Demethylating therapy increases cytotoxicity of CD44v6 CAR-T cells against acute myeloid leukemia

BackgroundCD44v6 chimeric antigen receptor T (CD44v6 CAR-T) cells demonstrate strong anti-tumor ability and safety in acute myeloid leukemia (AML). However, the expression of CD44v6 on T cells leads to transient fratricide and exhaustion of CD44v6 CAR-T cells, which affect the application of CD44v6 CAR-T. The exhaustion and function of T cells and CD44v6 expression of AML cells are associated with DNA methylation. Hypomethylating agents (HAMs) decitabine (Dec) and azacitidine (Aza) have been widely used to treat AML. Therefore, there may be synergy between CD44v6 CAR-T cells and HAMs in the treatment of AML.MethodsCD44v6 CAR-T cells pretreated with Dec or Aza were co-cultured with CD44v6+ AML cells. Dec or aza pretreated AML cells were co-cultured with CD44v6 CAR-T cells. The cytotoxicity, exhaustion, differentiation and transduction efficiency of CAR-T cells, and CD44v6 expression and apoptosis in AML cells were detected by flow cytometry. The subcutaneous tumor models were used to evaluate the anti-tumor effect of CD44v6 CAR-T cells combined with Dec in vivo. The effects of Dec or Aza on gene expression profile of CD44v6 CAR-T cells were analyzed by RNA-seq.ResultsOur results revealed that Dec and Aza improved the function of CD44v6 CAR-T cells through increasing the absolute output of CAR+ cells and persistence, promoting activation and memory phenotype of CD44v6 CAR-T cells, and Dec had a more pronounced effect. Dec and Aza promoted the apoptosis of AML cells, particularly with DNA methyltransferase 3A (DNMT3A) mutation. Dec and Aza also enhanced the CD44v6 CAR-T response to AML by upregulating CD44v6 expression of AML cells regardless of FMS-like tyrosine kinase 3 (FLT3) or DNMT3A mutations. The combination of Dec or Aza pretreated CD44v6 CAR-T with pretreated AML cells demonstrated the most potent anti-tumor ability against AML.ConclusionDec or Aza in combination with CD44v6 CAR-T cells is a promising combination therapy for AML patients

Multivariable optimization of two-stage thermoelectric refrigerator driven by two-stage thermoelectric generator with external heat transfer

731-742The finite time thermodynamic model of a combined thermoelectric device, two-stage thermoelectric refrigerator driven by two-stage thermoelectric generator with heat transfer irreversibility is built by combining non-equilibrium thermodynamic theory with finite time thermodynamics theory. The solution procedure of optimal performance and the corresponding optimal variables are given and the cooling load and COP of the combined thermoelectric device are optimized. The control equation of the combined thermoelectric system is obtained. For fixed total number of thermoelectric elements and fixed total external thermal conductance of the device, the allocations of thermoelectric elements and thermal conductance are optimized for maximum cooling load and COP, respectively. The effects of the heat source temperature of the two-stage thermoelectric generator and the heat source (cooling space) temperature of the two-stage thermoelectric refrigerator on the optimal performance and optimal variables selection are analyzed by detailed numerical examples. The numerical simulation results show that the optimization is necessary and effective. By optimization, the performance is improved. When the two-stage thermoelectric generator works at a difference of 150 K, a cooling temperature difference of about 60 K could be reached. When the two-stage thermoelectric refrigerator works at a difference of 20 K, a COP of about 0.10 could be reached. These are considerable for application in a wide-scale for specific purpose

Influences of the Thomson Effect on the Performance of a Thermoelectric Generator-Driven Thermoelectric Heat Pump Combined Device

A thermodynamic model of a thermoelectric generator-driven thermoelectric heat pump (TEG-TEH) combined device is established considering the Thomson effect and the temperature dependence of the thermoelectric properties based on non-equilibrium thermodynamics. Energy analysis and exergy analysis are performed. New expressions for heating load, maximum working temperature difference, coefficient of performance (COP), and exergy efficiency are obtained. The performance is analyzed and optimized using numerical calculations. The general performance, optimal performance, optimum variables, optimal performance ranges, and optimum variable ranges are obtained. The results show that the Thomson effect decreases the general performance and optimal performance, and narrows the optimal operating ranges and optimum variable ranges. Considering the Thomson effect, more thermoelectric elements should be allocated to the thermoelectric generator when designing the devices. The optimum design variables for the maximum exergy efficiency are different from those for the maximum COP. The results can provide more scientific guidelines for designing TEG-TEH devices

Study on City-Level Optimization of Tourism Industry Spatial Organization Nodes and Organization Mode for Tourist Destinations

