Zinc oxide nanoparticles reduce cadmium accumulation in hydroponic lettuce (Lactuca sativa L.) by increasing photosynthetic capacity and regulating phenylpropane metabolism.

Due to the continuous production of industrial wastes and the excessive use of chemical fertilizers and pesticides, severe cadmium (Cd) pollution in soil has occurred globally. This study investigated the impacts of incorporating zinc oxide nanoparticles (ZnONPs) into hydroponically grown lettuce (Lactuca sativa) under cadmium stress conditions, to seek effective methods to minimize Cd buildup in green leafy vegetables. The results showed that 1 mg/L of Cd significantly inhibited lettuce growth, decreasing in leaves (29 %) and roots (33 %) biomass. However, when lettuce was exposed to 2.5 mg/L ZnONPs under cadmium stress, the growth, chlorophyll content, net photosynthetic rate (Pn), stomatal conductance (Gs), actual photochemical efficiency of PSII (φPSII), and activity of key enzymes in photosynthesis were all significantly enhanced. Furthermore, ZnONPs significantly decreased the accumulation of Cd in lettuce leaves (36 %) and roots (13 %). They altered the subcellular distribution and chemical morphology of Cd in lettuce by modifying the composition of cell walls (such as pectin content) and the levels of phenolic compounds, resulting in a reduction of 27 % in Cd translocation from roots to leaves. RNA sequencing yielded 45.9 × 107 and 53.4 × 107 clean reads from plant leaves and roots in control (T0), Cd (T1), Cd+ZnONPs (T2), and ZnONPs (T3) treatment groups respectively, and 3614 and 1873 differentially expressed genes (DEGs) were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified photosynthesis, carbon fixation, and phenylpropanoid metabolism as the main causes of ZnONPs-mediated alleviation of Cd stress in lettuce. Specifically, the DEGs identified included 12 associated with photosystem I, 13 with photosystem II and 23 DEGs with the carbon fixation pathway of photosynthesis. Additionally, DEGs related to phenylalanine ammonia-lyase, caffeoyl CoA 3-O-methyltransferase, peroxidase, 4-coumarate-CoA ligase, hydroxycinnamoyl transferase, and cytochrome P450 proteins were also identified. Therefore, further research is recommended to elucidate the molecular mechanisms by which ZnONPs reduce Cd absorption in lettuce through phenolic acid components in the phenylpropanoid metabolism pathway. Overall, treatments with ZnONPs are recommended to effectively reduce Cd accumulation in the edible portion of lettuce.

NK cell based immunotherapy against oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC), a major subtype of head and neck cancers, presents significant challenges due to its aggressive feature and limited therapeutic efficacy of conventional treatments. In response to these challenges, Natural Killer (NK) cells, a vital component of the innate immune system, are being explored for their therapeutic potential in OSCC due to their inherent ability to target and eliminate cancer cells without prior sensitization. This review uniquely focuses on the evolving role of NK cells specifically in OSCC, incorporating recent advancements in CAR-NK cell engineering and personalized therapy approaches that have not been comprehensively covered in previous reviews. The mechanisms through which NK cells exert cytotoxic effects on tumor cells include direct killing through the engagement of natural cytotoxic receptors and antibody-dependent cellular cytotoxicity (ADCC), making them promising agents in cancer immunotherapy. Additionally, the article explores recent advancements in engineering NK cells to enhance their antitumor activity, such as the modification with chimeric antigen receptors (CARs) to target specific tumor antigens. Clinical implications of NK cell-based therapies, including the challenges of integrating these treatments with existing protocols and the potential for personalized therapy, are examined. The review highlights the promise of NK cell therapies in improving outcomes for OSCC patients and outlines future directions for research in this dynamic field of oncological immunotherapy.

Robotic distal gastrectomy using a novel pre-emptive supra-pancreatic approach without duodenal transection in the dissection of D2 lymph nodes for gastric cancer.

