Di-(2-ethylhexyl) phthalate (DEHP) contamination suppressed soil microbial biomass carbon and mitigated CO2 emissions against the background of alfalfa from different soils.

Plastic mulching and organic amendments are prevalent agricultural practices worldwide. Plastic mulching has long been suspected as a significant source of DEHP contamination in terrestrial ecosystems. However, effects of DEHP contamination on greenhouse gas emissions and microbial biomass carbon (MBC) remain unclear. Here, a microcosm experiment was set up to assess the impact of DEHP exposure on MBC and carbon dioxide (CO2) emission in two different soils (acidic and alkaline) with the inclusion of alfalfa straw. The treatment includes: (i) control with no amendment (T1); (ii) alfalfa straw addition (20 g kg-1) (T2); (iii) DEHP (10 mg kg-1) + alfalfa straw (T3); and (iv) DEHP (100 mg kg-1) + alfalfa straw (T4). Against the background of alfalfa inclusion, DEHP exposure led to a potential reduction in cumulative CO2 emissions by 16.35 % and 6.91 % in alkaline soil and 12.27 % and 13.65 % in acidic soil for T3 and T4, respectively. The addition of DEHP triggered CO2 emissions and manifested a detrimental negative priming effect in both soil types. In both soils, average CO2 emission fluxes were highest for the T2 treatment. The MBC fluctuated at around 80 mg kg-1 for the control group, alfalfa straw alone (T2) treatment considerably enhanced MBC contents, whereas DEHP contamination in T3 and T4 treatments suppressed the stimulatory effect of alfalfa on MBC in both alkaline and acidic soils. Furthermore, a positive relationship was observed between soil CO2 emissions and MBC in both soils. Overall, these findings highlight the toxic impact of DEHP on MBC and its role in mitigating CO2 emissions in diverse soils. DEHP exposure counters the CO2 emissions induced by alfalfa straw. In addition, the inhibitory effect of DEHP on CO2 fluxes in alkaline soil is less pronounced than in acidic soil. Therefore, further cutting-edge research is crucial since DEHP contamination poses serious ecological threats to agroecosystems.

20(R)-ginsenoside Rg3 attenuates cerebral ischemia-reperfusion injury by mitigating mitochondrial oxidative stress via the Nrf2/HO-1 signaling pathway.

Reducing mitochondrial oxidative stress has become an important strategy to prevent neuronal death in ischemic stroke. Previous studies have shown that 20(R)-ginsenoside Rg3 can significantly improve behavioral abnormalities, reduce infarct size, and decrease the number of apoptotic neurons in cerebral ischemia/reperfusion injury rats. However, it remains unclear whether 20(R)-ginsenoside Rg3 can inhibit mitochondrial oxidative stress in ischemic stroke and the potential molecular mechanism. In this study, we found that 20(R)-ginsenoside Rg3 notably inhibited mitochondrial oxidative stress in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and maintained the stability of mitochondrial structure and function. Treatment with 20(R)-ginsenoside Rg3 also decreased the levels of mitochondrial fission proteins (Drp1 and Fis1) and increased the levels of fusion proteins (Opa1, Mfn1, and Mfn2) in MCAO/R rats. Furthermore, we found that 20(R)-ginsenoside Rg3 promoted nuclear aggregation of nuclear factor erythroid2-related factor 2 (Nrf2) but did not affect Kelch-like ECH-associated protein-1 (Keap1), resulting in the downstream expression of antioxidants. In in vitro oxygen-glucose deprivation/reperfusion stroke models, the results of PC12 cells treated with 20(R)-ginsenoside Rg3 were consistent with animal experiments. After transfection with Nrf2 short interfering RNA (siRNA), the protective effect of 20(R)-ginsenoside Rg3 on PC12 cells was reversed. In conclusion, the inhibition of mitochondrial oxidative stress plays a vital position in the anti-cerebral ischemia-reperfusion injury of 20(R)-ginsenoside Rg3, and its neuroprotective mechanism is related to the activation of the nuclear factor erythroid2-related factor 2/heme oxygenase 1 signaling pathway.

