Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary ß-glucan-induced inflammatory adaptation.

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages' functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal ß-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, ß-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.

Viruses inhibit TIR gcADPR signalling to overcome bacterial defence.

The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants and animals1-3. In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signalling molecule whose molecular structure remains elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function1. We identified a large family of phage-encoded proteins, denoted here as Thoeris anti-defence 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are 'sponges' that bind and sequester the immune signalling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. Tad1 can also efficiently sequester molecules derived from a plant TIR-domain protein, and a high-resolution crystal structure of Tad1 bound to a plant-derived molecule showed a unique chemical structure of 1 ''-2' glycocyclic ADPR (gcADPR). Our data furthermore suggest that Thoeris TIR proteins produce a closely related molecule, 1''-3' gcADPR, which activates ThsA an order of magnitude more efficiently than the plant-derived 1''-2' gcADPR. Our results define the chemical structure of a central immune signalling molecule and show a new mode of action by which pathogens can suppress host immunity.

Limits on gas impermeability of graphene.

Despite being only one-atom thick, defect-free graphene is considered to be completely impermeable to all gases and liquids1-10. This conclusion is based on theory3-8 and supported by experiments1,9,10 that could not detect gas permeation through micrometre-size membranes within a detection limit of 105 to 106 atoms per second. Here, using small monocrystalline containers tightly sealed with graphene, we show that defect-free graphene is impermeable with an accuracy of eight to nine orders of magnitude higher than in the previous experiments. We are capable of discerning (but did not observe) permeation of just a few helium atoms per hour, and this detection limit is also valid for all other gases tested (neon, nitrogen, oxygen, argon, krypton and xenon), except for hydrogen. Hydrogen shows noticeable permeation, even though its molecule is larger than helium and should experience a higher energy barrier. This puzzling observation is attributed to a two-stage process that involves dissociation of molecular hydrogen at catalytically active graphene ripples, followed by adsorbed atoms flipping to the other side of the graphene sheet with a relatively low activation energy of about 1.0 electronvolt, a value close to that previously reported for proton transport11,12. Our work provides a key reference for the impermeability of two-dimensional materials and is important from a fundamental perspective and for their potential applications.

Huayu Qutan Recipe promotes lipophagy and cholesterol efflux through the mTORC1/TFEB/ABCA1-SCARB1 signal axis.

This study aims to investigate the mechanism of the anti-atherosclerosis effect of Huayu Qutan Recipe (HYQT) on the inhibition of foam cell formation. In vivo, the mice were randomly divided into three groups: CTRL group, MOD group and HYQT group. The HYQT group received HYQT oral administration twice a day (20.54 g/kg/d), and the plaque formation in ApoE-/- mice was observed using haematoxylin-eosin (HE) staining and oil red O (ORO) staining. The co-localization of aortic macrophages and lipid droplets (LDs) was examined using fluorescent labelling of CD11b and BODIPY fluorescence probe. In vitro, RAW 264.7 cells were exposed to 50 µg/mL ox-LDL for 48 h and then treated with HYQT for 24 h. The accumulation of LDs was evaluated using ORO and BODIPY. Cell viability was assessed using the CCK-8 assay. The co-localization of LC3b and BODIPY was detected via immunofluorescence and fluorescence probe. LysoTracker Red and BODIPY 493/503 were used as markers for lysosomes and LDs, respectively. Autophagosome formation were observed via transmission electron microscopy. The levels of LC3A/B II/LC3A/B I, p-mTOR/mTOR, p-4EBP1/4EBP1, p-P70S6K/P70S6K and TFEB protein level were examined via western blotting, while SQSTM1/p62, Beclin1, ABCA1, ABCG1 and SCARB1 were examined via qRT-PCR and western blotting. The nuclear translocation of TFEB was detected using immunofluorescence. The components of HYQT medicated serum were determined using Q-Orbitrap high-resolution MS analysis. Molecular docking was employed to identify the components of HYQT medicated serum responsible for the mTOR signalling pathway. The mechanism of taurine was illustrated. HYQT has a remarkable effect on atherosclerotic plaque formation and blood lipid level in ApoE-/- mice. HYQT decreased the co-localization of CD11b and BODIPY. HYQT (10% medicated serum) reduced the LDs accumulation in RAW 264.7 cells. HYQT and RAPA (rapamycin, a mTOR inhibitor) could promote cholesterol efflux, while chloroquine (CQ, an autophagy inhibitor) weakened the effect of HYQT. Moreover, MHY1485 (a mTOR agonist) also mitigated the effects of HYQT by reduced cholesterol efflux. qRT-PCR and WB results suggested that HYQT improved the expression of the proteins ABCA1, ABCG1 and SCARB1.HYQT regulates ABCA1 and SCARB1 protein depending on the mTORC1/TFEB signalling pathway. However, the activation of ABCG1 does not depend on this pathway. Q-Orbitrap high-resolution MS analysis results demonstrated that seven core compounds have good binding ability to the mTOR protein. Taurine may play an important role in the mechanism regulation. HYQT may reduce cardiovascular risk by promoting cholesterol efflux and degrading macrophage-derived foam cell formation. It has been observed that HYQT and ox-LDL regulate lipophagy through the mTOR/TFEB signalling pathway, rather than the mTOR/4EBP1/P70S6K pathway. Additionally, HYQT is found to regulate cholesterol efflux through the mTORC1/TFEB/ABCA1-SCARB1 signal axis, while taurine plays a significant role in lipophagy.

