The innate immune system can be boosted in response to subsequent triggers by pre-exposure to microbes or microbial products, known as “trained immunity”. Compared to classical immune memory, innate trained immunity has several different features. Firstly, the molecules involved in trained immunity differ from those involved in classical immune memory. Innate trained immunity mainly involves innate immune cells (e.g., myeloid immune cells, natural killer cells, innate lymphoid cells) and their effector molecules (e.g., pattern recognition receptor (PRR), various cytokines), as well as some kinds of non-immune cells (e.g., microglial cells). Secondly, the increased responsiveness to secondary stimuli during innate trained immunity is not specific to a particular pathogen, but influences epigenetic reprogramming in the cell through signaling pathways, leading to the sustained changes in genes transcriptional process, which ultimately affects cellular physiology without permanent genetic changes (e.g., mutations or recombination). Finally, innate trained immunity relies on an altered functional state of innate immune cells that could persist for weeks to months after initial stimulus removal. An appropriate inducer could induce trained immunity in innate lymphocytes, such as exogenous stimulants (including vaccines) and endogenous stimulants, which was firstly discovered in bone marrow derived immune cells. However, mature bone marrow derived immune cells are short-lived cells, that may not be able to transmit memory phenotypes to their offspring and provide long-term protection. Therefore, trained immunity is more likely to be relied on long-lived cells, such as epithelial stem cells, mesenchymal stromal cells and non-immune cells such as fibroblasts. Epigenetic reprogramming is one of the key molecular mechanisms that induces trained immunity, including DNA modifications, non-coding RNAs, histone modifications and chromatin remodeling. In addition to epigenetic reprogramming, different cellular metabolic pathways are involved in the regulation of innate trained immunity, including aerobic glycolysis, glutamine catabolism, cholesterol metabolism and fatty acid synthesis, through a series of intracellular cascade responses triggered by the recognition of PRR specific ligands. In the view of evolutionary, trained immunity is beneficial in enhancing protection against secondary infections with an induction in the evolutionary protective process against infections. Therefore, innate trained immunity plays an important role in therapy against diseases such as tumors and infections, which has signature therapeutic effects in these diseases. In organ transplantation, trained immunity has been associated with acute rejection, which prolongs the survival of allografts. However, trained immunity is not always protective but pathological in some cases, and dysregulated trained immunity contributes to the development of inflammatory and autoimmune diseases. Trained immunity provides a novel form of immune memory, but when inappropriately activated, may lead to an attack on tissues, causing autoinflammation. In autoimmune diseases such as rheumatoid arthritis and atherosclerosis, trained immunity may lead to enhance inflammation and tissue lesion in diseased regions. In Alzheimer’s disease and Parkinson’s disease, trained immunity may lead to over-activation of microglial cells, triggering neuroinflammation even nerve injury. This paper summarizes the basis and mechanisms of innate trained immunity, including the different cell types involved, the impacts on diseases and the effects as a therapeutic strategy to provide novel ideas for different diseases.

Objective To evaluate the pharmacokinetics characteristics of single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects.Methods This was a single-center,randomized,double-blind,placebo-controlled study.Twelve healthy adult Chinese subjects were randomized to receive single-dose of Etripamil nasal spray 70 mg(n=10)or placebo nasal spray(n=2).Blood and urine samples were collected prior and post dose.Etripamil in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry.The pharmacokinetic parameters were calculated by WinNonlin non-compartmental model.Results Following the single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects,the peak concentration of Etripamil in plasma was quickly attained,with a Cmax of(66.76±56.61)ng·mL-1 and a median(range)tmax of 4.00(3.00-5.00)min.The plasma concentrations of Etripamil had fallen approximately 65％from peak value at 25 min after dosing,and close to 80％within 50 min.The AUC0-last and AUC0-∞ were(3 104.16±2 654.46)and(4 048.77±2 682.38)ng·min·mL-1,respectively.The urine excretion percentage of Etripamil during 24 h was(0.01±0.01)％.Among the 12 subjects who were treated with Etripamil or placebo,10 subjects reported a total of 29 treatment-emergent adverse events(TEAEs).All of the TEAEs were mild in severity.The most common TEAEs were rhinorrhoea and lacrimation increased.Conclusion Etripamil was quickly absorbed after intranasal administration,followed by rapid distribution and elimination(not primarily excreted by renal);Etripamil 70 mg was safe and well tolerated by the healthy Chinese adult subjects.

