An integrated analysis of prognostic and immune infiltrates for hub genes as potential survival indicators in patients with lung adenocarcinoma.

OBJECTIVE: Lung adenocarcinoma (LUAD) is one of the major subtypes of lung cancer that is associated with poor prognosis. The aim of this study was to identify useful biomarkers to enhance the treatment and diagnosis of LUAD. METHODS: GEO2R was used to identify common up-regulated differentially expressed genes (DEGs) in the GSE32863, GSE40791, and GSE75037 datasets. The DEGs were submitted to Metascape for gene ontology and pathway enrichment analysis as well as construction of the protein-protein interaction (PPI) network, while the molecular complex detection (MCODE) plug-in was employed to filter important subnetworks. The expression levels of the hub genes and their prognostic values were evaluated using the UALCAN, GEPIA2, and Kaplan-Meier plotter databases. The timer algorithm was utilized to determine the correlation between immune cell infiltration and the expression levels of hub genes in LUAD tissues. In addition, the hub gene mutation landscape and the correlation analysis with tumor mutational burden (TMB) score were evaluated using maftools package and ggstatsplot package in R software, respectively. RESULTS: We identified 156 common up-regulated DEGs, with gene ontology and pathway enrichment analysis indicating that they were mostly enriched in mitotic cell cycle process and cell cycle pathway. DEGs in the subnetwork with the largest number of genes were AURKB, CCNB2, CDC20, CDCA5, CDCA8, CENPF, and KNTC1. The seven hub genes were highly expressed in LUAD tissues and were associated with poor prognosis. These hub genes were negatively correlated with most immune cells. The somatic mutation landscape showed that AURKB, CDC20, CENPF, and KNTC1 had mutations and were positively correlated with TMB scores. CONCLUSIONS: Our findings demonstrate that increased expression of seven hub genes is associated with poor prognosis for LUAD patients. Additionally, the TMB score indicates that the high expression of hub gene increases immune cell infiltration in patients with lung adenocarcinoma which may significantly improve response to immunotherapy.

Study on the expression of c-Met in gastric cancer and its correlation with preoperative serum tumor markers and prognosis.

BACKGROUND: Studies have found that c-Met plays a critical role in the progression of solid tumors. This study aimed to investigate the expression of c-Met in gastric cancer (GC) and its correlation with preoperative serum tumor markers and prognosis, in order to provide a more theoretical basis for targeting c-Met in the treatment of GC. METHODS: Ninety-seven patients who underwent curative gastrectomy in our hospital from December 2013 to September 2015 were included in this study. The tissue microarray was constructed by paraffin-embedded tumor tissue of enrolled patients, including 97 GC points and 83 paracancerous points. Then, it was used for c-Met immunohistochemical staining, followed by an immunological H-score. The clinical baseline data and 5-year survival of patients with low and high c-Met expression were compared. Besides, the correlation between the expression of c-Met in tumor tissues and preoperative serum tumor markers was investigated. Finally, multivariate Cox regression analysis was used to explore the survival risk factors of patients. RESULTS: c-Met has a high expression rate in GC tissues 64.95% (63/97). The expression of c-Met was significantly different in different clinicopathological stages (p < 0.05); the high expression group also had a higher M stage and clinicopathological stage of GC. The correlation test between the c-Met H-score and CA125 was statistically significant (p = 0.004), indicating a positive correlation. Furthermore, high c-Met expression correlated with poor overall survival (OS) for 5 years (p = 0.005). It was also found that the high expression of c-Met in stage I-II patients was correlative with poor OS for 5 years (p = 0.026), while stage III-IV patients had no statistical significance (p > 0.05). Multivariate Cox regression analysis showed that c-Met might be an independent risk factor for survival 5 years after surgery. CONCLUSION: This study found that the high expression of c-Met in GC tissues was associated with poor 5-year OS in GC patients and was an independent risk factor for 5-year survival after curative gastrectomy. The expression of c-Met in GC tissues was also positively correlated with preoperative serum CA125.

Association between delta anion gap and hospital mortality for patients in cardiothoracic surgery recovery unit: a retrospective cohort study.

