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关键词： cancer   chimeric antigen receptor   IKK epsilon   immunotherapy   lentivirus   natural killer   TBK1   VSV-G  

摘要： Background aims: Vesicular stomatitis virus G (VSV-G)-pseudotyped lentiviral vectors (LVs) are widely used to reliably generate genetically modified, clinical-grade T-cell products. However, the results of genetically modifying natural killer (NK) cells with VSV-G LVs have been variable. The authors explored whether inhibition of the IKK-related protein kinases TBK1 and IKK epsilon, key signaling molecules of the endosomal TLR4 pathway, which is activated by VSV-G, would enable the reliable transduction of NK cells by VSV-G LVs. Methods: The authors activated NK cells from peripheral blood mononuclear cells using standard procedures and transduced them with VSV-G LVs encoding a marker gene (yellow fluorescent protein [YFP]) or functional genes (chimeric antigen receptors [CARs], co-stimulatory molecules) in the presence of three TBK1/IKK epsilon inhibitors (MRT67307, BX-795, amlexanox). NK cell transduction was evaluated by flow cytometry and/or western blot and the functionality of expressed CARs was evaluated in vitro. Results: Blocking TBK1/IKK epsilon during transduction of NK cells enabled their efficient transduction by VSV-G LVs as judged by YFPexpression of 40-50%, with half maximal effective concentrations of 1.1 mu M (MRT67307), 5 mu M (BX-795) and 24.8 mu M (amlexanox). Focusing on MRT67307, the authors successfully generated NK cells expressing CD19-CARs or HER2-CARs with an inducible co-stimulatory molecule. CAR NK cells exhibited increased cytolytic activity and ability to produce cytokines in comparison to untreated controls, confirming CAR functionality. Conclusions: The authors demonstrate that inhibition of TBK1/IKK epsilon enables the reliable generation of genetically modified NK cells using VSV-G LVs. The authors' protocol can be readily adapted to generate clinical-grade NK cells and thus has the potential to facilitate the clinical evaluation of genetically modified NK cell-based therapeutics in the future. (C) 2021 International Society for C

摘要： Using toric geometry we give an explicit construction of the compact steady solitons for pluriclosed flow first constructed in by the first author in 2019. This construction also reveals that these solitons are generalized Kahler in two distinct ways, with vanishing and nonvanishing Poisson structure. This gives the first examples of generalized Kahler structures with nonvanishing Poisson structure on nonstandard Hopf surfaces, completing the existence question for such structures. Moreover, this gives a complete answer to the existence question for generalized Kahler-Ricci solitons on compact complex surfaces. In the setting of generalized Kahler geometry with vanishing Poisson structure, we show that these solitons are unique. We show that these solitons are global attractors for the generalized Kahler-Ricci flow among metrics with maximal symmetry. (c) 2020 Wiley Periodicals LLC

关键词： Always on   clock-free multi-function detectors   event-driven architecture   Internet of Things (IoTs)   level-crossing ADC (LCADC)   random sparse events (RSEs)   software-defined functions   time shielding (TS) technique   ultra-low power (ULP)   wake up  

摘要： This work presents an ultra-low-power software-defined always-on wake-up system to drastically decrease the system power of Internet of Things (IoTs) devices, which usually operate in random-sparse-event (RSE) scenarios. It mainly thanks to a clock-free time-shielding level-crossing ADC (TS-LCADC), software-defined clock-free multi-function detectors, and an asynchronous pipelined event-driven architecture. First, by quantifying RSE noisy signals with clock-free adaptive sampling in a signal-noise-rejecting manner, the proposed TS-LCADC reduces number of sampling points and power, and consumes only 41 nW when on-call waiting for IoT events. Second, the proposed clock-free multi-function detectors with offline and online programmability are able to character the signal features of versatile IoTs events and allow versatile and dynamic wake-up functions. Third, the proposed asynchronous pipelined event-driven architecture minimizes the system activity and thus power, because a power-hungry high-performance system (HPS) is only woken up when a detected parameter crosses its corresponding threshold. As such, the long-term average power (LTA-power) is dominated by the always-on circuits in RSE scenarios. The measurement results achieve 71-75 nW for three typical applications, i.e., heart rate, epilepsy, and keyword envelope detection. The LTA power is only 57 nW when waiting for RSE events, which is 30x lower than a prior general-purpose wake-up chip. Compared with other works of dedicated voice and acoustic wake-up functions, this work consumes 2x and 17x less power, respectively, while featuring 16x higher signal bandwidth and a broader versatility.

