Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS.

Self-nonself discrimination is vital for the immune system to mount responses against pathogens while maintaining tolerance toward the host and innocuous commensals during homeostasis. Here, we investigated how indiscriminate DNA sensors, such as cyclic GMP-AMP synthase (cGAS), make this self-nonself distinction. Screening of a small-molecule library revealed that spermine, a well-known DNA condenser associated with viral DNA, markedly elevates cGAS activation. Mechanistically, spermine condenses DNA to enhance and stabilize cGAS-DNA binding, optimizing cGAS and downstream antiviral signaling. Spermine promotes condensation of viral, but not host nucleosome, DNA. Deletion of viral DNA-associated spermine, by propagating virus in spermine-deficient cells, reduced cGAS activation. Spermine depletion subsequently attenuated cGAS-mediated antiviral and anticancer immunity. Collectively, our results reveal a pathogenic DNA-associated molecular pattern that facilitates nonself recognition, linking metabolism and pathogen recognition.

Host RNA N6-methyladenosine and incoming DNA N6-methyldeoxyadenosine modifications cooperatively elevate the condensation potential of DNA to activate immune surveillance.

Self-nonself discrimination is fundamental to life, thereby even microbes can apply DNA modifications to recognize nonself-DNA. However, mammalian cytosolic DNA sensors indiscriminately bind DNA, necessitating specific mechanism(s) for self-nonself discrimination. Here, we show that mammalian RNA N6-methyladenosine (m6A) and incoming DNA N6-methyldeoxyadenosine (6mdA) cooperatively elevate the condensation potential of DNA to activate immunosurveillance. RNA m6A modification was found to enhance the activation of cyclic GMP-AMP synthase (cGAS) via increasing DNA phase separation. And 6mdA further increased the phase separation potential of DNA. Consistently, host RNA m6A and incoming DNA 6mdA modifications cooperatively elevated the incoming DNA condensation and cGAS activation. Moreover, we developed a prodrug, QKY-613. QKY-613 promoted a discriminative incorporation of 6mdA into viral DNAs to elevate host immune surveillance, and decreased mortality in virus-infected aged mice. Our results link nucleic acid modification diversity with immune surveillance via phase separation, which might be targeted for therapeutic intervention.

[Construction and Validation of Prediction Models of Risk Factors for Early Death in Patients With Metastatic Melanoma]. / è½¬ç§»æ€§é»‘è‰²ç´ ç˜¤æ‚£è€ æ—©æœŸæ­»äº¡é£Žé™©çš„é¢„æµ‹æ¨¡åž‹æž„å»ºåŠéªŒè¯.

Objective: To construct nomogram models to predict the risk factors for early death in patients with metastatic melanoma (MM). Methods: The study covered 2138 cases from the Surveillance, Epidemiology, and End Results Program (SEER) database and all these patients were diagnosed with MM between 2010 and 2015. Logistic regression was performed to identify independent risk factors affecting early death in MM patients. These risk factors were then used to construct nomograms of all-cause early death and cancer-specific early death. The efficacy of the model was assessed with receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). In addition, external validation of the model was performed with clinicopathologic data of 105 patients diagnosed with MM at Sichuan Cancer Hospital between January 2015 and January 2020. Results: According to the results of logistic regression, marital status, the primary site, N staging, surgery, chemotherapy, bone metastases, liver metastases, lung metastases, and brain metastases could be defined as independent predictive factors for early death. Based on these factors, 2 nomograms were plotted to predict the risks of all-cause early death and cancer-specific early death, respectively. For the models for all-cause and cancer-specific early death, the areas under the curve (AUCs) for the training group were 0.751 (95% confidence interval [CI]: 0.726-0.776) and 0.740 (95% CI: 0.714-0.765), respectively. The AUCs for the internal validation group were 0.759 (95% CI: 0.722-0.797) and 0.757 (95% CI: 0.718-0.780), respectively, while the AUCs for the external validation group were 0.750 (95% CI: 0.649-0.850) and 0.741 (95% CI: 0.644-0.838), respectively. The calibration curves showed high agreement between the predicted and the observed probabilities. DCA analysis indicated high clinical application value of the models. Conclusion: The nomogram models demonstrated good performance in predicting early death in MM patients and can be used to help clinical oncologists develop more individualized treatment strategies.

Neoadjuvant sintilimab combined with chemotherapy in resectable locally advanced non-small cell lung cancer: case series and literature review.

