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Abstract Human natural killer (NK) cell-based therapies are under assessment for treating various cancers, but cryopreservation reduces both the recovery and function of NK cells, thereby limiting their therapeutic feasibility. Using cryopreservation protocols optimized for T cells, here we find that ~75% of NK cells die within 24 h post-thaw, with the remaining cells displaying reduced cytotoxicity. Using CRISPR-Cas9 gene editing and confocal microscopy, we find that cryopreserved NK cells largely die via apoptosis initiated by leakage of granzyme B from cytotoxic vesicles. Pretreatment of NK cells with a combination of Interleukins-15 (IL-15) and IL-18 prior to cryopreservation improves NK cell recovery to ~90-100% and enables equal tumour control in a xenograft model of disseminated Raji cell lymphoma compared to non-cryopreserved NK cells. The mechanism of IL-15 and IL-18-induced protection incorporates two mechanisms: a transient reduction in intracellular granzyme B levels via degranulation, and the induction of antiapoptotic genes.

Abstract Objective To analyze the efficacy and adverse effects of anti‐PD‐1 immune checkpoint inhibitors aimed at nasopharyngeal carcinoma (NPC). Methods During the first stage of the study, using 40 patients with stage III/IVa NPC treated with anti‐PD‐1 immune checkpoint inhibitors in combination with chemoradiotherapy as a first‐line treatment (observation group) and 70 patients with NPC treated with chemoradiotherapy alone (control group). In the second stage of the study, 88 patients with NPC treated with immune checkpoint inhibitors were grouped according to the number of lines of immunotherapy, the number of times, and the types of application. Results Observation of the short‐term effects in the first stage indicated that the objective response rate (ORR) of the observation group and the control group against primary foci of NPC was 75.0% versus 40.0%; the mortality rate of the observation group was much lower than that of the control group. The overall first‐line treatment evaluation of the observation vs. control groups were as follows: ORR (67.5% vs. 38.6%); median PFS (17.52 vs. 17.21 months); and median OS (18.68 vs. 18.14 months), respectively (p

Abstract Background Extracellular vesicles (EVs) can be secreted by a wide variety of cells, including tumor cells, and contain some bioactive molecules from the source cells. Therefore, they can potentially be used as biomarkers for early diagnosis of tumors and for tumor therapy. In addition, EVs can affect the features of target cells and participate in regulating the development process of tumors. Methods A literature review was conducted to elucidate the role of extracellular vesicles in the progression and treatment of nasopharyngeal carcinoma. Results In this review, we discuss the molecular mechanisms of cell proliferation, angiogenesis, epithelial‐mesenchymal transformation and metastasis, immune response, and chemo‐radiotherapy resistance that are induced by EVs. We also reviewed the potential applications of EVs as biomarkers, therapeutic agents, and carriers so as to determine new directions for the early diagnosis and targeted therapy of nasopharyngeal carcinoma. The application limitations have also been discussed in this review, further work is needed to ensure optimal outcomes for patients. Conclusion Although the roles of extracellular vesicles in the progression of nasopharyngeal carcinoma have been summarized, some aspects are still unclear and need to be further studied. In addition, the applications of extracellular vesicles in the treatment of nasopharyngeal carcinoma still need to optimize conditions to produce better therapeutic outcomes for patients with nasopharyngeal carcinoma.

ABSTRACT Aims/Introduction To explore the predicting factors of exercise response (whether the participants converted to diabetes) in elderly patients with prediabetes. Materials and Methods This is a retrospective subgroup analysis of the registered clinical trial with previous publication of the same cohort. A total of 248 participants with prediabetes were randomized to the aerobic training (n = 83) group, resistance training (n = 82) group and control group (n = 83). The patients who finished the 2‐year exercise intervention were included in this analysis to explore the factors impacting exercise response. Results A total of 113 patients with prediabetes completed 2 years of exercise, with 56 participants in the aerobic exercise group and 57 in the resistance exercise group. Patients who reversed to normal glucose tolerance, remained in prediabetes and developed diabetes were 18 (15.90%), 70 (62.00%) and 25 (22.10%), respectively. Logistic regression showed that baseline, homeostatic model 2 assessment of β‐cell function (β = −0.143, P = 0.039), hemoglobin A1c (β = 3.301, P = 0.007) and body mass index (β = 0.402, P = 0.012) were related to exercise response, whereas the waist‐to‐hip ratio (β = −3.277, P = 0.693) and types of exercise (β = 1.192, P = 0.093) were not significantly related to exercise response. Conclusions Baseline homeostatic model 2 assessment of β‐cell function, hemoglobin A1c and body mass index were the predictors for the response to exercise in elderly patients with prediabetes.