A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL.

The bispecific T-cell engager (BiTE) blinatumomab against CD19 and CD3 has emerged as the most successful bispecific antibody (bsAb) to date; however, a significant proportion of patients do not respond to the treatments or eventually experience relapse after an initial response, and the recurrence rate increases significantly due to escape or downregulation of the CD19 antigen. To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19/CD22/CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19/CD22/CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell-specific cytotoxicity and cytokine production against CD19+ and/or CD22+ tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell-redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.

Diagnostic performance of transvaginal sonography vs. magnetic resonance imaging for rectovaginal septum deep infiltrating endometriosis: a head-to-head comparative meta-analysis.

AIM: We aimed to compare the diagnostic performance of transvaginal sonography (TVS) versus magnetic resonance imaging (MRI) in identifying deep infiltrating endometriosis (DIE) in the rectovaginal septum (RVS) of affected patients. MATERIALS AND METHODS: An extensive search was conducted in the PubMed, Embase databases to identify available publications up to November 2023. Studies evaluating the diagnostic perfor-mance of TVS and MRI for DIE in patients with rectovaginal septum involvement were all included. Sensitivity and specificity analyses employed the DerSi-monian and Laird method, complemented by the Freeman-Tukey double arc-sine trans-formation. Additionally, the study quality was rigorously evaluated using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) method. RESULTS: The meta-analysis encompassed 8 articles with a total of 721 patients. It revealed that the overall sensitivity of TVS was 0.51 (95% CI: 0.31-0.72), contrasted with 0.74 (95% CI: 0.66-0.82) for MRI. This finding suggests a higher sensitivity of MRI compared to TVS (P=0.04). Conversely, the overall specificity was 0.97 (95%CI: 0.94-1.00) for TVS and 0.93 (95% CI: 0.84-0.99) for MRI, indicating a comparable level of specificity between the two modalities (P=0.22). CONCLUSION: Our meta-analysis reveals that MRI exhibits higher sensitivity and comparable specificity to TVS in patients with DIE of the RVS. However, the limited number of articles included may affect the evidence of these results. Therefore, further d number of articles included may affect the evidence of these results. Therefore, further research with larger sample sizes and prospective designs is essential to validate these findings.

Association between infarct location and haemorrhagic transformation of acute ischaemic stroke after intravenous thrombolysis.

AIM: To evaluate the association between computed tomography (CT)-based imaging variables at the time of admission and haemorrhagic transformation (HT) after intravenous thrombolysis (IVT). MATERIALS AND METHODS: One hundred and eight patients who were treated with IVT for acute ischaemic stroke (AIS) during January 2021 to July 2023 were analysed retrospectively. The infarct location was classified as cortical or subcortical in accordance with the Alberta Stroke Program Early CT Score (ASPECTS) system. Logistic regression and receiver operating characteristic curve analyses were performed to determine the relationship between ischaemic variables and HT. RESULTS: Of the total, 18 (16.7%) patients had HT and seven (6.5%) had symptomatic intracerebral haemorrhage (sICH). Multivariate analysis revealed that cortical ASPECTS was independently associated with HT (odds ratio [OR], 0.197; 95% confidence interval [CI], 0.076-0.511; p=0.001) and cortical ASPECTS was independently associated with sICH (OR, 0.066; 95% CI, 0.009-0.510; p=0.009). To predict HT and sICH, cortical ASPECTS (HT area under the curve [AUC] = 0.881, sICH AUC = 0.971) provided a higher AUC compared with ASPECTS (HT AUC = 0.850, sICH AUC = 0.918). CONCLUSION: Cortical ASPECTS seen on CT at the time of admission is associated with HT and sICH after IVT.