Background: Robot-assisted surgery has shown remarkable progress as a minimally invasive procedure for gastric cancer. This study aimed to compare the pre-emptive suprapancreatic approach without duodenal transection and the conventional approach in terms of perioperative feasibility and short-term surgical outcomes. Methods: We retrospectively analyzed all patients who underwent robotic distal gastrectomy with D2 lymph node dissection using the da Vinci Xi robotic system between December 2021 and April 2023 and categorized them into two groups for comparison. Patients treated using the pre-emptive suprapancreatic approach (observation group) were compared with those who received the conventional approach (control group). Employing one-to-one propensity score matching, we evaluated the postoperative morbidity and short-term outcomes in these two distinct groups to assess the efficacy and safety of the novel surgical technique. Results: This study enrolled 131 patients: 70 in the observation group and 61 in the control group. After propensity score matching, the operative times were significantly longer in the control group than in the observation group (229.10 ± 33.96 vs. 174.84 ± 18.37, p <0.001). The mean blood loss was lower in the observation group than in the control group (25.20 ± 11.18 vs. 85.00 ± 38.78, p <0.001). Additionally, the observation group exhibited a higher number of retrieved lymph nodes, including suprapyloric, perigastric, and superior pancreatic lymph nodes (28.69 ± 5.48 vs. 19.21 ± 2.89, p <0.001; 4.98 ± 1.27 vs. 4.29 ± 1.21, p = 0.012; 10.52 ± 2.39 vs. 5.50 ± 1.62, p <0.001; 6.26 ± 2.64 vs. 5.00 ± 1.72, p = 0.029). Drain amylase levels in the observation group were significantly lower than those in the control group (30.08 ± 33.74 vs. 69.14 ± 66.81, p <0.001). Conclusion: This study revealed that using the pre-emptive suprapancreatic approach without duodenal transection in the dissection of D2 lymph nodes for gastric cancer is a safe and feasible procedure in terms of surgical outcomes.

Targeting aryl hydrocarbon receptor to prevent cancer in barrier organs.

The skin, lung, and gut are important barrier organs that control how the body reacts to environmental stressors such as ultraviolet (UV) radiation, air pollutants, dietary components, and microorganisms. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that plays an important role in maintaining homeostasis of barrier organs. AhR was initially discovered as a receptor for environmental chemical carcinogens such as polycyclic aromatic hydrocarbons (PAHs). Activation of AhR pathways by PAHs leads to increased DNA damage and mutations which ultimately lead to carcinogenesis. Ongoing evidence reveals an ever-expanding role of AhR. Recently, AhR has been linked to immune systems by the interaction with the development of natural killer (NK) cells, regulatory T (Treg) cells, and T helper 17 (Th17) cells, as well as the production of immunosuppressive cytokines. However, the role of AhR in carcinogenesis is not as straightforward as we initially thought. Although AhR activation has been shown to promote carcinogenesis in some studies, others suggest that it may act as a tumor suppressor. In this review, we aim to explore the role of AhR in the development of cancer that originates from barrier organs. We also examined the preclinical efficacy data of AhR agonists and antagonists on carcinogenesis to determine whether AhR modulation can be a viable option for cancer chemoprevention.

Effects of exogenous glycine betaine and cycloleucine on photosynthetic capacity, amino acid composition, and hormone metabolism in Solanum melongena L.

Although exogenous glycine betaine (GB) and cycloleucine (Cyc) have been reported to affect animal cell metabolism, their effects on plant growth and development have not been studied extensively. Different concentrations of exogenous glycine betaine (20, 40, and 60 mmol L-1) and cycloleucine (10, 20, and 40 mmol L-1), with 0 mmol L-1 as control, were used to investigate the effects of foliar spraying of betaine and cycloleucine on growth, photosynthesis, chlorophyll fluorescence, Calvin cycle pathway, abaxial leaf burr morphology, endogenous hormones, and amino acid content in eggplant. We found that 40 mmol L-1 glycine betaine had the best effect on plant growth and development; it increased the fresh and dry weight of plants, increased the density of abaxial leaf hairs, increased the net photosynthetic rate and Calvin cycle key enzyme activity of leaves, had an elevating effect on chlorophyll fluorescence parameters, increased endogenous indoleacetic acid (IAA) content and decreased abscisic acid (ABA) content, and increased glutamate, serine, aspartate, and phenylalanine contents. However, cycloleucine significantly inhibited plant growth; plant apical dominance disappeared, plant height and dry and fresh weights decreased significantly, the development of abaxial leaf hairs was hindered, the net photosynthetic rate and Calvin cycle key enzyme activities were inhibited, the endogenous hormones IAA and ABA content decreased, and the conversion and utilization of glutamate, arginine, threonine, and glycine were affected. Combined with the experimental results and plant growth phenotypes, 20 mmol L-1 cycloleucine significantly inhibited plant growth. In conclusion, 40 mmol L-1 glycine betaine and 20 mmol L-1 cycloleucine had different regulatory effects on plant growth and development.