Using Ex Situ Seedling Baiting to Capture Seedling-Associated Mycorrhizal Fungi in Medicinal Orchid Dendrobium officinale.

Using orchid mycorrhizal fungi (OMFs) to facilitate orchid proliferation is considered an effective method of orchid conservation. Based on the success of using in situ seedling baiting to obtain plant growth-promoting fungi in our previous study, in this study, we developed the method of using ex situ seedling baiting to capture seedling-associated fungi from Dendrobium officinale. We collected substrates (e.g., litters, barks and mosses) from six original habitats of D. officinale in different geographical locations in China, and then, transplanted in vitro-produced seedlings of D. officinale into the substrates. After cultivation for 75 days, it was obvious that fungi colonized the seedling roots and formed large numbers of pelotons in all six groups. From these seedling roots, a total of 251 fungal strains, which were divided into 16 OMF and 11 non-OMF species, were successfully isolated. The 16 OMFs included 13 Tulasnella and 3 Serendipitaceae species. The fungal species isolated from the different groups (original habitat sources) were not identical, but the dominant OMFs with high isolation frequencies (more than 10 times) were commonly isolated from more than four original sources. Among the 11 non-OMFs, Fusarium oxysporum TP-18 and Muscodor sp. TP-26 were the dominant endophytes. Fusarium oxysporum is a common endophyte associated with many orchid species, including D. officinale. The results suggest that ex situ seedling baiting is an easy and efficient approach to obtaining seedling-associated fungi for this species and could be performed for other over-collected species, especially orchids for which wild plants have disappeared in the field but their original habitats are known. This approach has great potential for application in OMF studies in the future.

CD58 loss in tumor cells confers functional impairment of CAR T cells.

Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in treating a variety of hematologic malignancies, but resistance to this treatment in some patients limited its wider application. Using an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) screening, we identified and validated loss of CD58 conferred immune evasion from CAR T cells in vitro and in vivo. CD58 is a ligand of the T-cell costimulatory molecule CD2, and CD58 mutation or downregulated expression is common in hematological tumors. We found that disruption of CD58 in tumor cells induced the formation of suboptimal immunological synapse (IS) with CAR T cells, which conferred functional impairment of CAR T cells, including the attenuation of cell expansion, degranulation, cytokine secretion, and cytotoxicity. In summary, we describe a potential mechanism of tumor-intrinsic resistance to CAR T-cell therapy and suggest that this mechanism may be leveraged for developing therapeutic strategies to overcome resistance to CAR T-cell therapy in B-cell malignancies.

Oxidative Stress and Ginsenosides: An Update on the Molecular Mechanisms.

Ginsenosides are a class of active components extracted from ginseng plants (such as Panax ginseng, Panax quinquefolium, and Panax notoginseng). Ginsenosides have significant protective effects on the nervous system, cardiovascular system, and immune system, so they have been widely used in the treatment of related diseases. Entry of a variety of endogenous or exogenous harmful substances into the body can lead to an imbalance between the antioxidant defense system and reactive oxygen species, thus producing toxic effects on a variety of tissues and cells. In addition, oxidative stress can alter multiple signaling pathways, including the Keap1/Nrf2/ARE, PI3K/AKT, Wnt/ß-catenin, and NF-κB pathways. With the deepening of research in this field, various ginsenoside monomers have been reported to exert antioxidant effects through multiple signaling pathways and thus have good application prospects. This article summarized the research advancements regarding the antioxidative effects and related mechanisms of ginsenosides, providing a theoretical basis for experimental research on and clinical treatment with ginsenosides.

Identification of NOXA as a pivotal regulator of resistance to CAR T-cell therapy in B-cell malignancies.