HMGN1 down-regulation in the diabetic kidney attenuates tubular cells injury and protects against renal inflammation via suppressing MCP-1 and KIM-1 expression through TLR4.

BACKGROUND: Renal tubular injury, accompanied by damaging inflammation, has been identified to drive diabetic kidney disease (DKD) toward end-stage renal disease. However, it is unclear how damage-associated molecular patterns (DAMPs) activate innate immunity to mediate tubular epithelial cell (TEC) injury, which in turn causes with subsequent sterile inflammation in diabetic kidneys. High mobility group nucleosome-binding protein 1 (HMGN1) is a novel DAMP that contributes to generating the innate immune response. In this study, we focused on determining whether HMGN1 is involved in DKD progression. METHODS: Streptozotocin (STZ)-induced diabetic mice model was established. Then we downrergulated HMGN1 expression in kidney with or without HMGN1 administration. The renal dysfunction and morphological lesions in the kidneys were evaluated. The expressions of KIM-1, MCP-1, F4/80, CD68, and HMGN1/TLR4 signaling were examined in the renal tissue. In vitro, HK2 cells were exposed in the high glucose with or without HMGN1, and further pre-incubated with TAK242 was applied to elucidate the underlying mechanism. RESULTS: We demonstrated that HMGN1 was upregulated in the tubular epithelial cells of streptozotocin (STZ)-induced type 1 and type 2 diabetic mouse kidneys compared to controls, while being positively correlated with increased TLR4, KIM-1, and MCP-1. Down-regulation of renal HMGN1 attenuated diabetic kidney injury, decreased the TLR4, KIM-1, and MCP-1 expression levels, and reduced interstitial infiltrating macrophages. However, these phenotypes were reversed after administration of HMGN1. In HK-2 cells, HMGN1 promoted the expression of KIM-1 and MCP-1 via regulating MyD88/NF-κB pathway; inhibition of TLR4 effectively diminished the in vitro response to HMGN1. CONCLUSIONS: Our study provides novel insight into HMGN1 signaling mechanisms that contribute to tubular sterile injury and low-grade inflammation in DKD. The study findings may help to develop new HMGN1-targeted approaches as therapy for immune-mediated kidney damage rather than as an anti-infection treatments.

Resistance to a CRISPR-based gene drive at an evolutionarily conserved site is revealed by mimicking genotype fixation.

CRISPR-based homing gene drives can be designed to disrupt essential genes whilst biasing their own inheritance, leading to suppression of mosquito populations in the laboratory. This class of gene drives relies on CRISPR-Cas9 cleavage of a target sequence and copying ('homing') therein of the gene drive element from the homologous chromosome. However, target site mutations that are resistant to cleavage yet maintain the function of the essential gene are expected to be strongly selected for. Targeting functionally constrained regions where mutations are not easily tolerated should lower the probability of resistance. Evolutionary conservation at the sequence level is often a reliable indicator of functional constraint, though the actual level of underlying constraint between one conserved sequence and another can vary widely. Here we generated a novel adult lethal gene drive (ALGD) in the malaria vector Anopheles gambiae, targeting an ultra-conserved target site in a haplosufficient essential gene (AGAP029113) required during mosquito development, which fulfils many of the criteria for the target of a population suppression gene drive. We then designed a selection regime to experimentally assess the likelihood of generation and subsequent selection of gene drive resistant mutations at its target site. We simulated, in a caged population, a scenario where the gene drive was approaching fixation, where selection for resistance is expected to be strongest. Continuous sampling of the target locus revealed that a single, restorative, in-frame nucleotide substitution was selected. Our findings show that ultra-conservation alone need not be predictive of a site that is refractory to target site resistance. Our strategy to evaluate resistance in vivo could help to validate candidate gene drive targets for their resilience to resistance and help to improve predictions of the invasion dynamics of gene drives in field populations.