Zinc oxide nanoparticles improve lettuce (Lactuca sativa L.) plant tolerance to cadmium by stimulating antioxidant defense, enhancing lignin content and reducing the metal accumulation and translocation.

Cadmium (Cd) contamination is a serious global concern that warrants constant attention. Therefore, a hydroponic study was conducted to evaluate the effect of different concentrations (0, 1, 2.5, 5, 10, 15 mg/l) of zinc oxide nanoparticles (ZnONPs) on the Cd content in lettuce (Lactuca sativa L.) under Cd stress conditions. The results showed that Cd stress triggered a decrease in plant biomass, an increase in relative electrolyte conductivity (REC), a decrease in root activity, accumulation of reactive oxygen species (ROS) accumulation, and nutrient imbalance. The application of ZnONPs reduced the toxicity symptoms of lettuce seedlings under Cd stress, with the most pronounced effect being observed 2.5 mg/l. ZnONPs promoted the growth of lettuce under Cd stress, mainly in terms of increase in biomass, chlorophyll content, antioxidant enzyme activity, and proline content, as well as reduction in Cd content, malondialdehyde, and reactive oxygen species (ROS) in plant tissues. ZnONPs also enhanced the uptake of ions associated with photosynthesis, such as iron, manganese, magnesium, and zinc. In addition, ZnONPs increase the amount of lignin in the roots, which blocks or reduces the entry of Cd into plant tissues.

Effects of Plant Hormones, Metal Ions, Salinity, Sugar, and Chemicals Pollution on Glucosinolate Biosynthesis in Cruciferous Plant.

Cruciferous vegetable crops are grown widely around the world, which supply a multitude of health-related micronutrients, phytochemicals, and antioxidant compounds. Glucosinolates (GSLs) are specialized metabolites found widely in cruciferous vegetables, which are not only related to flavor formation but also have anti-cancer, disease-resistance, and insect-resistance properties. The content and components of GSLs in the Cruciferae are not only related to genotypes and environmental factors but also are influenced by hormones, plant growth regulators, and mineral elements. This review discusses the effects of different exogenous substances on the GSL content and composition, and analyzes the molecular mechanism by which these substances regulate the biosynthesis of GSLs. Based on the current research status, future research directions are also proposed.

Effect of Methyl Jasmonate Treatment on Primary and Secondary Metabolites and Antioxidant Capacity of the Substrate and Hydroponically Grown Chinese Chives.

Hydroponic culture has become a commercial planting model for leafy vegetables, herbs, and other plants with medicinal value. Methyl jasmonate (MeJA) is involved in primary and secondary plant metabolism; moreover, it regulates plant bioactive compounds and enhances the nutritional and medicinal value of plants. We performed targeted metabolomic analysis of the primary and secondary metabolites in substrate-grown and hydroponic Chinese chive leaves sprayed with MeJA (0, 300, 500, and 800 µM). Using ultra-performance liquid chromatography (UPLC), UPLC tandem mass spectrometry, and chemometric tools, and analyzed the antioxidant activity of these plants. We identified the biomarkers of amino acids (serine, proline, lysine, and arginine) and phenolic compounds (4-coumaric acid and protocatechuic acid) using chemometric tools to distinguish between substrate-grown and hydroponic Chinese chives treated with MeJA. MeJA (500 µM) treatment significantly increased the total sugar and amino acid (essential and non-essential amino acids and sulfur-containing amino acids) contents of hydroponically grown Chinese chives. However, the changes in total sugar and amino acid contents in Chinese chive grown in substrates showed the opposite trend. The organic acid content of hydroponically grown Chinese chives treated with MeJA decreased significantly, whereas that of substrate-grown plants treated with 300 µM MeJA increased significantly. Further, MeJA treatment significantly increased the phenolic content of substrate-grown Chinese chives. Treatment with 800 µM MeJA significantly increased the carotenoid content of substrate-grown Chinese chives and the phenolic content of hydroponic Chinese chives. In addition, the 500 µM MeJA treatment significantly increased the antioxidant activity of Chinese chives in both substrate-grown and hydroponic cultures, and promoted the accumulation of nutrients and bioactive substances. This treatment also improved the flavor quality of these plants and their nutritional and medicinal value. Thus, the results suggested that MeJA-treated plants could be used as value-added horticultural products.

