Matrine exhibits antiviral activities against PEDV by directly targeting Spike protein of the virus and inducing apoptosis via the MAPK signaling pathway.

Porcine Epidemic Diarrhea Virus (PEDV) is a highly contagious virus that causes Porcine Epidemic Diarrhea (PED). This enteric disease results in high mortality rates in piglets, leading to significant financial losses in the pig industry. However, vaccines cannot provide sufficient protection against epidemic strains. Spike (S) protein exposed on the surface of virion mediates PEDV entry into cells. Our findings imply that matrine (MT), a naturally occurring alkaloid, inhibits PEDV infection targeting S protein of virions and biological process of cells. The GLY434 residue in the autodocking site of the S protein and MT conserved based on sequence comparison. This study provides a comprehensive analysis of viral attachment, entry, and virucidal effects to investigate how that MT inhibits virus replication. MT inhibits PEDV attachment and entry by targeting S protein. MT was added to cells before, during, or after infection, it exhibits anti-PEDV activities and viricidal effects. Network pharmacology focuses on addressing causal mechanisms rather than just treating symptoms. We identified the key genes and screened the cell apoptosis involved in the inhibition of MT on PEDV infection in network pharmacology. MT significantly promotes cell apoptosis in PEDV-infected cells to inhibit PEDV infection by activating the MAPK signaling pathway. Collectively, we provide the biological foundations for the development of single components of traditional Chinese medicine to inhibit PEDV infection and spread.

Iguratimod suppresses plasma cell differentiation and ameliorates experimental Sjögren's syndrome in mice by promoting TEC kinase degradation.

Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren's syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg-1·d-1) or hydroxychloroquine (50 mg·kg-1·d-1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg-1·d-1) was more effective than hydroxychloroquine (50 mg·kg-1·d-1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.

Analysis of the relationship between starch molecular conformation and enzymatic hydrolysis efficiency.

Resistant starch (RS) is important in controlling diabetes. The primary objective of this study is to examine the impact of molecular conformation on the enzymatic hydrolysis efficiency of starch by α-amylase. And the interactions between starch molecules with different conformations and α-amylase were analysed by using molecule dynamics simulation and molecular docking. It was found, the natural conformational starch molecule was hydrolysed from the middle of the starch chain by α-amylase, producing polysaccharides. The bent PS-conformational starch molecules with multiple O2-O3 intramolecular hydrogen bonds produced by high-pressure was hydrolysed from the head of the starch chain to produce glucose, which is not conducive to RS formation. The stretched H-conformation without intramolecular hydrogen bonds produced by heat treatment was not hydrolysed by α-amylase. However, it occupied the active groove and formed strong interactions with α-amylase, which prevented other starch molecules from binding to α-amylase, thus reducing hydrolysis efficiency. Moreover, the total interaction energies between the three starch molecules and α-amylase were approximately 78 kJ/mol. And several hydrogen bonds were formed between the starch molecules and α-amylase, which provides evidence for the continuous sliding hydrolysis hypothesis of α-amylase. Moreover, these results provide an important reference for elucidating the mechanism of RS formation.

Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

Automotive Augmented Reality Head-Up Displays.

As the next generation of in-vehicle intelligent platforms, the augmented reality heads-up display (AR-HUD) has a huge information interaction capacity, can provide drivers with auxiliary driving information, avoid the distractions caused by the lower head during the driving process, and greatly improve driving safety. However, AR-HUD systems still face great challenges in the realization of multi-plane full-color display, and they cannot truly achieve the integration of virtual information and real road conditions. To overcome these problems, many new devices and materials have been applied to AR-HUDs, and many novel systems have been developed. This study first reviews some key metrics of HUDs, investigates the structures of various picture generation units (PGUs), and finally focuses on the development status of AR-HUDs, analyzes the advantages and disadvantages of existing technologies, and points out the future research directions for AR-HUDs.

Observation of Chiral Symmetry Breaking in Toroidal Vortices of Light.

