c-Met is a chimeric antigen receptor T-cell target for treating recurrent nasopharyngeal carcinoma.

BACKGROUND AIMS: Radiation therapy is the standard treatment for patients with nasopharyngeal carcinoma (NPC), but relapse occurs in 10% to 20% of patients. The treatment of recurrent nasopharyngeal carcinoma (rNPC) remains challenging. Chimeric antigen receptors (CAR)-T-cell therapy has achieved good outcomes in the treatment of leukemia and seems to be a promising therapeutic strategy for solid tumors. c-Met has been found to be highly expressed in multiple cancer types, and the activation of c-Met leads to the proliferation and metastasis of cancer cells. However, the expression of c-Met in rNPC tissues and whether it can be used as a target for CAR-T therapy in rNPC remain to be investigated. METHODS: We detected the expression of c-Met in 24 primary human rNPC tissues and three NPC cell lines and constructed two different antibody-derived anti-c-Met CARs, namely, Ab928z and Ab1028z. To estimate the function of these two different c-Met-targeted CAR-T cells, CD69 expression, cytotoxicity and cytokine secretion of CAR-T cells were assessed after coculture with target cells. A cell line-derived xenograft mouse model also was used to evaluate these two anti-c-Met CAR-T cells. Furthermore, we determined whether combination with an anti-EGFR antibody could promote the antitumor effect of CAR-T cells in a patient-derived xenograft mouse model. RESULTS: High c-Met expression was detected in 23 of 24 primary human rNPC tissues by immunohistochemistry staining and in three NPC cell lines by flow cytometry. Ab928z-T cells and Ab1028z-T cells showed significantly upregulated expression of CD69 after coculture with targeted cells. However, Ab1028z-T cells showed superior cytokine secretion and antitumor activity. Furthermore, Ab1028z-T cells effectively suppressed tumor growth compared with control CAR-T cells, and the combination with nimotuzumab further enhanced the tumor-clearing ability of Ab1028z-T cells. CONCLUSIONS: We found that c-Met is highly expressed in rNPC tissues and confirmed its potential as a CAR-T target for rNPC. Our study provides a new idea for the clinical treatment of rNPC.

Photo-Activating Biomimetic Polyoxomolybdate for Boosting Oxygen Evolution in Neutral Electrolytes.

Inspired by the metal-oxo cluster structural feature and charge separation behaviour of the oxygen evolving center (OEC) in photosystem II (PS-II) under photoirradiation, a new crystalline photochromic polyoxomolybdate, MV2 [ß-Mo8 O26 ] (1, MV=methyl viologen cation), is designed as a biomimetic oxygen evolution reaction (OER) catalyst in neutral electrolytes. After photoinduced electron transfer (PIET) with colour change from colourless to grey, it remains in an ultra-stable charge-separated state over a year under ambient conditions. The observed overpotential at 10 mA ⋅ cm-2 and Tafel slope decrease by 49 mV and 62.8 mV ⋅ dec-1 after coloration, respectively. The outstanding OER performance of the coloured state in neutral electrolytes even outperforms the commercial RuO2 benchmark. Experimental and theoretical studies show that oxygen holes within polyanions after irradiation serve as sites for enhancing direct O-O coupling, thus effectively promoting OER. This is the first successful application of electron-transfer photochromism to realize OER activity gain.

White-Light Emission and Circularly Polarized Luminescence from a Chiral Copper(I) Coordination Polymer through Symmetry-Breaking Crystallization.

Achieving white-light emission, especially white circularly polarized luminescence (CPL) from a single-phase material is challenging. Herein, a pair of chiral CuI coordination polymers (1-M and 1-P) have been prepared by the asymmetrical assembly of achiral ligands and Cu2 I2 clusters. The compounds display dual emission bands and can be used as single-phase white-light phosphors, achieving a "warm"-white-light-emitting diode with an ultra-high color rendering index (CRI) of 93.4 and an appropriate correlated color temperature (CCT) of 3632 K. Meanwhile, corresponding CPL signals with maximum dissymmetry factor |glum |=8×10-3 have been observed. Hence, intrinsic white-light emission and CPL have been realized simultaneously in coordination polymers for the first time. This work gains insight into the nature of chiral assembly from achiral units and offers a prospect for the development of single-phase white-CPL materials.

