Reactive oxygen species produced by photodynamic therapy enhance docosahexaenoic acid lipid peroxidation and induce the death of breast cancer cells.

Breast cancer remains a serious threat to women's physical and emotional health. The combination therapies can overcome the deficiency of single therapy, enhance the therapeutic effects and reduce the side effects at the same time. In this study, we synthesize a novel nanomedicine that enhanced the therapeutic effects of breast cancer treatment by combining photodynamic therapy and chemotherapy. The doxorubicin (DOX) and photosensitizer methyl pyropheophorbide-a (MPPa) are loaded into the nano-drug delivery system as DPSPFA/MPPa/DOX. In response to near-infrared (NIR) laser, the drugs were quickly released to the cancer cells. The MPPa produces reactive oxygen species (ROS) under the action of photodynamics. Unsaturated fatty acids with ROS promotes lipid peroxidation and the combination of chemotherapy and photodynamic therapy. The data shows that the DPSPFA/MPPa/DOX has a spherical shape, good dispersibility and stability, and the particle size is roughly 200 nm. The drug loading capability of DOX is about 13 %. Both of MCF7 cell model in vitro and breast cancer model in vivo, DPSPFA/MPPa/DOX showed an excellent anti-tumor effect of 86.9 % and without any obvious side effects. These findings might offer potential for a new approach for breast cancer treatment.

Targeting ESE3/EHF With Nifurtimox Inhibits CXCR2+ Neutrophil Infiltration and Overcomes Pancreatic Cancer Resistance to Chemotherapy and Immunotherapy.

BACKGROUND & AIMS: Because pancreatic cancer responds poorly to chemotherapy and immunotherapy, it is necessary to identify novel targets and compounds to overcome resistance to treatment. METHODS: This study analyzed genomic single nucleotide polymorphism sequencing, single-cell RNA sequencing, and spatial transcriptomics. Ehf-knockout mice, KPC (LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx1-Cre) mice, CD45.1+ BALB/C nude mice, and CD34+ humanized mice were also used as subjects. Multiplexed immunohistochemistry and flow cytometry were performed to investigate the proportion of tumor-infiltrated C-X-C motif chemokine receptor 2 (CXCR2)+ neutrophils. In addition, multiplexed cytokines assays and chromatin immunoprecipitation assays were used to examine the mechanism. RESULTS: The TP53 mutation-mediated loss of tumoral EHF increased the recruitment of CXCR2+ neutrophils, modulated their spatial distribution, and further induced chemo- and immunotherapy resistance in clinical cohorts and preclinical syngeneic mice models. Mechanistically, EHF deficiency induced C-X-C motif chemokine ligand 1 (CXCL1) transcription to enhance in vitro and in vivo CXCR2+ neutrophils migration. Moreover, CXCL1 or CXCR2 blockade completely abolished the effect, indicating that EHF regulated CXCR2+ neutrophils migration in a CXCL1-CXCR2-dependent manner. The depletion of CXCR2+ neutrophils also blocked the in vivo effects of EHF deficiency on chemotherapy and immunotherapy resistance. The single-cell RNA-sequencing results of PDAC treated with Nifurtimox highlighted the therapeutic significance of Nifurtimox by elevating the expression of tumoral EHF and decreasing the weightage of CXCL1-CXCR2 pathway within the microenvironment. Importantly, by simultaneously inhibiting the JAK1/STAT1 pathway, it could significantly suppress the recruitment and function of CXCR2+ neutrophils, further sensitizing PDAC to chemotherapy and immunotherapies. CONCLUSIONS: The study demonstrated the role of EHF in the recruitment of CXCR2+ neutrophils and the promising role of Nifurtimox in sensitizing pancreatic cancer to chemotherapy and immunotherapy.

Hippocampal-derived extracellular vesicle synergistically deliver active adenosine hippocampus targeting to promote cognitive recovery after stroke.

