Synergistic π-Conjugation Organic Cathode for Ultra-Stable Aqueous Aluminum Batteries.

Rechargeable aqueous aluminum batteries (AABs) are promising energy storage technologies owing to their high safety and ultra-high energy-to-price ratio. However, either the strong electrostatic forces between high-charge-density Al3+ and host lattice, or sluggish large carrier-ion diffusion toward the conventional inorganic cathodes generates inferior cycling stability and low rate-capacity. To overcome these inherent confinements, a series of promising redox-active organic materials (ROMs) are investigated and a π-conjugated structure ROMs with synergistic C═O and C═N groups is optimized as the new cathode in AABs. Benefiting from the joint utilization of multi-redox centers and rich π-π intermolecular interactions, the optimized ROMs with unique ion coordination storage mechanism facilely accommodate complex active ions with mitigated coulombic repulsion and robust lattice structure, which is further validated via theoretical simulations. Thus, the cathode achieves enhanced rate performance (153.9 mAh g-1 at 2.0 A g-1 ) and one of the best long-term stabilities (125.7 mAh g-1 after 4,000 cycles at 1.0 A g-1 ) in AABs. Via molecular exploitation, this work paves the new direction toward high-performance cathode materials in aqueous multivalent-ion battery systems.

High Entropy Oxides Modulate Atomic-Level Interactions for High-Performance Aqueous Zinc-Ion Batteries.

The strong electrostatic interaction between high-charge-density zinc ions (112 C mm-3 ) and the fixed crystallinity of traditional oxide cathodes with delayed charge compensation hinders the development of high-performance aqueous zinc-ion batteries (AZIBs). Herein, to intrinsically promote electron transfer efficiency and improve lattice tolerance, a revolutionary family of high-entropy oxides (HEOs) materials with multipath electron transfer and remarkable structural stability as cathodes for AZIBs is proposed. Benefiting from the unique "cock-tail" effect, the interaction of diverse type metal-atoms in HEOs achieves essentially broadened d-band and lower degeneracy than monometallic oxides, which contribute to convenient electron transfer and one of the best rate-performances (136.2 mAh g-1 at 10.0 A g-1 ) in AZIBs. In addition, the intense lattice strain field of HEOs is highly tolerant to the electrostatic repulsion of high-charge-density Zn2+ , leading to the outstanding cycling stability in AZIBs. Moreover, the super selectability of elements in HEOs exhibits significant potential for AZIBs.

Future time perspective and academic procrastination among nursing students: The mediating role of mindfulness.

AIM: To explore the relationship between university nursing students' academic procrastination, mindfulness, and future time perspective. DESIGN: A cross-sectional study. METHODS: A total of 343 university nursing students recruited from eight provinces in China have reported procrastination characteristics through fulfilling an online website link. The main instruments involved Mindfulness Attention Awareness Scale (MAAS), Zimbardo Time Perspective Scale, and Procrastination Assessment Scale (PASS). RESULTS: Participants who self-assessed higher frequency and degree of academic procrastination tended to possess lower future time consciousness, and lower mindfulness. Mindfulness served as a mediation effect between future time perspective and academic procrastination. The study indicates that weakening an individual's procrastination can be alleviated through future time awareness and mindfulness. Concentrating on influencing factors, strengthening nursing student's future time perspective, and practicing mindfulness training could assist educators to decrease students' procrastination intentions and behaviours.

Cu-catalyzed cascade difluoroalkylation/5-endo cyclization/ß-fluorine cleavage of ynones.

A copper-catalyzed, redox-neutral cascade difluoroalkylation/5-endo annulation/ß-fluorine cleavage of ynones is developed, providing a direct and stereoselective method to access synthetically important α-monofluoroalkenyl cyclopentanones. Mechanistic studies suggest an unprecedented CuII-assisted ß-fluorine fragmentation, which may be valuable for the challenging but important C-F bond activation. Moreover, the in situ generated difluorocarbene was found to serve as an effective reductant for the regeneration of copper(I) catalyst, thus avoiding the addition of external reductants.

Screening and characterization of a ß-xylosidase from Bifidobacterium breve K-110 and its application in the biotransformation of the total flavonoids of epimedium to icariin with α-l-rhamnosidase.