BACKGROUNDS: High level of anion gap (AG) was associated with organic acidosis. This study aimed to explore the relationship between delta AG (ΔAG = AGmax - AGmin) during first 3 days after intensive care unit (ICU) admission and hospital mortality for patients admitted in the cardiothoracic surgery recovery unit (CSRU). METHODS: In this retrospective cohort study, we identified patients from the open access database called Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC III). A logistic regression model was established to predict hospital mortality by adjusting confounding factors using a stepwise backward elimination method. We conducted receiver operating characteristic (ROC) curves to compare the diagnostic performance of acid-base variables. Cox regression model and Kaplan Meier curve were applied to predict patients' 90-day overall survival (OS). RESULTS: A total of 2,860 patients were identified. ΔAG was an independent predictive factor of hospital mortality (OR = 1.24 per 1 mEq/L increase, 95% CI: 1.11-1.39, p < 0.001). The area under curve (AUC) values of ΔAG suggested a good diagnostic accuracy (AUC = 0.769). We established the following formula to estimate patients' hospital mortality: Logit(P) = - 15.69 + 0.21ΔAG + 0.13age-0.21BE + 2.69AKF. After calculating Youden index, patients with ΔAG ≥ 7 was considered at high risk (OR = 4.23, 95% CI: 1.22-14.63, p = 0.023). Kaplan Meier curve demonstrated that patients with ΔAG ≥ 7 had a poorer 90-day OS (Adjusted HR = 3.20, 95% CI: 1.81-5.65, p < 0.001). CONCLUSION: ΔAG is a prognostic factor of hospital mortality and 90-day OS. More prospective studies are needed to verify and update our findings.

Robotic bariatric surgery for the obesity: a systematic review and meta-analysis.

OBJECTIVE: The aim of this meta-analysis is to evaluate the safety and efficacy of bariatric surgery (BS) in patients with obesity by robotic bariatric surgery (RBS) compared with laparoscopic bariatric surgery (LBS). METHODS: The study was performed through searching in Pubmed, Web of Science, Embase database and Cochrane Library until March 31, 2020 comparing RBS with LBS. Data were calculated on the following endpoints: operative time, length of hospital stay, reoperation within 30 days, overall complications, leak, stricture, pulmonary embolisms, estimated blood loss and mortality. Data as relative risks (OR), or weighted mean difference (WMD) were summarized with 95% confidence interval (CI). Risk of publication bias was assessed through standard methods. RESULTS: Thirty eligible trials including 7,239 robotic and 203,181 laparoscopic surgery cases showed that RBS was referred to attain longer operative time [WMD = 27.61 min; 95%CI (16.27-38.96); P < 0.01] and lower mortality [OR 2.40; 95% CI (1.24-4.64); P = 0.009] than LBS. Length of hospital stay [WMD = - 0.02; 95% CI (- 0.19-0.15); P = 0.819], reoperation within 30 days [OR 1.36; 95% CI (0.65-2.82); P = 0.411], overall complications [OR 0.88; 95% CI (0.68-1.15); P = 0.362], leak [OR 1.04; 95% CI (0.43-2.51); P = 0.933], stricture [OR 1.05; 95% CI (0.52-2.12); P = 0.895], pulmonary embolisms [OR 1.97; 95% CI (0.93-4.17); P = 0.075], estimated blood loss[WMD = - 1.93; 95% CI (- 4.61-0.75); P = 0.158] were almost similar in both RBS group and LBS group. Three was no statistically significant difference between RRYGB and LRYGB in EWL%, no statistical significance between RSG and LSG after 1 year, 2 years and 3 years. CONCLUSION: RBS presented lower mortality within 90 days and longer operative time in this meta-analysis with similar safety and efficacy for the obesity compared with LBS in other outcomes. Additionally, RBS might be beneficial in the future if it would be evaluated in comprehensive and long-term endpoints.

Synaptotagmin 12 (SYT12) Gene Expression Promotes Cell Proliferation and Progression of Lung Adenocarcinoma and Involves the Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Pathway.

