Dynamic Near-Infrared Circularly Polarized Luminescence Encoded by Transient Supramolecular Chiral Assemblies.

Circularly polarized luminescence (CPL) is promising for applications in many fields. However, most systems involving CPL are within the visible range; near‒infrared (NIR) CPL‒active materials, especially those that exhibit high glum values and can be controlled spatially and temporally, are rare. Herein, dynamic NIR‒CPL with a glum value of 2.5[[EQUATION]]10‒2 was achieved through supramolecular coassembly and energy transfer strategies. The chiral assemblies formed by the coassembly between adenosine triphosphate (ATP) and a pyrene derivative exhibit a red CPL signal (glum of 10‒3). The further introduction of sulfo‒cyanine5 resulted in a cooperative energy transfer process, which not only aroused the NIR CPL but also increased the glum value to 10‒2. Temporal control of these chiral assemblies was realized by introducing alkaline phosphatase to fabricate a biomimetic enzyme‒catalyzed network, allowing the dynamic NIR CPL signal to be turned on. Based on these enzyme-regulated temporally controllable dynamic CPL-active chiral assemblies, a multilevel information encryption system was further developed. Our work provides a pioneering example for constructing dynamic NIR CPL materials holding the ability to perform temporal control via the supramolecular assembly strategy, which is expected to aid in the design of supramolecular complex systems that more closely resemble natural biological systems.

Chondroitin sulfate-modified tragacanth gum-gelatin composite nanocapsules loaded with curcumin nanocrystals for the treatment of arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease of yet undetermined etiology that is accompanied by significant oxidative stress, inflammatory responses,  and damage to joint tissues. In this study, we designed chondroitin sulfate (CS)-modified tragacanth gum-gelatin composite nanocapsules (CS-Cur-TGNCs) loaded with curcumin nanocrystals (Cur-NCs), which rely on the ability of CS to target CD44 to accumulate drugs in inflamed joints. Cur was encapsulated in the form of nanocrystals into tragacanth gum-gelatin composite nanocapsules (TGNCs) by using an inborn microcrystallization method, which produced CS-Cur-TGNCs with a particle size of approximately 80 ± 11.54 nm and a drug loading capacity of 54.18 ± 5.17%. In an in vitro drug release assay, CS-Cur-TGNCs showed MMP-2-responsive properties. During the treatment of RA, CS-Cur-TGNCs significantly inhibited oxidative stress, promoted the polarization of M2-type macrophages to M1-type macrophages, and decreased the expression of inflammatory factors (TNF-α, IL-1ß, and IL-6). In addition, it also exerted excellent anti-inflammatory effects, and significantly alleviated the swelling of joints during the treatment of gouty arthritis (GA). Therefore, CS-Cur-TGNCs, as a novel drug delivery system, could lead to new ideas for clinical therapeutic regimens for RA and GA.

Genomic characteristics and immune landscape of super multiple primary lung cancer.

BACKGROUND: In recent years, a growing number of patients with multiple primary lung cancer (MPLC) are being diagnosed, and a subset of these patients is found to have a large number of lesions at the time of diagnosis, which are referred to as 'super MPLC'. METHODS: Here, we perform whole exome sequencing (WES) and immunohistochemistry (IHC) analysis of PD-L1 and CD8 on 212 tumor samples from 42 patients with super MPLC. FINDINGS: We report the genomic alteration landscape of super MPLC. EGFR, RBM10 and TP53 mutation and TERT amplification are important molecular events in the evolution of super MPLC. We propose the conception of early intrapulmonary metastasis, which exhibits different clinical features from conventional metastasis. The IHC analyses of PD-L1 and CD8 reveal a less inflamed microenvironment of super MPLC than that of traditional non-small cell lung cancer (NSCLC). We identify the potentially susceptible germline mutations for super MPLC. INTERPRETATION: Our study depicts the genomic characteristics and immune landscape, providing insights into the pathogenesis and possible therapeutic guidance of super MPLC. FUNDING: A full list of funding bodies that supported this study can be found in the Acknowledgements section.

Zinc remodels mitochondrial network through SIRT3/Mfn2-dependent mitochondrial transfer in ameliorating spinal cord injury.