Among the flavonoids of epimedium, epimedin B, epimedin C, and icariin are considered to be representative components and their structures are quite similar. Besides sharing the same backbone, the main difference is the sugar groups attached at the positions of C-3 and C-7. Despite their structural similarities, their potencies differ significantly, and only icariin is currently included in the Chinese Pharmacopoeia as a quality marker (Q-marker) for epimedium flavonoids. Furthermore, icariin has the functions of anti-aging, anti-inflammation, antioxidation, anti-osteoporosis, and ameliorating fibrosis. We used bioinformatics to look for the GH43 family ß-xylosidase genes BbXyl from Bifidobacterium breve K-110, which has a length of 1347 bp and codes for 448 amino acids. This will allow us to convert epimedin B and epimedin C into icariin in a specific way. The expression level of recombinant BbXyl in TB medium containing 1 % inulin as carbon source, with an inducer concentration of 0.05 mmol/L and a temperature of 28 °C, was 86.4 U/mL. Previous studies found that the α-l-rhamnosidase BtRha could convert epoetin C to produce icariin, so we combined BbXyl and BtRha to catalyze the conversion of epimedium total flavonoids in vitro and in vivo to obtain the product icariin. Under optimal conditions, in vitro hydrolysis of 5 g/L of total flavonoids of epimedium eventually yielded a concentration of icariin of 678.1 µmol/L. To explore the conversion of total flavonoids of epimedium in vivo. Under the optimal conditions, the yield of icariin reached 97.27 µmol/L when the total flavonoid concentration of epimedium was 1 g/L. This study is the first to screen xylosidases for the targeted conversion of epimedin B to produce icariin, and the first to report that epimedin B and epimedin C in the raw epimedium flavonoids can convert efficiently to icariin by a collaborative of ß-xylosidase and α-l-rhamnosidase.

Enforced expression of Runx3 improved CAR-T cell potency in solid tumor via enhancing resistance to activation-induced cell death.

Limited T cell persistence restrains chimeric antigen receptor (CAR)-T cell therapy in solid tumors. To improve persistence, T cells have been engineered to secrete proinflammatory cytokines, but other possible methods have been understudied. Runx3 has been considered a master regulator of T cell development, cytotoxic T lymphocyte differentiation, and tissue-resident memory T (Trm)-cell formation. A study using a transgenic mouse model revealed that overexpression of Runx3 promoted T cell persistence in solid tumors. Here, we generated CAR-T cells overexpressing Runx3 (Run-CAR-T cells) and found that Run-CAR-T cells had long-lasting antitumor activities and achieved better tumor control than conventional CAR-T cells. We observed that more Run-CAR-T cells circulated in the peripheral blood and accumulated in tumor tissue, indicating that Runx3 coexpression improved CAR-T cell persistence in vivo. Tumor-infiltrating Run-CAR-T cells showed less cell death with enhanced proliferative and effector activities. Consistently, in vitro studies indicated that AICD was also decreased in Run-CAR-T cells via downregulation of tumor necrosis factor (TNF) secretion. Further studies revealed that Runx3 could bind to the TNF promoter and suppress its gene transcription after T cell activation. In conclusion, Runx3-armored CAR-T cells showed increased antitumor activities and could be a new modality for the treatment of solid tumors.

Superlattice-Stabilized WSe2 Cathode for Rechargeable Aluminum Batteries.

Rechargeable aluminum batteries (RABs), with abundant aluminum reserves, low cost, and high safety, give them outstanding advantages in the postlithium batteries era. However, the high charge density (364 C mm-3 ) and large binding energy of three-electron-charge aluminum ions (Al3+ ) de-intercalation usually lead to irreversible structural deterioration and decayed battery performance. Herein, to mitigate these inherent defects from Al3+ , an unexplored family of superlattice-type tungsten selenide-sodium dodecylbenzene sulfonate (SDBS) (S-WSe2 ) cathode in RABs with a stably crystal structure, expanded interlayer, and enhanced Al-ion diffusion kinetic process is proposed. Benefiting from the unique advantage of superlattice-type structure, the anionic surfactant SDBS in S-WSe2 can effectively tune the interlayer spacing of WSe2 with released crystal strain from high-charge-density Al3+ and achieve impressively long-term cycle stability (110 mAh g-1 over 1500 cycles at 2.0 A g-1 ). Meanwhile, the optimized S-WSe2 cathode with intrinsic negative attraction of SDBS significantly accelerates the Al3+ diffusion process with one of the best rate performances (165 mAh g-1 at 2.0 A g-1 ) in RABs. The findings of this study pave a new direction toward durable and high-performance electrode materials for RABs.