Micro-deformation response of a holographic sensor in highly stretchable polymer hydrogel.

A volume grating-based holographic sensor in highly stretchable PVA/AA polymer for sensing its micro-deformation and, hence, the displacement has been studied. One-dimensional micro-displacement induced by tensile stress is analyzed using a diffraction spectrum in two kinds of sensor construction methods, i.e., transmission and reflection. The dependence of the peak wavelength on the displacement presents a good linear relationship which provides a quantitative sensing strategy for hydrogel micro-deformation. The available sensitivity is better than 4 µm/0.5 nm (displacement/wavelength shift) using a commercial spectrometer with a resolution of 0.5 nm. Finally, the reversible deformation response further validates the practical applicability of a holographic sensor constructed by photosensitive hydrogel. The optical measurement of micro-displacement as a novel sensing strategy can accelerate the development of the holographic optical element.

Enhancement of spectrum strength in holographic sensing in nanozeolites dispersed acrylamide photopolymer.

Holographic sensing of organic vapor is characterized at transmission and reflection geometries in ZSM-5 nanozeolites dispersed acrylamide photopolymer. Nano-zeolites as absorption medium are dispersed into the polymer to enhance the absorptivity to organic vapor. Obvious enhancements of spectrum strength are observed during the sensing process. Two primary factors causing the enhancement, absorption of nanozeolites and photopolymerization induced by broadband white light, are analyzed experimentally. Significant increment provides a quick and intuitive identification strategy for holographic sensing. Accompanying with the wavelength blue-shift, the shrinkage of sample is measured quantitatively under homogeneous white light. It is further demonstrated that the significance of nanozeolites absorption. Finally a theoretical model with mutual diffusion is used to simulate the swelling process. This study provides significant foundation for the application of holographic sensor.

Holographic humidity response of slanted gratings in moisture-absorbing acrylamide photopolymer.

Holographic humidity response is characterized in detail using transmission and reflection geometry in moisture-absorbing acrylamide photopolymer. The diffraction spectrum and its temporal evolution at various relative humidity are measured and analyzed. The quantitative relations between relative humidity and holographic properties of slanted gratings are determined. The responsibility of holographic gratings for various relative humidity is observed by the spectrum response of gratings. The extracted humidity constants reflect the applicability of reflection and transmission gratings at different humidity regions. The humidity reversibility experiment is achieved for confirming repeatability of the sensor. These experiments provide a probability for improving the applicability of a holographic humidity sensor. Finally, the extended diffusion model is derived by introducing the expansion coefficient to describe the dynamic swelling process. This work can accelerate development of the holographic sensor and provide a novel strategy for exploring the swelling mechanism of photopolymer.

Enhanced intensity on preoperative double contrast-enhanced sonography as a useful indicator of lymph node metastasis in patients with gastric cancer.

OBJECTIVES: The aim of this study was to investigate the predictive value of enhanced intensity on double contrast-enhanced sonography in assessing lymph node metastasis of gastric cancer. METHODS: A total of 357 patients with gastric cancer were enrolled in this study. Double contrast-enhanced sonography, in which an oral ultrasound contrast agent is combined with an intravenous contrast agent, was performed preoperatively, and the data were analyzed quantitatively. The predictive ability of enhanced intensity, a quantitative double contrast-enhanced sonographic measure, for lymph node metastasis was evaluated retrospectively. RESULTS: Compared to negative lymph node metastasis cases, the presence of thicker lesions, deeper invasion, poorer differentiation, and higher enhanced intensity were found in positive cases (P< .05). An enhanced intensity cutoff value of 16.91 dB was the best point for balancing the sensitivity and specificity (71.50% and 79.30%, respectively) for prediction of lymph node metastasis, with the highest Youden index of 0.508. The area under the receiver operating characteristic curve was 0.828 (P < .001; 95% confidence interval, 0.786-0.870). In cases in which the lesions were hyperenhanced (enhanced intensity >16.91 dB), the lesions were significantly thicker and had deeper invasion, poorer differentiation, and more positive metastasis findings compared to non-hyperenhanced cases (enhanced intensity ≤16.91 dB; P < .05). On logistic regression analysis, the enhanced intensity of primary tumors and the invasion depth were significantly associated with lymph node metastasis. CONCLUSIONS: Double contrast-enhanced sonography with quantitative analysis may be considered a novel alternative imaging modality for noninvasive preoperative evaluation of lymph node metastasis with good reliability.