BACKGROUND: In recent years, neoadjuvant immunotherapy with chemotherapy has shown increasing promise for locally advanced non-small cell lung cancer (NSCLC). However, to establish its clinical efficacy and safety, it is imperative to amass more real-world clinical data. This retrospective study aims to assess the safety and effectiveness of combing sintilimab, a PD-1 inhibitor, with chemotherapy as a neoadjuvant treatment modality in patients diagnosed with potentially resectable NSCLC. METHODS: We retrospectively reviewed patients with stage II-III NSCLC receiving neoadjuvant chemoimmunotherapy in Sichuan Cancer Hospital between February 2021 and February 2023. Sintilimab injection (intravenously,200 mg, iv, d1, q3w) and platinum-based chemotherapy were administered intravenously every 3 weeks, with radical lung cancer resection planned approximately 4-11 weeks after the last dose. The primary endpoint of the study was pathologic complete response (pCR). The secondary endpoints were objective response rate (ORR), and safety. RESULT: Thirteen patients were enrolled, they were mostly diagnosed with stage III NSCLC (IIB 15.4% IIIA 38.5%; IIIB 46.2%). Most of them had pathologically confirmed squamous cell carcinoma (69.2%). All patients received sintilimab combined with platinum-based chemotherapy for 2 to 4 cycles. Notably, none of the patients necessitated a reduction in initial dosages or treatment postponement due to intolerable adverse events. Then, all of them underwent surgical operation. Impressively, nine patients (69.2%) achieved a pathologic complete response. The objective response rate (ORR) stood at 46.15%. Nine patients experienced neoadjuvant treatment-related adverse events (TRAEs), with only one patient (7.6%) encountering a grade 4 neoadjuvant TRAE. CONCLUSION: Therefore, the current study suggested that neoadjuvant sintilimab plus platinum-based chemotherapy can be a safe approach in increasing the efficiency of treatment and hopefully improving the prognosis of patients with potentially resectable locally advanced NSCLC.

Carbon nitride derivatives as photocatalysts for the CO2 reduction reaction: computational study.

Photocatalytic reduction of CO2 to hydrocarbons is considered to be a promising strategy to solve the energy crisis and environmental problems. Herein, the electronic and optical properties, and catalytic performance of g-C3N4 derivatives [C6N7(C6H4)1.5]n (systems 1 and 2), and [C6N7(C12H8)1.5]n (system 3) were studied by density functional theory (DFT) computations. Compared to g-C3N4 the band gaps of systems 1-3 are smaller, and the absorption intensities of the three derivatives in the visible light region increase, indicating that these derivatives can produce more electrons under visible light irradiation and enhance the photocatalytic performance. The computational results show that the main products of CO2 reduction catalyzed by system 1 are HCOOH and CH3OH. The rate-determining step is CO2→ COOH* with a ΔG of 1.22 eV. Therefore, system 1 is predicted to be a promising catalyst for the CO2 reduction reaction.

[Short-term memory characteristics of vibro-tactile perception in human fingertips].

This paper discusses the short-term memory of vibro-tactile perception of human fingertips. By using a self-developed vibro-tactile expression device, a recall experiment was firstly carried out among 20 subjects aged 20-30 (10 males and 10 females) to discover the memory span about the vibro-tactile perception of human fingertips. Within this memory span, a cognitive experiment analyzing the recognition accuracy and the reaction time was carried out. The results showed: (1) The vibro-tactile memory span of human fingertip is 4 ± 1; (2) The vibro-tactile memory span increases as the discrete intensity between vibration stimuli increases; (3) Too long or too short vibration duration will reduce the vibro-tactile memory span, and the optimal vibration duration for men is 400 ms, for women is 300 ms; (4) The more the number of vibration stimuli is perceived by the human fingertip, the lower the recognition accuracy and the longer the reaction time it needs; (5) Compared with the vibration stimuli in disorder, people are more likely to remember the vibration stimuli in increasing/decreasing order; (6) The information extraction mechanism of the short-term memory about fingertip vibro-tactile perception bases a point to point scanning process among these stimuli. These results help to understand the human fingertip tactile characteristics and provide a physiological basis for the study of tactile feedback technologies.

Adverse childhood experiences and falls in older adults: The mediating role of depression.

