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摘要： Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with the development of hematopoietic cancers of B-lymphocyte origin, including AIDS-related non-Hodgkin lymphoma (AIDS-NHL). Primary infection of B-cells with EBV results in their polyclonal activation and immortalization. The transferrin receptor 1 (TfR1), also known as CD71, is important for iron uptake and regulation of cellular proliferation. TfR1 is highly expressed in proliferating cells, including activated lymphocytes and malignant cells. We developed a mouse/human chimeric antibody targeting TfR1 (ch128.1/IgG1) that has previously shown significant antitumor activity in immunosuppressed mouse models bearing human malignant B-cells, including multiple myeloma and AIDS-NHL cells. In this article, we examined the effect of targeting TfR1 to inhibit EBV-driven activation and growth of human B-cells in vivo using an immunodeficient ***-Prkdc(scid) Il2rg(tm1Wjl)/SzJ [NOD/SCID gamma (NSG)] mouse model. Mice were implanted with T-cell-depleted, human peripheral blood mononuclear cells (PBMCs), either without EBV (EBV-), or exposed to EBV in vitro (EBV+), intravenously via the tail vein. Mice implanted with EBV+ cells and treated with an IgG1 control antibody (400 mg/mouse) developed lymphoma-like growths of human B-cell origin that were EBV+, whereas mice implanted with EBV+ cells and treated with ch128.1/IgG1 (400 mg/mouse) showed increased survival and significantly reduced inflammation and B-cell activation. These results indicate that ch128.1/IgG1 is effective at preventing the growth of EBV+ human B-cell tumors in vivo, thus, indicating that there is significant potential for agents targeting TfR1 as therapeutic strategies to prevent the development of EBV- associated B-cell malignancies. Significance: An anti-TfR1 antibody, ch128.1/IgG1, effectively inhibits the activation, growth, and immortalization of EBV+ human B-cells in vivo, as well as the development of these cells into lymphoma-like

关键词： COVID-19   SARS-CoV-2   Spike protein   Binding free energy   Molecular dynamics simulation  

摘要： SARS-CoV-2 is the causative agent of the ongoing viral pandemic of COVID-19. After the emergence of this virus, it became a global public health concern and quickly evolved into a pandemic. Mexico is currently in the third position in the number of deaths due to SARS-CoV-2. To date, there have been several lineages of SARS-CoV-2 worldwide;in the Mexican population, two variants of the spike protein (S-protein) are found, localized at H49Y and D614G, which have been related to increased infectivity with respect to the wild-type S-protein. To understand how these differences impact the structural behavior of the S-protein of SARS-CoV-2, as well as binding with ACE2, we performed MD simulations combined with the molecular mechanics generalized Born/PoissonBoltzmann surface area (MMGB(PB)SA) approach starting from X-ray crystallography data. Energetic and structural analysis showed that the differences in infectivity can be explained by differences in affinity of the protein-protein interface between the wild-type and mutant S-protein with ACE2. Conformational analysis showed that molecular recognition between the S-protein and ACE2 is linked to a decrease in the conformational flexibility of wild-type and mutant S-protein;however, an increase in the conformational mobility of ACE2 could also contribute to the binding affinity observed using the MMGB(PB)SA method.

关键词： cutaneous squamous cell carcinoma   survival   recurrence   neck dissection   adjuvant radiotherapy  

摘要： Objectives: Advanced cutaneous squamous cell carcinoma of the head and neck (CSCCHN) is associated with poor outcome despite multimodality therapy. Comprehensive risk stratification may pinpoint the most suitable adjuvant treatment. This study aimed to evaluate the outcomes of surgically treated locoregional CSCCHN and to identify prognostic indicators of treatment outcomes. Methods: We retrospectively analyzed disease variables, pathologic characteristics, and management in association with treatment outcomes of all consecutive advanced CSCCHN patients who underwent surgical resection at Tel Aviv Sourasky Medical Center. Results: From 2008 to 2018, 74 patients met the inclusion criteria. Only perineural invasion (PNI) was significantly associated with worse overall survival (OS) (P = .001). Location within the facial "mask areas" was significantly associated with pathologically negative cervical disease (P = .001). Forty-seven patients underwent adjuvant radiation therapy (RT) which significantly improved OS and disease-free survival versus surgery alone (P = .025 and P = 0.035, respectively). Conclusion: PNI was associated with worse OS in surgically treated advanced CSCCHN. Adjuvant RT conferred better outcomes despite high risk features.