In this Letter, we explore the intersection of chirality and recently discovered toroidal spatiotemporal optical vortices (STOVs). We introduce "photonic conchs" theoretically as a new type of toroidal-like state exhibiting geometrical chirality, and experimentally observe these wave packets with controllable topological charges. Unlike toroidal STOVs, photonic conchs exhibit unique chirality-related dynamical evolution in free space and possess an orbital angular momentum correlated with all the dimensions of space-time. This research deepens our understanding of toroidal light states and potentially advances various fields by unveiling similar wave phenomena in a broader scope of physics systems, including acoustics and electronics.

Astragaloside-IV promotes autophagy via the Akt/mTOR pathway to improve cellular lipid deposition.

The current study aimed to investigate the potential role of astragaloside IV (AS-IV) in improving cellular lipid deposition and its underlying mechanism. A fatty liver cell model was established by treating hepatoma cells with palmitic acid. AS-IV and SC79 were used for treatment. Oil Red O staining was applied to detect intracellular lipid deposition, and transmission electron microscopy was utilized to assess autophagosome formation. Immunofluorescence double staining was applied to determine microtubule-associated proteins 1A/1B light chain 3 (LC3) expression. Western blot analysis was performed to detect the expression of LC3, prostacyclin, Beclin-1, V-akt murine thymoma viral oncogene homolog (Akt), phosphorylated Akt, mTOR, and phosphorylated mTOR. Oil Red O staining revealed that AS-IV reduced intracellular lipid accumulation. Further, it increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in the cells. It also reduced the phosphorylation levels of Akt and mTOR and the levels of prostacyclin. However, the effects of AS-IV decreased with SC79 treatment. In addition, LC3B + BODIPY493/503 fluorescence double staining showed that AS-IV reduced intracellular lipid deposition levels by enhancing autophagy. AS-IV can reduce lipid aggregation in fatty liver cells, which can be related to enhanced hepatocyte autophagy by inhibiting the Akt/mTOR signaling pathway.

Safety of Hepatitis B Vaccines (Monovalent or as Part of Combination) in Preterm Infants: A Systematic Review.

Introduction: The World Health Organization (WHO) recommends vaccination against hepatitis B as soon as possible following birth for all infants, regardless of prematurity. Hepatitis B vaccination at birth is clearly justified, represents a crucial step in the global control of perinatally acquired hepatitis B and there are no safety concerns in infants born at term. However, there is limited information on the safety of the hepatitis B vaccine in preterm infants, whose immune responses and morbidity risk differ from those in infants born at term. Objectives: The objectives of this paper are to systematically review the literature regarding the safety and risk of adverse events following immunisation (AEFIs) associated with the administration of the hepatitis B vaccine (monovalent or as part of a combination vaccine) to preterm infants. Methods: We performed a search for relevant papers published between 1 January 2002 and 30 March 2023 in the Ovid MEDLINE, Ovid Embase, Cochrane Central Register of Controlled Trials and CINAHL Plus databases. Two authors independently reviewed and analysed each article to include in the systematic review. Narrative synthesis is presented. Results: Twenty-one relevant papers were identified and included in this systematic review. The vast majority of data pertained to multi-antigen (combination) vaccine preparations and vaccination episodes from 6 weeks of age onwards. We found no publications investigating the timing of the birth dose of the hepatitis B vaccine, and AEFI reporting was exclusively short-term (hours to days following administration). There was substantial variability in the reported rate of AEFIs between studies, ranging from 0% to 96%. Regardless of frequency, AEFIs were mostly minor and included injection site reactions, temperature instability and self-limiting cardiorespiratory events. Six studies reported serious adverse events (SAEs) such as the requirement for escalation of respiratory support. However, these occurred predominantly in high-risk infant populations and were rare (~1%). Using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, the certainty of evidence was assessed as very low. Conclusions: Despite substantial variability between the relatively small number of published studies in terms of cohort selection, definitions, vaccine preparations and reporting, hepatitis B-containing vaccines (mostly as combination vaccines) appear to be relatively well tolerated in preterm infants from 6 weeks of age. Research focusing on the safety of hepatitis B vaccine in preterm infants specifically within 7 days of birth is lacking, particularly regarding long-term morbidity risk. Further research in this area is required.