Spinal cord injury (SCI) is a traumatic neuropathic condition that results in motor, sensory and autonomic dysfunction. Mitochondrial dysfunction caused by primary trauma is one of the critical pathogenic mechanisms. Moderate levels of zinc have antioxidant effects, promote neurogenesis and immune responses. Zinc normalises mitochondrial morphology in neurons after SCI. However, how zinc protects mitochondria within neurons is unknown. In the study, we used transwell culture, Western blot, Quantitative Real-time Polymerase Chain Reaction (QRT-PCR), ATP content detection, reactive oxygen species (ROS) activity assay, flow cytometry and immunostaining to investigate the relationship between zinc-treated microglia and injured neurons through animal and cell experiments. We found that zinc promotes mitochondrial transfer from microglia to neurons after SCI through Sirtuin 3 (SIRT3) regulation of Mitofusin 2 protein (Mfn2). It can rescue mitochondria in damaged neurons and inhibit oxidative stress, increase ATP levels and promote neuronal survival. Therefore, it can improve the recovery of motor function in SCI mice. In conclusion, our work reveals a potential mechanism to describe the communication between microglia and neurons after SCI, which may provide a new idea for future therapeutic approaches to SCI.

Tumor-derived KLK8 predicts inferior survival and promotes an immune-suppressive tumor microenvironment in lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is the second most common lung cancer worldwide, leading to millions of deaths annually. Although immunotherapy has expanded the therapeutic choices for LUSC and achieved considerable efficacy in a subset of patients, many patients could not benefit, and resistance was pervasive. Therefore, it is significant to investigate the mechanisms leading to patients' poor response to immunotherapies and explore novel therapeutic targets. Using multiple public LUSC datasets, we found that Kallikrein-8 (KLK8) expression was higher in tumor samples and was correlated with inferior survival. Using a LUSC cohort (n = 190) from our center, we validated the bioinformatic findings about KLK8 and identified high KLK8 expression as an independent risk factor for LUSC. Function enrichment showed that several immune signaling pathways were upregulated in the KLK8 low-expression group and downregulated in the KLK8 high-expression group. For patients with low KLK8 expression, they were with a more active TME, which was both observed in the TCGA database and immune marker immunohistochemistry, and they had extensive positive relations with immune cells with tumor-eliminating functions. This study identified KLK8 as a risk factor in LUSC and illustrated the associations between KLK8 and cancer immunity, suggesting the potentiality of KLK8 as a novel immune target in LUSC.

Undescribed matrine-type alkaloids from Sophora alopecuroides with anti-inflammatory activity.

A phytochemical investigation on the alkaloid fractions of Sophora alopecuroides L. led to the production of 11 undescribed matrine-type alkaloids, sophaloseedlines I-S (1-11), 12 known analogs (12-23), and an unexpected artificial matrine-derived Al(III) complex (24). The corresponding structures were elucidated by the interpretation of spectroscopic analyses, quantum chemical calculation, and six instances (1-4, 18, and 24), verified by X-ray crystallography. The biological activities screening demonstrated that none of the isolates exhibited cytotoxicity against four human cancer cell lines (HepG2, A549, THP-1, and MCF-7) and respiratory syncytial virus (RSV) at 50 µM, while moderate anti-inflammatory activity with IC50 value from 15.6 to 47.8 µM was observed. The key structure-activity relationships of those matrine-type alkaloids for anti-inflammatory effects have been summarized. In addition, the most potent 7-epi-sophoramine (19) and aluminum sophaloseedline T (24) could effectively inhibit the release of pro-inflammatory factors (TNF-α, IL-6, and IL-1ß), as well as the expression of iNOS and COX-2 proteins.

Functionalized Cerium Dioxide Nanoparticles with Antioxidative Neuroprotection for Alzheimer's Disease.