Site-Specific Dinitrophenylation of Single-Chain Antibody Fragments for Redirecting a Universal CAR-T Cell against Cancer Antigens.

We have previously developed a universal chimeric antigen receptor (CAR), which recognizes dinitrophenyl (DNP) and can redirect T and NK cells to target cancer and HIV antigens using DNP-conjugated antibodies as adaptor molecules. However, the DNP-antibody conjugates are generated by random modification, which may not be optimal for this modular system. Here, we report the development of enhanced adaptor molecules by site-specific DNP modification. We use the genetic code expansion technology to generate single-chain fragment variable (scFv) antibodies with site-specific DNP. We compare four anti-CD19 scFv mutants and find that the one with DNP at the flexible peptide linker between VL and VH is the most effective in redirecting anti-DNP CAR-T cells against CD19+ cells. The other three mutants are ineffective in doing so due to reduced DNP exposure or abrogated CD19 binding. We also use the anti-CD22 scFv as another model adaptor molecule and again find that the peptide linker is ideal for DNP derivatization. Our approach can potentially be used to design enhanced adaptor molecules to redirect the DNP-mediated universal CAR against other tumor antigens.

Clinical Experience of Intracorporeal Hand-sewn Anastomosis Following Totally Laparoscopic Pylorus-Preserving Gastrectomy for Middle-Third Early Gastric Cancer.

INTRODUCTION: Pylorus-preserving gastrectomy (PPG) has been accepted as a representative function-preserving procedure for early gastric cancer (EGC) in the middle stomach. Totally, intracorporeal laparoscopic gastrectomy can provide better aesthetics, be less invasive, and allow faster postoperative recovery. Here, we first describe the surgical procedure of totally laparoscopic pylorus-preserving gastrectomy with intracorporeal hand-sewn anastomosis (TLPPG-IHSA). METHODS: After standard procedure of lymph node dissection and middle stomach resection, we used two double-needle barbed sutures to perform a layer-to-layer manual anastomosis of the anterior and posterior walls in the abdominal cavity. Twelve patients with preoperatively diagnosed clinical EGC located in the middle third of the stomach underwent TLPPG-IHSA between August 2019 and January 2021. RESULTS: A total of 12 patients with EGC successfully underwent TLPPG-IHSA. Only one patient (8.3%) suffered postoperative gastric stasis. No complications or recurrence occurred in other patients during half a year after surgery. CONCLUSION: TLPPG-IHSA is considered technically feasible to treat EGC located in the middle third of the stomach.

Targeting HLA-DR loss in hematologic malignancies with an inhibitory chimeric antigen receptor.

Chimeric antigen receptor natural killer (CAR-NK) cells have remarkable cytotoxicity against hematologic malignancies; however, they may also attack normal cells sharing the target antigen. Since human leukocyte antigen DR (HLA-DR) is reportedly lost or downregulated in a substantial proportion of hematologic malignancies, presumably a mechanism to escape immune surveillance, we hypothesize that the anti-cancer specificity of CAR-NK cells can be enhanced by activating them against cancer antigens while inhibiting them against HLA-DR. Here, we report the development of an anti-HLA-DR inhibitory CAR (iCAR) that can effectively suppress NK cell activation against HLA-DR-expressing cells. We show that dual CAR-NK cells, which co-express the anti-CD19 or CD33 activating CAR and the anti-HLA-DR iCAR, can preferentially target HLA-DR-negative cells over HLA-DR-positive cells in vitro. We find that the HLA-DR-mediated inhibition is positively correlated with both iCAR and HLA-DR densities. We also find that HLA-DR-expressing surrounding cells do not affect the target selectivity of dual CAR-NK cells. Finally, we confirm that HLA-DR-positive cells are resistant to dual CAR-NK cell-mediated killing in a xenograft mouse model. Our approach holds great promise for enhancing CAR-NK and CAR-T cell specificity against malignancies with HLA-DR loss.

Exogenous silicon enhances the systemic defense of cucumber leaves and roots against CA-induced autotoxicity stress by regulating the ascorbate-glutathione cycle and photosystem II.