Objective To evaluate tolerability,safety and pharmacokinetics of JS026 and JS026-JS016 single dose intravenous infusion in healthy adults.Methods This phase 1,randomized,double-blind,placebo-controlled,dose-escalation study totally included 48 participants:32 healthy subjects were enrolled in JS026 single intravenous infusion groups and 16 healthy subjects were enrolled in JS026-JS016 groups.JS026 was sequentially administered from low dose to high dose(30-1 000 mg),with intravenous infusion of JS026 or placebo in JS026 single-dose groups,and intravenous infusion of JS026-JS016 or placebo in the combination drug groups.Blood was collected according to the time point designed for trial.Serum concentrations of JS026 and JS016 were determined by enzyme linked immunosorbnent assay(ELISA),and pharmacokinetics parameters were calculated by WinNonlin 8.2.The power model method was used to evaluate the linear analysis of dose and drug exposure.Results 47 subjects completed trial and 1 subject lost to follow-up.After a single intravenous injection of JS026 of 30 mg,100 mg,300 mg,600 mg,and 1 000 mg,mean Cmax were(9.47±1.53),(33.20±4.95),(96.10±13.70),(177.00±22.20)and(353.00±56.70)μg·mL-1,respectively;mean AUC0-∞ were(4 225.00±607.00),(1.78 × 104±3 268.00),(5.83 × 104±1 038.00),(1.07 × 105±152.00),(1.66 × 105±327.00)μg·h·mL-1,respectively;mean t1/2 of JS026 were 563-709 h.The Cmax and AUC0-∞ of JS026 were basically similar alone or in combination with JS016.The results of Power model showed that Cmax and AUC0-∞ increased approximately linearly with the increasing dose of JS026.Treatment emergent adverse event was not increasing when dose increased and most of adverse event associated with drugs were abnormal on laboratory tests and haematuria,thus JS026 and JS016 was well tolerated in all groups.Conclusion The single intravenous infusion of JS026 can almost be thought to be a linear relationship between the doses and drug serum exposure.JS016 had no significant effect on serum concentration of JS026 and JS026 was well tolerated and safe in healthy subjects within 30-1 000 mg.

Objective To investigate the clinical value of coronary computed tomography angiography(CCTA)based CT derived fractional flow reserve(CT-FFR)and ΔCT-FFR in improving the diagnostic efficiency for coronary abnormal hemodynamics in patients with severe calcification.Methods We retrospectively analyzed the clinical data of coronary artery disease(CAD)patients who underwent CCTA,CT-FFR,invasive coronary angiography(ICA)and FFR during hospitalization from January 2018 to June 2019 in Chinese PLA General Hospital.Severe calcification was defined as coronary artery calcium score(CACS)≥100 on single vessel level.A total of 107 CAD patients with 149 coronary arteries were included in the present study.The enrolled coronary arteries were assigned to CACS≥100 group(n=56)and CACS<100 group(n=93).CT-FFR was performed on the deep FFR platform based on machine learning(ML)algorithms and ΔCT-FFR was defined as CT-FFR difference between proximal and distal to the coronary lesion.The correlation and consistency between CT-FFR and FFR values were analyzed by Pearson and Bland-Altman methods.We attempted to analyze the incremental value of ΔCT-FFR for coronary functional evaluation,especial for coronary arteries with severe calcification,regarding FFR≤0.8 as the diagnostic gold standard.Comparison of receiver operating characteristic curves(ROC)between different diagnostic methods was presented by Delong test.Results Pearson and Bland-Altman analyses showed appreciable correlation(CACS≥100 group,r=0.71,P<0.01;CACS<100 group,r=0.73,P<0.01)and consistency(CACS≥100 group,Mean=-0.01,P=0.25;CACS<100 group,Mean=0,P=0.96)between CT-FFR and FFR values in both groups.FFR(0.80±0.08 vs.0.84±0.09,P=0.004)and CT-FFR(0.81±0.06 vs.0.85±0.06,P<0.001)levels were significant lower in CACS≥100 group than those in CACS<100 group,while ΔCT-FFR(0.14±0.06 vs.0.09±0.06,P<0.001)levels were significant higher in CACS≥100 group.Moreover,the diagnostic efficiency of CT-FFR in CACS≥100 group was inferior to that in CACS<100 group[AUC=0.792(95%CI 0.663-0.889)vs.AUC=0.929(95%CI 0.856-0.972),P=0.04],while it achieved significant improvement after ΔCT-FFR adjustment[AUC=0.876(95%CI 0.760-0.949)vs.AUC=0.792(95%CI 0.663-0.889),P=0.02]and was similar to that in CACS<100 group(P=0.37).Conclusion For coronary arteries with severe calcification,CT-FFR demonstrated significant incremental value in improving the diagnostic efficiency of coronary abnormal hemodynamics after ΔCT-FFR adjustment.