BACKGROUND This study aimed to use bioinformatics analysis to compare data from tissue microarrays from patients with lung adenocarcinoma (LUAD) and normal lung tissue, and human lung adenocarcinoma cells with normal lung epithelial cells in vitro to investigate the role of synaptotagmin 12 (SYT12) gene expression in LUAD. MATERIAL AND METHODS Human lung adenocarcinoma cell lines (A549, SPC-A-1, H1299, H1975, and PC9) and the normal HBE cell line were compared, and tumor xenografts were developed in mice. The Cancer Genome Atlas (TCGA) tissue microarray data were used to compare SYT12 expression and overall survival (OS). The in vivo and in vitro effects of down-regulation and upregulation of SYT12 were studied using short-interfering RNA (si-RNA) and overexpression plasmids, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway analysis, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and Western blot investigated the molecular mechanisms of SYT12 expression in LUAD. RESULTS SYT12 expression was increased in tissues from patients with LUAD from TCGA and was associated with advanced tumor stage and reduced prognosis. Knockdown of SYT12 suppressed the proliferation and migration of LUAD cells, and upregulation of SYT12 increased the proliferation and migration of LUAD cells in vitro. Phosphorylation of PIK3R3 activated the PI3K/AKT/mTOR pathway. In the mouse xenograft model, expression of SYT12 increased the volume and weight of the xenograft tumors. CONCLUSIONS Bioinformatics analysis, human LUAD cells, and mouse xenograft studies showed that SYT12 acted as a possible oncogene by phosphorylation of PIK3R3 to activate the PI3K/AKT/mTOR signaling pathway.

Ultrasound-mediated nanobubbles loaded with STAT6 siRNA inhibit TGF-ß1-EMT axis in LUSC cells via overcoming the polarization of M2-TAMs.

M2-like tumor-associated macrophages (M2-TAMs) are closely correlated with metastasis and poor clinical outcomes in lung squamous cell carcinoma (LUSC). Previous studies have demonstrated that STAT6 is an important signaling molecule involved in the polarization of M2-TAMs, EMT is the main way for TAMs to promote tumor progression. However, little attention has been paid to the effect of STAT6 inhibition on LUSC, and it is difficult to achieve an ideal gene silencing effect in immune cells using traditional gene transfection methods. Here, we investigated the optimal concentration of 12-myristic 13-acetate (PMA), lipopolysaccharide (LPS) for the induction of THP-1 into M1-TAMs and M2-TAMs. The expression of pSTAT6 and STAT6 was confirmed in three types of macrophages, and it was demonstrated that pSTAT6 can be used as a specific target of M2-TAMs derived from THP-1. Ultrasound-mediated nanobubble destruction (UMND) is a non-invasive and safe gene delivery technology. We also synthesized PLGA-PEI nanobubbles (NBs) to load and deliver STAT6 small interfering RNA (siRNA) into M2-TAMs via UMND. The results show that the NBs could effectively load with siRNA and had good biocompatibility. We found that UMND enhanced the transfection efficiency of siRNA, as well as the silencing effect of pSTAT6 and the inhibition of M2-TAMs. Simultaneously, when STAT6 siRNA entered M2-TAMs by UMND, proliferation, migration, invasion and EMT in LUSC cells could be inhibited via the transforming growth factor-ß1 (TGF-ß1) pathway. Therefore, our results confirm that UMND is an ideal siRNA delivery strategy, revealing its potential to inhibit M2-TAMs polarization and ultimately treat LUSC.

A nine-gene signature as prognostic biomarker in gastric cancer by bioinformatics analysis.

PURPOSE: The prognosis of advanced gastric cancer (GC) remains poor. It is urgent and necessary to find suitable prognostic markers. miR-619-5p is highly expressed in GC. However, the value of miR-619-5p and its target genes as prognostic biomarkers of GC is unclear. METHODS: RT-PCR was performed to verify the expression of miR-619-5p in GC cell lines and their exosomes. Western blotting and transmission electron microscope were used to identify exosomes. The target genes of miR-619-5p were predicted by RNA22 and TargetScan. The differentially expressed genes (DEGs) and prognosis-related genes (PRGs) were obtained using The Cancer Genome Atlas (TCGA) database. The DAVID database was used to analyse pathway enrichment and functional annotation of common target genes. The STRING database and Cytoscape software were used to screen key genes and visualize their functional modules. The survival analysis was conducted using TCGA and Kaplan-Meier Plotter (KMP) databases. Finally, a prognostic model was constructed on the foundation of the key genes to assess the reliability of the screening process. RESULTS: The expression of miR-619-5p in GC cells and their exosomes was proved to be significantly higher than that in normal cell lines. There are 129 common target genes involved in 3 pathways and 28 functional annotations. Finally, nine key target genes of GC (BRCA1, RAD51, KIF11, ERCC6L, BRIP1, TIMELESS, CDC25A, CLSPN and NCAPG2) were identified, and a prognostic model was successfully constructed with a good predictive ability. CONCLUSIONS: The model of 9-gene signature could effectively predict the prognosis of GC, and have great potential to be novel prognostic factors and therapeutic targets for patients with GC.