Effects of weaning and inactivated Lactobacillus helveticus supplementation on dairy calf behavioral and physiological indicators of affective state.

The objectives of this study were to determine if weaning would induce behavioral and physiological indicators of a negative affective state, and if supplementation of inactivated Lactobacillus helveticus (ILH) to dairy calves would reduce those indicators of negative affect during weaning. Male Holstein calves (n = 23) were enrolled in the study on d 1 of life. The calves were housed in individual pens in 1 of 4 rooms for the 42 d study. Calves began a stepdown weaning from 9 L/d of milk replacer (MR), at 150 g of MR powder/L, on d 35 and received 6 L/d on d 35 - 36, 3 L/d on d 37 - 38, and 0.4 L/d on d 39 - 42. The MR was divided between 3 meals/d until the last 0.4 L/d phase which was divided between 2 meals/d. Calves had ad libitum water access throughout the study and calf starter from d 28 onwards. Within room, calves were assigned to 1 of 2 treatments: 1) control (CON; n = 11) and 2) 5 g of ILH/d split over and mixed into the 0800 h and 2000 h milk feedings from d 3-42 (ILH; n = 12). Lying behavior was recorded using HOBO data loggers from d 21-41. On d 33, 37 and 41, infrared eye images were taken to determine maximum eye temperature (MET), saliva samples were collected to determine cortisol concentration, and play assessments were conducted to quantify play behavior. On d 34, 38, and 42, blood samples were collected to determine blood serotonin concentration, whereas on d 38 and 39, calves were tested with a cognitive task. A subset of calves (n = 5/treatment) were euthanized to collect gut and brain tissue samples for serotonin concentration on d 43. Weaning resulted in fewer (d 37-41, tendency: d 36), but longer (d 38-41, tendency: d 37), lying bouts and reduced play (d 41), although no changes in lying time, MET, saliva cortisol, nor blood serotonin were detected with initiation of weaning. Supplementation of ILH was associated with lower lying time throughout the study, and reduced play duration and higher salivary cortisol and MET during weaning. No differences in lying bouts, play count, blood and tissue (colon, ileum, prefrontal cortex and brain stem) serotonin concentration, and time to complete the cognitive task were detected between the treatments. Overall, weaning induced behavioral changes indicative of negative affective state, and some behavioral differences were observed with ILH supplementation both before and during weaning, with some physiological changes observed during weaning.

Socio-economic factors and medical conditions affecting regular stomach cancer screening in Korea: a retrospective longitudinal study using national public health data for 11 years.

OBJECTIVE: This study aimed to explore socio-economic factors and medical conditions that affect regular stomach cancer (SC) screening among Korean adults. STUDY DESIGN: This was a retrospective observational study. METHODS: Study subjects were 5545 adults aged ≥40 years who participated in the 2007-2012 Korean National Health and Nutrition Examination Survey and were followed up to year 2017 based on data linking to the Korean National Health Insurance Service and Korean Health Insurance Review and Assessment. Socio-economic factors included sex, age, residential area, education, occupation, marital status, disability, public and private health insurance, service through local public health organizations, history of cancer except for SC, and family history of SC. Medical factors included six gastric lesions with the possibility of facilitating SC screening, including benign gastric neoplasm, chronic atrophic gastritis, gastric polyp, Helicobacter pylori infection, intestinal metaplasia, and peptic ulcers. The outcome was adherence to SC screening, which was divided into non-adherence, irregular adherence, and regular adherence. RESULTS: After adjusting for the effects of socio-economic factors, multivariate ordinal logistic regression revealed that participants with a history of four types of gastric lesions were more likely to regularly participate in SC screening: chronic atrophic gastritis (odds ratio [OR] 1.567; 95% confidence interval [CI] = 1.276-1.923), gastric polyps (OR 1.565; 95% CI = 1.223-2.003), H. pylori infection (OR 1.637; 95% CI = 1.338-2.003), and peptic ulcer (OR 2.226; 95% CI 1.750-2.831). CONCLUSIONS: To improve participation in SC screening, it is necessary to implement personalized strategies for individuals at risk for gastric cancer in addition to population-based strategies for vulnerable groups.

Vegetation-fire feedbacks increase subtropical wildfire risk in scrubland and reduce it in forests.