[Characterization of Reductive Dechlorination of Chlorinated Ethylenes by Anaerobic Consortium].

Tetrachloroethylene （PCE） and trichloroethylene （TCE） are typical volatile halogenated organic compounds in groundwater that pose serious threats to the ecological environment and human health. To obtain an anaerobic microbial consortium capable of efficiently dechlorinating PCE and TCE to a non-toxic end product and to explore its potential in treating contaminated groundwater， an anaerobic microbial consortium W-1 that completely dechlorinated PCE and TCE to ethylene was obtained by repeatedly feeding PCE or TCE into the contaminated groundwater collected from an industrial site. The dechlorination rates of PCE and TCE were （120.1 ±4.9） µmol·ï¼ˆL·d）-1 and （172.4 ±21.8） µmol·ï¼ˆL·d）-1 in W-1， respectively. 16S rRNA gene amplicon sequencing and quantitative PCR （qPCR） showed that the relative abundance of Dehalobacter increased from 1.9% to 57.1%， with the gene copy number increasing by 1.7×107 copies per 1 µmol Cl- released when 98.3 µmol of PCE was dechlorinated to cis-1，2-dichloroethylene （cis-1，2-DCE）. The relative abundance of Dehalococcoides increased from 1.1% to 53.8% when cis-1，2-DCE was reductively dechlorinated to ethylene. The growth yield of Dehalococcoides gene copy number increased by 1.7×108 copies per 1 µmol Cl- released for the complete reductive dechlorination of PCE to ethylene. The results indicated that Dehalobacter and Dehalococcoides cooperated to completely detoxify PCE. When TCE was used as the only electron acceptor， the relative abundance of Dehalococcoides increased from （29.1 ±2.4）% to （7.7 ±0.2）%， and gene copy number increased by （1.9 ±0.4）×108 copies per 1 µmol Cl- released， after dechlorinating 222.8 µmol of TCE to ethylene. The 16S rRNA gene sequence of Dehalococcoides LWT1， the main functional dehalogenating bacterium in enrichment culture W-1， was obtained using PCR and Sanger sequencing， and it showed 100% similarity with the 16S rRNA gene sequence of D. mccartyi strain 195. The anaerobic microbial consortium W-1 was also bioaugmented into the groundwater contaminated by TCE at a concentration of 418.7 µmol·L-1. The results showed that （69.2 ±9.8）% of TCE could be completely detoxified to ethylene within 28 days with a dechlorination rate of （10.3 ±1.5） µmol·ï¼ˆL·d）-1. This study can provide the microbial resource and theoretical guidance for the anaerobic microbial remediation in PCE or TCE-contaminated groundwater.

Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.

Tumors employ diverse strategies for immune evasion. Unraveling the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here, we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as a pivotal immune suppressor. FGF21 is upregulated in multiple types of tumors and promotes tumor progression. Tumor-secreted FGF21 significantly disrupts anti-tumor immunity by rewiring cholesterol metabolism of CD8+T cells. Mechanistically, FGF21 sustains the hyperactivation of AKT-mTORC1-sterol regulatory-element-binding protein 1 (SREBP1) signal axis in the activated CD8+T cells, resulting in the augment of cholesterol biosynthesis and T cell exhaustion. FGF21 knockdown or blockade using a neutralizing antibody normalizes AKT-mTORC1 signaling and reduces excessive cholesterol accumulation in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings reveal FGF21 as a "secreted immune checkpoint" that hampers anti-tumor immunity, suggesting that inhibiting FGF21 could be a valuable strategy to enhance the cancer immunotherapy efficacy.

A Single-Atom Manganese Nanozyme Mn-N/C Promotes Anti-Tumor Immune Response via Eliciting Type I Interferon Signaling.