Ultrasound-Mediated PLGA-PEI Nanobubbles Carrying STAT6 SiRNA Enhances NSCLC Treatment via Repolarizing Tumor-associated Macrophages from M2 to M1 Phenotypes.

BACKGROUND: Tumor-associated macrophages (TAMs) are crucial for non-small cell lung cancer (NSCLC) development. OBJECTIVE: In this study, polylactic acid-co-glycolic acid (PLGA)-polyethylenimine (PEI) nanobubbles (NBs) carrying STAT6 siRNA were prepared and combined with ultrasound-mediated nanobubbles destruction (UMND) to silence the STAT6 gene, ultimately repolarizing TAMs from the M2 to the M1 phenotype, treating NSCLC in vitro. METHODS: PLGA-PEI NBs-siRNA were prepared and characterised, and their respective ultrasound imaging, biological stabilities and cytotoxicities were detected. Transfection efficiency was evaluated by fluorescence microscopy and flow cytometry. Repolarization of THP-1-derived M2-like macrophages was determined by qPCR and flow cytometry. NSCLC cells (A549) were co-cultured with transfected M2-like macrophages or their associated conditioned medium (CM). Western blotting was used to detect STAT6 gene silencing in M2-like macrophages and markers of epithelial and mesenchymal in A549 cells. The proliferation of A549 cells was detected using CCK-8 and cell colony formation assays. Transwell assays were used to detect the migration and invasion of A549 cells. RESULTS: PLGA-PEI NBs-siRNA had an average size of 223.13±0.92nm and a zeta potential of about -5.59±0.97 mV. PLGA-PEI NBs showed excellent ultrasonic imaging capability in addition to biological stability to protect siRNA from degradation. UMND enhanced PLGA-PEI NBs-STAT6 siRNA transfection in M2-like macrophages, which made M2-like macrophages repolarize to M1-like macrophages and prevented proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in A549 cells. CONCLUSION: UMND enhanced PLGA-PEI NBs-STAT6 siRNA to repolarize TAMs from the M2 to the M1 phenotype, thus treating NSCLC. These findings provide a promising therapeutic approach for enhancing NSCLC immunotherapy.

Laser-assisted failure recovery for dielectric elastomer actuators in aerial robots.

Insects maintain remarkable agility after incurring severe injuries or wounds. Although robots driven by rigid actuators have demonstrated agile locomotion and manipulation, most of them lack animal-like robustness against unexpected damage. Dielectric elastomer actuators (DEAs) are a class of muscle-like soft transducers that have enabled nimble aerial, terrestrial, and aquatic robotic locomotion comparable to that of rigid actuators. However, unlike muscles, DEAs suffer local dielectric breakdowns that often cause global device failure. These local defects severely limit DEA performance, lifetime, and size scalability. We developed DEAs that can endure more than 100 punctures while maintaining high bandwidth (>400 hertz) and power density (>700 watt per kilogram)-sufficient for supporting energetically expensive locomotion such as flight. We fabricated electroluminescent DEAs for visualizing electrode connectivity under actuator damage. When the DEA suffered severe dielectric breakdowns that caused device failure, we demonstrated a laser-assisted repair method for isolating the critical defects and recovering performance. These results culminate in an aerial robot that can endure critical actuator and wing damage while maintaining similar accuracy in hovering flight. Our work highlights that soft robotic systems can embody animal-like agility and resilience-a critical biomimetic capability for future robots to interact with challenging environments.

Cyclooxygenase-2 -765 G/C polymorphisms and susceptibility to hepatitis B-related liver cancer in Han Chinese population.