OBJECTIVES: To explore the relationship between adverse childhood experiences and falls in older adults, and the mediating effects of depression on such associations. METHODS: This is a prospective study used survey data from the China Health and Retirement Longitudinal Study. Twelve expanded ACEs obtained from the 2014 Life History Survey. Depression levels were assessed using the Centre for Epidemiologic Studies Depression Scale-10. Self-reported outcomes of falling evaluated based on "Have you fallen down since the last survey?" and "How many times have you fallen down seriously enough to need medical treatment?" Logistic regression models were used to explore the relationship between ACEs with falls and recurrent falls. Poisson regression models were used to explore the relationship between ACEs and number of severe falls. Besides, mediation analysis was used to explore whether depression mediates the relationship between ACEs and falls in older adults. RESULTS: The more adverse childhood experiences experienced, the higher the risk of fall and recurrent falls, and the more severe the falls. Additionally, depression partially mediated the relationship between adverse childhood experiences and falls. Besides, middle-aged individuals were more susceptible to the impact of adverse childhood experiences on falls than older individuals, especially males. CONCLUSIONS: Exposure to adverse childhood experiences is associated with falls in older adults, and depression partially mediates this association. Middle-aged adults were more susceptible to the impact of adverse childhood experiences on falls. These offer important information for clinical practice and public health interventions to prevent falls and reduce fall-related injuries among older adults.

LncRNA-HOXC-AS2 regulates tumor-associated macrophage polarization through the STAT1/SOCS1 and STAT1/CIITA pathways to promote the progression of non-small cell lung cancer.

Tumor-associated macrophages (TAMs) mainly exhibit the characteristics of M2-type macrophages, and the regulation of TAM polarization is a new target for cancer therapy, among which lncRNAs are key regulatory molecules. This study aimed to explore the effects of lncRNA-HOXC-AS2 on non-small cell lung cancer (NSCLC) by regulating TAM polarization. THP-1 cells were used to differentiate into macrophages, and TAMs were obtained by coculture with A549 cells. The M1/M2 cell phenotype and HOXC-AS2 expression were detected, and A549-derived exosomes (A549-exo) were used to elucidate the effects of A549 on macrophage polarization and HOXC-AS2 expression. Then, by interfering with HOXC-AS2 or STAT1, the effects of HOXC-AS2 regulation of STAT1 on the TAM phenotype and STAT1/SOCS1 and STAT1/CIITA pathways were analyzed, and the proliferation and metastasis of NSCLC cells in the coculture system were also detected. Results showed that HOXC-AS2 expression in M2 macrophages and TAMs was significantly higher than that in M1 macrophages, and A549-exo promoted HOXC-AS2 expression and M2 polarization. Intervention HOXC-AS2 resulted in increased M1 marker expression, decreased M2 marker expression, and activation of STAT1/SOCS1 and STAT1/CIITA pathways in TAMs. In addition, HOXC-AS2 was mainly expressed in the cytoplasm of TAMs and could bind to STAT1. Further experiments confirmed that intervention HOXC-AS2 promoted the M1 polarization of TAMs by targeting STAT1 and weakened the promoting effects of TAMs on the proliferation and metastasis of NSCLC. In conclusion, HOXC-AS2 inhibited the activation of STAT1/SOCS1 and STAT1/CIITA pathways and promoted M2 polarization of TAMs by binding with STAT1, thus promoting NSCLC.

Risk factors and predictive models for early death in patients with advanced melanoma: A population-based study.

The prognosis for advanced melanoma (AM) is extremely poor. Some patients are already in an advanced stage at the time of their first diagnosis and face a significant risk of early death. This study predicted all-cause early death and cancer-specific early death in patients with AM by identifying independent risk factors, building 2 separate nomogram models, and validating the efficiency of the models. A total of 2138 patients diagnosed with AM from 2010 to 2015 were registered in the Surveillance, Epidemiology and End Results (SEER) database and randomly assigned to a training cohort and a validation cohort. Logistic regression models were used to identify the associated independent risk factors. These factors have also been used to build nomograms for early deaths. Next, we validated the model's predictive power by examining subject operating characteristic curves, then applied calibration curves to assess the accuracy of the models, and finally, tested the net benefit of interventions based on decision curve analysis. The results of the logistic regression model showed that marital status, primary site, histological type, N stage, surgery, chemotherapy, bone, liver, lung and brain metastases were significant independent risk factors for early death. These identified factors contributed to the creation of 2 nomograms, which predict the risk of all-cause early death and cancer-specific early death in patients with AM. In the all-cause early death model, the area under the curve was 0.751 and 0.759 for the training and validation groups, respectively, whereas in the cancer-specific early death model, the area under the curve was 0.740 and 0.757 for the training and validation groups. Calibration curves indicated a high degree of agreement between the predicted and observed probabilities, and the decision curve analysis demonstrated a high value for the model in terms of its applicability in clinical settings. These nomograms have practical applications in predicting the risk of early death in patients with AM, helping oncologists to intervene early and develop more personalized treatment strategies.

Lipocalin family proteins and their diverse roles in cardiovascular disease.