关键词： Parkinson’   s disease   Human amniotic epithelial cells   Neuroprotection   Dopaminergic neurons   Anti-inflammatory factors   Anti-oxidative stress  

摘要： Human amniotic epithelial cells (hAECs) have been reported to have neuroprotective roles in Parkinson's disease (PD) animal models. However, the molecular mechanism is not fully understood. The present study was designed to explore the possible mechanism by which hAECs ameliorate PD symptoms and the important paracrine factors produced by hAECs that attribute to the recovery of dopaminergic neurons. Thus, we performed in vivo and in vitro experiments with hAECs in PD models or lesioned dopaminergic neurons, respectively. First, hAECs were transplanted into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice and motor deficits were significantly attenuated. Second, the grafts prevented the loss of nigral dopaminergic neurons and promoted the outgrowth of neurites and striatal axon fibers in PD mice. In addition, decreased microglial activation, inflammatory factor levels and MPTP-induced excessive reactive oxygen species (ROS) levels were also observed in hAEC-treated PD mice. In vitro, we found that the conditioned medium (CM) from hAECs promoted the survival of mesencephalic dopaminergic neurons stimulated with 1-methyl-4-phenylpyridine (MPP+) and induced neurite outgrowth. Next, analysis of hAEC-CM with an antibody array of 507 soluble target proteins revealed that the levels of many neurotrophic factors, growth factors, neuronal cell adhesion molecule (NrCAM) and anti-inflammatory factors were evidently high. In addition, antibody neutralization experiments showed that many of these factors contributed to the survival and growth of dopaminergic neurons and neurite outgrowth. More importantly, we found that the anti-inflammatory factor interleukin-1 receptor antagonist (IL-1ra) also augmented the survival of dopaminergic neurons, demonstrating for the first time an anti-oxidative and anti-inflammatory role of hAECs in PD mice, which represents a novel molecular mechanism of hAECs in the treatment of *** molecular mechanism of hAE

关键词： Cryptic species   morphology   Phlebotominae   taxonomic problem   vector-borne disease   vector competence   vectors  

摘要： A species complex (= species group, species series) is an assemblage of species, which are related morphologically and phylogenetically. Recent research has revealed several arthropod vector species that were believed to be a single nominal species actually representing a group of closely related species, which are sometimes morphologically indistinguishable at one or more developmental stages. In some instances, differences in terms of vector competence, capacity, or both have been recorded. It highlights the importance of detecting and studying species complexes to improve our understanding of pathogen transmission patterns, which may be vectored more or less efficiently by different species within the complex. Considering more than 540 species, about one-third of the phlebotomine sand flies in the New World present males and/or females morphologically indistinguishable to one or more species. Remarkably, several of these species may act in transmission of pathogenic agents. In this article, we review recent research on species complexes in phlebotomine sand flies from the Americas. Possible practical implications of recently acquired knowledge and future research needs are also discussed.

关键词： Arsenic   In vitro   Genomics   Mode of action   Carcinogenicity  

摘要： Evidence from both in vivo and in vitro studies suggests that gene expression changes from long-term exposure to arsenite evolve markedly over time, including reversals in the direction of expression change in key regulatory genes. In this study, human uroepithelial cells from the ureter segments of 4 kidney-donors were continuously treated in culture with arsenite at concentrations of 0.1 or 1 mu M for 60 days. Gene expression at 10, 20, 30, 40, and 60 days was determined using Affymetrix human genome microarrays and signal pathway analysis was performed using GeneGo Metacore. Arsenic treated cells continued to proliferate for the full 60-day period, whereas untreated cells ceased proliferating after approximately 30 days. A peak in the number of gene changes in the treated cells compared to untreated controls was observed between 30 and 40 days of exposure, with substantially fewer changes at 10 and 60 days, suggesting remodeling of the cells over time. Consistent with this possibility, the direction of expression change for a number of key genes was reversed between 20 and 30 days, including CFOS and MDM2. While the progression of gene changes was different for each subject, a common pattern was observed in arsenic treated cells over time, with early upregulation of oxidative stress responses (HMOX1, NQ01, TXN, TXNRD1) and down-regulation of immune/inflammatory responses (IKK alpha). At around 30 days, there was a transition to increased inflammatory and proliferative signaling (AKT, CFOS), evidence of epithelial-to-mesenchymal transition (EMT), and alterations in DNA damage responses (MDM2, ATM). A common element in the changing response of cells to arsenite over time appears to involve up-regulation of MDM2 by inflammatory signaling (through AP-1 and NF-kappa B), leading to inhibition of P53 function.

关键词： Thyroid gland   T lymphocytes   Lymphoproliferative disorders   Hashimoto disease   Tertiary lymphoid structures  

摘要： Thyroid lymphoproliferative disorder is known to be associated with Hashimoto thyroiditis. The major histological types of thyroid lymphoproliferative disorders are malignant lymphoma, such as diffuse large B cell lymphoma, extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT), and follicular lymphoma. All of these are B cell lymphomas;however, T cell lymphoproliferative disorders represent only a minority of cases. Since T cell lymphoproliferative disorder rarely develops and T cell lymphoma is a heterogeneous entity, it is difficult to concisely summarize this complex topic. Here, we present a case of primary thyroid T cell lymphoproliferative disorder reminiscent of indolent T cell lymphoproliferative disorder of the gastrointestinal tract: the pathological findings from this case also were similar to those of MALT lymphoma such as small lymphoid cells, lymphoepithelial lesions, and a low Ki-67 labeling index. T cell lymphoproliferative disorders with these pathological features have been reported in the thyroid gland, lymph nodes, palate, spleen, and gastrointestinal tract. Furthermore, we reviewed and summarized the studies on thyroid T cell lymphoproliferative disorders and compared the cases and their clinicopathological characteristics.