Despite the remarkable success of chimeric antigen receptor (CAR) T-cell therapy for treating hematologic malignancies, resistance and recurrence still occur, while the markers or mechanisms underlying this resistance remain poorly understood. Here, via an unbiased genome-wide CRISPR/Cas9 screening, we identified loss of NOXA, a B-cell lymphoma 2 (BCL2) family protein in B-cell malignancies, as a pivotal regulator of resistance to CAR T-cell therapy by impairing apoptosis of tumor cells both in vitro and in vivo. Notably, low NOXA expression in tumor samples was correlated with worse survival in a tandem CD19/20 CAR T clinical trial in relapsed/refractory B-cell lymphoma. In contrast, pharmacological augmentation of NOXA expression by histone deacetylase (HDAC) inhibitors dramatically sensitized cancer cells to CAR T cell-mediated clearance in vitro and in vivo. Our work revealed the essentiality of NOXA in resistance to CAR T-cell therapy and suggested NOXA as a predictive marker for response and survival in patients receiving CAR T-cell transfusions. Pharmacological targeting of NOXA might provide an innovative therapeutic strategy to enhance CAR T-cell therapy.

Comprehensive Analysis of the Effect of 20(R)-Ginsenoside Rg3 on Stroke Recovery in Rats via the Integrative miRNA-mRNA Regulatory Network.

MicroRNAs (miRNAs) are a class of small, endogenous, noncoding RNAs. Recent research has proven that miRNAs play an essential role in the occurrence and development of ischemic stroke. Our previous studies confirmed that 20(R)-ginsenosideRg3 [20(R)-Rg3] exerts beneficial effects on cerebral ischemia-reperfusion injury (CIRI), but its molecular mechanism has not been elucidated. In this study, we used high-throughput sequencing to investigate the differentially expressed miRNA and mRNA expression profiles of 20(R)-Rg3 preconditioning to ameliorate CIRI injury in rats and to reveal its potential neuroprotective molecular mechanism. The results show that 20(R)-Rg3 alleviated neurobehavioral dysfunction in MCAO/R-treated rats. Among these mRNAs, 953 mRNAs were significantly upregulated and 2602 mRNAs were downregulated in the model group versus the sham group, whereas 437 mRNAs were significantly upregulated and 35 mRNAs were downregulated in the 20(R)-Rg3 group in contrast with those in the model group. Meanwhile, the expression profile of the miRNAs showed that a total of 283 differentially expressed miRNAs were identified, of which 142 miRNAs were significantly upregulated and 141 miRNAs were downregulated in the model group compared with the sham group, whereas 34 miRNAs were differentially expressed in the 20(R)-Rg3 treatment group compared with the model group, with 28 miRNAs being significantly upregulated and six miRNAs being significantly downregulated. Furthermore, 415 (391 upregulated and 24 downregulated) differentially expressed mRNAs and 22 (17 upregulated and 5 downregulated) differentially expressed miRNAs were identified to be related to 20(R)-Rg3's neuroprotective effect on stroke recovery. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that 20(R)-Rg3 could modulate multiple signaling pathways related to these differential miRNAs, such as the cGMP-PKG, cAMP and MAPK signaling pathways. This study provides new insights into the protective mechanism of 20(R)-Rg3 against CIRI, and the mechanism may be partly associated with the regulation of brain miRNA expression and its target signaling pathways.

Algorithm for wireless sensor networks in ginseng field in precision agriculture.

In the research on energy-efficient networking methods for precision agriculture, a hot topic is the energy issue of sensing nodes for individual wireless sensor networks. The sensing nodes of the wireless sensor network should be enabled to provide better services with limited energy to support wide-range and multi-scenario acquisition and transmission of three-dimensional crop information. Further, the life cycle of the sensing nodes should be maximized under limited energy. The transmission direction and node power consumption are considered, and the forward and high-energy nodes are selected as the preferred cluster heads or data-forwarding nodes. Taking the cropland cultivation of ginseng as the background, we put forward a particle swarm optimization-based networking algorithm for wireless sensor networks with excellent performance. This algorithm can be used for precision agriculture and achieve optimal equipment configuration in a network under limited energy, while ensuring reliable communication in the network. The node scale is configured as 50 to 300 nodes in the range of 500 × 500 m2, and simulated testing is conducted with the LEACH, BCDCP, and ECHERP routing protocols. Compared with the existing LEACH, BCDCP, and ECHERP routing protocols, the proposed networking method can achieve the network lifetime prolongation and mitigate the decreased degree and decreasing trend of the distance between the sensing nodes and center nodes of the sensor network, which results in a longer network life cycle and stronger environment suitability. It is an effective method that improves the sensing node lifetime for a wireless sensor network applied to cropland cultivation of ginseng.