Reasonable spatial organization of the tourism industry can improve the utilization efficiency of regional tourism industry elements. Taking Dalian City in China as an example, this paper collects various types of tourism industry data and introduces GIS network analysis technology into tourism studies to determine the location, scale, and number of tourism nodes in Dalian and optimize the spatial organization nodes and organization models of the tourism industry. This will help ease the pressure on tourism reception in the southern area of Dalian and promote better development and utilization of tourism resources and tourism facilities in the central and northern regions. The results show that (1) when using the “minimizing facility points” model, a total of 17 second-level tourism nodes and 5 first-level tourism nodes are obtained after optimization. The location of these nodes is highly correlated with the level of tourist scenic spots, while tourist scenic spots play a significant role in leading and driving tourism nodes. (2) Using the “maximum coverage” model for optimization, 3138 tourism enterprises are connected with tourism nodes, thus realizing the shortest traffic path between tourism enterprises and tourism nodes, which minimizes the total cost of network services. Compared with suburban areas, enterprises in urban tourism areas are densely distributed, meaning that a smaller service radius of tourism nodes can cover more enterprises. (3) A total of 10 first-level tourism channels and 12 second-level tourism channels are optimized using the “nearest facility” model. The first-level tourism channels are mainly distributed in the central and southern areas of Dalian. These channels connect nodes mainly through national and provincial roads. The second-level tourism channels are mainly distributed in the central and northern areas of Dalian. (4) This study aims to analyze the evolution process of the spatial organization mode of Dalian’s tourism industry and construct a hub-spoke network tourism industry spatial organization mode composed of 17 hubs, 22 spokes, and 22 tourism domains. The analysis and construction are designed according to the optimization results of tourism nodes and tourism channels. The research results enrich the theories and technical means of tourism industry spatial organization and provide references and suggestions for local governments or tourism planning decision-makers; they also provide a scientific basis for the rational allocation of tourism industry elements and promote the rational distribution of tourism industry

New fossil leaves and fruits of Lauraceae from the Middle Miocene of Fujian, southeastern China differentiated using a cluster analysis

<p>The fossil record of Lauraceae can be traced back to the Early Cretaceous of eastern Asia based on fossil flowers. Here, we refer a number of new occurrences of leaf and fruit fossils of Lauraceae from the Middle Miocene of Zhangpu, Fujian, China, to seven species. These data provide evidence supporting the fact that a diverse subtropical, or tropical, Lauraceae-dominated evergreen forest surrounded this region 15 million years ago (Mya). The Lauraceae fossils presented in this paper provide evidence for the evolution of this group as well as new materials that enable the study of the Fujian Province Neogene flora. The fossils described in this paper fill in the gaps in studies about Lauraceae pollen in the Middle Miocene from Fotan, Fujian, China. In addition, these fossils also enrich the Middle Miocene fossil records of Lauraceae in eastern Asia, especially improving the study of the macrostructures and reproductive organs of fossil Lauraceae from southern China. The similarity between fossil and modern fruits shows that during the Middle Miocene the fruit morphological of Lauraceae have changed very little. We also identify families where the fossils we report belong to their closest relatives and can be used to reconstruct the paleoenvironment of Fujian in the Middle Miocene.</p

Identification of two new species of Meliolinites associated with Lauraceae leaves from the middle Miocene of Fujian, China

Several studies have investigated both the paleoclimate and the well-preserved fossil remains from the middle Miocene found in China\u27s Fujian Province. This study describes two new species of Meliolinites, including their fungal hyphae, reproductive structures, and spores. The distribution of modern Meliolaceae indicates that they live in warm, humid, subtropical to tropical climates. Moreover, the fossil leaves and the epiphyllous fungal remains, indicate the prevalence of a warm, humid, subtropical to tropical climate in this area during the middle Miocene. In addition, it was observed that the surrounding cells of the fungi found on the uninfected host leaves were normal, whereas the infected host leaves themselves were abnormally dim. These features are a reflection of self-protection, and it can, therefore, be inferred that the host leaves were alive when they were infected. The present study used fossil angiosperm leaves with cuticles obtained from the Fotan sediments from Fujian to investigate not only the taxonomy of the fossils but also to interpret the paleoclimate and paleoecology

The diversity and paleoenvironmental significance of <i>Calophyllum</i> (Clusiaceae) from the Miocene of southeastern China

<p>Three species within the genus <i>Calophyllum</i> collected from middle Miocene Fotan Group sediments in Zhangpu County, Fujian, southeastern China are described in this paper. These fossils include <i>Calophyllum zhangpuensis</i> sp. nov., <i>Calophyllum striatum</i>, and <i>Calophyllum suraikholaensis</i>. The new fossil species <i>C. zhangpuensis</i> sp. nov. is oval, possesses entire leaves with closely spaced parallel secondary veins and has a round, or slightly retuse, apex. These specimens represent the first known fossil records of this relative wide leaf-type form of <i>Calophyllum</i> from China and have a length:width (L:W) ratio less than 3:1. In combination with the known modern geographic distribution and habitats of this wide leaf-type <i>Calophyllum</i> and other plants, data suggest that the middle Miocene Fotan flora is indicative of a warm climate. Thus, based on available fossil data, we speculate that this genus probably originated in India during the Paleocene before spreading from India to Bangladesh and into China, Sumatra, Malaysia, Indonesia, and Java during the Neogene, leading to its modern distribution. At least, the 3 fossil species in this region can explain floristic exchange between India, Fujian, and South China, which is consistent with previous studies; the occurrence of these 3 species indicates that <i>Calophyllum</i> began to diversity in China no later than the Miocene.</p