Distributed Acoustic Sensing for Monitoring Linear Infrastructures: Current Status and Trends.

Linear infrastructures, such as railways, tunnels, and pipelines, play essential roles in economic and social development worldwide. However, under the influence of geohazards, earthquakes, and human activities, linear infrastructures face the potential risk of damage and may not function properly. Current monitoring systems for linear infrastructures are mainly based on non-contact detection (InSAR, UAV, GNSS, etc.) and geotechnical instrumentation (extensometers, inclinometers, tiltmeters, piezometers, etc.) techniques. Regarding monitoring sensitivity, frequency, and coverage, most of these methods have some shortcomings, which make it difficult to perform the accurate, real-time, and comprehensive monitoring of linear infrastructures. Distributed acoustic sensing (DAS) is an emerging sensing technology that has rapidly developed in recent years. Due to its unique advantages in long-distance, high-density, and real-time monitoring, DAS arrays have shown broad application prospects in many fields, such as oil and gas exploration, seismic observation, and subsurface imaging. In the field of linear infrastructure monitoring, DAS has gradually attracted the attention of researchers and practitioners. In this paper, recent research and the development activities of applying DAS to monitor different types of linear infrastructures are critically reviewed. The sensing principles are briefly introduced, as well as the main features. This is followed by a summary of recent case studies and some critical problems associated with the implementation of DAS monitoring systems in the field. Finally, the challenges and future trends of this research area are presented.

The influence of minimally invasive esophagectomy versus open esophagectomy on postoperative pulmonary function in esophageal cancer patients: a meta-analysis.

OBJECTIVE: To compare the influence of minimally invasive esophagectomy (MIE) and open esophagectomy (OE) on postoperative pulmonary function in patients with esophageal cancer. METHODS: Studies about the influence of MIE and OE on postoperative pulmonary function in esophageal cancer patients were searched from PubMed, EMBASE, the Cochrane Library, CNKI, Chinese Science and Technology Journal Database, CBM, and Wanfang Data from inception to March 18, 2021. Meta-analysis was performed using the RevMan 5.3. RESULTS: This analysis included eight studies, enrolling 264 patients who underwent MIE and 257 patients who underwent OE. The meta-analysis results showed that the MIE group had a higher outcome regarding the percent predicted vital capacity (%VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximum voluntary ventilation (MVV) 1 month after surgery than the OE group. In addition, those who underwent MIE had lower ΔVC%, ΔFVC, and ΔFEV1 between pre-operation and 1 month after surgery than those who underwent OE. There is no statistical difference between the two groups in ΔMVV. CONCLUSION: Compared with OE, MIE has a more protective effect on postoperative pulmonary function. However, due to the small number of included literature and all cohort studies, this finding needs to be validated with larger samples and higher quality RCT studies.

Synthesis and biological evaluation of scutellarein derivatives as neuroprotective agents via activating Nrf2/HO-1 pathway.

Oxidative stress has been considered as the main factor of neurodegenerative diseases. Activation of the Nrf2/HO-1 pathway, as one of the most crucial endogenous protection systems, was regarded as an effective strategy to against oxidative injury. Here, a series of phosphate esters or phosphonates of scutellarein derivatives were designed, synthesized and evaluated on SH-SY5Y cell lines to examine neuroprotective effects against H2O2 induced damage. Among them, compound 16d exhibited more potent cytoprotective effect than the lead compound scutellarin. Preliminary mechanism studies showed that compound 16d could prevent H2O2 induced neuronal apoptosis, significantly decrease ROS generation, elevate SOD and reduce MDA levels in a dose-dependent manner in SH-SY5Y cell lines. Furthermore, western blot assay disclosed that compound 16d could activate Nrf2, and increase the expression of its downstream genes HO-1 in a concentration-dependent manner, thus displaying potent neuroprotective activity. Overall, these findings demonstrated that compound 16d, as a promising neuroprotective agent, deserved further development.