Cinnamic acid (CA), one of the main autotoxins secreted by cucumber roots during continuous cropping, inhibits plant growth and reduces yield. Silicon (Si) is an environmentally friendly element that alleviates abiotic stresses in plants, but the mechanism underlying its resistance to autotoxicity remain unclear. Here, we used 0.8 mmol L-1 CA to study the effects of Si application on the growth, chlorophyll fluorescence, and ascorbate-glutathione (AsA-GSH) cycle of cucumber seedlings under CA inducing conditions. Our results indicated that CA significantly induced photoinhibition and overaccumulation of reactive oxygen species (ROS), thereby inhibiting cucumber growth. Treatment with 1.0 mmol L-1 Si improved plant height, stem diameter and biomass accumulation, and protected the photosynthetic electron transport function of photosystem II in the presence of CA. Similarly, Si application maintained the ROS status by increasing ascorbate (AsA) and glutathione (GSH) production, as well as the ratios of AsA/DHA and GSH/GSSG in both leaves and roots during CA stress. In addition, Si application in CA-treated seedlings enhanced the activity of key enzymes such as ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), glutathione reductase (GR), glutathione S-transferase (GST), and the transcription of several enzyme genes (CsAPX, CsMDHAR and CsGR） from the AsA-GSH cycle. These results suggest that exogenous Si enhances CA tolerance in cucumber seedlings by protecting photosystem II activity, upregulating AsA-GSH pathway, and reducing ROS levels.

Site-specific antibody-drug conjugates with variable drug-to-antibody-ratios for AML therapy.

Random conjugations of chemotherapeutics to monoclonal antibodies result in heterogeneous antibody-drug conjugates (ADCs) with suboptimal pharmacological properties. We recently developed a new technology for facile generation of homogeneous ADCs by harnessing human CD38 catalytic domain and its dinucleotide-derived covalent inhibitor, termed ADP-ribosyl cyclase-enabled ADCs (ARC-ADCs). Herein we advance this technology by designing and synthesizing ARC-ADCs with customizable drug-to-antibody ratios (DARs). Through varying numbers and locations of CD38 fused to an antibody targeting human C-type lectin-like molecule-1 (hCLL-1), ARC-ADCs featuring DARs of 2 and 4 were rapidly generated via a single step with cytotoxic monomethyl auristatin F (MMAF) as payloads. In contrast to anti-hCLL-1 ARC-ADC carrying 2 drug molecules, anti-hCLL-1 ARC-ADC with a DAR of 4 shows highly potent activity in killing hCLL-1-positive acute myeloid leukemia (AML) cells both in vitro and in vivo. This work provides novel ADC candidates for combating AML and supports ARC-ADC as a general and versatile approach for producing site-specific ADCs with defined DARs.

Proteomic analysis reveals key proteins involved in ethylene-induced adventitious root development in cucumber (Cucumis sativus L.).

The mechanisms involved in adventitious root formation reflect the adaptability of plants to the environment. Moreover, the rooting process is regulated by endogenous hormone signals. Ethylene, a signaling hormone molecule, has been shown to play an essential role in the process of root development. In the present study, in order to explore the relationship between the ethylene-induced adventitious rooting process and photosynthesis and energy metabolism, the iTRAQ technique and proteomic analysis were employed to ascertain the expression of different proteins that occur during adventitious rooting in cucumber (Cucumis sativus L.) seedlings. Out of the 5,014 differentially expressed proteins (DEPs), there were 115 identified DEPs, among which 24 were considered related to adventitious root development. Most of the identified proteins were related to carbon and energy metabolism, photosynthesis, transcription, translation and amino acid metabolism. Subsequently, we focused on S-adenosylmethionine synthase (SAMS) and ATP synthase subunit a (AtpA). Our findings suggest that the key enzyme, SAMS, upstream of ethylene synthesis, is directly involved in adventitious root development in cucumber. Meanwhile, AtpA may be positively correlated with photosynthetic capacity during adventitious root development. Moreover, endogenous ethylene synthesis, photosynthesis, carbon assimilation capacity, and energy material metabolism were enhanced by exogenous ethylene application during adventitious rooting. In conclusion, endogenous ethylene synthesis can be improved by exogenous ethylene additions to stimulate the induction and formation of adventitious roots. Moreover, photosynthesis and starch degradation were enhanced by ethylene treatment to provide more energy and carbon sources for the rooting process.

