Acceleration of ferromagnetic resonance measurements by Bayesian experimental design.

Ferromagnetic resonance (FMR) is a broadly used dynamical measurement used to characterize a wide range of magnetic materials. Applied research and development on magnetic thin film materials is growing rapidly alongside a growing commercial appetite for magnetic memory and computing technologies. The ability to execute high-quality, fast FMR surveys of magnetic thin films is needed to meet the demanding throughput associated with rapid materials exploration and quality control. Here, we implement optimal Bayesian experimental design software developed by [McMichael et al. J. Res. Natl. Inst. Stand. Technol. 126, 126002 (2021)] in a vector network analyzer-FMR setup to demonstrate an unexplored opportunity to accelerate FMR measurements. A systematic comparison is made between the optimal Bayesian measurement and the conventional measurement. Reduced uncertainties in the linewidth and resonance frequency ranging from 40% to 60% are achieved with the Bayesian implementation for the same measurement duration. In practical terms, this approach reaches a target uncertainty of ±5 MHz for the linewidth and ±1 MHz for the resonance frequency in 2.5× less time than the conventional approach. As the optimal Bayesian approach only decreases random errors, we evaluate how large systematic errors may limit the full advantage of the optimal Bayesian approach. This approach can be used to deliver gains in measurement speed by a factor of 3 or more and as a software add-on has the flexibility to be added on to any FMR measurement system to accelerate materials discovery and quality control measurements, alike.

Genetically Supported Drug Targets and Dental Traits: A Mendelian Randomization Study.

Current interventions for oral/dental diseases heavily rely on operative/surgical procedures, while the discovery of novel drug targets may enable access to noninvasive pharmacotherapy. Therefore, this study aims to leverage large-scale data and Mendelian randomization (MR) techniques, utilizing genetic variants as instruments, to identify potential therapeutic targets for oral and dental diseases supported by genetic evidence. By intersecting 4,302 druggable genes with expression quantitative trait loci from 31,684 blood samples, we identified 2,580 druggable targets as exposures. Single nucleotide polymorphisms associated with dental disease/symptom traits were collected from FinnGen R9, the Gene-Lifestyle Interactions in Dental Endpoints consortium, and the UK Biobank to serve as outcomes for both discovery and replication purposes. Through MR analysis, we identified 43 druggable targets for various dental disease/symptom traits. To evaluate the viability of these targets, we replicated the analysis using circulating protein quantitative trait loci as exposures. Additionally, we conducted sensitivity, colocalization, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes annotation, protein-protein interaction analyses, and validated dental trait-associated druggable gene expression in animal models. Among these targets, IL12RB1 (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.01-1.01) and TNF (OR, 0.98; 95% CI, 0.97-0.99) exhibited therapeutic promise for oral ulcers, whereas CXCL10 (OR, 0.84; 95% CI, 0.76-0.91) was for periodontitis. Through a rigorous quality control and validation pipeline, our study yields compelling evidence for these druggable targets, which may enhance the clinical prognosis by developing novel drugs or repurposing existing ones.

[Progression and application of circulating tumor DNA in lymphoma].

Lymphomas are a highly heterogeneous group of tumors that are classified into several subtypes. The gold standard method for the molecular profiling of lymphoma is based on invasive lymph node or tissue biopsy. However, this method cannot accurately capture spatial tumor heterogeneity in each patient as well as systemic tumor invasion and tumor burden. Circulating tumor DNA (ctDNA) is an emerging and highly versatile biomarker that overcomes the basic limitations of imaging scanning and tissue biopsy; has the characteristics of being simple, rapid, and non-invasive; and has good specificity and high sensitivity. ctDNA testing has been applied to a variety of subtypes of lymphoma and has been used for somatic mutation genotyping, efficacy monitoring during treatment, detection of minimal residual disease, and the prediction of survival, which may help clinicians make better clinical decisions in the diagnosis and treatment of lymphoma patients. Furthermore, this study also aims to review the different methods of ctDNA analysis and describe the specific applications of ctDNA in different lymphoma subtypes.

Ultra-high-energy gamma-ray bubble around microquasar V4641 Sgr.

Microquasars are laboratories for the study of jets of relativistic particles produced by accretion onto a spinning black hole. Microquasars are near enough to allow detailed imaging of spatial features across the multiwavelength spectrum. The recent extension measurement of the spatial morphology of a microquasar, SS 433, to TeV gamma rays1 localizes the acceleration of electrons at shocks in the jet far from the black hole2. V4641 Sagittarii (V4641 Sgr) is a similar binary system with a black hole and B-type main-sequence companion star and has an orbit period of 2.8 days (refs. 3,4). It stands out for its super-Eddington accretion5 and for its radio jet, which is one of the fastest superluminal jets in the Milky Way. Previous observations of V4641 Sgr did not report gamma-ray emission6. Here we report TeV gamma-ray emission from V4641 Sgr that reveals particle acceleration at similar distances from the black hole as SS 433. Furthermore, the gamma-ray spectrum of V4641 Sgr is among the hardest TeV spectra observed from any known gamma-ray source and is detected above 200 TeV. Gamma rays are produced by particles, either electrons or protons, of higher energies. Because energetic electrons lose energy more quickly the higher their energy, such a spectrum either very strongly constrains the electron-production mechanism or points to the acceleration of high-energy protons. This suggests that large-scale jets from microquasars could be more common than previously expected and that they could be a notable source of galactic cosmic rays7-9.