The lipocalin (LCN) family members, a group of small extracellular proteins with 160-180 amino acids in length, can be detected in all kingdoms of life from bacteria to human beings. They are characterized by low similarity of amino acid sequence but highly conserved tertiary structures with an eight-stranded antiparallel ß-barrel which forms a cup-shaped ligand binding pocket. In addition to bind small hydrophobic ligands (i.e., fatty acids, odorants, retinoids, and steroids) and transport them to specific cells, lipocalins (LCNs) can interact with specific cell membrane receptors to activate their downstream signaling pathways, and with soluble macromolecules to form the complex. Consequently, LCNs exhibit great functional diversity. Accumulating evidence has demonstrated that LCN family proteins exert multiple layers of function in the regulation of many physiological processes and human diseases (i.e., cancers, immune disorders, metabolic disease, neurological/psychiatric disorders, and cardiovascular disease). In this review, we firstly introduce the structural and sequence properties of LCNs. Next, six LCNs including apolipoprotein D (ApoD), ApoM, lipocalin 2 (LCN2), LCN10, retinol-binding protein 4 (RBP4), and Lipocalin-type prostaglandin D synthase (L-PGDS) which have been characterized so far are highlighted for their diagnostic/prognostic values and their potential effects on coronary artery disease and myocardial infarction injury. The roles of these 6 LCNs in cardiac hypertrophy, heart failure, diabetes-induced cardiac disorder, and septic cardiomyopathy are also summarized. Finally, their therapeutic potential for cardiovascular disease is discussed in each section.

Oleic Acid Dissolves cGAS-DNA Phase Separation to Inhibit Immune Surveillance.

Phase separation (PS) is a fundamental principle in diverse life processes including immunosurveillance. Despite numerous studies on PS, little is known about its dissolution. Here, it is shown that oleic acid (OA) dissolves the cyclic GMP-AMP synthase (cGAS)-deoxyribonucleic acid (DNA) PS and inhibits immune surveillance of DNA. As solvent components control PS and metabolites are abundant cellular components, it is speculated that some metabolite(s) may dissolve PS. Metabolite-screening reveals that the cGAS-DNA condensates formed via PS are markedly dissolved by long-chain fatty acids, including OA. OA revokes intracellular cGAS-PS and DNA-induced activation. OA attenuates cGAS-mediated antiviral and anticancer immunosurveillance. These results link metabolism and immunity by dissolving PS, which may be targeted for therapeutic interventions.

DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance.

DNA is well-documented to stimulate immune response. However, the nature of the DNA to activate immune surveillance is less understood. Here, we show that the activation of cyclic GMP-AMP synthase (cGAS) depends on DNA mechanical flexibility, which is controlled by DNA-sequence, -damage and -length. Consistently, DNA-sequence was shown to control cGAS activation. Structural analyses revealed that a conserved cGAS residue (mouse R222 or human R236) contributed to the DNA-flexibility detection. And the residue substitution neutralised the flexibility-controlled DNA-potential to activate cGAS, and relaxed the DNA-length specificity of cGAS. Moreover, low dose radiation was shown to mount cGAS-mediated acute immune surveillance (AIS) via repairable (reusable) DNAs in hrs. Loss of cGAS-mediated AIS decreased the regression of local and abscopal tumours in the context of focal radiation and immune checkpoint blockade. Our results build a direct link between immunosurveillance and DNA mechanical feature.

Schisandra Inhibit Bleomycin-Induced Idiopathic Pulmonary Fibrosis in Rats via Suppressing M2 Macrophage Polarization.

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause and limited to the lungs. Schisandrae chinensis fructus (Wuweizi, Schisandra) is commonly used traditional Chinese medicines (TCM) for the treatment of pulmonary fibrosis, bronchitis, and other lung diseases in China. In this study, we investigated the therapeutic effect of Schisandra on IPF which is induced by bleomycin (BLM) in rats and the inhibition of alternatively activated macrophage (M2) polarization. Bleomycin-induced pulmonary fibrosis was used as a model for IPF, and rats were given drug interventions for 7 and 28 days to evaluate the role of Schisandra in the early oxidative phase and late fibrotic phases of BLM-induced pulmonary injury. The data showed that Schisandra exerted protective effects on BLM-induced pulmonary injury in two phases, which were improving inflammatory cell infiltration and severe damages of lung architectures and decreasing markers of M2 subtype. In order to prove the inhibitory effect of Schisandra on M2 polarization, in vitro experiments, we found that Schisandra downregulated the M2 ratio, which confirmed that the polarization of M2 was suppressed. Moreover, Schisandra blocked TGF-ß1 signaling in AMs by reducing the levels of Smad3 and Smad4; meanwhile, the upregulation of Smad7 by Schisandra also promoted the effect of inhibition on the TGF-ß1/Smad pathway. These results demonstrate that suppression of M2 polarization by Schisandra is associated with the development of IPF in rats.