To investigate the relationship of cyclooxygenase-2 (COX-2) polymorphisms [COX-2 -765 G/C (rs 20417)] and susceptibility to hepatitis B-related liver cancer in Han Chinese population. The polymorphisms of COX-2 -765 G/C was detected by polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) in 300 patients with hepatitis B, 300 patients with cirrhosis, 300 patients with primary liver carcinoma and 300 health controls. The COX-2 -765 G/C genotypes were GG, GC and CC. There frequencies in the hepatitis B patients were 80.33, 17.67 and 2.00%; in the cirrhosis patients were 77.67, 18.00 and 4.33%; in the patients with primary liver carcinoma were 65.67, 28.33 and 6.00% and in the heathy controls were 87.00, 12.33 and 0.67%, respectively, COX-2 -765 C allele carriers had an increased risk of hepatitis B-related liver cancer. COX-2 -765 C allele carriers having drinking history or family history of liver cancer had higher risk for HCC. COX-2 -765 C allele genotype, drinking history and family history of liver cancer may increase the susceptibility to hepatitis B-related liver cancer in Gansu province, China.

Design, Characterization, and Liftoff of an Insect-Scale Soft Robotic Dragonfly Powered by Dielectric Elastomer Actuators.

Dragonflies are agile and efficient flyers that use two pairs of wings for demonstrating exquisite aerial maneuvers. Compared to two-winged insects such as bees or flies, dragonflies leverage forewing and hindwing interactions for achieving higher efficiency and net lift. Here we develop the first at-scale dragonfly-like robot and investigate the influence of flapping-wing kinematics on net lift force production. Our 317 mg robot is driven by two independent dielectric elastomer actuators that flap four wings at 350 Hz. We extract the robot flapping-wing kinematics using a high-speed camera, and further measure the robot lift forces at different operating frequencies, voltage amplitudes, and phases between the forewings and hindwings. Our robot achieves a maximum lift-to-weight ratio of 1.49, and its net lift force increases by 19% when the forewings and hindwings flap in-phase compared to out-of-phase flapping. These at-scale experiments demonstrate that forewing-hindwing interaction can significantly influence lift force production and aerodynamic efficiency of flapping-wing robots with passive wing pitch designs. Our results could further enable future experiments to achieve feedback-controlled flights.

A High-Lift Micro-Aerial-Robot Powered by Low-Voltage and Long-Endurance Dielectric Elastomer Actuators.

Dielectric elastomer actuators (DEAs) are a special class of artificial muscles that have been used to construct animal-like soft robotic systems. However, compared with state-of-the-art rigid actuators such as piezoelectric bimorphs and electromagnetic motors, most DEAs require higher driving voltages, and their power density and lifetime remain substantially lower. These limitations pose significant challenges for developing agile and powered autonomous soft robots. Here, a low-voltage, high-endurance, and power-dense DEA based on novel multiple-layering techniques and electrode-material optimization, is reported. When operated at 400 Hz, the 143 mg DEA generates forces of 0.36 N and displacements of 1.15 mm. This DEA is incorporated into an aerial robot to demonstrate high performance. The robot achieves a high lift-to-weight ratio of 3.7, a low hovering voltage of 500 V, and a long lifetime that exceeds 2 million actuation cycles. With 20 s of hovering time, and position and attitude error smaller than 2.5 cm and 2°, respectively, the robot demonstrates the longest and best-performing flight among existing sub-gram aerial robots. This important milestone demonstrates that soft robots can outperform their state-of-the-art rigid counterparts, and it provides an important step toward realizing power autonomy in soft robotic flights.

Identification of differentially expressed miRNAs derived from serum exosomes associated with gastric cancer by microarray analysis.