Effect of Propofol in the Cardiovascular System and its Related Mechanism Research Progress.

Propofol is the most widely used short-acting intravenous anesthetic in clinical practice. Existing studies have shown that propofol has many effects on the cardiovascular system in addition to its anesthetic effect. Propofol can antagonize a variety of tachyarrhythmias and reduce the risk of recurrence, regulate autonomic balance of the heart, modulate circulatory dynamics, thereby increasing blood perfusion to vital organs such as the kidney, intestine, and brain, and exert myocardial protection and cerebral protection during ischemia-reperfusion injury. In this paper, we review the potential mechanisms of these effects and provide and ideas for future research and novel drug development of propofol and its derivatives in cardiac electrophysiology and circulatory dynamics.

[Olfactory neuroblastoma in children: clinical analysis of five cases].

The clinical data of five patients diagnosed with olfactory neuroblastoma (ONB) who were admitted to the Department of Pediatrics, Beijing Tongren Hospital Affiliated to Capital Medical University from January 2012 to January 2024 were retrospectively analyzed. Two males and three females aged 6.2 (5.7-15.8) years were included. The symptoms mainly covered nasal congestion, increased nasal secretions, headache, decreased vision and so on. Pathological grade Ⅱ, Ⅲ and Ⅳ was identified in two cases, one case and two cases, respectively. Modified Kadish stage B, C and D was detected in one case, two cases and two cases, respectively. All patients underwent surgery, chemotherapy, and radiation therapy. Among the five patients, four survived and one died. The follow-up time was 22.3 (10.4-56.4) months, and the recurrence rate was 0. ONB should be suspected when tumors are presented in the upper and middle parts of the nasal cavity, especially dumbbell shaped masses that grow towards the nasal cavity and intracranial area based on imaging. The multimodality therapy of ONB comprising of surgery and chemotherapy, can achieve good therapeutic effects and prognosis, but long-term follow-up is required.

[Analysis of loss to follow-up status and influencing factors of children born to pregnant women with HIV infection in China in 2019].

Objective: To understand the loss to follow-up of children born to pregnant women with HIV infection (HIV-exposed children) and analyze its influencing factors in China in 2019. Methods: The data were collected from the follow-up records of pregnant women with HIV infection and their children reported by the national "Management Information System for the Prevention of HIV, syphilis and Hepatitis B Mother-to-Child Transmission" in 2019. HIV-exposed children were defined as those who were not followed up after birth or who were not followed up at 18 months of age and who were not followed up at 21 months of age. The univariate and multivariate influencing factors of loss to follow-up of children born to HIV-infected pregnant women were analyzed by χ2 test and logistic regression model. SPSS 25.0 software was used for statistical analysis. Results: The number of HIV-infected pregnant women was 5 039, the number of live-born children was 5 035, the number of loss to follow-up children within 18 months of age was 283, and the loss to follow-up rate children was 5.62%(283/5 035). The results of multivariate logistic regression analysis showed that the rate of loss to follow-up of exposed children born to pregnant women who worked as farmers (animal husbandry and fishery) (aOR=0.34, 95%CI: 0.22-0.53), unmarried (aOR=0.47, 95%CI: 0.24-0.93), first marriage (aOR=0.38, 95%CI: 0.22-0.67), remarriage (aOR=0.36, 95%CI: 0.20-0.67) and cohabiting (aOR=0.47, 95%CI: 0.23-0.97), and knew they had HIV infection before this pregnancy (aOR=0.53, 95%CI: 0.40-0.70) was lower. Han nationality (aOR=1.52, 95%CI: 1.09-2.13), primary school (aOR=2.06, 95%CI: 1.10-3.89) and junior middle school (aOR=1.81, 95%CI: 1.03-3.17) educational level, non-use of antiviral drugs (aOR=6.21, 95%CI: 4.32-8.93) and delivery in township (street) level midwifery institutions (aOR=5.72, 95%CI: 1.61-20.27) had higher rates of loss to follow-up among infants born to HIV-infected pregnant women. Conclusions: HIV-exposed children still have a specific rate of loss to follow-up in China in 2019. In order to further reduce the rate of loss to follow-up, it is of great significance to improve the detection rate of HIV before pregnancy and the rate of antiviral drugs used in pregnant women with HIV infection, which is of great significance for the effective implementation of comprehensive intervention measures of prevention of mother-to-child transmission of HIV.