There are huge differences between tumor cells and normal cells in material metabolism, and tumor cells mainly show increased anabolism, decreased catabolism, and imbalance in substance metabolism. These differences provide the necessary material basis for the growth and reproduction of tumor cells, and also provide important targets for the treatment of tumors. Ferroptosis is an iron-dependent form of cell death characterized by an imbalance of iron-dependent lipid peroxidation and lipid membrane antioxidant systems in cells, resulting in excessive accumulation of lipid peroxide, causing damage to lipid membrane structure and loss of function, and ultimately cell death. The regulation of ferroptosis involves a variety of metabolic pathways, including glucose metabolism, lipid metabolism, amino acid metabolism, nucleotide metabolism and iron metabolism. In order for tumor cells to grow rapidly, their metabolic needs are more vigorous than those of normal cells. Tumor cells are metabolically reprogrammed to meet their rapidly proliferating material and energy needs. Metabolic reprogramming is mainly manifested in glycolysis and enhancement of pentose phosphate pathway, enhanced glutamine metabolism, increased nucleic acid synthesis, and iron metabolism tends to retain more intracellular iron. Metabolic reprogramming is accompanied by the production of reactive oxygen species and the activation of the antioxidant system. The state of high oxidative stress makes tumor cells more susceptible to redox imbalances, causing intracellular lipid peroxidation, which ultimately leads to ferroptosis. Therefore, in-depth study of the molecular mechanism and metabolic basis of ferroptosis is conducive to the development of new therapies to induce ferroptosis in cancer treatment. Ferroptosis, as a regulated form of cell death, can induce ferroptosis in tumor cells by pharmacologically or genetically targeting the metabolism of substances in tumor cells, which has great potential value in tumor treatment. This article summarizes the effects of cellular metabolism on ferroptosis in order to find new targets for tumor treatment and provide new ideas for clinical treatment.