Background: Oxidative stress induced reactive oxygen species (ROS) and aggregation of amyloid ß (Aß) in the nervous system are significant contributors to Alzheimer's disease (AD). Cerium dioxide and manganese oxide are known as to be effective and recyclable ROS scavengers with high efficiency in neuroprotection. Methods: A hollow-structured manganese-doped cerium dioxide nanoparticle (LMC) was synthesized for loading Resveratrol (LMC-RES). The LMC-RES were characterized by TEM, DLS, Zeta potential, and X-ray energy spectrum analysis. We also tested the biocompatibility of LMC-RES and the ability of LMC-RES to cross the blood-brain barrier (BBB). The antioxidant effects of LMC-RES were detected by SH-SY5Y cells. Small animal live imaging was used to detect the distribution of LMC-RES in the brain tissue of AD mice. The cognitive abilities of mice were tested by water maze and nesting experiments. The effects of LMC-RES in reducing oxidative stress and protecting neurons was also explored by histological analysis. Results: The results showed that LMC-RES had good sustained release effect and biocompatibility. The drug release rate of LMC-RES at 24 hours was 80.9 ± 2.25%. Meanwhile, LMC-RES could cross the BBB and enrich in neurons to exert antioxidant effects. In Aß-induced SH-SY5Y cells, LMC-RES could inhibits oxidative stress through the Nrf-2/HO-1 signaling pathway. In AD model mice, LMC-RES was able to reduce ROS levels, inhibit Aß-induced neurotoxicity, and protect neurons and significantly improve cognitive deficits of AD mice after drug administration. Conclusion: LMC-RES can effectively across the BBB, reduce oxidative stress, inhibit Aß aggregation, and promote the recovery of neurological function.

CXXC finger protein 1 (CFP1) bridges the reshaping of genomic H3K4me3 signature to the advancement of lung adenocarcinoma.

Histone H3 lysine 4 trimethylation (H3K4me3) is a canonical chromatin modification associated with active gene transcription, playing a pivotal role in regulating various cellular functions. Components of the H3K4me3 methyltransferase complex, known as the proteins associated with SET1 (COMPASS), have been implicated in exerting cancer-protective or cancer-inhibitory effects through inducive H3K4me3 modification. However, the role of the indispensable non-catalytic component of COMPASS CXXC-type zinc finger protein 1 (CFP1) in malignant progression remains unclear. We have unveiled that CFP1 promote lung adenocarcinoma (LUAD) cell proliferation, migration, and invasion while impairing cell apoptosis through in vitro and in vivo models. In addition, high CFP1 expression was identified as emerged as an adverse prognostic indicator across multiple public and in-house LUAD datasets. Notably, CFP1 deficiency led to dual effects on cancer cell transcriptome including extensive inactivation of cancer-promoting as well as activation of cancer repressors. Combining this with the chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we showed that CFP1 ablation reshaped the genomic H3K4me3 distribution signature, with prominent effects on TGF-ß and WNT signaling pathways. Collectively, our study proposes that CFP1 mediates tumorigenesis by genomic histone methylation reprogramming, offering insights for future investigations into epigenetic modifications in cancer progression and potential therapeutic advancements.

Encapsulation of Selenium Nanoparticles and Metformin in Macrophage-Derived Cell Membranes for the Treatment of Spinal Cord Injury.

Spinal cord injury is an impact-induced disabling condition. A series of pathological changes after spinal cord injury (SCI) are usually associated with oxidative stress, inflammation, and apoptosis. These pathological changes eventually lead to paralysis. The short half-life and low bioavailability of many drugs also limit the use of many drugs in SCI. In this study, we designed nanovesicles derived from macrophages encapsulating selenium nanoparticles (SeNPs) and metformin (SeNPs-Met-MVs) to be used in the treatment of SCI. These nanovesicles can cross the blood-spinal cord barrier (BSCB) and deliver SeNPs and Met to the site of injury to exert anti-inflammatory and reactive oxygen species scavenging effects. Transmission electron microscopy (TEM) images showed that the SeNPs-Met-MVs particle size was approximately 125 ± 5 nm. Drug release assays showed that Met exhibited sustained release after encapsulation by the macrophage cell membrane. The cumulative release was approximately 80% over 36 h. In vitro cellular experiments and in vivo animal experiments demonstrated that SeNPs-Met-MVs decreased reactive oxygen species (ROS) and malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and reduced the expression of inflammatory (TNF-α, IL-1ß, and IL-6) and apoptotic (cleaved caspase-3) cytokines in spinal cord tissue after SCI. In addition, motor function in mice was significantly improved after SeNPs-Met-MVs treatment. Therefore, SeNPs-Met-MVs have a promising future in the treatment of SCI.

A Targeted Exosome Therapeutic Confers Both CfDNA Scavenging and Macrophage Polarization for Ameliorating Rheumatoid Arthritis.