Climate dictates wildfire activity around the world. But East and Southeast Asia are an apparent exception as fire-activity variation there is unrelated to climatic variables. In subtropical China, fire activity decreased by 80% between 2003 and 2020 amid increased fire risks globally. Here, we assessed the fire regime, vegetation structure, fuel flammability and their interactions across subtropical Hubei, China. We show that tree basal area (TBA) and fuel flammability explained 60% of fire-frequency variance. Fire frequency and fuel flammability, in turn, explained 90% of TBA variance. These results reveal a novel system of scrubland-forest stabilized by vegetation-fire feedbacks. Frequent fires promote the persistence of derelict scrubland through positive vegetation-fire feedbacks; in forest, vegetation-fire feedbacks are negative and suppress fire. Thus, we attribute the decrease in wildfire activity to reforestation programs that concurrently increase forest coverage and foster negative vegetation-fire feedbacks that suppress wildfire.

In ovo injection of AZD6244 suppresses feather follicle development by the inhibition of ERK and Wnt/ß-catenin pathways in goose embryos (Anser cygnoides).

1. Feathers are an important product from poultry, and the state of feather growth and development plays an important role in their economic value.2. In total, 120 eggs were selected for immunoblotting and immunolocalisation experiments of ERK and ß-catenin proteins in different developmental stages of goose embryos. The ERK protein was highly expressed in the early stage of goose embryo development, while ß-catenin protein was highly expressed in the middle stage of embryo development.3. The 120 eggs were divided into four treatment groups, including an uninjected group (BLANK), a group injected with 100 µl of cosolvent (CK), a group injected with 100 µl of AZD6244 containing cosolvent in a dose of 5 mg/kg AZD6244 containing cosolvent (AZD5) and a group injected with 100 µl of AZD6244 containing cosolvent in a dose of 15 mg/kg AZD6244 containing cosolvent (AZD15). The eggs were injected on the ninth day of embryonic development (E9). Samples were collected at E21.5 to observe feather width, feather follicle diameter, ERK and Wnt/ß-catenin pathway protein expression.4. The AZD5 and AZD15 doses were within the embryonic safety range compared to the BLANK and CK groups and had no significant effect on the survival rate and weight at the inflection point, but significantly reduced the feather width and feather follicle diameter (p < 0.05). The AZD6244 treatment inhibited ERK protein phosphorylation levels and blocked the Wnt/ß-catenin pathway, which in turn significantly down-regulated the expression levels of FZD4, ß-catenin, TCF4 and LEF1 (p < 0.05), with an inhibitory effect in the AZD15 group being more significant. The immunohistochemical results of ß-catenin and p-ERK were consistent with Western blot results.5. The small molecule inhibitor AZD6244 regulated the growth and development of feather follicles in goose embryos by the ERK and Wnt/ß-catenin pathways.

[Application of super-resolution and ultrafast ultrasound to reveal the characteristics of vascular blood flow changes after rat spinal cord injury at different segments].

Objective: To investigate the changes of spinal vascular blood flow in SD rats after cervical, thoracic and lumbar spinal cord injury (SCI) using super-resolution ultrafast ultrasound technology. Methods: A total of 9 SD rats were used to construct SCI models at different segments using a 50 g aneurysm clip. Super-resolution ultrafast ultrasound technology was used to perform vascular blood flow imaging on the spinal cord of rats before and after injury at 6 hours, obtaining quantitative information such as spinal cord vascular density and blood flow velocity. Results: Ultrasound imaging showed that after SCI, the vascular density in the thoracic segment decreased (18.16%±1.04%) more than in the cervical segment (11.42%±1.39%) and lumbar segment (13.88%±1.43%, both P<0.05). The length of the spinal cord with decreased vascular density in the thoracic segment [(4.80±0.34)mm] was longer than that in the cervical segment [(2.80±0.57)mm] and lumbar segment [(3.10±0.36)mm, both P<0.05]. After injury, the decrease of blood flow in the thoracic segment [(8.87±0.85)ml/min] was higher than that in the cervical segment [(4.88±0.56)ml/min] and lumbar segment [(6.19±0.71)ml/min, both P<0.05]. HE staining and Nissl staining showed that the proportion of cavity area after thoracic SCI (11.53%±0.93%) was higher than that in the cervical segment (4.90%±1.72%) and lumbar segment (7.64%±0.84%, both P<0.05). The number of Nissl bodies in the thoracic segment (18.0±5.3) was also lower than that in the cervical segment (32.3±5.1) and lumbar segment (37.0±5.6) (both P<0.05). Conclusions: There are different changes in vascular blood flow after SCI in different segments of rats. The same injury causes the most severe damage to blood vessels in the thoracic spinal cord, followed by the lumbar spinal cord, and the cervical spinal cord has the least damage.