Ischemic stroke is a neurological disease that leads to brain damage and severe cognitive impairment. In this study, extracellular vesicles(Ev) derived from mouse hippocampal cells (HT22) were used as carriers, and adenosine (Ad) was encapsulated to construct Ev-Ad to target the damaged hippocampus. The results showed that, Ev-Ad had significant antioxidant effect and inhibited apoptosis. In vivo, Ev-Ad reduced cell death and reversed inflammation in hippocampus of ischemic mice, and improved long-term memory and learning impairment by regulating the expression of the A1 receptor and the A2A receptor in the CA1 region. Thus, the developmental approach based on natural carriers that encapsulating Ad not only successfully restored nerves after ischemic stroke, but also improved cognitive impairment in the later stage of ischemic stroke convalescence. The development and design of therapeutic drugs provides a new concept and method for the treatment of cognitive impairment in the convalescent phase after ischemic stroke.

Preparation of injectable porcine skin-derived collagen and its application in delaying skin aging by promoting the adhesion and chemotaxis of skin fibroblasts.

Collagen, as the main component of human skin, plays a vital role in maintaining dermal integrity. Its loss will lead to dermis destruction and collapse, resulting in skin aging. At present, injection of exogenous collagen is an important means to delay skin aging. In this study, high-purity collagen was extracted from porcine skin. Our research revealed that it can effectively promote the adhesion and chemotaxis of HSF cells. It can also reduce the expression of ß-galactosidase, decrease ROS levels, and increase the expression of the collagen precursors, p53 and p16 in HSF cells during senescence. After local injection into the aging skin of rats, it was found that the number of cells and type I collagen fibers in the dermis increased significantly, and the arrangement of these fibers became more uniform and orderly. Moreover, the important thing is that it is biocompatible. To sum up, the porcine skin collagen we extracted is an anti-aging biomaterial with application potential.

Irbesartan overcomes gemcitabine resistance in pancreatic cancer by suppressing stemness and iron metabolism via inhibition of the Hippo/YAP1/c-Jun axis.

BACKGROUND: Chemoresistance is the main reason for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Thus, there is an urgent need to screen out new targets and compounds to reverse chemotherapeutic resistance. METHODS: We established a bio-bank of human PDAC organoid models, covering a representative range of PDAC tumor subtypes. We screened a library of 1304 FDA-approved compounds to identify candidates efficiently overcoming chemotherapy resistance. The effects of the compounds were evaluated with a CellTiter-Glo-3D assay, organoid apoptosis assay and in vivo patient-derived xenograft (PDX), patient-derived organoid (PDO) and LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) genetically engineered mouse models. RNA-sequencing, genome editing, sphere formation assays, iron assays and luciferase assays were conducted to elucidate the mechanism. RESULTS: High-throughput drug screening of chemotherapy-resistant PDOs identified irbesartan, an angiotensin ‖ type 1 (AT1) receptor antagonist, which could synergistically enhance the ability of chemotherapy to kill PDAC cells. In vitro and in vivo validation using PDO, PDX and KPC mouse models showed that irbesartan efficiently sensitized PDAC tumors to chemotherapy. Mechanistically, we found that irbesartan decreased c-Jun expression by inhibiting the Hippo/YAP1 pathway and further overcame chemotherapy resistance in PDAC. We also explored c-Jun, a potential target of irbesartan, which can transcriptionally upregulate the expression of key genes involved in stemness maintenance (SOX9/SOX2/OCT4) and iron metabolism (FTH1/FTL/TFRC). More importantly, we observed that PDAC patients with high levels of c-Jun expression demonstrated poor responses to the current standard chemotherapy regimen (gemcitabine plus nab-paclitaxel). Moreover, patients with PDAC had significant survival benefits from treatment with irbesartan plus a standard chemotherapy regimen in two-center retrospective clinical cohorts and patients with high c-Jun expression exhibited a better response to combination chemotherapy. CONCLUSIONS: Irbesartan could be used in combination with chemotherapy to improve the therapeutic efficacy in PDAC patients with high levels of c-Jun expression. Irbesartan effectively inhibited chemotherapy resistance by suppressing the Hippo/YAP1/c-Jun/stemness/iron metabolism axis. Based on our findings, we are designing an investigator-initiated phase II clinical trial on the efficacy and safety of irbesartan plus a standard gemcitabine/nab-paclitaxel regimen in the treatment of patients with advanced III/IV staged PDAC and are hopeful that we will observe patient benefits.