Melatonin alleviates imidacloprid phytotoxicity to cucumber (Cucumis sativus L.) through modulating redox homeostasis in plants and promoting its metabolism by enhancing glutathione dependent detoxification.

Melatonin (Mel), a powerful antioxidant that has the ability to regulate physiological and biochemical processes in plants under abiotic stresses. However, its roles in pesticide detoxification is poorly understood. Herein, selecting leaf spraying insecticide imidacloprid (IMD) as the model, we demonstrated the detoxification mechanism underlying root pretreatment of Mel on IMD in cucumber. IMD treatment affected the primary light conversion efficiency of photosystem II (Fv/Fm), reduced the quantum yield, and increased hydrogen peroxide and superoxide anions contents as well as the levels of membrane lipid peroxidation, indicating that excessive IMD treatment induces oxidative stress. Nonetheless, by increasing the appropriate levels of exogenous Mel, the photosynthesis of cucumber under IMD treatment reached the control levels, effectively removing reactive oxygen species. Furthermore, the content and ratio of ascorbate (AsA) and glutathione (GSH) were decreased under IMD treatment; Mel treatment enhanced the AsA/DHA and GSH/GSSG ratios, as well as the activities of MDHAR, DHAR and GR, suggesting that Mel could alleviate oxidative stress of cucumber treated with IMD by regulating the ascorbic acid-glutathione cycle. Importantly, IMD degradation rate and glutathione S-transferase (GST) activity increased after Mel treatment. The levels of transcripts encoding antioxidant enzymes GPX and GST (GST1,2 and 3) were also increased, indicating that Mel accelerated IMD degradation. These results suggest that Mel plays an important role in the detoxification of IMD by promoting GST activity and transcription and the AsA-GSH cycle, thus providing an approach for plants to reduce IMD residue through the plant's own detoxification mechanism.

Foliar application of abscisic acid mitigates cadmium stress and increases food safety of cadmium-sensitive lettuce (Lactuca sativa L.) genotype.

Cadmium (Cd2 +) is among the toxic non-essential heavy metals that adversely affect plants metabolic processes and the safety of produce. However, plant hormones can improve plant's tolerance to various stresses. This study investigated the effect of exogenous abscisic acid (ABA) on the biochemical and physiological processes and food safety of cadmium (Cd2 +)-sensitive lettuce genotype (Lüsu). Seedlings were subjected to five treatments: [(i) Control (untreated plants), (ii) 100 µM CdCl2, (iii) 100 µM CdCl2+10 µg L-1 ABA (iv) 10 µg L-1 ABA, and (v) 0.01 g L-1 ABA-inhibitor (fluridone)] for fourteen days in hydroponic system. The 100 µM CdCl2 increased the contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA), decreased photosynthesis and plant biomass. Moreover, it decreased the contents of essential nutrients (except copper) in the leaves but increased the contents of toxic Cd2 + in the leaves and roots of the plants. Foliar application of fluridone (0.01 g L-1) also caused oxidative stress by increasing the contents of H2O2 and MDA. It also decreased the contents of nutrient elements in the leaves of the plants. However, exogenous ABA (10 µg L-1) mitigated the Cd2 +-induced stress, increased antioxidant enzymes activities, photosynthesis and plant biomass under CdCl2 treatment. Remarkably, exogenous ABA increased the contents of essential nutrient elements but decreased the Cd2 + content in leaves under the CdCl2 treatment. Our results have demonstrated that foliar application of ABA mitigates Cd2 + stress and increases the nutritional quality and food safety of Cd2 +-sensitive lettuce genotype under CdCl2 treatment.

CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies.

CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell-specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient-derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants.

Root tolerance and biochemical response of Chinese lettuce (Lactuca sativa L.) genotypes to cadmium stress.