[Efficacy of venetoclax-based induction regimen in newly diagnosed pediatric acute myeloid leukemia].

Objective: To explore the efficacy of venetoclax-based induction regimen for children with newly diagnosed acute myeloid leukemia (AML). Methods: Children with newly diagnosed AML in Beijing Children's Hospital Affiliated to Capital Medical University and Baoding Hospital Affliliated to Capital Medical University from November 2019 and December 2023 were prospectively included. The patients were divided into DAH group (daunorubicin, cytarabine and homoharringtonine) and VAH group (venetoclax, cytarabine and homoharringtonine) according to induction regimen. The clinical data of the children were collected, the clinical characteristics and induced remission rate between the two groups were compared, and multivariate logistic regression was used to analyze the related factors affecting the induced remission rate. Results: A total of 135 patients were enrolled, including 96 cases in the DAH group (54 males and 42 females), aged [M (Q1, Q3)] 6.4 (3.9, 11.6) years and 39 cases in the VAH group (26 males and 13 females), aged 8.0 (6.2, 13.2) years. Among patients initially diagnosed with low-medium risk AML, the morphologic complete remission rates were 94.7% (18/19) in the VAH group and 84.4% (38/45) in the DAH group, respectively, and the negativity conversion rates of minirnal residual disease (MRD) were 57.9% (11/19) and 46.7% (21/45), respectively, with no statistically difference (all P>0.05). Among patients initially diagnoised with high-risk AML, the morphologic complete remission rates in the VAH group was higher than that in the DAH group [95.0% (19/20) vs 70.6% (36/51), P=0.027], and negativity conversion rates of MRD were 45.0% (9/20) and 33.3% (17/51), respectively, with no statistically difference (P=0.359). The induction regimen (venetoclax, cytarabine and homoharringtonin) was beneficial to morphological remission (OR=0.126, 95%CI: 0.025-0.629). FLT3 mutation was not conducive to morphological remission (OR=5.832, 95%CI: 1.778-19.124) and negative MRD (OR=4.166, 95%CI: 1.396-12.433). Conclusion: Venetoclax-based induction regimen is more effective than traditional chemotherapy regimen for newly diagnosed pediatric AML.

[Spatial distribution pattern of local tumor progression analysis after microwave ablation of hepatocellular carcinoma based on three-dimensional magnetic resonance imaging].

Objective: To investigate the spatial distribution pattern of local tumor progression (LTP) for hepatocellular carcinoma (HCC) ≤5 cm after microwave ablation. Methods: A retrospective analysis was performed on 169 HCCs with matched MRI before and after ablation from December 2009 to December 2019. A tumor MRI was reconstructed using three-dimensional visualization technology. LTP was classified as contact or non-contact, early or late stage, according to whether LTP was in contact with the edge of the ablation zone and the occurrence time (24 months). The tumor-surrounded area was divided into eight quadrants by using the eight-quadrant map method. An analysis was conducted on the spatial correlation between the quadrant where the ablative margin (AM) safety boundary was located and the quadrant where different types of LTP occurred. The t-test, or rank-sum test, was used for the measurement data. 2-test for count data was used to compare the difference between the two groups. Results: The AM quadrant had a distribution of 54.4% LTP, 64.2% early LTP stage, and 69.1% contact LTP, suggesting this quadrant was much more concentrated than the other quadrants (P < 0.001). Additionally, the AM quadrant had only 15.2% of non-contact type LTP and 17.1% of late LTP, which was not significantly different from the average distribution probability of 12.5% (100/8%) among the eight quadrants (P = 0.667, 0.743). 46.6% of early contact type LTP was located at the ablation needle tip, 25.2% at the body, and 28.1% at the caudal, while the location distribution probabilities of non-early contact LTP were 34.8%, 31.8%, and 33.3%, respectively. Conclusion: LTP mostly occurs in areas where the ablation safety boundary is the shortest. However, non-contact LTP and late LTP stages exhibit the feature of uniform distribution. Thus, this type of LPT may result from an inadequate non-ablation safety boundary.