Artificial intelligence-based comprehensive analysis of immune-stemness-tumor budding profile to predict survival of patients with pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. CD8+ T cells, cancer stem cells (CSCs), and tumor budding (TB) have been significantly correlated with the outcome of patients with PDAC, but the correlations have been independently reported. In addition, no integrated immune-CSC-TB profile for predicting survival in patients with PDAC has been established. METHODS: Multiplexed immunofluorescence and artificial intelligence (AI)-based comprehensive analyses were used for quantification and spatial distribution analysis of CD8+ T cells, CD133+ CSCs, and TB. In vivo humanized patient-derived xenograft (PDX) models were established. Nomogram analysis, calibration curve, time-dependent receiver operating characteristic curve, and decision curve analyses were performed using R software. RESULTS: The established 'anti-/pro-tumor' models showed that the CD8+ T cell/TB, CD8+ T cell/CD133+ CSC, TB-adjacent CD8+ T cell, and CD133+ CSC-adjacent CD8+ T cell indices were positively associated with survival of patients with PDAC. These findings were validated using PDX-transplanted humanized mouse models. An integrated nomogram-based immune-CSC-TB profile that included the CD8+ T cell/TB and CD8+ T cell/CD133+ CSC indices was established and shown to be superior to the tumor-node-metastasis stage model in predicting survival of patients with PDAC. CONCLUSIONS: 'Anti-/pro-tumor' models and the spatial relationship among CD8+ T cells, CSCs, and TB within the tumor microenvironment were investigated. Novel strategies to predict the prognosis of patients with PDAC were established using AI-based comprehensive analysis and machine learning workflow. The nomogram-based immune-CSC-TB profile can provide accurate prognosis prediction for patients with PDAC.

SDCBP promotes pancreatic cancer progression by preventing YAP1 from ß-TrCP-mediated proteasomal degradation.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumour with limited treatment options. Here, we identified syndecan binding protein (SDCBP), also known as syntenin1, as a novel targetable factor in promoting PDAC tumour progression. We also explored a therapeutic strategy for suppressing SDCBP expression. DESIGN: We used samples from patients with PDAC, human organoid models, LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse models, and PDX mouse models. Immunostaining, colony formation assay, ethynyl-2-deoxyuridine incorporation assay, real-time cell analysis, cell apoptosis assay, automated cell tracking, invadopodia detection and gelatin degradation assays, coimmunoprecipitation, and pull-down assays were performed in this study. RESULTS: The median overall survival and recurrence-free survival rates in the high-SDCBP group were significantly shorter than those in the low-SDCBP group. In vitro and in vivo studies have demonstrated that SDCBP promotes PDAC proliferation and metastasis. Mechanically, SDCBP inhibits CK1δ/ε-mediated YAP-S384/S387 phosphorylation, which further suppresses ß-TrCP-mediated YAP1 ubiquitination and proteasome degradation by directly interacting with YAP1. SDCBP interacts with the TAD domain of YAP1, mainly through its PDZ1 domain. Preclinical KPC mouse cohorts demonstrated that zinc pyrithione (ZnPT) suppresses PDAC tumour progression by suppressing SDCBP. CONCLUSIONS: SDCBP promotes the proliferation and metastasis of PDAC by preventing YAP1 from ß-TrCP-mediated proteasomal degradation. Therefore, ZnPT could be a promising therapeutic strategy to inhibit PDAC progression by suppressing SDCBP.

KAP1 modulates osteogenic differentiation via the ERK/Runx2 cascade in vascular smooth muscle cells.