Comprehensive analysis of lncRNA expression profiles in rats with cerebral ischemia-reperfusion injury after treatment with 20(R)-ginsenoside Rg3.

This study was aimed at investigating the differentially expressions of long noncoding RNAs (lncRNAs) and mRNAs in the brains of a middle cerebral artery occlusion/reperfusion (MCAO/R) group and a MCAO/R + 20(R)-Rg3 group. Biological enrichment analysis was performed, and a lncRNA-mRNA coexpression network was constructed, to reveal the targets and pathways of 20(R)-Rg3 involved in the regulation of cerebral ischemia-reperfusion injury (CIRI). The RNA-seq high-throughput sequencing method was employed to detect differentially-expressed genes between the groups, which were verified by RT-PCR. Functional enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to explore the biological functions and relevant pathways. The coexpression network of the screened lncRNAs and mRNAs was built by using Cytoscape software. The results identified 77 upregulated lncRNAs, 162 downregulated lncRNAs, 66 upregulated mRNAs and 472 downregulated mRNAs in the MCAO/R + 20(R)-Rg3 group, compared with those in the MCAO/R group. GO enrichment analysis showed that the GO terms were mainly enriched in stimulation response, cellular response, and stress response. KEGG pathways were mainly related to the tumor necrosis factor (TNF), NF-κB, cytokine, and other receptor signaling pathways. In addition, the coexpression analysis between lncRNA and mRNA identified 314 nodes and 515 connections between 6 lncRNAs and 308 mRNAs, of which 511 were positive and 4 were negative. Among them, ENSRNOG-00000059555 was strongly correlated with AABR07001160.1. This study revealed multiple lncRNAs were involved in the neuroprotection of 20(R)-Rg3 against CIRI and thereby provided new insights into the use of 20(R)-Rg3 as a novel neuro protectant in ischemic stroke management.

Antiatherosclerotic effects of corilagin via suppression of the LOX-1/MyD88/NF-κB signaling pathway in vivo and in vitro.

Corilagin, a natural polyphenol compound isolated from Phyllanthus urinaria L., exerts various pharmacological effects, such as antihyperglycemic, antitumor, and antioxidative stress properties, but the mechanisms underlying the antiatherosclerotic effects of corilagin have not been entirely elucidated. In the present study, we investigated the antiatherosclerotic effects of corilagin using a high-fat diet (HFD)-induced atherosclerotic rabbit model and ox-LDL-induced vascular smooth muscle cells (VSMCs) and explored the underlying molecular mechanisms. The serum lipid levels were measured through an enzymatic colorimetric assay. A histological analysis of rabbit aortas was performed after hematoxylin-eosin and oil red O staining. The proliferation of ox-LDL-induced VSMCs was detected using MTT assays, and the migration of cells was determined by wound scratch assays. In addition, the mRNA and protein expression levels of lectin-like ox-LDL receptor-1 (LOX-1), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNF-α) were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting assays. Our results indicate that corilagin significantly reduced the serum levels of TC, TG and LDL-C, increased the HDL-C levels, decreased the intimal thickening in the thoracic aorta, and reduced the formation of foam cells in an HFD-induced rabbit atherosclerosis model. Moreover, corilagin suppressed the proliferation and migration of ox-LDL-induced VSMCs and reduced LOX-1, MyD88, NF-κB, MCP-1, and TNF-α mRNA and protein expression in vivo and in vitro. These data demonstrate that corilagin exerts antiatherosclerotic effects in vivo and in vitro and that the mechanisms may be closely associated with downregulation of the LOX-1/MyD88/NF-κB pathway.

Image Reconstruction Algorithm Based on Total Least Squares Target Correction for ECT.