[Curative effect of percutaneous microwave ablation therapy on hepatocellular carcinoma survival: a 15-year real-world study].

Objective: To evaluate the long-term efficacy of percutaneous microwave ablation (MWA) therapy for hepatocellular carcinoma. Methods: 2054 cases with Barcelona Clinic Liver Cancer (BCLC) stage 0~B at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital from January 2006 to September 2020 were retrospectively collected. All patients were followed up for at least 2 years. The primary endpoint of overall survival and secondary endpoints (tumor-related survival, disease-free survival, and postoperative complications) of patients treated with ultrasound-guided percutaneous MWA were analyzed. Kaplan-Meier method was used for stratified survival rate analysis. Fine-and-Gray competing risk model was used to analyze overall survival. Results: A total of 5 503 HCC nodules [mean tumor diameter (2.6±1.6) cm] underwent 3 908 MWAs between January 2006 and September 2020, with a median follow-up time of 45.6 (24.0 -79.2) months.The technical effectiveness rate of 5 375 tumor nodules was 97.5%. The overall survival rates at 5, 10, and 15-years were 61.6%, 38.8%, and 27.0%, respectively. The tumor-specific survival rates were 67.1%, 47.2%, and 37.7%, respectively. The free tumor survival rates were 25.8%, 15.7%, and 9.9%, respectively. The incidence rate of severe complications was 2.8% (108/3 908). Further analysis showed that the technical effectiveness and survival rate over the passing three time periods from January 2006-2010, 2011-2015, and 2016-September 2020 were significantly increased, with P < 0.001, especially for liver cancer 3.1~5.0 cm (P < 0.001). Conclusion: Microwave ablation therapy is a safe and effective method for BCLC stage 0-B, with significantly enhanced technical efficacy and survival rate over time.

[Comparison of the efficacy of different surgical strategies in the treatment of patients with initially resectable gastric cancer liver metastases].

Objective: To examine the impact of varied surgical treatment strategies on the prognosis of patients with initial resectable gastric cancer liver metastases (IR-GCLM). Methods: This is a retrospective cohort study. Employing a retrospective cohort design, the study selected clinicopathological data from the national multi-center retrospective cohort study database, focusing on 282 patients with IR-GCLM who underwent surgical intervention between January 2010 and December 2019. There were 231 males and 51 males, aging (M(IQR)) 61 (14) years (range: 27 to 80 years). These patients were stratified into radical and palliative treatment groups based on treatment decisions. Survival curves were generated using the Kaplan-Meier method and distinctions in survival rates were assessed using the Log-rank test. The Cox risk regression model evaluated HR for various factors, controlling for confounders through multivariate analysis to comprehensively evaluate the influence of surgery on the prognosis of IR-GCLM patients. A restricted cubic spline Cox proportional hazard model assessed and delineated intricate associations between measured variables and prognosis. At the same time, the X-tile served as an auxiliary tool to identify critical thresholds in the survival analysis for IR-GCLM patients. Subgroup analysis was then conducted to identify potential beneficiary populations in different surgical treatments. Results: (1) The radical group comprised 118 patients, all undergoing R0 resection or local physical therapy of primary and metastatic lesions. The palliative group comprised 164 patients, with 52 cases undergoing palliative resections for gastric primary tumors and liver metastases, 56 cases undergoing radical resections for gastric primary tumors only, 45 cases undergoing palliative resections for gastric primary tumors, and 11 cases receiving palliative treatments for liver metastases. A statistically significant distinction was observed between the groups regarding the site and the number of liver metastases (both P<0.05). (2) The median overall survival (OS) of the 282 patients was 22.7 months (95%CI: 17.8 to 27.6 months), with 1-year and 3-year OS rates were 65.4% and 35.6%, respectively. The 1-year OS rates for patients in the radical surgical group and palliative surgical group were 68.3% and 63.1%, while the corresponding 3-year OS rates were 42.2% and 29.9%, respectively. A comparison of OS between the two groups showed no statistically significant difference (P=0.254). Further analysis indicated that patients undergoing palliative gastric cancer resection alone had a significantly worse prognosis compared to other surgical options (HR=1.98, 95%CI: 1.21 to 3.24, P=0.006). (3) The size of the primary gastric tumor significantly influenced the patients' prognosis (HR=2.01, 95%CI: 1.45 to 2.79, P<0.01), with HR showing a progressively increasing trend as tumor size increased. (4) Subgroup analysis indicates that radical treatment may be more effective compared to palliative treatment in the following specific cases: well/moderately differentiated tumors (HR=2.84, 95%CI 1.49 to 5.41, P=0.001), and patients with liver metastases located in the left lobe of the liver (HR=2.06, 95%CI 1.19 to 3.57, P=0.010). Conclusions: In patients with IR-GCLM, radical surgery did not produce a significant improvement in the overall prognosis compared to palliative surgery. However, within specific patient subgroups (well/moderately differentiated tumors, and patients with liver metastases located in the left lobe of the liver), radical treatment can significantly improve prognosis compared to palliative approaches.