A nomogram for predicting postoperative pulmonary infection in esophageal cancer patients.

BACKGROUND: Although postoperative pulmonary infection (POI) commonly occurs in patients with esophageal cancer after curative surgery, a patient-specific predictive model is still lacking. The main aim of this study is to construct and validate a nomogram for estimating the risk of POI by investigating how perioperative features contribute to POI. METHODS: This cohort study enrolled 637 patients with esophageal cancer. Perioperative information on participants was collected to develop and validate a nomogram for predicting postoperative pulmonary infection in esophageal cancer. Predictive accuracy, discriminatory capability, and clinical usefulness were evaluated by calibration curves, concordance index (C-index), and decision curve analysis (DCA). RESULTS: Multivariable logistic regression analysis indicated that length of stay, albumin, intraoperative bleeding, and perioperative blood transfusion were independent predictors of POI. The nomogram for assessing individual risk of POI indicated good predictive accuracy in the primary cohort (C-index, 0.802) and validation cohort (C-index, 0.763). Good consistency between predicted risk and observed actual risk was presented as the calibration curve. The nomogram for estimating POI of esophageal cancer had superior net benefit with a wide range of threshold probabilities (4-81%). CONCLUSIONS: The present study provided a nomogram developed with perioperative features to assess the individual probability of infection may conducive to strengthen awareness of infection control and provide appropriate resources to manage patients at high risk following esophagectomy.

Estrogen protects against acidosis-mediated articular chondrocyte injury by promoting ASIC1a protein degradation.

Epidemiological data suggest that the incidence of rheumatoid arthritis (RA) increases in postmenopausal women, which may be related to estrogen deficiency. Tissue acidosis is a common symptom of RA. Acid-sensitive ion channel 1a (ASIC1a), a member of the extracellular H+-activated cation channel family, could be activated by changes in extracellular pH and plays a crucial role in the pathogenesis of RA. As the only cellular component in cartilage tissue, chondrocytes play an extremely important role in maintaining cartilage tissue homeostasis. The aim of this study was to investigate whether estrogen could protect acid-stimulated chondrocytes by regulating the expression of ASIC1a and explore the possible mechanism. The results showed that estrogen could protect against acid-induced chondrocyte injury by reducing ASIC1a protein expression. Moreover, lysosome inhibitor chloroquine (CQ) and autophagy inhibitor 3-methyladeniine (3-MA) could reverse the reduction of ASIC1a protein caused by estrogen, indicating that autophagy-lysosome pathway contributes to estrogen-induced degradation of ASIC1a protein. Furthermore, the down-regulation of ASIC1a expression by estrogen was attenuated by MPP, a specific inhibitor of estrogen-related receptor-alpha (Esrra), indicating that Esrra is involved in the process of estrogen regulating the expression of ASIC1a. Additionally, adenosine 5'-monophosphate (AMP)-activated protein kinase/unc-51-like kinase 1 (AMPK-ULK1) signaling pathway was activated by estrogen treatment, which was abrogated by Esrra-silencing, and AMPK-specific inhibitor Compound C pretreatment could reduce estrogen-induced downregulation of ASIC1a protein. Taken together, these results indicate that estrogen could promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced cytotoxicity, the mechanisms of which might relate to Esrra-AMPK-ULK1 signaling pathway.

ASIC1a promotes the proliferation of synovial fibroblasts via the ERK/MAPK pathway.