AIMS: To explore the differentially expressed microRNAs (DEMs) in serum exosomes between gastric cancer (GC) patients and healthy people to provide new targets for GC diagnosis and treatment. METHODS: DEMs in serum exosomes were screened by microarray analysis and verified by RT-qPCR. The target genes of DEMs were predicted using Targetscan and miRTarBase databases and then overlapped with the DEGs of STAD in TCGA database to obtain the common target genes. Biological function and pathway enrichment were analyzed using enrichr database, and a PPI network was constructed using STRING database. The potential target genes of DEMs were identified using the MCODE and cytoHubba plug-ins of Cytoscape software. Survival analysis were conducted using KMP and TCGA databases. The DEMs -target genes-pathways network was established using Cytoscape software. A Cox proportional hazards regression model formed by optimal target genes was used to access the reliability of this prediction process. RESULTS: Three serum exosomal microRNAs (exo-miRNAs, has-miR-1273 g-3p, has-miR-4793-3p, has-miR-619-5p) were identified to be highly expressed in GC patients and performed excellent diagnostic ability. A total of 179 common target genes related to GC were predicted. They were mainly involved in 79 GO functional annotations and 6 KEGG pathways. The prognostic model formed by eight optimal target genes (TIMELESS, DNA2, MELK, CHAF1B, DBF4, PAICS, CHEK1 and NCAPG2), which were low-risk genes of GC, also performed perfect prognostic ability. CONCLUSIONS: Serum exosomal has-miR-1273 g-3p, has-miR-4793-3p and has-miR-619-5p can be used as new diagnostic biomarkers for GC. Among them, serum exosomal hsa-miR-1273 g-3p / hsa-miR-4793-3p targets MELK and hsa-miR-619-5p targets NCAPG2 were identified as novel mechanisms involved in the development of GC. It provides new targets for the diagnosis and treatment of GC by exo-miRNAs.

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.

Background: Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD). Methods: Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2. Results: BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming. Conclusions: In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.

Application of Immunotherapy in Hepatocellular Carcinoma.

Hepatocellular carcinoma is one of the most common malignancies globally. It not only has a hidden onset but also progresses rapidly. Most HCC patients are already in the advanced stage of cancer when they are diagnosed, and have even lost the opportunity for surgical treatment. As an inflammation-related tumor, the immunosuppressive microenvironment of HCC can promote immune tolerance through a variety of mechanisms. Immunotherapy can activate tumor-specific immune responses, which brings a new hope for the treatment of HCC. At the present time, main immunotherapy strategies of HCC include immune checkpoint inhibitors, tumor vaccines, adoptive cell therapy, and so on. This article reviews the application and research progress of immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapy in the treatment of HCC.

Reactions Related to CAR-T Cell Therapy.

The application of chimeric antigen receptor (CAR) T-cell therapy as a tumor immunotherapy has received great interest in recent years. This therapeutic approach has been used to treat hematological malignancies solid tumors. However, it is associated with adverse reactions such as, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), off-target effects, anaphylaxis, infections associated with CAR-T-cell infusion (CTI), tumor lysis syndrome (TLS), B-cell dysplasia, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) and coagulation disorders. These adverse reactions can be life-threatening, and thus they should be identified early and treated effectively. In this paper, we review the adverse reactions associated with CAR-T cells, the mechanisms driving such adverse reactions, and strategies to subvert them. This review will provide important reference data to guide clinical application of CAR-T cell therapy.

Gene-Edited Interleukin CAR-T Cells Therapy in the Treatment of Malignancies: Present and Future.

In recent years, chimeric antigen receptor T cells (CAR-T cells) have been faced with the problems of weak proliferation and poor persistence in the treatment of some malignancies. Researchers have been trying to perfect the function of CAR-T by genetically modifying its structure. In addition to the participation of T cell receptor (TCR) and costimulatory signals, immune cytokines also exert a decisive role in the activation and proliferation of T cells. Therefore, genetic engineering strategies were used to generate cytokines to enhance tumor killing function of CAR-T cells. When CAR-T cells are in contact with target tumor tissue, the proliferation ability and persistence of T cells can be improved by structurally or inductively releasing immunoregulatory molecules to the tumor region. There are a large number of CAR-T cells studies on gene-edited cytokines, and the most common cytokines involved are interleukins (IL-7, IL-12, IL-15, IL-18, IL-21, IL-23). Methods for the construction of gene-edited interleukin CAR-T cells include co-expression of single interleukin, two interleukin, interleukin combined with other cytokines, interleukin receptors, interleukin subunits, and fusion inverted cytokine receptors (ICR). Preclinical and clinical trials have yielded positive results, and many more are under way. By reading a large number of literatures, we summarized the functional characteristics of some members of the interleukin family related to tumor immunotherapy, and described the research status of gene-edited interleukin CAR-T cells in the treatment of malignant tumors. The objective is to explore the optimized strategy of gene edited interleukin-CAR-T cell function.