Tumor microenvironment (TME)-induced nanocatalytic therapy is a promising strategy for cancer treatment, but the low catalytic efficiency limits its therapeutic efficacy. Single-atom catalysts (SACs) are a new type of nanozyme with incredible catalytic efficiency. Here, a single-atom manganese (Mn)-N/C nanozyme is constructed. Mn-N/C catalyzes the conversion of cellular H2O2 to ∙OH through a Fenton-like reaction and enables the sufficient generation of reactive oxygen species (ROS), which induces immunogenic cell death (ICD) of tumor cells and significantly promotes CD8+T anti-tumor immunity. Moreover, RNA sequencing analysis reveals that Mn-N/C treatment activates type I interferon (IFN) signaling, which is critical for Mn-N/C-mediated anti-tumor immune response. Mechanistically, the release of cytosolic DNA and Mn2+ triggered by Mn-N/C collectively activates the cGAS-STING pathway, subsequently stimulating type I IFN induction. A highly efficient single-atom nanozyme, Mn-N/C, which enhances anti-tumor immune response and exhibits synergistic therapeutic effects when combined with the anti-PD-L1 blockade, is proposed.

Reforestation of Cunninghamia lanceolata changes the relative abundances of important prokaryotic families in soil.

Over the past decades, many forests have been converted to monoculture plantations, which might affect the soil microbial communities that are responsible for governing the soil biogeochemical processes. Understanding how reforestation efforts alter soil prokaryotic microbial communities will therefore inform forest management. In this study, the prokaryotic communities were comparatively investigated in a secondary Chinese fir forest (original) and a reforested Chinese fir plantation (reforested from a secondary Chinese fir forest) in Southern China. The results showed that reforestation changed the structure of the prokaryotic community: the relative abundances of important prokaryotic families in soil. This might be caused by the altered soil pH and organic matter content after reforestation. Soil profile layer depth was an important factor as the upper layers had a higher diversity of prokaryotes than the lower ones (p < 0.05). The composition of the prokaryotic community presented a seasonality characteristic. In addition, the results showed that the dominant phylum was Acidobacteria (58.86%) with Koribacteraceae (15.38%) as the dominant family in the secondary Chinese fir forest and the reforested plantation. Furthermore, soil organic matter, total N, hydrolyzable N, and NH4+-N were positively correlated with prokaryotic diversity (p < 0.05). Also, organic matter and NO3--N were positively correlated to prokaryotic abundance (p < 0.05). This study demonstrated that re-forest transformation altered soil properties, which lead to the changes in microbial composition. The changes in microbial community might in turn influence biogeochemical processes and the environmental variables. The study could contribute to forest management and policy-making.

Systematic review: What is the impact of triage implementation on clinical outcomes and process measures in low- and middle-income country emergency departments?

INTRODUCTION: Triage is widely regarded as an essential function of emergency care (EC) systems, especially in resource-limited settings. Through a systematic search and review of the literature, we investigated the effect of triage implementation on clinical outcomes and process measures in low- and middle-income country (LMIC) emergency departments (EDs). METHODS: Structured searches were conducted using MEDLINE, CENTRAL, EMBASE, CINAHL, and Global Health. Eligible articles identified through screening and full-text review underwent risk-of-bias assessment using the Newcastle-Ottawa Scale. The quality of evidence for each effect measure was summarized using GRADE. RESULTS: Among 10,394 articles identified through the search strategy, 58 underwent full-text review and 16 were included in the final synthesis. All utilized pre-/postintervention methods and a majority were single center. Effect measures included mortality, waiting time, length of stay, admission rate, and patient satisfaction. Of these, ED mortality and time to clinician assessment were evaluated most frequently. The majority of studies using these outcomes identified a positive effect, namely a reduction in deaths and waiting time among patients presenting for EC. The quality of the evidence was moderate for these measures but low or very low for all other outcomes and process indicators. CONCLUSIONS: There is moderate quality of evidence supporting an association between the introduction of triage and a reduction in deaths and waiting time. Although the available data support the value of triage in LMIC EDs, the risk of confounding and publication bias is significant. Future studies will benefit from more rigorous research methods.

Ferroelectricity and Thermochromism in a 2D Dion-Jacobson Organic-Inorganic Hybrid Perovskite.