Only a minority of rheumatoid arthritis (RA) patients achieve disease remission, so the exploration of additional pathogenic factors and the development of new therapeutics are needed. Here, strong correlations among the cell-free DNA (cfDNA) level and the inflammatory response in clinical synovial fluid samples and RA disease activity are discovered. The important role of cfDNA in disease development in a collagen-induced arthritis (CIA) murine model is also demonstrated. Building on these findings, a novel therapeutic based on anti-inflammatory (M2) macrophage-derived exosomes as chassis, that are modified with both oligolysine and matrix metalloproteinase (MMP)-cleavable polyethylene glycol (PEG) on the membrane, is developed. After intravenous injection, PEG-enabled prolonged circulation and C─C motif chemokine ligand-directed accumulation together result in enrichment at inflamed joints. Following subsequent MMP cleavage, the positively charged oligolysine is exposed for cfDNA scavenging, while exosomes induce M2 polarization. By using a classical CIA murine model and a newly established CIA canine model, it is demonstrated that the rationally designed exosome therapeutic substantially suppresses inflammation in joints and provides strong chondroprotection and osteoprotection, revealing its potential for effective CIA amelioration.

Curcumin-Loaded Macrophage-Derived Exosomes Effectively Improve Wound Healing.

This study aims to investigate the potential therapeutic effect of exosomes derived from macrophages loaded with curcumin (Exos-cur) on the healing of diabetic wounds. As a new type of biomaterial, Exos-cur has better stability, anti-inflammation, and antioxidation biological activity. In in vitro experiments, Exos-cur can promote the proliferation, migration, and angiogenesis of HUVECs (human umbilical vein endothelial cells) while reducing the ROS (reactive oxygen species) produced by HUVECs induced by high glucose, regulating the mitochondrial membrane potential, reducing cell oxidative damage, and inhibiting oxidative stress and inflammation. In the in vivo experiment, the Exos-cur treatment group had an increased percentage of wound closure and contraction compared with the diabetic wound control group. Hematoxylin-eosin staining (HE) and Masson staining showed that the Exos-cur treatment group had more advanced re-epithelialization, and the generated mature granulation tissue was rich in a large number of capillaries and newly deposited collagen fibers. Western blot and immunofluorescence analyses showed that Exos-cur can inhibit inflammation by activating the Nrf2/ARE pathway, upregulate the expression of wound healing-related molecules, promote angiogenesis, and accelerate wound healing in diabetic rats. These results show that Exos-cur has a good therapeutic effect on diabetic skin defects and provide experimental evidence for the potential clinical benefits of Exos-cur.

H3K4 trimethylation regulates cancer immunity: a promising therapeutic target in combination with immunotherapy.

With the advances in cancer immunity regulation and immunotherapy, the effects of histone modifications on establishing antitumor immunological ability are constantly being uncovered. Developing combination therapies involving epigenetic drugs (epi-drugs) and immune checkpoint blockades or chimeric antigen receptor-T cell therapies are promising to improve the benefits of immunotherapy. Histone H3 lysine 4 trimethylation (H3K4me3) is a pivotal epigenetic modification in cancer immunity regulation, deeply involved in modulating tumor immunogenicity, reshaping tumor immune microenvironment, and regulating immune cell functions. However, how to integrate these theoretical foundations to create novel H3K4 trimethylation-based therapeutic strategies and optimize available therapies remains uncertain. In this review, we delineate the mechanisms by which H3K4me3 and its modifiers regulate antitumor immunity, and explore the therapeutic potential of the H3K4me3-related agents combined with immunotherapies. Understanding the role of H3K4me3 in cancer immunity will be instrumental in developing novel epigenetic therapies and advancing immunotherapy-based combination regimens.

Orthogonally Engineered Albumin with Attenuated Macrophage Phagocytosis for the Targeted Visualization and Phototherapy of Liver Cancer.

The five-year survival rate of hepatocellular carcinoma (HCC) remains unsatisfactory. This reflects, in part, the paucity of effective methods that allow the target-specific diagnosis and therapy of HCC. Here, we report a strategy based on engineered human serum albumin (HSA) that permits the HCC-targeted delivery of diagnostic and therapeutic agents. Covalent cysteine conjugation combined with the exploitation of host-guest chemistry was used to effect the orthogonal functionalization of HSA with two functionally independent peptides. One of these peptides targets glypican-3 (GPC-3), an HCC-specific biomarker, while the second reduces macrophage phagocytosis through immune-checkpoint stimulation. This orthogonally engineered HSA proved effective for the GPC-3-targeted delivery of near-infrared fluorescent and phototherapeutic agents, thus permitting target-specific optical visualization and photodynamic ablation of HCC in vivo. This study thus offers new insights into specificity-enhanced fluorescence-guided surgery and phototherapy of HCC through the orthogonal engineering of biocompatible proteins.