[Advance in studies on effective components in wheat bran and their pharmacological activities].

Wheat bran, as the testa of wheat, has a long history of medication. Modern studies have discovered that wheat bran contains dietary fiber, phenolic compounds, proteins, vitamins, minerals and many other compounds, and boasts wide pharmacological activities such as blood glucose reduction, hypertension reduction, lipid reduction, anti-oxidation, anti-bacteria, anti-inflammatory, antivirus, prevention of colon cancer and mutations, immunomodulation and adsorption of heavy metals. With great development and utilization values, wheat bran has long attracted wide attention from Chinese and foreign scholars. The paper summarizes the latest advance in domestic and foreign studies on effective components in wheat bran and their pharmacological effect, and gives a brief introduction of the limiting factors in the comprehensive development and utilization of wheat bran, in order to provide new preference for the development and utilization of abundant wheat bran resources in China.

Characteristics of phosgene aspiration lung injury analyzed based on transcriptomics and proteomics.

Background: Phosgene is a chemical material widely used worldwide. No effective method has been developed to reverse its pathological injuries. Some studies have shown that neuronal inflammation in lung tissue is involved, but the specific mechanism has not been reported. Objective: To analyze the expression alterations of whole transcriptome gene sequencing bioinformatics and protein expression profile in lung tissue after phosgene aspiration lung injury (P-ALI) and find the main factors and pathways affecting the prognosis of P-ALI. Methods: Rat models of P-ALI were made by phosgene. Rats were divided into a P-ALI group and a blank group. Hematoxylin-eosin (HE) staining and lung wet/dry ratio measurement were used to evaluate the lung injury. The levels of inflammatory factors were measured by ELISA. High-throughput sequencing was used to measure the expression profile of each gene. Protein expression profiles were determined by label-free relative quantification of the differential proteome. Results: Lung injury such as the disordered structure of alveolar wall and inflammatory factors (IL-1ß, IL-18, and IL-33) were significantly increased in the P-ALI group (p < 0.05). There were 225 differentially expressed lncRNAs, including 85 upregulated and 140 downregulated genes. They were also the genomes with the most significant changes in transcriptome gene expression, mainly constituting cytoplasmic, synaptic structures and transporters, and involved in amino acid and carbon metabolism. There were 42 differentially expressed circRNAs, including 25 upregulated genes and 17 downregulated genes, mainly involved in cell composition, growth, differentiation, and division. There were only 10 differentially expressed miRNAs genes, all upregulated and mainly involved in the inflammatory response pathway. Proteome identification showed 79 differentially expressed proteins. KEGG enrichment analysis showed that it was mainly involved in the N-glycan biosynthesis pathway. Conclusion: We discovered that differentially regulated genes (lncRNAs, circRNAs, and miRNAs) were primarily associated with neuronal reflexes and synaptic signaling, including neurotransmitter transmission, ion signaling pathway conduction, neuronal projection, and synaptic vesicle circulation. They affected inflammatory factors and other metabolic pathways. This finding could be explored in future studies.

Hollow fiber-based liquid membrane microextraction combined with high-performance liquid chromatography for extraction and determination of trimetazidine in human plasma.

A hollow fiber-based liquid phase microextraction strategy combined with high-performance liquid chromatography was evaluated for the quantitative determination of trimetazidine in human plasma. Trimetazidine was extracted from a 2.1 mL basified plasma sample (donor phase) into the organic solvent (n-octanol) impregnated in the pores of a hollow fiber and then extracted into an acidic solution (acceptor phase) inside the lumen of the hollow fiber. The result showed that transport of drugs from alkaline sample solution into 0.5 m HCl occurred efficiently when 25 µL of 250 mm sodium 1-octanesulfonate was added into the donor phase. Several parameters influencing the efficiency of the method, such as the nature of organic solvent used to impregnate the membrane, compositions of donor phase and acceptor phase, type and concentration of carrier, extraction time, stirring rate and salt concentration, were investigated and optimized. Under the optimal conditions, the calibration curves were obtained in the range of 5-200 ng/mL with reasonable linearity (r > 0.9980). The method was successfully applied to determine the concentration of trimetazidine in human plasma.