BACKGROUND: Osteoblast phenotypic transition in vascular smooth muscle cells (VSMCs) has been unveiled as a common cause of vascular calcification (VC). Krüppel-Associated Box (KRAB)-Associated Protein 1(KAP1) is a transcriptional corepressor that modulates various intracellular pathological processes from gene expression to DNA repair to signal transduction. However, the function and mechanism of KAP1 on the osteoblastic differentiation of VSMCs have not been evaluated yet. METHODS AND RESULTS: We demonstrate that the expression of KAP1 in VSMCs is significantly enhanced in vivo and in vitro calcification models. Downregulating the expression of KAP1 suppresses the osteoblast phenotypic transition of VSMCs, which is indicated by a decrease in the expression of osteoblast marker collagenase type I (COL I) and an increase in the expression of VSMC marker α-smooth muscle actin (α-SMA). Conversely, exogenous overexpression of KAP1 could promote osteoblast phenotypic transition of VSMCs. Moreover, KAP1 upregulated the expression of RUNX family transcription factor 2 (Runx2), an inducer of osteoblast that positively regulates many osteoblast-related genes, such as COL I. Evaluation of the potential mechanism demonstrated that KAP1 promoted osteoblast phenotypic transition of VSMCs by activating the extracellular regulated protein kinases (ERK) signaling pathway, which could activate Runx2. In support of this finding, KAP1-induced cell osteoblast phenotypic transition is abolished by treatment with PD0325901, a specific ERK inhibitor. CONCLUSIONS: The present study suggested that KAP1 participated in the osteoblast differentiation of VSMCs via the ERK/Runx2 cascade and served as a potential diagnostics and therapeutics target for vascular calcification.

Distributed Fault-Tolerant Containment Control Protocols for the Discrete-Time Multiagent Systems via Reinforcement Learning Method.

This article investigates the model-free fault-tolerant containment control problem for multiagent systems (MASs) with time-varying actuator faults. Depending on the relative state information of neighbors, a distributed containment control method based on reinforcement learning (RL) is adopted to achieve containment control objective without prior knowledge on the system dynamics. First, based on the information of agent itself and its neighbors, a containment error system is established. Then, the optimal containment control problem is transformed into an optimal regulation problem for the containment error system. Furthermore, the RL-based policy iteration method is employed to deal with the corresponding optimal regulation problem, and the nominal controller is proposed for the original fault-free system. Based on the nominal controller, a fault-tolerant controller is further developed to compensate for the influence of actuator faults on MAS. Meanwhile, the uniform boundedness of the containment errors can be guaranteed by using the presented control scheme. Finally, numerical simulations are given to show the effectiveness and advantages of the proposed method.

Event-Triggered Multigradient Recursive Reinforcement Learning Tracking Control for Multiagent Systems.

In this article, the tracking control problem of event-triggered multigradient recursive reinforcement learning is investigated for nonlinear multiagent systems (MASs). Attention is focused on the distributed reinforcement learning approach for MASs. The critic neural network (NN) is applied to estimate the long-term strategic utility function, and the actor NN is designed to approximate the uncertain dynamics in MASs. The multigradient recursive (MGR) strategy is tailored to learn the weight vector in NN, which eliminates the local optimal problem inherent in gradient descent method and decreases the dependence of initial value. Furthermore, reinforcement learning and event-triggered mechanism can improve the energy conservation of MASs by decreasing the amplitude of the controller signal and the controller update frequency, respectively. It is proved that all signals in MASs are semiglobal uniformly ultimately bounded (SGUUB) according to the Lyapunov theory. Simulation results are given to demonstrate the effectiveness of the proposed strategy.

ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4.