Synovial hyperplasia, a profound alteration in the structure of synovial tissue, is the basis for cumulative joint destruction in rheumatoid arthritis (RA). It is generally accepted that controlling synovial hyperplasia can delay the progression of RA. As one of the most intensively studied isoforms of acid-sensing ion channels (ASICs), ASIC1a contributes to various physiopathologic conditions, including RA, due to its unique property of being permeable to Ca2+. However, the role and the regulatory mechanisms of ASIC1a in synovial hyperplasia are poorly understood. Here, rats induced with adjuvant arthritis (AA) and human primary synovial fibroblasts were used in vivo and in vitro to investigate the role of ASIC1a in the proliferation of RA synovial fibroblasts (RASFs). The results show that the expression of ASIC1a was significantly increased in synovial tissues and RASFs obtained from patients with RA as well as in the synovium of rats with AA. Moreover, extracellular acidification improved the ability of RASFs colony formation and increased the expression of proliferation cell nuclear antigen (PCNA) and Ki67, which was abrogated by the specific ASIC1a inhibitor psalmotoxin-1 (PcTX-1) or ASIC1a-short hairpin RNA (ASIC1a-shRNA), suggesting that extracellular acidification promotes the proliferation of RASFs by activating ASIC1a. In addition, the activation of c-Raf and extracellular signal-regulated protein kinases (ERKs) signaling was blocked with PcTX-1 or ASIC1a-shRNA and the proliferation of RASFs was further inhibited by the ERK inhibitor (U0126), indicating that ERK/MAPK signaling contributes to the proliferation process of RASFs promoted by the activation of ASIC1a. These findings gave us an insight into the role of ASIC1a in the proliferation of RASFs, which may provide solid foundation for ASIC1a as a potential target in the treatment of RA.

A novel all-trans retinoic acid derivative regulates cell cycle and differentiation of myelodysplastic syndrome cells by USO1.

4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, has been demonstrated that it had a variety of anti-tumor effects by exerting regulation on cellular proliferation, apoptosis and differentiation. Here, we found that ATPR is critical for alleviating myelodysplastic syndrome (MDS) and acute myelogenous leukemia. USO1, vesicle transport factor, belongs to tether protein family and involved in endoplasmic reticulum to Golgi trafficking of protein which is important to tumorigenesis. How USO1 contribute to MDS remain elusive. USO1 is aberrantly activated in MDS and AML in vivo and vitro, aberration of which might be a dominant mechanism for MDS cell survival. During the ATPR-induced remission of MDS, in vitro, USO1 presents a time and concentration-dependent decrease. Silencing of USO1 promotes myeloid differentiation of MDS cells and inhibits MDS cellular proliferation while USO1 over-expression has the opposite effect, suggesting that reduction of USO1 enhances the sensitivity of SKM-1 cells to ATPR treatment. Mechanistically, USO1 exerts its oncogenic role by inactivating Raf/ERK signaling, while ATPR is access to revise it. Notably, the activity of Raf/ERK pathway is required for the development and maintenance of MDS cell proliferation. Collectively, our results demonstrate the USO1- Raf/ERK signaling axis in MDS and highlight the negative role of USO1 in ATPR-regulated remission of MDS.

Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice.

A hostile tumor microenvironment is one of the major obstacles for the efficacy of chimeric antigen receptor modified T (CAR-T) cells, and combination treatment might be a potential way to overcome this obstacle. Poly(ADP-ribose) polymerase inhibitor (PARPi) has demonstrated tremendous potential in breast cancer. In this study, we explored the possible combination of the PAPRi olaparib with EGFRvIII-targeted CAR (806-28Z CAR) T cells in immunocompetent mouse models of breast cancer. The results indicated that the administration of olaparib could significantly enhance the efficacy of 806-28Z CAR-T cells in vivo. Interestingly, we observed that olaparib could suppress myeloid-derived suppressor cell (MDSC) migration and promote the survival of CD8+ T cells in tumor tissue. Mechanistically, olaparib was shown to reduce the expression of SDF1α released from cancer-associated fibroblasts (CAFs) and thereby decreased MDSC migration through CXCR4. Taken together, this study demonstrated that olaparib could increase the antitumor activities of CAR-T cell therapy at least partially through inhibiting MDSC migration via the SDF1α/CXCR4 axis. These findings uncover a novel mechanism of PARPi function and provide additional mechanistic rationale for combining PARPi with CAR-T cells for the treatment of breast cancer.

Coexpression of IL7 and CCL21 Increases Efficacy of CAR-T Cells in Solid Tumors without Requiring Preconditioned Lymphodepletion.