2D organic-inorganic hybrid perovskites (OIHPs) have become one of the hottest research topics due to their excellent environmental stability and unique optoelectronic properties. Recently, the ferroelectricity and thermochromism of 2D OIHPs have attracted increasing interests. Integrating ferroelectricity and thermochromism into perovskites can significantly promote the development of multichannel intelligent devices. Here, a novel 2D Dion-Jacobson OIHP of the formula (3AMP)PbI4 (where 3AMP is 3-(aminomethyl)pyridinium) is reported, which has a remarkable spontaneous polarization value (Ps) of 15.6 µC cm-2 and interesting thermochromism. As far it is known, such a large Ps value is the highest for 2D OIHPs recorded so far. These findings will inspire further exploration and application of multifunctional perovskites.

Sacubitril/valsartan attenuates myocardial inflammation, hypertrophy, and fibrosis in rats with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3ß (GSK-3ß) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-ß1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF.

Lipid mediator resolvin D2 inhibits ATP currents in rat primary sensory neurons.

Resolvin D2 (RvD2), an endogenous lipid mediator derived from docosahexaenoic acid, has been demonstrated to have analgesic effects. However, little is known about the mechanism underlying RvD2 in pain relief. Herein, we demonstrate that RvD2 targeted the P2X3 receptor as an analgesic. The electrophysiological activity of P2X3 receptors was suppressed by RvD2 in rat dorsal root ganglia (DRG) neurons. RvD2 pre-application dose-dependently decreased α,ß-methylene-ATP (α,ß-meATP)-induced inward currents. RvD2 remarkably decreased the maximum response to α,ß-meATP, without influencing the affinity of P2X3 receptors. RvD2 also voltage-independently suppressed ATP currents. An antagonist of the G protein receptor 18 (GPR18), O-1918, prevented the RvD2-induced suppression of ATP currents. Additionally, intracellular dialysis of the Gαi/o -protein antagonist pertussis toxin (PTX), the PKA antagonist H89, or the cAMP analog 8-Br-cAMP also blocked the RvD2-induced suppression. Furthermore, α,ß-meATP-triggered depolarization of membrane potential along with the action potential bursts in DRG neurons were inhibited by RvD2. Lastly, RvD2 attenuated spontaneous nociceptive behaviors as well as mechanical allodynia produced by α,ß-meATP in rats via the activation of the peripheral GPR18. These findings indicated that RvD2 inhibited P2X3 receptors in rat primary sensory neurons through GPR18, PTX-sensitive Gαi/o -proteins, and intracellular cAMP/PKA signaling, revealing a novel mechanism that underlies its analgesic effects by targeting P2X3 receptors.

Giant unilateral electric-field control of magnetic anisotropy in MgO/Rh2CoSb heterojunctions.

A large voltage-controlled magnetic anisotropy (VCMA) effect is highly desirable for applications of voltage-torque magnetic random access memory. In this work, the dependence of magnetic anisotropy (MA) on the electric field in a MgO-based heterojunction consisting of a new Heusler alloy, Rh2CoSb, is studied using first-principles calculations. We find that the Rh-terminated MgO/Rh2CoSb heterojunction has a perpendicular MA and a giant VCMA coefficient of 7024 fJ V-1 m-1. Furthermore, the VCMA coefficient shows a characteristic of dependence on the electric-field direction. The origins of these behaviors are elucidated by orbital-resolved MA and second-order perturbation theoretical analysis. As the spin-down states of the in-plane orbital, dxy, are close to the Fermi level, the shift of these states induced by the electric field gives rise to significant changes of magnetic anisotropy energy, which is mainly responsible for the giant VCMA effect.

Low-dose metronomic chemotherapy triggers oxidized mtDNA sensing inside tumor cells to potentiate CD8+T anti-tumor immunity.