Objective:To investigate the safety of early antiplatelet therapy for non-cardioembolic mild stroke patients with thrombocytopenia.Methods:Data of acute ischemic stroke patients with baseline National Institutes of Health Stroke Scale(NIHSS)score≤3 and a platelet count<100×109/L were obtained from a multicenter register.Those who required anticoagulation or had other contraindications to antiplatelet therapy were excluded.Short-term safety outcomes were in-hospital bleeding events,while the long-term safety outcome was a 1-year all-cause death.The short-term neurological outcomes were evaluated by modified Rankin scale(mRS)score at discharge.Results:A total of 1868 non-cardioembolic mild stroke patients with thrombocytopenia were enrolled.Multivariate regression analyses showed that mono-antiplatelet therapy significantly increased the proportion of mRS score of 0-1 at discharge(OR=1.657,95%CI:1.253-2.192,P<0.01)and did not increase the risk of intracranial hemorrhage(OR=2.359,95%CI:0.301-18.503,P>0.05),compared with those without antiplatelet therapy.However,dual-antiplatelet therapy did not bring more neurological benefits(OR=0.923,95%CI:0.690-1.234,P>0.05),but increased the risk of gastrointestinal bleeding(OR= 2.837,95%CI:1.311-6.136,P<0.01)compared with those with mono-antiplatelet therapy.For patients with platelet counts≤75×109/L and>90×109/L,antiplatelet therapy significantly improved neurological functional outcomes(both P<0.05).For those with platelet counts(>75-90)×109/L,antiplatelet therapy resulted in a significant improvement of 1-year survival(P<0.05).For patients even with concurrent coagulation abnormalities,mono-antiplatelet therapy did not increase the risk of various types of bleeding(all P>0.05)but improved neurological functional outcomes(all P<0.01).There was no significant difference in the occurrence of bleeding events,1-year all-cause mortality risk,and neurological functional outcomes between aspirin and clopidogrel(all P>0.05).Conclusions:For non-cardioembolic mild stroke patients with thrombocytopenia,antiplatelet therapy remains a reasonable choice.Mono-antiplatelet therapy has the same efficiency as dual-antiplatelet therapy in neurological outcome improvement with lower risk of gastrointestinal bleeding.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective Mobile artificial lumbar complex(MALC)which suitable for reconstruction after subtotal lumbar resection in goats was developed,and to test stability of the complex and postoperative lumbar segmental motor function.Methods Eighteen male boer goats aged from 1 to 2 years old(weighted from 35 to 45 kg)were selected and divided into con-trol group,fusion group and non-fusion group,with 6 goats in each group.According to preoperative CT scans and MRI exami-nations of lumbar,the goat MALC was designed and performed by 3D printed for non-fusion group.Operation was performed on three groups respectively,and only vertebral body and disc were exposed in control group.In fusion group,L4 part of vertebral body and the upper and lower complete disc tissues were removed,and the lumbar spine bone plate fixation was performed with titanium mesh bone grafting.In non-fusion group,vertebral body and disc were removed in the same way,and MALC was im-planted.AP and lateral X-rays of lumbar vertebrae in goat were taken at 6 months after surgery,in order to understand whether the plant was dislocated,displaced and fractured.Biomechanical tests were performed on the specimens by mechanical instru-ment to measure range of motion(ROM)of L2,3,L,4,L4,5intervertebral space and the overall ROM of L2-5 lumbar vertebrae.Results MALC of lumbar vertebra was designed by 3D printing,and its component artificial vertebrae and upper and lower ar-tificial end plates were manufactured.The semi-spherical structure was fabricated by precision lathe using high-crosslinked polyethylene material,and the prosthesis was assembled.Postoperative AP and lateral X-rays of lumbar vertebra at 6 months showed the implant position of implant and MALC were good without displacement and dislocation.In vitro biomechanical test of lumbar vertebrae specimens:(1)There were no statistical significance in ROM of lumbar intervertebral space flexion and extension,lateral flexion and rotation on L.4 and L4,5,between non-fusion group and control group(P＞0.05),while ROM of fu-sion group was significantly reduced compared with the other two groups(P＜0.05).There were no significant difference in ROM of L2.3 intervertebral flexion and extension,lateral flexion and rotation between non-fusion group and control group(P＞0.05),while fusion group was significantly increased compared with the other two groups(P＜0.001).(2)There was no signifi-cant difference in overall lumbar ROM of L2-5(P＞0.05).Conclusion The individual MALC could restore intervertebral height of lumbar vertebra while maintaining the stability of lumbar vertebra and re-establishing motor function of lumbar space.