PURPOSE: T-cell recruitment, survival, and proliferation are the important limitations to chimeric antigen receptor (CAR) T cells therapy in the treatment of solid tumors. In this study, we engineered CAR-T cells to coexpress cytokines IL7 and CCL21 (7 × 21 CAR-T), a cytokine combination in order to improve proliferation and chemotaxis of CAR-T cells. EXPERIMENTAL DESIGN: CLDN18.2-specific second-generation CAR-T cells coexpressing cytokines were prepared using retroviral vector transduction. The proliferation and migration of genetically engineered CAR-T cells were evaluated in vitro. The antitumor activities of genetically engineered CAR-T cells were evaluated against multiple solid tumors in C57BL/6 mice in vivo. RESULTS: In vitro, the proliferation and chemotaxis of 7 × 21 CAR-T cells are significantly improved when compared with those of the conventional CAR-T cells. In vivo, 7 × 21 CAR-T cells revealed superior therapeutic effects to either conventional CAR-T cells or 7 × 19 CAR-T cells which coexpress IL7 and CCL19 as previously reported in three different solid tumors without cyclophosphamide precondition. Interestingly, 7 × 21 CAR-T cells could also suppress the tumor growth with heterogeneous antigen expression and even induce tumor complete remission. Mechanistically, IL7 and CCL21 significantly improved survival and infiltration of CAR-T cells and dendritic cells in tumor. In addition, CCL21 also inhibited the tumor angiogenesis as proved by IHC. CONCLUSIONS: Coexpression of IL7 and CCL21 could boost CAR-T cells' antitumor activity, and 7 × 21 CAR-T cells may be served as a promising therapy strategy for solid tumors.

Efficacy of transcatheter arterial chemoembolization combined with sorafenib in inhibiting tumor angiogenesis in a rabbit VX2 liver cancer model.

BACKGROUND: The aim of this study was to investigate the effects of transcatheter arterial chemoembolization (TACE) combined with sorafenib on tumor angiogenesis. MATERIALS AND METHODS: Thirty New Zealand rabbit VX2 liver cancer model animals were divided into five groups, which received either normal saline (A), TACE (B), sorafenib (C), sorafenib followed by TACE (D), or TACE followed by sorafenib (E). Serum vascular endothelial growth factor (VEGF) levels were measured before and after TACE via ELISA. Immunohistochemistry for CD34 was performed to evaluate microvessel density (MVD), and ultrasonography was used to access tumor volume. RESULTS: VEGF levels declined in group C but increased significantly on the 3rd post-operative day in groups B, D, and E. Levels decreased after the 7th post-operative day. Peak levels were significantly lower in group D than in groups B and E. On the 14th post-operative day, VEGF levels were the lowest in group C, followed by those in groups D and B. MVD was the lowest in group C followed by that in group D and E, and was the highest in group B. Group D had the smallest tumor volume. HE staining of tumor tissues from group C showed apoptosis in a scattered patchy pattern, whereas in groups B, D, and E, large areas of tumor cell necrosis were visible. CONCLUSION: TACE can up-regulate serum VEGF levels, which in turn accelerates the formation of new blood vessels. Thus, TACE combined with sorafenib inhibits VEGF and angiogenesis, and pre-operative administration of sorafenib has a more superior anti-angiogenic effect than post-operative administration.

Source apportionment of heavy metal and their health risks in soil-dustfall-plant system nearby a typical non-ferrous metal mining area of Tongling, Eastern China.