Sophflarine A, a novel matrine-derived alkaloid from Sophora flavescens with therapeutic potential for non-small cell lung cancer through ROS-mediated pyroptosis and autophagy.

BACKGROUND: Novel compounds and more efficient treatment options are urgently needed for the treatment of non-small cell lung cancer (NSCLC). The decoction of Sophora flavescens has been used to treat NSCLC in the clinic, and matrine-type alkaloids are generally considered to be the key pharmacodynamic material basis. But the previous study showed that common matrine-type alkaloids exhibit significant cytotoxicity only when at concentrations close to the millimolar (mM) level. The key antitumor alkaloids in S. flavescens seem to have not yet been revealed. PURPOSE: The aim of this study was to screen water-soluble matrine alkaloid with novel skeleton and enhanced activity from S. flavescens, and to reveal the pharmacological mechanism of its therapeutic effect on NSCLC. METHODS: Alkaloid was obtained from S. flavescens by chromatographic separation methods. The structure of alkaloid was determined by spectroscopic methods, and single-crystal X-ray diffraction. The mechanism of anti-NSCLC in vitro with cellular models was evaluated by MTT assay, western blotting, cell migration and invasion assay, plate colony-formation assay, tube formation assay, immunohistochemistry assay, hematoxylin and eosin staining. The antitumor efficacy in vivo was test in NSCLC xenograft models. RESULTS: A novel water-soluble matrine-derived alkaloid incorporating 6/8/6/6 tetracyclic ring system, named sophflarine A (SFA), was isolated from the roots of S. flavescens. SFA had significantly enhanced cytotoxicity compared with the common matrine-type alkaloids, having an IC50 value of 11.3 µM in A549 and 11.5 µM in H820 cells at 48 h. Mechanistically, SFA promoted NSCLC cell death by inducing pyroptosis via activating the NLRP3/caspase-1/GSDMD signaling pathway, and inhibited cancer cell proliferation by increasing the ROS production to activate autophagy via blocking the PI3K/AKT/mTOR signaling pathway. Additionally, SFA also inhibited NSCLC cell migration and invasion by suppressing EMT pathway, and inhibited cancer cell colony formation and human umbilical vein endothelial cell angiogenesis. In concordance with the above results, SFA treatment blocked tumor growth in an A549 cell-bearing orthotopic mouse model. CONCLUSION: This study revealed a potential therapeutic mechanism of a novel matrine-derived alkaloid, which not only described a rational explanation for the clinical utilization of S. flavescens, but also provided a potential candidate compound for NSCLC treatment.

[p53 regulates primordial follicle activation through the mTOR signaling pathway].

This paper aimed to investigate the role and potential mechanism of p53 on primordial follicle activation. Firstly, the p53 mRNA expression in the ovary of neonatal mice at 3, 5, 7 and 9 days post-partum (dpp) and the subcellular localization of p53 were detected to confirm the expression pattern of p53. Secondly, 2 dpp and 3 dpp ovaries were cultured with p53 inhibitor Pifithrin-µ (PFT-µ, 5 µmol/L) or equal volume of dimethyl sulfoxide for 3 days. The function of p53 in primordial follicle activation was determined by hematoxylin staining and whole ovary follicle counting. The proliferation of cell was detected by immunohistochemistry. The relative mRNA levels and protein levels of the key molecules involved in the classical pathways associated with the growing follicles were examined by immunofluorescence staining, Western blot and real-time PCR, respectively. Finally, rapamycin (RAP) was used to intervene the mTOR signaling pathway, and ovaries were divided into four groups: Control, RAP (1 µmol/L), PFT-µ (5 µmol/L), PFT-µ (5 µmol/L) + RAP (1 µmol/L) groups. The number of follicles in each group was determined by hematoxylin staining and whole ovary follicle counting. The results showed that the expression of p53 mRNA was decreased with the activation of primordial follicles in physiological condition. p53 was expressed in granulosa cells and oocyte cytoplasm of the primordial follicles and growing follicles, and the expression of p53 in the primordial follicles was higher than that in the growing follicles. Inhibition of p53 promoted follicle activation and reduced the primordial follicle reserve. Inhibition of p53 promoted the proliferation of the granulosa cells and oocytes. The mRNA and protein expression levels of key molecules in the PI3K/AKT signaling pathway including AKT, PTEN, and FOXO3a were not significantly changed after PFT-µ treatment, while the expression of RPS6/p-RPS6, the downstream effectors of the mTOR signaling pathway, was upregulated. Inhibition of both p53 and mTOR blocked p53 inhibition-induced primordial follicle activation. Collectively, these findings suggest that p53 may inhibit primordial follicle activation through the mTOR signaling pathway to maintain the primordial follicle reserve.