[Determination of artemisinic acid in Artemisia annua at different growth stages based on spot area].

OBJECTIVE: Based on the important medicinal applications of artemisinic acid and the superiority of Thin Layer Chromagraphy (TLC), the spot area method of TLC was presented to determine the content changes of artemisinic acid of Artemisia annua at different growing stages. METHODS: The separation conditions including chromatographic solutions and chromogenic agent were optimized. The detection limit and the linear concentration range were analyzed. And the content changes of artemisinic acid of Artemisia annua at different growing stages were detected. RESULTS: The results showed that artemisinic acid extracted from Artemisia annua could be separated completely by the chromatographic solutions composed by petroleum ether,acetone and ethyl acetate (80: 19: 1). The artemisinic acid was clearly colored using the chromogenic agent consisting by ethanol, bromophenol blue and sulfuric acid. The detection limit of TLC was 0.05 mg/mL. The spot area of TLC had a good linear relationship within the range of 0.05-0.6 mg/mL, accorded with regression equation of y = 11.162 x + 0.0823. The results showed that the content of artemisinic acid at 0.041 mg/g in April which below the detection limit of TLC had no color spot. Contrarily, the spots of artemisinic acid were obvious in materials growing from May to September, and content was about 0.7, 1.2, 2.1, 2.4 and 2.7 mg/g, respectively corresponding to results by HPLC. CONCLUSION: The method can be applied to the quantitative analysis of artemisinic acid in Artemisia annua.

High throughput sequencing technology reveals alteration of lower respiratory tract microbiome in severe aspiration pneumonia and its association with inflammation.

BACKGROUND: Aspiration pneumonia is a common and severe clinical condition. The microbiome present in the lower respiratory tract plays a crucial role in regulating human inflammatory response. However, the relationship between the altered lower respiratory tract microbiome and inflammation in aspiration pneumonia remains inadequately explored. PURPOSE: To investigate the alteration of the lower respiratory tract microbiome in severe aspiration pneumonia patients and explore the potential correlation between microbiome components and inflammatory response. METHOD: Patients in the severe aspiration pneumonia group and control group were enrolled from the intensive care unit of Jinshan Hospital, Fudan University between December 31, 2020 and August 19, 2021. Sputum specimens were collected from all participants and subsequently subjected to 16S rDNA high throughput sequencing technology. The concentration of inflammatory cytokines in serum was measured using enzyme-linked immunosorbent assay (ELISA) kits, and collected data including patients' demographic information, clinical data, and laboratory examination results were recorded for further analysis. RESULTS: Alteration in the lower respiratory tract microbiome was observed in severe aspiration pneumonia. Compared to the control group, a significant decrease in the relative abundance of Firmicutes was found at the phylum level (P < 0.01). At the family level, the relative abundance of Corynebacteriaceae, Enterobacteriaceae and Enterococcaceae increased significantly (P < 0.001, P < 0.05, P < 0.01). There were no significant differences in community diversity of the lower respiratory tract between the two groups. Patients in the severe aspiration pneumonia group exhibited significantly higher levels of inflammation compared to those in the control group. Correlation analysis showed that the relative abundance of Corynebacteriaceae was positively correlated with the expression level of IL-1ß and IL-18 (P = 0.002, P = 0.02); the relative abundance of Enterobacteriaceae was negatively correlated with IL-4 (P = 0.011); no other significant correlations have been identified between microbiome and inflammatory indicators thus far (P > 0.05). CONCLUSIONS: Alteration of the lower respiratory tract microbiome is critically involved in inflammation and disease progression in severe cases of aspiration pneumonia. The potential inflammation regulation properties of the microbiome hold promising value for developing novel therapeutic approaches aimed at mitigating the severity of the disease.

Early platelet level reduction as a prognostic factor in intensive care unit patients with severe aspiration pneumonia.