关键词： gastrointestinal tract   clear cell sarcoma   gastrointestinal clear cell sarcoma-like tumor   malignant gastrointestinal neuroectodermal tumor   FISH   NGS  

摘要： As the concept of clear cell sarcoma-like tumor or malignant gastrointestinal neuroectodermal tumor (CCS-LT/MGNET) has been widely accepted, primary CCS of the gastrointestinal tract (CCS-GI) is becoming a rare entity. In this article, we describe a case of primary CCS-GI that occurred in the ileum of a 65-year-old male to further illustrate its rare occurrence. Similar to CCS of soft tissue (CCS-ST), the tumor was composed of spindled to epithelioid cells displaying fascicular, nested, or pseudopapillary arrangement. The tumor cells had large round to ovoid nuclei with vesicular chromatin and prominent nucleoli, containing eosinophilic to pale cytoplasm. In contrast to CCS-LT/MGNET, immunohistochemical study also showed variable positivity of HMB45, melan A, and MiTF besides the strong and diffuse staining of S100 protein and SOX10. Fluorescence in situ hybridization (FISH) using fusion probes identified EWSR1 and ATF1 genes rearrangement. Next-generation sequencing (NGS) analysis further revealed EWSR1 exons9/8-ATF1 exon4 and ATF1 exon3- EWSR1 exon11 fusion genes. CCS-GI and CCS-LT/MGNET possibly represent 2 related entities of the same spectrum, which differentiate along 2 different pathways.

关键词： HHT   Hereditary hemorrhagic telangiectasia   ENG   Endoglin   EC   Endothelial cell   HUVEC   Human umbilical vein endothelial cell   HMVEC-L   Human lung microvascular endothelial cell   AVM   Arteriovenous malformation   ALK   Activin receptor-like kinase   SMAD   Mothers against decapentaplegic homolog   TGF-β   Transforming growth factor-beta   ANGPT   Angiopoietin   siRNA   Small interfering RNA   RT-qPCR   Reverse transcription-quantitative polymerase chain reaction   ERK   Extracellular signal-regulated kinase   VEGF-A   Vascular endothelial growth factor A   VEGFR2   Vascular endothelial growth factor receptor 2   TIE2 and TEK   Tyrosine-protein kinase receptor   FGF2   fibroblast growth factor 2   FGFR   Fibroblast growth factor receptor   NF-kB   Nuclear factor kappa B   Sp1   Specific protein 1   Rac1   Ras-related C3 botulinum toxin substrate 1   GAPDH   Glyceraldehyde 3-phosphate dehydrogenase  

摘要： Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular dysplasia. Mutations of the endoglin (ENG) gene that encodes a co-receptor of the transforming growth factor beta 1 signaling pathway cause type I HHT. ENG is primarily expressed in endothelial cells (ECs), but its interaction with other key angiogenic pathways to control angiogenesis has not been well addressed. The aim of this study is to investigate ENG interplay with VEGFR2, FGFR1 and TIE2 in primary human ECs. ENG was knocked-down with siRNA in human umbilical vein ECs (HUVECs) and human lung microvascular ECs (HMVEC-L). Gene expression was measured by RT-qPCR and Western blotting. Cell signaling pathway activation was analyzed by detecting phosphor-ERK and phosphor-AKT levels. Cell migration and apoptosis were assessed using the Boyden chamber assay and the CCK-8 Kit, respectively. Loss of ENG in HUVECs led to significantly reduced expression of VEGFR2 but not TIE2 or FGFR1, which was also confirmed in HMVEC-L. HUVECs lacking ENG had significantly lower levels of active Rac1 and a substantial reduction of the transcription factor Sp1, an activator of VEGFR2 transcription, in nuclei. Furthermore, VEGF- but not bFGF- or angiopoietin-1-induced phosphor-ERK and phosphorAKT were suppressed in ENG deficient HUVECs. Functional analysis revealed that ENG knockdown inhibited cell migratory but enhanced anti-apoptotic activity induced by VEGF. In contrast, bFGF, angiopoietin-1 and -2 induced HUVEC migration and anti-apoptotic activities were not affected by ENG knockdown. In conclusion, ENG deficiency alters the VEGF/VEGFR2 pathway, which may play a role in HHT pathogenesis. (Translational Research 2021;235:129-143)

关键词： thin filament   muscle   sarcomere   actin   myopathy  

摘要： Striated muscle is intricately designed to provide efficient and powerful muscle contractions. Recently, a long sought-after missing component of the thin filament pointed- end machinery was discovered: cyclase- associated protein 2 (CAP2). CAP2 was identified as a crucial contributor to actin polymerization, striated muscle development, and severe muscle disease when mutated.