Obstacles and Coping Strategies of CAR-T Cell Immunotherapy in Solid Tumors.

Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that enables T cells to express specific CARs on their surface, then returns these T cells to tumor patients to kill the corresponding tumor cells. Significant strides in CAR-T cell immunotherapy against hematologic malignancies have elicited research interest among scholars in the treatment of solid tumors. Nonetheless, in contrast with the efficacy of CAR-T cell immunotherapy in the treatment of hematologic malignancies, its general efficacy against solid tumors is insignificant. This has been attributed to the complex biological characteristics of solid tumors. CAR-T cells play a better role in solid tumors, for instance by addressing obstacles including the lack of specific targets, inhibition of tumor microenvironment (TME), homing barriers of CAR-T cells, differentiation and depletion of CAR-T cells, inhibition of immune checkpoints, trogocytosis of CAR-T cells, tumor antigen heterogeneity, etc. This paper reviews the obstacles influencing the efficacy of CAR-T cell immunotherapy in solid tumors, their mechanism, and coping strategies, as well as economic restriction of CAR-T cell immunotherapy and its solutions. It aims to provide some references for researchers to better overcome the obstacles that affect the efficacy of CAR-T cells in solid tumors.

Shape Memory Alloy (SMA) Actuator With Embedded Liquid Metal Curvature Sensor for Closed-Loop Control.

We introduce a soft robot actuator composed of a pre-stressed elastomer film embedded with shape memory alloy (SMA) and a liquid metal (LM) curvature sensor. SMA-based actuators are commonly used as electrically-powered limbs to enable walking, crawling, and swimming of soft robots. However, they are susceptible to overheating and long-term degradation if they are electrically stimulated before they have time to mechanically recover from their previous activation cycle. Here, we address this by embedding the soft actuator with a capacitive LM sensor capable of measuring bending curvature. The soft sensor is thin and elastic and can track curvature changes without significantly altering the natural mechanical properties of the soft actuator. We show that the sensor can be incorporated into a closed-loop "bang-bang" controller to ensure that the actuator fully relaxes to its natural curvature before the next activation cycle. In this way, the activation frequency of the actuator can be dynamically adapted for continuous, cyclic actuation. Moreover, in the special case of slower, low power actuation, we can use the embedded curvature sensor as feedback for achieving partial actuation and limiting the amount of curvature change.

Bioinformatic Evidence Reveals that Cell Cycle Correlated Genes Drive the Communication between Tumor Cells and the Tumor Microenvironment and Impact the Outcomes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive cancer type with poor prognosis; thus, there is especially necessary and urgent to screen potential prognostic biomarkers for early diagnosis and novel therapeutic targets. In this study, we downloaded target data sets from the GEO database, and obtained codifferentially expressed genes using the limma R package and identified key genes through the protein-protein interaction network and molecular modules, and performed GO and KEGG pathway analyses for key genes via the clusterProfiler package and further determined their correlations with clinicopathological features using the Oncomine database. Survival analysis was completed in the GEPIA and the Kaplan-Meier plotter database. Finally, correlations between key genes, cell types infiltrated in the tumor microenvironment (TME), and hypoxic signatures were explored based on the TIMER database. From the results, 11 key genes related to the cell cycle were determined, and high levels of these key genes' expression were focused on advanced and higher grade status HCC patients, as well as in samples of TP53 mutation and vascular invasion. Besides, the 11 key genes were significantly associated with poor prognosis of HCC and also were positively related to the infiltration level of MDSCs in the TME and the HIF1A and VEGFA of hypoxic signatures, but a negative correlation was found with endothelial cells (ECs) and hematopoietic stem cells. The result determined that 11 key genes (RRM2, NDC80, ECT2, CCNB1, ASPM, CDK1, PRC1, KIF20A, DTL, TOP2A, and PBK) could play a vital role in the pathogenesis of HCC, drive the communication between tumor cells and the TME, and act as probably promising diagnostic, therapeutic, and prognostic biomarkers in HCC patients.