable to rid the body of latently infected cells. Here, we show that a combination of investigational agents-ixazomib plus venetoclax-which reactivate latent virus and predispose infected cells to apoptosis may reduce latent virus in a T cell model, but at the expense of nonspecific toxicity in primary cells.