Objective To explore mechanism of piracetam for the treatment of spinal cord injury in rats through mitogen-activated protein kinase(MAPK)pathway.Methods Fifty-four healthy 6-week-old SD female rats with body weight of 80 to 100 g were divided into sham operation group,spinal cord injury group and piracetam group by random number table method,with 18 rats in each group.Spinal cord injury model was established in spinal cord injury group and piracetam group using percussion apparatus,while sham operation group did not damage spinal cord.Piracetam group was injected with pirac-etam injection through tail vein according to 5 ml·kg-1 standard,once a day for 3 days;the other two groups were injected with normal saline at the same dose,the same frequency and the same duration.The rats were sacrificed at 1,3,and 7 days after surgery,and changes of Basso,Beattie and Bresnahan(BBB)locomotor rating scale was observed and compared.Enzyme-linked immunosorbent assay(ELISA)was used to detect spinal cord inflammatory factors,such as interleukin-6(IL-6),in-terleukin-10(IL-10),interleukin-1β(interleukin-1β),necrosis factor-α(IL-1β)and tumor necrosis factor-α(TNF-α);HE staining was used to observe morphological changes of rats with spinal cord injury,and immunohistochemistry was used to observe expression level of aquaporin 4(AQP4).The activation of MAPK signaling pathway in spinal cord of rats after spinal cord injury was observed by western blotting(WB).Results BBB scores of sham operation group on 1,3 and 7 day were 21 points.In spinal cord injury group,the scores were(1±1),(4±1)and(7±2);piracetam group was(1±1),(5±1),(9±2),re-spectively;the difference between spinal cord injury group and sham operation group was statistically significant(P＜0.05).HE staining showed that no abnormality was found in sham operation group.In spinal cord injury group,bleeding and degeneration of spinal cord tissue appeared at 1 day after operation;flaky necrotic areas were appeared in spinal cord at 3 days after surgery,and spinal cord tissue began to slowly repair at 7 days after surgery.In piracetam group,the bleeding area was less than that of spinal cord injury group at 1 day after surgery;at 3 days after operation,the necrotic area was reduced and the range of nuclear disappearance was reduced;and the spinal cord began to recover slowly at 7 days after surgery.AQP4 staining of spinal cord of rats in sham operation group was weak at 1,3 and 7 days after modeling,AQP4 staining was deepened and area increased in spinal cord injury group,AQP4 staining of piracetam group was lighter than that of spinal cord injury group,and the positive cells were slightly increased and the staining was slightly darker than that of sham operation group.At 1,3 and 7 days,the level of IL-6,IL-10,IL-1β and TNF-α in spinal cord injury group were higher than those in sham operation group and piracetam group(P＜0.05).Compared with spinal cord injury group,the area of spinal cord bleeding and necrosis were de-creased by HE staining in piracetam group,and AQP4 staining was decreased by immunohistochemistry.WB results showed that P-ERK,P-JNK and P-P38 levels in spinal cord injury group at 3 days were higher than those in sham operation group and piracetam group(P＜0.05).Conclusion Piracetam not only showed significant effect in promoting motor function recovery after spinal cord injury,but also showed positive therapeutic potential in reducing lesion area,regulating AQP4 expression to reduce edema,and reducing inflammatory response by regulating MAPK signaling pathway.

Objective To observe the value of feature pyramid network(FPN)for automatic segmentation and semantic feature classification of spontaneous intracerebral hemorrhage(sICH)hematoma showed on non-contrast CT.Methods Non-contrast CT images of 408 sICH patients in hospital A(training set)and 103 sICH patients in hospital B(validation set)were retrospectively analyzed.Deep learning(DL)segmentation model was constructed based on FPN to segment the hematoma region,and its efficacy was assessed using intersection over union(IoU),Dice similarity coefficient(DSC)and accuracy.Then DL classification model was established to identify the semantic features of sICH hematoma.Receiver operating characteristic curves were drawn,and the area under the curves(AUC)were calculated to evaluate the efficacy of DL classification model for recognizing semantic features of sICH hematoma.Results The IoU,DSC and accuracy of DL segmentation model for 95％sICH hematoma in training set was 0.84±0.07,0.91±0.04 and(88.78±8.04)％,respectively,which was 0.83±0.07,0.91±0.05 and(88.59±7.76)％in validation set,respectively.The AUC of DL classification model for recognizing irregular shape,uneven density,satellite sign,mixed sign and vortex sign of sICH hematoma were 0.946-0.993 and 0.714-0.833 in training set and validation set,respectively.Conclusions FPN could accurately,effectively and automatically segment hematoma of sICH,hence having high efficacy for identifying semantic features of sICH hematoma.