The agricultural land-atmospheric dustfall-plant system around the mining area is at high risks of heavy metal pollution caused by mining-smelting activities. In this study, 118 samples (including rhizospheric soils, background soils, soil-forming parent rocks, crops, vegetables, medicinal plants and atmospheric dustfall) were collected nearby Tongling Cu-Fe-Au mining area, Eastern China. We studied the concentrations, migration, sources, and health risks through consumption of two main crops (corn and rice), six kinds of vegetables, and medicinal plants (Fengdan, Paeonia ostii) for six metal elements (Cu, Zn, Cr, Cd, Pb and Hg). Results revealed Cr and Cd in soils, and Cd, Cr, Pb, Cu and Zn in dustfall showed a relatively high contamination degree. The mean contents of Cr and Pb in corn kernels, as well as Cd, Cr and Pb in rice grains and all vegetables, and Cr in Fengdan cortex moutan exceeded the corresponding food safety limits in China. The transfer capability of Cr in corn kernels and rice grains, Pb in edible vegetables, and Cd in cortex moutan were the strongest, respectively. Health risk assessment results showed Cr had the greatest non-carcinogenic risk, followed by Pb and Cd. The results of pearson's correlation analysis (CA), hierarchical cluster analysis (HCA), and principal component analysis (PCA) indicated Zn-Cr, Pb and Cd-Cu-Hg in the plants might derive from different geochemical end-members. Source apportionment based on lead isotope showed that mining-smelting activities were the major source of Pb in atmospheric dustfall and agricultural soils, with the average contribution rates of 66% and 50%, respectively. Vehicle emissions from diesel fuels (50%-68%) and mining-smelting activities (16%-25%) contributed mainly to Pb accumulation in plants. Hence, our study suggested the accumulations of Pb in plants might be mainly from the direct foliar uptake of atmospheric Pb related to vehicle emissions and mining-smelting activities.

Combined Antitumor Effects of Sorafenib and GPC3-CAR T Cells in Mouse Models of Hepatocellular Carcinoma.

Our previous study indicated that GPC3-targeted chimeric antigen receptor (CAR) T cell therapy has a high safety profile in patients with hepatocellular carcinoma (HCC). However, the response rate requires further improvement. Here, we analyzed the combined effect of GPC3-CAR T cells and sorafenib in both immunocompetent and immunodeficient mouse models of hepatocellular carcinoma. In immunocompetent mouse model, mouse CAR (mCAR) T cells induced regression of small tumors (approximately 130 mm3 tumor volume) but had no effect on large, established tumors (approximately 400 mm3 tumor volume). Sorafenib, at a subpharmacologic but not a pharmacologic dose, augmented the antitumor effects of mCAR T cells, in part by promoting IL12 secretion in tumor-associated macrophages (TAMs) and cancer cell apoptosis. In an immunodeficient mouse model, both subpharmacologic and pharmacologic doses of sorafenib had limited impacts on the function of human CAR (huCAR) T cells in vitro and showed synergistic effects with huCAR T cells in vivo, which can at least partially be ascribed to the upregulated tumor cell apoptosis induced by the combined treatment. Thus, this study applied two of the most commonly used mouse models for CAR T cell research and demonstrated the clinical potential of combining sorafenib with GPC3-targeted CAR T cells against HCC.

Target-Dependent Expression of IL12 by synNotch Receptor-Engineered NK92 Cells Increases the Antitumor Activities of CAR-T Cells.

IL12 is an immune-stimulatory cytokine for key immune cells including T cells and NK cells. However, systemic administration of IL12 has serious side effects that limit its clinical application in patients. Recently, synthetic Notch (synNotch) receptors have been developed that induce transcriptional activation and deliver therapeutic payloads in response to the reorganization of specific antigens. NK92 cell is a human natural killer (NK) cell line which has been developed as tools for adjuvant immunotherapy of cancer. Here, we explored the possibility of using synNotch receptor-engineered NK92 cells to selectively secrete IL12 at the tumor site and increase the antitumor activities of chimeric antigen receptor (CAR)-modified T cells. Compared with the nuclear factor of activated T-cells (NFATs) responsive promoter, which is another regulatory element, the synNotch receptor was better at controlling the expression of cytokines. NK92 cells transduced with the GPC3-specific synNotch receptor could produce the proinflammatory cytokine IL12 (GPC3-Syn-IL12-NK92) in response to GPC3 antigen expressed in cancer cells. In vivo GPC3-Syn-IL12-NK92 cells controlling IL12 production could enhance the antitumor ability of GPC3-redirected CAR T cells and increase the infiltration of T cells without inducing toxicity. Taken together, our results demonstrated that IL12 supplementation by synNotch-engineered NK92 cells could secrete IL12 in a target-dependent manner, and promote the antitumor efficiency of CAR-T cells. Local expression of IL12 by synNotch-engineered NK92 cells might be a safe approach to enhance the clinical outcome of CAR-T cell therapy.