Gastric cancer (GC) ranks as the most common gastrointestinal cancer and is among the leading causes of cancer death worldwide. Glaucocalyxin A (GLA), an entkauranoid diterpene isolated from Rab-dosia japonica var., possesses various bioactivities. To date, the data on the effect of GLA on GC are still minimal, and the molecular mechanisms remain largely unknown. Herein, we found that GLA could significantly inhibit the proliferation, cell adhesion, and invasion of HGT-1, SNU-1, SNU-6, and NCI-N87 GC cells in a dose-dependent manner. GLA enhanced the apoptosis of the GC cells as evidenced by the increased caspase-3 activity and the elevated levels of cleaved caspase-3 and cleaved PARP in GC cells in the presence of GLA. We then showed that the downregulation of Murine Double Minute Clone 2 (MDM2) and Ring Finger Protein 6 (RNF6) by GLA was implicated in the GLA-induced inhibition of the GC cells. Furthermore, MDM2 and RNF6 were identified as the targets of miR-3658 that was downregulated in the GC cells and upregulated by GLA. Moreover, it was shown that miR-3658 was hypermethylated in the GC cells, and GLA could rescue the expression of miR-3658 via demethylation by abrogating EZH2-mediated epigenetic silencing. In addition to the miR-3658-MDM2/RNF6 regulatory axis, activation of the SMG1-UPF mRNA decay pathway contributed to the downregulation of MDM2 and RNF6 by GLA in the GC cells. The inhibitory effect of GLA on gastric cancer and the expression of MDM2 and RNF6 was also validated in in vivo study. Our findings suggest that has the therapeutic potential for GC by downregulating oncogenes via posttranscriptional regulation.

ObjectiveThis study aimed to explore the relationship between short-term (≤12 months) changes in the estimated glomerular filtration rate (eGFR) and hemoglobin A1c (HbA1c) in patients with type 2 diabetes (T2D).MethodA total of 2,599 patients with T2D were enrolled if they were registered in the Diabetes Sharecare Information System, were aged 18–75 years, and had 2–3 HbA1c and eGFR measurements within the preceding 12 months. The studied patients were categorized into five groups based on eGFR, i.e., the relatively stable (RS), fast decline (FD), modest decline (MD), modest increase (MI), and fast increase (FI) groups.ResultsThe median eGFR changes from baseline were −22.14, −6.44, 0.00, 6.32, and 20.00 ml/min per 1.73 m2 for patients in the FD, MD, RS, MI, and FI groups, respectively. Up to 1,153 (44.4%) subjects experienced an eGFR decline of ≥3.5 ml/min per 1.73 m2, including 821 (31.6%) FD subjects and 332 (12.8%) MD subjects. A decreased trend was found between the eGFR change and HbA1c decrease category, even after multivariable adjustment. In general, an eGFR FD was frequently found in patients who had an HbA1c reduction of ≥3.00% and a baseline HbA1c ≥8.0%; alternatively, such a result was also observed for a urinary albumin-to-creatinine ratio (UACR) of 30.0–300.0 mg/g, regardless of a diabetes duration of

Objective. This research attempted to explore the neuroprotective effect of choline and establish evidence for future dietary recommendations and nutritional interventions to maintain a proper cognitive function among elders aged >60 years in the US. Method. This cross-sectional study retrieved data of 2,393 eligible elderly participants from the 2011-2014 National Health and Nutrition Examination Survey. Combining dietary and supplement choline intake, total choline intake was evaluated using the 24-hour dietary recall method and the dietary supplement questionnaire. Total choline intake was categorized into tertiles, which ranged at 399.50 mg/day (T3). The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning subtest, Animal Fluency (AF) test, and Digit Symbol Substitution test (DSST) was used to measure cognitive function. Participants who scored the lowest 25th percentile in each cognitive test were classified in the low cognitive function (LC) group. Logistic regression models were implemented to examine the association between total choline intake and the incidence of LC. Results. In the CERAD test, the risk of LC was significantly lower in T2 than T1 (OR: 0.668, 95% CI: 0.493-0.904, and P=0.006) when adjusted for age, gender, BMI, alcohol consumption, and hypertension. Similarly, T2 was associated with a significantly lower risk of LC when assessed by the AF test (OR: 0.606, 95% CI: 0.580-0.724, and P

Background: Self-expanding devices, such as the Enterprise VRD (EP-VRD) have widely used for stent-assisted coiling treatment in wided-necked aneuryms while some thromboembolic complications were reported due to its incomplete stent apposition (ISA). We report our experiences on the novel Enterprise2 (EP-VRD2) stent in vivo in the treatment of intracranial and cranial cervical junction aneurysms.Methods: Twenty-five consecutive patients with intracranial or cranial cervical junction aneurysms were treated with EP-VRD2 stents retrospectively collected in our institution. We use the ‘jailing' technique in all cases and deployed the stent by using pushing over the outer curve technique. The 3- or 6-monthS follow-up was done regularly by DSA.Results: Twenty-five EP-VRD2 stents were implanted to treat 21 aneurysms at the siphon segment of internal carotid artery (ICA), one at the petrous segment, two at the cervical segment, one at the verteral artery with five accompanied with stenosis. Two patients had kinking during the procedure and were solved by microwire or microcatheter massaging. Four patients with a larger arc angle and a smaller radius of the parent vessel was detected ISA. No patient underwent the ischemic event after the operation. Twenty-three of 25 patients were evaluated after 3- or 6-months by DSA, 22 showed complete occlusion (RROC1), one slight re-stenosis in the follow-up within those five patients with stenosis. A length of 23 mm seemed associated with ISA (p < 0.01).Conclusion: The EP-VRD2 performed well in our small patient series; however, ISA could still occur with a sharp angle of the parent vessel.