Introduction: This study investigates risk factors underlying the prognosis of severe aspiration pneumonia (SAP) in intensive care unit (ICU) patients and attempts to provide early prognosis reference for clinical tasks. Methods: Patients diagnosed with SAP and admitted to the ICU of Jinshan Hospital, Fudan University, Shanghai, China, between January 2021 and December 2021 were recruited in this retrospective cohort study. Clinical data on a patient's general condition, underlying diseases, laboratory indicators, and 90-day outcomes (survival or death) were recorded. Results: Multivariate logistic regression analysis showed that a low platelet count was an independent risk factor affecting the prognosis of death (OR = 6.68, 95% CI:1.10-40.78, ß = 1.90, P = 0.040). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of variables; cut-off values were calculated and the area under the curve was 0.7782 [(95% CI:0.686-0.871), p < 0.001] for the prediction of death at 90 days in all patients. The Kaplan-Meier curve used for survival analysis showed that, compared with the normal platelet group, the overall survival rate of patients with low platelet levels was significantly lower, and the difference was statistically significant [HR = 2.11, (95% CI:1.47-3.03), p = 0.0001, z = 4.05, X 2 = 14.89]. Cox regression analysis, used to further verify the influence of prognostic risk factors, showed that a concurrent low platelet count was the most important independent risk factor affecting the prognosis of SAP (HR = 2.12 [95% CI:1.12-3.99], X2 = 50.95, p = 0.021). Conclusion: These findings demonstrate an association between SAP mortality and platelet levels on admission. Thus, platelet level at admission may be used as a readily available marker for assessing the prognosis of patients with SAP.

CD318 is a target of chimeric antigen receptor T cells for the treatment of colorectal cancer.

Colorectal cancer (CRC) currently has a poor prognosis with a 6.9-year median survival time; to relieve this malignant cancer, we proposed to establish CRC xenografts that can be used to evaluate the cytotoxicity of adoptive chimeric antigen receptor (CAR)-T cells and accelerate the clinical translation of CAR-T cells for use against CRC. We first verified that CD318 had a higher expression level in primary human CRC tissues than in normal tissues based on hundreds of clinical samples. Then, we redirected CAR-T cells containing anti-CD318 single-chain variable fragment (anti-CD318 scFv), CD3ζ, CD28, and Toll-like receptor 2 (TLR2) domains. Next, we evaluated the function of these CAR-T cells in vitro in terms of surface phenotype changes, cytotoxicity and cytokine secretion when they encountered CD318+ CRC cells. Finally, we established two different xenograft mouse models to assess in vivo antitumor activity. The results showed that CAR318 T cells were significantly activated and exhibited strong cytotoxicity and cytokine-secreting abilities against CRC cells in vitro. Furthermore, CAR318 T cells induced CRC regression in different xenograft mouse models and suppressed tumors compared with CAR19 T cells. In summary, our work demonstrates that CAR318 T cells possess strong antitumor capabilities and represent a promising therapeutic approach for CRC.

The onco-embryonic antigen ROR1 is a target of chimeric antigen T cells for colorectal cancer.

Colorectal cancer is globally ranked second in both incidence and mortality rate. It usually develops during the middle or late stages of diagnosis, and is characterized by easy metastasis, poor prognosis, and a significant decline in postoperative quality of life. ROR1 is an excellent oncoembryonic antigen in numerous immunotherapy treatments for tumors. Additionally, it is overexpressed in colorectal cancer. To fill the void in CRC treatment with ROR1 as a target of CAR-T immunotherapy, we designed and prepared antiROR1-CART. This third-generation CAR-T cell can effectively inhibit the growth of colorectal cancer in vitro and in vivo.

Disruption of CISH promotes the antitumor activity of human T cells and decreases PD-1 expression levels.

Tumor cells and the immunosuppressive tumor microenvironment suppress the antitumor activity of T cells through immune checkpoints, including the PD-L1/PD-1 axis. Cytokine-inducible SH2-containing protein (CISH), a member of the suppressor of cytokine signaling (SOCS) family, inhibits JAK-STAT and T cell receptor (TCR) signaling in T and natural killer (NK) cells. However, its role in the regulation of immune checkpoints in T cells remains unclear. In this study, we ablated CISH in T cells with CRISPR-Cas9 and found that the sensitivity of T cells to TCR and cytokine stimulation was increased. In addition, chimeric antigen receptor T cells with CISH deficiency exhibited longer survival and higher cytokine secretion and antitumor activity. Notably, PD-1 expression was decreased in activated CISH-deficient T cells in vitro and in vivo. The level of FBXO38, a ubiquitination-regulating protein that reduces PD-1 expression, was elevated in activated T cells after CISH ablation. Hence, this study reveals a mechanism by which CISH promotes PD-1 expression by suppressing the expression of FBXO38 and proposes a new strategy for augmenting the therapeutic effect of CAR-T cells by inhibiting CISH.