Near-infrared AIEgens with high singlet-oxygen yields for mitochondria-specific imaging and antitumor photodynamic therapy.

AIE-active photosensitizers (PSs) are promising for antitumor therapy due to their advantages of aggregation-promoted photosensitizing properties and outstanding imaging ability. High singlet-oxygen (1O2) yield, near-infrared (NIR) emission, and organelle specificity are vital parameters to PSs for biomedical applications. Herein, three AIE-active PSs with D-π-A structures are rationally designed to realize efficient 1O2 generation, by reducing the electron-hole distribution overlap, enlarging the difference on the electron-cloud distribution at the HOMO and LUMO, and decreasing the ΔEST. The design principle has been expounded with the aid of time-dependent density functional theory (TD-DFT) calculations and the analysis of electron-hole distributions. The 1O2 quantum yields of AIE-PSs developed here can be up to 6.8 times that of the commercial photosensitizer Rose Bengal under white-light irradiation, thus among the ones with the highest 1O2 quantum yields reported so far. Moreover, the NIR AIE-PSs show mitochondria-targeting capability, low dark cytotoxicity but superb photo-cytotoxicity, and satisfactory biocompatibility. The in vivo experimental results demonstrate good antitumor efficacy for the mouse tumour model. Therefore, the present work will shed light on the development of more high-performance AIE-PSs with high PDT efficiency.

H3K4me3-related lncRNAs signature and comprehensive analysis of H3K4me3 regulating tumor immunity in lung adenocarcinoma.

BACKGROUD: The role of epigenetic modifications in tumorigenesis has been widely reported. However, the role and mechanism of H3K4me3 modification in lung adenocarcinoma (LUAD) are rarely reported systematically. We, therefore, sought to analyze the characteristics of LUAD associated with H3K4me3 modification, build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD and clarify the potential value of H3K4me3 in immunotherapy of LUAD. METHODS: We evaluated H3K4me3-lncRNA patterns and H3K4me3-lncRNA scores of 477 LUAD samples based on 53 lncRNAs closely correlated to H3K4me3 regulators and comprehensive analyzed the role of these patterns in tumorigenesis and tumor immunity. Using Gene set variation analysis (GSVA), we systematically evaluated the H3K4me3 level of every sample and deeply analyzed the effect of H3K4me3 on the prognosis of LUAD. In addition, we included two independent immunotherapy cohorts to study the impact of high H3K4me3 score on the prognosis of patients. We also used an independent cohort with 52 matched paraffin specimens of LUAD to verify the impact of high H3K3me3 expression on the prognosis of patients. RESULTS: We identified three H3K4me3-lncRNA patterns that exhibited specific immune characteristics. Characterized by immunosuppressive and increased TGFß-mediated epithelial-mesenchymal transition (EMT), patients with high H3K4me3-lncRNA score had a poor overall survival and decreased H3K4me3 score. H3K4me3 score was significantly positively correlated with CD4+T-cell and CD8+T-cell activation, programmed cell death and immune checkpoints (ICs) expression, and was negatively correlated with MYC pathway, TP53 pathway, and cell proliferation. Patients with high H3K4me3 score showed elevated expression of ICs, potentiated CD4 T-cell and CD8 T-cell activation, increased programmed cell death, and suppressed cell proliferation and TGFß-mediated EMT. Patients with high H3K4me3 score and high expression of CTLA4, ICOS, TIGIT, PDCD1LG2, IDO1, CD274, PDCD1, LAG3, or HAVCR2 had the best survival advantage. Two independent immunotherapy cohorts verified that patients with high H3K4me3 score showed an increased inflamed tumor microenvironment (TME) phenotype and enhanced anti-PD-1/L1 immunotherapy response. Immunohistochemistry (IHC) data from 52 matched paraffin specimens of LUAD confirmed that the protein level of H3K4me3 in tumor was significantly lower than that of paracancerous tissues and H3K4me3 brought significant survival benefits to patients with LUAD. CONCLUSIONS: We build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD. More importantly, this study revealed characteristics of H3K4me3 modification in LUAD and clarified the important potential role of H3K4me3 on tumor immunotherapy and patients' survival.