摘要： Purpose: There is controversy about the need to target the mucosa of the larynx and hypopharynx during radiation therapy (RT) for squamous cell carcinoma of an unknown primary site (SCCA-UP). By 1997, the policy in our department was to target only the oropharynx and nasopharynx in patients with SCCA-UP metastatic to the level II cervical nodes. The purpose of this study was to report the rate of cancer recurrence in the larynx or hypopharynx using an approach that excluded these areas from the RT target volumes. Methods and Materials: The inclusion criteria for this study were RT in our department for SCCA-UP between January 1, 1997, and December 31, 2019;no history of surgery that could disrupt the cervical lymphatics;predominant adenopathy in level IIA;and neck stage N1-2c. We excluded N3 because the incidental dose to the larynx and hypopharynx is usually high in patients with a >6-cm nodal conglomerate. Results: The study population was comprised of 50 patients with a median follow-up after RT of 7.1 years. No patient developed recurrent cancer in a mucosal site (0/50), 2% (1/50) developed a neck recurrence in a high-dose area with synchronous distant metastases, and 2% (1/50) developed distant metastases with no evidence of local or regional recurrence. Conclusions: When delivering RT for SCCA-UP metastatic predominantly to level IIA, it is not necessary to target the mucosa of the larynx or hypopharynx. The extent to which the incidental RT dose to these areas contributes to cancer control is not evaluated in this study. (c) 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

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： 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： Passive greenhouse systems   glazed balconies   temperature monitoring   multi-family buildings   adaptive comfort  

摘要： Greenhouse systems in the form of glazed balconies may be accomplished both in the newly designed buildings and in the existing ones, raising their energy standard in a quick and inexpensive way. However, basic parameters influencing the efficiency of the systems are often chosen intuitively, not allowing to fully benefit from the sunspaces or causing overheating of the rooms and discomfort for the users. These issues are common drawbacks of passive systems and may become especially important in the aspect of anthropogenic climate changes, including temperature rise and summer heatwaves. The paper presents results of a long-term summer temperature monitoring in flats with glazed balconies of different construction. They were located in prefabricated multi-family buildings, in residential districts of Lublin and Zamosc. The cities are situated in the south-eastern part of Poland, belonging to the warm-summer humid continental climate area. The monitoring enabled overheating assessment according to the concept of adaptive comfort and connecting it with the sunspace construction and the inhabitants' behaviour. These issues are new aspects in the research area, and the work is a part of extensive studies including monitoring and dynamic simulations of dwellings with passive greenhouse systems in Poland.

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： Focal segmental glomerulosclerosis   Serum immunoglobulin G   Class-switched memory B cells   Plasmablasts  

摘要： Background: Focal segmental glomerulosclerosis (FSGS) is a kidney-specific autoimmune disease, but its pathogenesis is not fully known. The present study detected the frequencies of circulating memory B cells and plasmablasts and other clinical parameters in FSGS. Methods: We monitored 16 primary FSGS patients and 23 healthy controls (HC). Flow cytometry was used to analyze circulating memory B cell and plasmablasts percentages. Serum IgG levels were detected using a cytometric bead array (CBA). Results: The proportions of CD27 + IgD-class-switched memory B cells (P = 0.0002), CD27 + IgD-IgG + class-switched memory B cells (P < 0.0001), CD27hiCD38hi plasmablasts (P < 0.0001) and CD138 + plasma cells (P < 0.0001) were markedly elevated in FSGS patients, and the frequency of CD38 + IgG + plasmablasts (P < 0.0001) and serum IgG levels (P < 0.0001) were lower compared to HC. In the FSGS patients, the frequency of CD27 + IgD-IgG + class-switched memory B cells negatively correlated with CD38 + IgG + plasmablasts (P = 0.0183, R = -0.3375), serum IgG levels (P = 0.0061, R = -0.4263) and estimated glomerular filtration rate (eGFR) (P = 0.0074, R = -0.4114) but positively correlated with 24-h urinary protein levels (P = 0.0077, R = 0.4085). The proportion of CD38 + IgG + plasmablasts positively correlated with serum IgG levels (P = 0.0151, R = 0.3538). Conclusions: We speculate that alterations in the frequencies of CD27 + IgD-IgG + class-switched memory B cells and plasmablasts may be responsible for the etiopathogenesis of FSGS.

摘要： Take Home MessageAdjuvant therapy with antiangiogenic agents in locoregional renal cell carcinoma did not translate into a sufficient benefit and highlight the crucial role of patient selection. Ongoing clinical trials with immune-targeted agents hold great promise for this unmet clinical need.