BACKGROUND AND AIMS: The crosstalk between cancer stem cells (CSCs) and their niche is required for the maintenance of stem cell-like phenotypes of CSCs. Here, we identified E26 transformation-specific homologous factor (EHF) as a key molecule in decreasing the sensitivity of pancreatic cancer (PC) cells to CSCs' niche stimulus. We also explored a therapeutic strategy to restore the expression of EHF. DESIGN: We used a LSL-KrasG12D/+mice, LSL-Trp53R172H/+ and Pdx1-Cre (KPC) mouse model and samples from patients with PC. Immunostaining, flow cytometry, sphere formation assays, anchorage-independent growth assay, in vivo tumourigenicity, reverse transcription PCR, chromatin immunoprecipitation (ChIP) and luciferase analyses were conducted in this study. RESULTS: CXCL12 derived from pancreatic stellate cells (PSCs) mediates the crosstalk between PC cells and PSCs to promote PC stemness. Tumorous EHF suppressed CSC stemness by decreasing the sensitivity of PC to CXCL12 stimulus and inhibiting the crosstalk between PC and CSC-supportive niches. Mechanically, EHF suppressed the transcription of the CXCL12 receptor CXCR4. EHF had a cell autonomous role in suppressing cancer stemness by inhibiting the transcription of Sox9, Sox2, Oct4 and Nanog. Rosiglitazone suppressed PC stemness and inhibited the crosstalk between PC and PSCs by upregulating EHF. Preclinical KPC mouse cohorts demonstrated that rosiglitazone sensitised PDAC to gemcitabine therapy. CONCLUSIONS: EHF decreased the sensitivity of PC to the stimulus from PSC-derived CSC-supportive niche by negatively regulating tumorous CXCR4. Rosiglitazone could be used to target PC stem cells and the crosstalk between CSCs and their niche by upregulating EHF.

Asynchronous Frequency-Dependent Fault Detection for Nonlinear Markov Jump Systems Under Wireless Fading Channels.

In this article, the asynchronous fault detection (FD) strategy is investigated in frequency domain for nonlinear Markov jump systems under fading channels. In order to estimate the system dynamics and meet the fact that not all the running modes can be observed exactly, a set of asynchronous FD filters is proposed. By using statistical methods and the Lynapunov stability theory, the augmented system is shown to be stochastic stable with a prescribed l2 gain even under fading transmissions. Then, a novel lemma is developed to capture the finite frequency performance. Some solvable conditions with less conservatism are subsequently deduced by exploiting novel decoupling techniques and additional slack variables. Besides, the FD filter gains could be calculated with the aid of the derived conditions. Finally, the effectiveness of the proposed method is shown by an illustrative example.

The complete chloroplast genome and phylogenetic analysis of Gentiana arethusae Burkill (Gentianaceae) from China.

Gentiana arethusae Burkill is a perennial herb classified in the Gentianaceae. In this study, the complete chloroplast genome of G. arethusae was sequenced and analyzed. The chloroplast genome is 137,458 bp in length and encodes a total of 116 genes, including 71 protein-coding, 37 tRNA, and eight rRNA genes. The genome has a low GC content of 38.0%. Phylogenetic analysis of the genome of G. arethusae resolved it in a clade with Gentiana obconica and Gentiana veitchiorum. The complete chloroplast genome of G. arethusae will be helpful to study the genetic diversity and phylogenetics of the Gentianaceae.

The complete chloroplast genome of Lilium amoenum (Liliopsida: Liliaceae) from Yunnan, China.

Lilium amoenum E. H. Wilson ex Sealy is classified in Liliaceae, and it is an important ornamental plant with wonderful rose-red color and pleasant rose fragrance. In this study, we sequenced the complete chloroplast genome of L. amoenum by Illumina Hiseq X Ten and PacBio RS technologies. The genome size of L. amoenum is 152,280 bp, and displays a typical quadripartite structure: one large single-copy (LSC, 81,977 bp), one small single-copy (SSC, 17,539 bp), and a pair of inverted repeat regions (IRs, 26,382 bp). The overall GC content was 37.0%. The complete genome contained 131 genes, including 85 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. Phylogenetic analysis showed that L. amoenum is closely related to L. taliense and L. bakerianum. The present study could afford crucial genetic information for further researches on the genus and related genera.

The complete chloroplast genome of Lilium nepalense (Liliaceae).