The anesthesia management of totally thoracoscopic cardiac surgery: A single-center retrospective study.

Anesthesia management of Totally thoracoscopic cardiac surgery (TTCS) has been the subject of much debate and discussion. In this single center retrospective study, we summarize the experience of clinical anesthesia management for TTCS by review the medical records of our medical center and look forward to its future development. In this retrospective study, 103 patients (49 male and 54 female) were enrolled, the mean age was 56.7 ± 14.4 years old. The participants underwent Mitral Valve Replacement (MVR) + Tricuspid Valve Annuloplasty (TVA) (42, 40.8%), Mitral Valve Annuloplasty (MVA) + TVA (38, 36.9%), MVA (21, 20.4%), and MVR (2, 1.9%)，respectively. Intraoperative hypoxemia, radiographic pulmonary infiltrates, and pneumonia were observed in 19 (18.4%), 84 (81.6%), and 13 (12.6%) patients, respectively. The LOS of ICU and POD were as follows: MVR + TVA (55.1 ± 25h, 9.9 ± 3.5 d), MVA + TVA (56.5 ± 28.4h, 9.4 ± 4.2d), MVA (37.9 ± 21.9h, 8.1 ± 2.3d) and MVR (48 ± 4.2h, 7.5 ± 2.1d). No reintubation, reoperations, postoperative cognitive dysfunction, 30-day mortality were observed in the present study. The present study demonstrated that applying this anesthesia management for TTCS associated with acceptable morbidity, intensive care unit and postoperative hospital lengths of stay. The finding from the present study might provide some new approach for Anesthesia management of TTCS.

Multiple primary lung cancer: Updates of clinical management and genomic features.

In recent decades, multiple primary lung cancer (MPLC) has been increasingly prevalent in clinical practice. However, many details about MPLC have not been completely settled, such as understanding the driving force, clinical management, pathological mechanisms, and genomic architectures of this disease. From the perspective of diagnosis and treatment, distinguishing MPLC from lung cancer intrapulmonary metastasis (IPM) has been a clinical hotpot for years. Besides, compared to patients with single lung lesion, the treatment for MPLC patients is more individualized, and non-operative therapies, such as ablation and stereotactic ablative radiotherapy (SABR), are prevailing. The emergence of next-generation sequencing has fueled a wave of research about the molecular features of MPLC and advanced the NCCN guidelines. In this review, we generalized the latest updates on MPLC from definition, etiology and epidemiology, clinical management, and genomic updates. We summarized the different perspectives and aimed to offer novel insights into the management of MPLC.

Genetic trajectory and clonal evolution of multiple primary lung cancer with lymph node metastasis.

Multiple primary lung cancer (MPLC) with lymph node metastasis (LNM) is a rare phenomenon of multifocal lung cancer. The genomic landscapes of MPLC and the clonal evolution pattern between primary lung lesions and lymph node metastasis haven't been fully illustrated. We performed whole-exome sequencing (WES) on 52 FFPE (Formalin-fixed Paraffin-Embedded) samples from 11 patients diagnosed with MPLC with LNM. Genomic profiling and phylogenetic analysis were conducted to infer the evolutional trajectory within each patient. The top 5 most frequently mutated genes in our study were TTN (76.74%), MUC16 (62.79%), MUC19 (55.81%), FRG1 (46.51%), and NBPF20 (46.51%). For most patients in our study, a substantial of genetic alterations were mutually exclusive among the multiple pulmonary tumors of the same patient, suggesting their heterogenous origins. Individually, the genetic profile of lymph node metastatic lesions overlapped with that of multiple lung cancers in different degrees but are more genetically related to specific pulmonary lesions. SETD2 was a potential metastasis biomarker of MPLC. The mean putative neo-antigen number of the primary tumor (646.5) is higher than that of lymph node metastases (300, p = 0.2416). Primary lung tumors and lymph node metastases are highly heterogenous in immune repertoires. Our findings portrayed the comprehensive genomic landscape of MPLC with LNM. We characterized the genomic heterogeneity among different tumors. We offered novel clues to the clonal evolution between MPLC and their lymphatic metastases, thus advancing the treatment strategies and preventions of MPLC with LNM.