Low-dose metronomic (LDM) chemotherapy, the frequent and continuous use of low doses of conventional chemotherapeutics, is emerging as a promising form of chemotherapy utilization. LDM chemotherapy exerts immunomodulatory effects. However, the underlying mechanism is not fully understood. Here we found that suppressing tumor growth by LDM chemotherapy was dependent on the activation of CD8+T cells. LDM chemotherapy potentiated the cytotoxic function of CD8+T cells by stimulating cancer-cell autonomous type I interferon (IFN) induction. Mechanistically, LDM chemotherapy evoked mitochondrial dysfunction and increased reactive oxygen species (ROS) production. ROS triggered the oxidation of cytosolic mtDNA, which was sensed by cGAS-STING, consequently inducing type I IFN production in the cancer cells. Moreover, the cGAS-STING-IFN axis increased PD-L1 expression and predicted favorable clinical responses to chemoimmunotherapy. Antioxidant N-acetylcysteine inhibited oxidized mtDNA-induced type I IFN production and attenuated the efficacy of combination therapy with LDM chemotherapy and PD-L1 blockade. This study elucidates the critical role of intratumoral oxidized mtDNA sensing in LDM chemotherapy-mediated activation of CD8+T cell immune response. These findings may provide new insights for designing combinatorial immunotherapy for cancer patients.

[Diagnostic and Prognostic Value of 18F-FDG PET/CT in Bone Marrow Infiltration of Newly Diagnosed Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To explore the diagnostic value of 18F-FDG PET/CT in bone marrow infiltration (BMI) of newly diagnosed diffuse large B-cell lymphoma (DLBCL), compared with the results of bone marrow biopsy (BMB) and investigate whether the BMI diagnosed by 18F-FDG PET/CT and other factors have independent prognostic values. METHODS: Ninety-four newly diagnosed DLBCL patients who underwent PET/CT in Clinical Medical College of Shanghai General Hospital of Nanjing Medical University were included. BMB was performed within 2 weeks before or after PET/CT, and standardized treatment was performed after PET/CT. The manifestations of bone marrow (BM) FDG uptake were recorded. The diagnostic criteria of BMI were BMB positive or focal BM FDG uptake confirmed by imaging follow-up. The relationship between clinical features and BM FDG uptake and the values of PET/CT and BMB in the diagnosis of BMI was analyzed. The progression-free survival (PFS) was analyzed by Kaplan-Meier survival curves, log-rank test was used to compare PFS rate, and Cox regression model was used to analyze the independent risk factors affecting PFS. RESULTS: Among 94 DLBCL patients, 34 patients showed focal BM uptake (fPET), 7 patients showed super BM uptake (sBMU), 11 patients showed diffuse homogenous uptake higher than liver (dPET), and the other 42 patients had normal BM uptake (nPET) (lower than liver). BMB positive was found in all sBMU patients, in 20.6%(7/34) of fPET patients, and in 27.3% (3/11) of dPET patients. All nPET patients had negative BMB results. dPET patients were associated with lower hemoglobin level and leukocyte count compared with nPET group (P < 0.001, P =0.026). Compared with fPET patients, sBMU patients were more likely to have B symptoms and elevated lactate dehydrogenase (LDH). A total of 44 patients were diagnosed BMI, including 17 cases with BMB+. The sensitivity and specificity of BMB in the diagnosis of BMI was 38.6% (17/44) and 100% (50/50), respectively. Using fPET and sBMU as criteria of PET BMI, the diagnostic sensitivity and specificity of PET/CT was 93.2% (41/44) and 100% (50/50), respectively. Kaplan-Meier analysis showed that there was no significant difference in 2-year PFS rate between nPET and dPET patients (P >0.05), while sBMU patients had lower 2-year PFS rate compared with fPET patients (P < 0.001). Multivariate analysis showed that higher Ann Arbor stage (HR=9.010, P =0.04) and sBMU (HR=3.964, P =0.002) were independent risk factors affecting PFS. CONCLUSIONS: Increased BM FDG uptake of DLBCL can be manifested as dPET, fPET and sBMU. fPET and sBMU can replace BMB to diagnose BMI. Although dPET cannot completely exclude the possibility of BMI, it does not affect the prognosis, so it can be diagnosed as PET BMI negative. sBMU is an independent prognostic risk factor.