Circular RNAs (circRNAs) are an emerging class of RNA species that may play a critical regulatory role in gene expression control, which can serve as diagnostic biomarkers for many diseases due to their abundant, stable, and cell- or tissue-specific expression. However, the association between circRNAs and atrial fibrillation (AF) is still not clear. In this study, we used RNA sequencing data to identify and quantify the circRNAs. Differential expression analysis of the circRNAs identified 250 up- and 126 down-regulated circRNAs in AF subjects compared with healthy donors, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the parental genes of the dysregulated circRNAs indicated that the up-regulated parental genes may participate in the process of DNA damage under oxidative stress. Furthermore, to annotate the dysregulated circRNAs, we constructed and merged the competing endogenous RNA (ceRNA) network and protein-protein interaction (PPI) network, respectively. In the merged network, 130 of 246 dysregulated circRNAs were successfully characterized by more than one pathway. Notably, the five circRNAs, including chr9:15474007-15490122, chr16:75445723-75448593, hsa_circ_0007256, chr12:56563313-56563992, and hsa_circ_0003533, showed the highest significance by the enrichment analysis, and four of them were enriched in cytokine-cytokine receptor interaction. These dysregulated circRNAs may mainly participate in biological processes of inflammatory response. In conclusion, the present study identified a set of dysregulated circRNAs, and characterized their potential functions, which may be associated with inflammatory responses in AF. To our knowledge, this is the first study to uncover the association between circRNAs and AF, which not only improves our understanding of the roles of circRNAs in AF, but also provides candidates of potentially functional circRNAs for AF researchers.

The path planning of Unmanned Aerial Vehicle (UAV) is a critical issue in emergency communication and rescue operations, especially in adversarial urban environments. Due to the continuity of the flying space, complex building obstacles, and the aircraft's high dynamics, traditional algorithms cannot find the optimal collision-free flying path between the UAV station and the destination. Accordingly, in this paper, we study the fast UAV path planning problem in a 3D urban environment from a source point to a target point and propose a Three-Step Experience Buffer Deep Deterministic Policy Gradient (TSEB-DDPG) algorithm. We first build the 3D model of a complex urban environment with buildings and project the 3D building surface into many 2D geometric shapes. After transformation, we propose the Hierarchical Learning Particle Swarm Optimization (HL-PSO) to obtain the empirical path. Then, to ensure the accuracy of the obtained paths, the empirical path, the collision information and fast transition information are stored in the three experience buffers of the TSEB-DDPG algorithm as dynamic guidance information. The sampling ratio of each buffer is dynamically adapted to the training stages. Moreover, we designed a reward mechanism to improve the convergence speed of the DDPG algorithm for UAV path planning. The proposed TSEB-DDPG algorithm has also been compared to three widely used competitors experimentally, and the results show that the TSEB-DDPG algorithm can archive the fastest convergence speed and the highest accuracy. We also conduct experiments in real scenarios and compare the real path planning obtained by the HL-PSO algorithm, DDPG algorithm, and TSEB-DDPG algorithm. The results show that the TSEB-DDPG algorithm can archive almost the best in terms of accuracy, the average time of actual path planning, and the success rate.

Increasing attention has been paid to the application of Unmanned Aerial Vehicles (UAVs) in traffic field. Existing studies on UAVs in road patrol task assignment rarely integrate the actual requirements of multiple bases, charging problems during inspection and multiple types of UAVs into the patrol model, and rarely consider the fastest time to complete the patrol of all task points as the optimization target. In addition, most existing solving algorithms are difficult to use to directly solve problem models meeting the above requirements and objectives, and some existing algorithms need to be improved in terms of solving quality. In order to solve those problems, a task assignment model for road patrol by multiple UAVs with multiple bases and rechargeable endurance is established, and a time-priority immune clonal selection algorithm with optimization-revision is proposed. The optimal sequence of task points is obtained by the immune clonal selection algorithm, and the time-priority method is adopted to divide the sequence of task points. The optimal UAV paths are further optimized and modified. With 20 task points, the experimental results show that the earliest completion time obtained by the proposed algorithm decreased by 1.071 and 2.1209 compared with the earliest reachable time particle swarm optimization algorithm and the improved dynamic programming ant colony algorithm, respectively. The results indicate that proposed algorithm achieves better performance in terms of solution quality. In addition, experiments with 50 and 100 task points show that the algorithm is also suitable for medium and large scale problems.

The Maccullochella peeli belongs to family Maccullochella, and is distributed in Australia and South America (mainly Argentina and Chile). In this paper, the complete mitochondrial genome of M. peeli was determined using next-generation sequencing. The whole mitogenome is a typical circular DNA molecule of 16,442 bp and contains 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and a D-loop region, with the base composition of A 31.6%, G 14.3%, T 26.3%, and C 27.8%. Phylogenetic analysis showed that M. peeli was the nearest sister to Macquaria australasica. Our whole mitogenome presented here would be useful for further study of M. peeli.