Synthesis and biological evaluation of novel N-acyl substituted quinolin-2(1H)-one derivatives as potential antimicrobial agents.

A series of novel N-acyl substituted quinolin-2(1H)-one derivatives were synthesized and screened in vitro for their antibacterial and antifungal activities by disc diffusion method. All the compounds exhibited moderate to good antimicrobial activities, some of these compounds displayed comparable or better antibacterial or antifungal activities against some tested strains compared to the reference drugs Streptomycin and Fluconazole.

[Variation of content of artemisic acid in different growth stages of Artemisia annua].

OBJECTIVE: To study the variation of content of Artemisic acid of Artemisia annua from eight areas of four provinces around Wuling Mountain. METHODS: Artemisic acid of plants were extracted by organic solvent method. Qualitative and quantitative analysis of Artemisic acid were measured by thin layer chromatography (TLC) and high performance thin layer chromatography (HPLC), respectively. RESULTS: The results showed the average levels of Artemisic acid in May and August changed from 0.964 to 2.288 mg/g and from 1.837 to 3.737 mg/g, respectively. The average level in August was 1.5 times as that in May. The Artemisic acid in cultured plants was higher than the levels in wild plants, and Artemisic acid in plant collected below 300 m altitude was higher than that of the plant collected above 300 m altitude. CONCLUSION: The biosynthesis of Artemisic acid depends on the plant growth stage,which is mainly accumulated in plant at the mature stage.

[The influence of suoquan capsule on the mRNA expression of CYP11B2 in deficiency of the kidney and diuresis rats].

OBJECTIVE: To explore the mechanism of nourishing kidney and reducing urine effect of suoquan capsule by discussing the adjusting action on ALD synthase. METHODS: Built the model of deficiency of the kidney and diuresis by adenine,inspectd the contents of Cort, ALD in blood and the mRNA expression of CYP11B2 with ELISA and RT-PCR technology of the mice. RESULTS: Compared with model group, Suoquan capsule could remarkedly increase the contents of Cort, ALD in blood and the mRNA expression of CYP1 1 B2 of model rats. CONCLUSIONS: Suoquan capsule can increase the contents of Cort, ALD in blood and the mRNA expression of CYP11B2 in deficiency of the kidney and diuresis rats. Promote the combining of ALD by adjusting the ALD synthase may be the mechanism of nourishing the kidney and reducing urine of Souquan capsule from ALD synthase approach.

Human Hyaluronidase PH20 Potentiates the Antitumor Activities of Mesothelin-Specific CAR-T Cells Against Gastric Cancer.

T cell infiltration into tumors is essential for successful immunotherapy against solid tumors. Herein, we found that the expression of hyaluronic acid synthases (HAS) was negatively correlated with patient survival in multiple types of solid tumors including gastric cancer. HA impeded in vitro anti-tumor activities of anti-mesothelin (MSLN) chimeric antigen receptor T cells (CAR-T cells) against gastric cancer cells by restricting CAR-T cell mobility in vitro. We then constructed a secreted form of the human hyaluronidase PH20 (termed sPH20-IgG2) by replacing the PH20 signal peptide with a tPA signal peptide and attached with IgG2 Fc fragments. We found that overexpression of sPH20-IgG2 promoted CAR-T cell transmigration through an HA-containing matrix but did not affect the cytotoxicity or cytokine secretion of the CAR-T cells. In BGC823 and MKN28 gastric cancer cell xenografts, sPH20-IgG2 promoted anti-mesothelin CAR-T cell infiltration into tumors. Furthermore, mice infused with sPH20-IgG2 overexpressing anti-MSLN CAR-T cells had smaller tumors than mice injected with anti-MSLN CAR-T cells. Thus, we demonstrated that sPH20-IgG2 can enhance the antitumor activity of CAR-T cells against solid tumors by promoting CAR-T cell infiltration.