In the image reconstruction of the electrical capacitance tomography (ECT) system, the application of the total least squares theory transforms the ill-posed problem into a nonlinear unconstrained minimization problem, which avoids calculating the matrix inversion. But in the iterative process of the coefficient matrix, the ill-posed problem is also produced. For the effect on the final image reconstruction accuracy of this problem, combined with the principle of the ECT system, the coefficient matrix is targeted and updated in the overall least squares iteration process. The new coefficient matrix is calculated, and then, the regularization matrix is corrected according to the adaptive targeting singular value, which can reduce the ill-posed effect. In this study, the total least squares iterative method is improved by introducing the mathematical model of EIV to deal with the errors in the measured capacitance data and coefficient matrix. The effect of noise interference on the measurement capacitance data is reduced, and finally, the high-quality reconstructed images are calculated iteratively.

Mutant B2M-HLA-E and B2M-HLA-G fusion proteins protects universal chimeric antigen receptor-modified T cells from allogeneic NK cell-mediated lysis.

Recent studies have indicated the antitumor activity and reduced allogeneic response of universal chimeric antigen receptor-modified T (UCAR T) cells lacking endogenous T cell receptors and beta-2 microglobulin (B2M) generated using gene-editing technologies. However, these cells are vulnerable to lysis by allogeneic natural killer (NK) cells due to their lack of human leukocyte antigen (HLA) class I molecule expression. Here, constitutive expression of mutant B2M-HLA-E (mBE) and B2M-HLA-G (mBG) fusion proteins in anti-CD19 UCAR T (UCAR T-19) cells was conducted to protect against allogeneic NK cell-mediated lysis. The ability of cells expressing mBE or mBG to resist NK cell-mediated lysis was observed in gene-edited Jurkat CAR19 cells. UCAR T-19 cells constitutively expressing the mBE and mBG fusion proteins were manufactured and showed effective and specific anti-tumor activity. Constitutive expression of the mBE and mBG fusion proteins in UCAR T-19 cells prevented allogeneic NK cell-mediated lysis. In addition, these cells were not recognizable by allogeneic T cells. Additional experiments, including those in animal models and clinical trials, are required to evaluate the safety and efficacy of UCAR T-19 cells that constitutively express mBE and mBG.

Expression EEG Multimodal Emotion Recognition Method Based on the Bidirectional LSTM and Attention Mechanism.

Due to the complexity of human emotions, there are some similarities between different emotion features. The existing emotion recognition method has the problems of difficulty of character extraction and low accuracy, so the bidirectional LSTM and attention mechanism based on the expression EEG multimodal emotion recognition method are proposed. Firstly, facial expression features are extracted based on the bilinear convolution network (BCN), and EEG signals are transformed into three groups of frequency band image sequences, and BCN is used to fuse the image features to obtain the multimodal emotion features of expression EEG. Then, through the LSTM with the attention mechanism, important data is extracted in the process of timing modeling, which effectively avoids the randomness or blindness of sampling methods. Finally, a feature fusion network with a three-layer bidirectional LSTM structure is designed to fuse the expression and EEG features, which is helpful to improve the accuracy of emotion recognition. On the MAHNOB-HCI and DEAP datasets, the proposed method is tested based on the MATLAB simulation platform. Experimental results show that the attention mechanism can enhance the visual effect of the image, and compared with other methods, the proposed method can extract emotion features from expressions and EEG signals more effectively, and the accuracy of emotion recognition is higher.

Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming.

Insufficient eradication capacity and dysfunction are common occurrences in T cells that characterize cancer immunotherapy failure. De novo DNA methylation promotes T cell exhaustion, whereas methylation inhibition enhances T cell rejuvenation in vivo. Decitabine, a DNA methyltransferase inhibitor approved for clinical use, may provide a means of modifying exhaustion-associated DNA methylation programmes. Herein, anti-tumour activities, cytokine production, and proliferation are enhanced in decitabine-treated chimeric antigen receptor T (dCAR T) cells both in vitro and in vivo. Additionally, dCAR T cells can eradicate bulky tumours at a low-dose and establish effective recall responses upon tumour rechallenge. Antigen-expressing tumour cells trigger higher expression levels of memory-, proliferation- and cytokine production-associated genes in dCAR T cells. Tumour-infiltrating dCAR T cells retain a relatively high expression of memory-related genes and low expression of exhaustion-related genes in vivo. In vitro administration of decitabine may represent an option for the generation of CAR T cells with improved anti-tumour properties.