This study was conducted to determine the root tolerance and biochemical responses of four Chinese Lactuca sativa L. genotypes (Lüsu, Lümeng, Yidali and Anyan) to cadmium (Cd2+) stress. Twenty-eight days old seedlings were exposed to Hoagland's nutrient solution supplied with or without 100 µM CdCl2 and monitored for seven days in a climate controlled room. The 100 µM CdCl2 significantly (P < 0.001) decreased all the root morphological indexes of the four genotypes. However, Yidali, which possessed the smallest root system, exhibited greater root tolerance to Cd2+ by having the highest tolerance indexes for root volume (46%), surface area (61%), projected area (74%) and numbers of root forks (63%) and root tips (58%). Moreover, Cd2+ stress also caused increases in H2O2 contents in the roots but the increase was least in Yidali which showed greater root tolerance to Cd2+stress. The effect of Cd2+ stress on the contents of hormones in the roots depended on the genotypes. Under Cd2+ stress, abscisic acid correlated positively with indole-3-acetic acid (r = 0.669*), gibberellic acid (r = 0.630*) and cytokinin (r = 0.785**). The antioxidant enzyme activities and proline responses of the four genotypes to Cd2+ stress were similar. The SOD activity was decreased whiles the CAT and POD activities, as well as the contents of proline increased in all the genotypes under the stress condition. These results suggest that lettuce genotypes with smaller root systems could be more tolerant to Cd2+ stress compared to those with larger root systems.

Downregulation of TNF-α/TNF-R1 Signals by AT-Lipoxin A4 May Be a Significant Mechanism of Attenuation in SAP-Associated Lung Injury.

Our previous studies verified the potent anti-inflammatory effects against severe acute pancreatitis (SAP) of AT-Lipoxin A4 and their analogues. However, the anti-inflammatory effects of AT-Lipoxin A4 on SAP-associated lung injury are not thoroughly known. We used western blot, polymerase chain reaction (PCR), and immunofluorescence to investigate the downregulation of TNF-α signals in cellular and animal models of SAP-associated lung injury following AT-Lipoxin A4 intervention. In vitro, we found that AT-Lipoxin A4 markedly suppressed protein expression in TNF-α signals in human pulmonary microvascular endothelial cell, such as tumor necrosis factor receptor-associated factor 2 (TRAF2), TNF-R1-associated death domain (TRADD), receptor-interacting protein (RIP), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Moreover, AT-Lipoxin A4 inhibited downstream signals activated by TNF-α, including NF-κB/p65, JNK/MAPK, and ERK/MAPK. In vivo, AT-Lipoxin A4 significantly decreased pathological scores of the pancreas and lungs and the serum levels of IL-6 and TNF-α. Immunofluorescence, western blotting, and real-time PCR assay showed that AT-Lipoxin A4 significantly attenuated the expression of TNF-R1, TRADD, TRAF2, and RIP in the lungs of SAP rats. In addition, the activation of NF-κB was also downregulated by AT-Lipoxin A4 administration as compared with SAP rats. AT-Lipoxin A4 could inhibit the production of proinflammatory mediators and activation of TNF-α downstream signals such as NF-κB and MAPK. Downregulation of TNF-α signals by AT-Lipoxin A4 may be a significant mechanism in the attenuation of SAP-associated lung injury.

[Expression of transcription factor SOX12 in lung adenocarcinoma and its clinical significance].

OBJECTIVE: To explore the expression patterns of transcription factor SOX12 in lung adenocarcinoma and its significance in the diagnosis and prognosis of the malignancy. METHODS: Large cancer genome databases were used to analyze SOX12 expression level in lung adenocarcinoma. Immunohistochemistry (IHC) and semiquantitative PCR were used to detect the expression of SOX12 in 36 specimens of lung adenocarcinoma tissues, 15 adjacent tissues and 21 normal lung tissues. The prognostic value of SOX12 in lung adenocarcinoma and lung squamous cell carcinoma were analyzed using Kaplan-Meier Plotter database, and the relationship between SOX12 expression and the overall survival (OS) and progression free survival (PPS) of the patients were analyzed. RESULTS: Analysis of TCGA database and GEO (GSE40419) database showed that SOX12 expression levels were significantly higher in in lung adenocarcinoma than in normal lung tissues (P < 0.001). The results of IHC and semiquantitative PCR revealed that SOX12 was expressed at significantly higher levels in lung adenocarcinoma than in normal lung tissues (P < 0.001). Kaplan-Meier survival analysis showed that patients with lung adenocarcinoma positive for SOX12 had a significantly shorter OS and PPS time than those negative for SOX12 (P < 0.05), but SOX12 positivity did not significantly affect OS and PPS of patients with lung squamous cell carcinoma. CONCLUSIONS: High expression levels of SOX12 in lung adenocarcinoma are significantly associated with a poor OS of the patients, suggesting the value of SOX12 to assist in early diagnosis and prognostic evaluation of lung adenocarcinoma.