[Research status of potential therapeutic targets for thyroid-associated ophthalmopathy].

Thyroid-associated ophthalmopathy (TAO) is an autoimmune eye disease that affects visual function and appearance, involving pathological remodeling processes of orbital tissue such as inflammatory reaction, oxidative stress, lipogenesis, and fibrosis. Current clinical first-line treatment options cannot be effective for all patients. This article summarizes the research on potential therapeutic targets of TAO at home and abroad in recent years, including receptor protein targets, immune cell targets, fat suppression targets, anti-fibrosis targets, transcription factor targets, and metabolic regulatory enzyme targets. Both non-natural compounds and natural compounds are introduced, with a view to providing clinical researchers with reference and ideas in the treatment of TAO and promoting the clinical application of new therapeutic drugs.

[Efficacy of sutureless intrascleral intraocular lens fixation with the modified Yamane technique].

Objective: To evaluate the efficacy of sutureless intrascleral intraocular lens (IOL) fixation with the modified Yamane technique. Methods: It was a retrospective case series study. Patients undergoing sutureless intrascleral IOL fixation with the modified Yamane technique were included at Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University from January 2022 to September 2023. Uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA), recorded as the logarithm of the minimum angle of resolution (logMAR), were measured before surgery and at 1 day, 3 days, 1 week, 1 month, and 3 months postoperatively. Refractive error and intraocular pressure were also checked. Anterior segment examination with a slit lamp microscope, fundus examination, anterior segment and posterior segment optical coherence tomography were performed. Intraoperative and postoperative ocular complications were documented. Results: A total of 53 patients (53 eyes) were included in this study, comprising 40 males and 13 females, with a median age of 60 (49, 68) years. Among them, the proportion of a history of trauma was 22.6% (12/53). There was 1 eye with intraoperative vitreous hemorrhage (1.9%). All eyes had no obvious hypotony, no obvious inflammation in the anterior chamber, and no pupillary abnormalities at 1 week after surgery. The mean follow-up time was (8.0±3.3) months (range, 3 to 16 months). There was no iris capture, re-dislocation, or haptic exposure of the IOL during the follow-up. The corneal endothelial cell density was (2 236±704) cells/mm2 preoperatively and (1 964±628) cells/mm2 at 1 month, with significant difference (P<0.001). The UCVA (logMAR) was 1.53±0.75 preoperatively, 0.18±0.17 at 1 month, 0.15±0.14 at 3 months, and 0.14±0.13 at the final visit (P<0.001). The UCVA (logMAR) at 1 month was significantly different from that at 3 months and the final visit (both P<0.05). At 1 month, 50.9% (27/53) of the eyes had an UCVA (logMAR)≤0.1, and the rate was 56.6% (30/53) at 3 months. The BCVA (logMAR) was 0.25±0.21, 0.03±0.06, 0.02±0.06, and 0.02±0.06 before surgery, at postoperative1 month, 3 months, and the final visit, respectively (P<0.001). The BCVA (logMAR) at 1 month was not significantly different from that at 3 months and the final visit (both P>0.05). The rate of the eyes with a BCVA (logMAR)≤0 was 81.1% (43/53) at 1 month and 83.0% (44/53) at 3 months. The IOL tilt was (5.18±2.60)° at postoperative 1 month and (5.08±2.48)° at postoperative 3 months, without statistically significant difference (P>0.05). The IOL decentration was (0.35±0.24) mm at postoperative 1 month and (0.32±0.24) mm at postoperative 3 months, without statistically significant difference (P>0.05). Conclusion: Sutureless intrascleral IOL fixation with the modified Yamane technique is simpler and more minimally invasive to achieve a stable and centered IOL implantation with fewer complications and good visual prognosis.