Lilium nepalense is a useful plant species not only for its showy flowers but also has high medicinal value. In this study, the whole chloroplast genome of L. nepalense was sequenced for the first time. The genome size of L. nepalense, was 152,956bp, with typical tetragonal structure: one large single copy (82,573 bp), one small single copy (17,527 bp), and a pair of inverted repeat regions (IRs, 26,428 bp). The overall GC content was 37.0%. The complete genome contained 131 genes, including 85 protein-coding genes, 38 tRNA genes, and 8 rRNA genes. Phylogenetic analysis showed that L. nepalense was a close relationship between L. leucanthum and L. henryi. Phylogenetic analysis placed L. nepalense under the family Liliaceae.

The complete chloroplast genome of Lilium rosthornii Diels (Liliopsida: Liliaceae) from Hunan, China.

Lilium rosthornii is the perennial herbaceous bulbous plant belonging to the Lily of the Liliaceae, with high ornamental value and medicinal values. In this present study, we sequenced the complete chloroplast genome of Lilium rosthornii by Illumina Hiseq X Ten and PacBio RS technologies firstly. The genome size of L. rosthornii, was 152,242bp, with typical tetragonal structure: one large single-copy (LSC, 81,875 bp), one small single-copy (SSC, 17,553 bp), and a pair of inverted repeat regions (IRs, 26,407 bp). The overall GC content was 37.02%. The complete genome contained 131 genes, including 85 protein-coding genes, 38 tRNA genes, and eight rRNA genes. Phylogenetic analysis placed L. rosthornii under the family Liliaceae.

Leukemia inhibitory factor is a novel biomarker to predict lymph node and distant metastasis in pancreatic cancer.

Pancreatic cancer has a low survival rate, and most patients have lymph node metastasis and distant metastasis at the time of diagnosis. Despite efforts to improve overall survival (OS) and recurrence free survival (RFS), the prognosis of pancreatic cancer remains poor, underscoring the importance of identifying new biomarkers to predict metastasis in patients with pancreatic cancer. Leukemia inhibitory factor (LIF) is overexpressed in many types of cancer and is involved in the development of various malignancies including pancreatic cancer. However, the role of LIF as a biomarker to predict metastasis in pancreatic cancer remains unclear. In this study, univariate and multivariate Cox regression analyses identified LIF expression in pancreatic tumor tissues as an independent risk factor related to worse OS and RFS. LIF overexpression was related to poor clinicopathological features such as lymph node metastasis and Pathological stage (pTNM) stage. Serum LIF levels were higher in pancreatic cancer patients than in healthy controls. The area under the receiver operating characteristic curve indicated that serum LIF is more effective than other biomarkers (CA199 and CEA) for predicting lymph node and distant metastasis.

Efficacy of Standardized Rehabilitation in the Treatment of Diastasis Rectus Abdominis in Postpartum Women.

PURPOSE: The incidence of diastasis rectus abdominis (DRA) in parturients is continuously increasing, which may cause uncomfortable and affect the quality of life. The present study aims to retrospectively summarize the experience and efficacy in the treatment of DRA via standardized rehabilitation procedures in Eastern China. METHODS: This retrospective study included the parturients with DRA admitted to the Xishan People's Hospital of Wuxi between January 2017 and May 2021. Patients were separated into standardized rehabilitation group (SR) and non-standardized rehabilitation group (non-SR). The outcomes were the change in rectus abdominis separation and Physical Functioning Scale (PFS). Measurement data were compared between the two groups, and multivariate linear regression was used to analyze the factors associated with the standardized rehabilitation process. P values < 0.05 were considered statistically significant. RESULTS: Among a total of 294 patients with DRA who were included in the study, 171 patients were treated with SR (SR), and the other 123 patients were treated without SR process (non-SR). Compared with non-SR, the separation of the rectus abdominis was significantly reduced in SR after standardized rehabilitation treatment (p value < 0.0001). The multiple linear regression model analysis results suggested that standardized rehabilitation was an independent factor influencing the prognosis of DRA in parturients (p < 0.0001). In addition, the quality of life of the study group was significantly improved (p < 0.0001). CONCLUSION: Standardized rehabilitation method revealed high efficiency in treating DRA in postpartum women and could improve the quality of life of parturients.