Adaptive T cell immunotherapy in cancer.

Impaired tumor-specific effector T cells contribute to tumor progression and unfavorable clinical outcomes. As a compensatory T cell-dependent cancer immunoediting strategy, adoptive T cell therapy (ACT) has achieved encouraging therapeutic results, and this strategy is now on the center stage of cancer treatment and research. ACT involves the ex vivo stimulation and expansion of tumor-infiltrating lymphocytes (TILs) with inherent tumor reactivity or T cells that have been genetically modified to express the cognate chimeric antigen receptor or T cell receptor (CAR/TCR), followed by the passive transfer of these cells into a lymphodepleted host. Primed T cells must provide highly efficient and long-lasting immune defense against transformed cells during ACT. Anin-depth understanding of the basic mechanisms of these living drugs can help us improve upon current strategies and design better next-generation T cell-based immunotherapies. From this perspective, we provide an overview of current developments in different ACT strategies, with a focus on frontier clinical trials that offer a proof of principle. Meanwhile, insights into the determinants of ACT are discussed, which will lead to more rational, potent and widespread applications in the future.

Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial.

Expressed by cancer stem cells of various epithelial cell origins and hepatocellular carcinoma (HCC), CD133 is an attractive therapeutic target for HCC. The marker CD133 is highly expressed in endothelial progenitor cells (EPC). EPCs circulate in increased numbers in the peripheral blood of patients with highly vascularized HCC and contribute to angiogenesis and neovascularization. This phase II study investigated CD133-directed chimeric antigen receptor (CAR) T (CART-133) cells in adults with HCC. Patients with histologically confirmed and measurable advanced HCC and adequate hematologic, hepatic, and renal functions received CART-133 cell infusions. The primary endpoints were safety in phase I and progression-free survival (PFS) and overall survival (OS) in phase II. Other endpoints included biomarkers for CART-133 T cell therapy. Between June 1, 2015, and September 1, 2017, this study enrolled 21 patients who subsequently received CART-133 T cells across phases I and II. The median OS was 12 months (95% CI, 9.3-15.3 months) and the median PFS was 6.8 months (95% CI, 4.3-8.4 months). Of 21 evaluable patients, 1 had a partial response, 14 had stable disease for 2 to 16.3 months, and 6 progressed after T-cell infusion. The most common high-grade adverse event was hyperbilirubinemia. Outcome was correlated with the baseline levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR2), stromal cell-derived factor (SDF)-1, and EPC counts. Changes in EPC counts, VEGF, SDF-1, sVEGFR2, and interferon (IFN)-γ after cell infusion were associated with survival. In patients with previously treated advanced HCC, CART-133 cell therapy demonstrates promising antitumor activity and a manageable safety profile. We identified early changes in circulating molecules as potential biomarkers of response to CART-133 cells. The predictive value of these proangiogenic and inflammatory factors as potential biomarkers of CART-133 cell therapy in HCC will be explored in prospective trials. This study is registered at ClinicalTrials.gov (NCT02541370).

Case Report: Low-Dose Decitabine Plus Anti-PD-1 Inhibitor Camrelizumab for Previously Treated Advanced Metastatic Non-Small Cell Lung Cancer.

Background: Although the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have markedly changed the strategies of cancer treatment, most patients with advanced non-small cell lung cancer (NSCLC) do not respond to PD-1/PD-L1 monotherapy. Epigenetic drugs have been hypothesized to possess the potential to sensitize PD-1/PD-L1 inhibitors. Case Presentation: Three patients with advanced metastatic NSCLC failed to respond to first-line systemic therapy and had a low tumor mutation burden, low tumor neoantigen burden, low microsatellite instability, and HLA loss of heterozygosity according to their target lesion biopsies, all of which were considered unfavorable factors for PD-1/PD-L1 blockage. However, all three patients responded to low-dose decitabine, an epigenetic drug, in combination with camrelizumab (anti-PD-1 antibody), with only controllable adverse events, indicating that low-dose decitabine can sensitize PD-1/PD-L1 inhibitors. Summary: We report a novel therapy with low-dose decitabine plus camrelizumab for advanced NSCLC on the basis of successful treatment of three patients, emphasizing the potential of epigenetic drugs to regulate PD-1/PD-L1 inhibitors in advanced NSCLC.

Chitosan/LiCl composite scaffolds promote skin regeneration in full-thickness loss.

Small molecules loaded into biological materials present a promising strategy for stimulating endogenous repair mechanisms for in situ skin regeneration. Lithium can modulate various biologic processes, promoting proliferation, angiogenesis, and decreasing inflammation. However, its role in skin repair is rarely reported. In this study, we loaded lithium chloride (LiCl) into the chitosan (CHI) hydrogel and develop a sterile and biocompatible sponge scaffold through freeze-drying. In-vitro assessment demonstrated that the CHI-LiCl composite scaffolds (CLiS) possessed favorable cytocompatibility, swelling and biodegradation. We created full-thickness skin wounds in male C57BL/c mice to evaluate the healing capacity of CLiS. Compared with the wounds of control and CHI scaffold (CS) groups, the wounds in the CLiS-treated group showed reduced inflammation, improved angiogenesis, accelerated re-epithelialization, sustained high expression of ß-catenin with a small amount of regenerated hair follicles. Therefore, CLiS may be a promising therapeutic dressing for skin wound repair and regeneration.

Blocking CD38-driven fratricide among T cells enables effective antitumor activity by CD38-specific chimeric antigen receptor T cells.

Chimeric antigen receptor T-cell (CAR T) therapy is a kind of effective cancer immunotherapy. However, designing CARs remains a challenge because many targetable antigens are shared by T cells and tumor cells. This shared expression of antigens can cause CAR T cell fratricide. CD38-targeting approaches (e.g., daratumumab) have been used in clinical therapy and have shown promising results. CD38 is a kind of surface glycoprotein present in a variety of cells, such as T lymphocytes and tumor cells. It was previously reported that CD38-based CAR T cells may undergo apoptosis or T cell-mediated killing (fratricide) during cell manufacturing. In this study, a CAR containing a sequence targeting human CD38 was designed to be functional. To avoid fratricide driven by CD38 and ensure the production of CAR T cells, two distinct strategies based on antibodies (clone MM12T or clone MM27) or proteins (H02H or H08H) were used to block CD38 or the CAR single-chain variable fragment (scFv) domain, respectively, on the T cell surface. The results indicated that the antibodies or proteins, especially the antibody MM27, could affect CAR T cells by inhibiting fratricide while promoting expansion and enrichment. Anti-CD38 CAR T cells exhibited robust and specific cytotoxicity to CD38+ cell lines and tumor cells. Furthermore, the levels of the proinflammatory factors TNF-α, IFN-γ and IL-2 were significantly upregulated in the supernatants of A549CD38+ cells. Finally, significant control of disease progression was demonstrated in xenograft mouse models. In conclusion, these findings will help to further enhance the expansion, persistence and function of anti-CD38 CAR T cells in subsequent clinical trials.

Subspace structural constraint-based discriminative feature learning via nonnegative low rank representation.

Feature subspace learning plays a significant role in pattern recognition, and many efforts have been made to generate increasingly discriminative learning models. Recently, several discriminative feature learning methods based on a representation model have been proposed, which have not only attracted considerable attention but also achieved success in practical applications. Nevertheless, these methods for constructing the learning model simply depend on the class labels of the training instances and fail to consider the essential subspace structural information hidden in them. In this paper, we propose a robust feature subspace learning approach based on a low-rank representation. In our approach, the low-rank representation coefficients are considered as weights to construct the constraint item for feature learning, which can introduce a subspace structural similarity constraint in the proposed learning model for facilitating data adaptation and robustness. Moreover, by placing the subspace learning and low-rank representation into a unified framework, they can benefit each other during the iteration process to realize an overall optimum. To achieve extra discrimination, linear regression is also incorporated into our model to enforce the projection features around and close to their label-based centers. Furthermore, an iterative numerical scheme is designed to solve our proposed objective function and ensure convergence. Extensive experimental results obtained using several public image datasets demonstrate the advantages and effectiveness of our novel approach compared with those of the existing methods.