[Epidemiological analysis of the current prevalence of hepatitis B virus infection among pregnant and postpartum women in China from 2021 to 2023].

Objective: To analyze hepatitis B serologic tests and the current prevalence of hepatitis B virus (HBV) infection among pregnant and postpartum women in China from 2021 to 2023. Methods: Data on managing the prevention of mother-to-child transmission of HIV, syphilis, and hepatitis were retrieved from the National Information System. A positive serum HBsAg test was used to define HBV infection. The χ(2) test was used to compare the coverage rate of the hepatitis B serologic test across different years, in early-stage pregnancy, and the current HBV infection in pregnant and postpartum women. A two-sided P value of <0.05 was considered a statistically significant difference. Results: The coverage rate for hepatitis B serological detection in pregnant (including intrapartum) and postpartum women and early-stage pregnancy rose from 99.68% (10 463 059/10 496 883) and 82.96% (8 707 765/10 496 883) to 99.94% (8 678 777/8 684 387, P < 0.001) and 88.87% (7 717 857/8 684 387, P < 0.001) in China between 2021 and 2023. The current prevalence rate of HBV infection decreased from 4.98% (521 479/10 463 059) in 2021 to 4.56% (396 148/8 678 777) in 2023 among pregnant and postpartum women (P < 0.001). The current prevalence rate of HBV infection ranged from 1.53% to 10.39% among pregnant and postpartum women in various provinces of China in 2023. Conclusion: The coverage rate for hepatitis B serologic tests in China increased significantly between 2021 and 2023 in pregnant and postpartum women. Therefore, the current prevalence rate of HBV infection has decreased significantly in pregnant and postpartum women, but a regional difference still exists.

[The Development of SpCas9 Variants with High Specificity and Efficiency Based on the HH Theory].

Streptococcus pyogenes Cas9 (SpCas9) is the most popular tool in gene editing; however, off-target mutagenesis is one of the biggest impediments in its application. In our previous study, we proposed the HH theory, which states that sgRNA/DNA hybrid (hybrid) extrusion-induced enhancement of hydrophobic interactions between the hybrid and REC3/HNH is a key factor in cleavage initiation. Based on the HH theory, we analyzed the interactions between the REC3 domain and hybrid and obtained 8 mutant sites. We designed 8 SpCas9 variants (V1-V8), used digital droplet PCR to assess SpCas9-induced DNA indels in human cells, and developed high-fidelity variants. Thus, the HH theory may be employed to further optimize SpCas9-mediated genome editing systems, and the resultant V3, V6, V7, and V8 SpCas9 variants may be valuable for applications requiring high-precision genome editing.

300 million years apart: the extreme case of macromorphological skeletal convergence between deltocyathids and a turbinoliid coral (Anthozoa, Scleractinia).

The integration of morphological and molecular lines of evidence has enabled the family Deltocyathidae to be erected to accommodate Deltocyathus species that were previously ascribed to the family Caryophylliidae. However, although displaying the same morphological characteristics as other species of Deltocyathus , molecular data suggested that D. magnificus was phylogenetically distant from Deltocyathidae, falling within the family Turbinoliidae instead. To elucidate the enigmatic evolutionary history of this species and skeletal microstructural features, the phylogenetic relationships of Deltocyathidae and Turbinoliidae were investigated using nuclear ultraconserved and exon loci and complete mitochondrial genomes. Both nuclear and mitochondrial phylogenomic reconstructions confirmed the position of D. magnificus within turbinolids. Furthermore, a novel mitochondrial gene order was uncovered for Deltocyathidae species. This gene order was not present in Turbinoliidae or in D. magnificus that both have the scleractinian canonical gene order, further indicating the taxonomic utility of mitochondrial gene order. D. magnificus is therefore formally moved to the family Turbinoliidae and accommodated in a new genus (Dennantotrochus Kitahara, Vaga & Stolarski, gen. nov.). Surprisingly, turbinolids and deltocyathids do not differ in microstructural organisation of the skeleton that consists of densely packed, individualised rapid accretion deposits and thickening deposits composed of fibres perpendicular to the skeleton surface. Therefore, although both families are clearly evolutionarily divergent, macromorphological features indicate a case of skeletal convergence while these may still share conservative biomineralisation mechanisms. ZooBank: urn:lsid:zoobank.org:pub:5F1C0E25-3CC6-4D1F-B1F0-CD9D0014678E.

Low Temperature Dynamic Polaron Liquid in a Manganite Exhibiting Colossal Magnetoresistance.

Polarons-fermionic charge carriers bearing a strong companion lattice deformation-exhibit a natural tendency for self-localization due to the recursive interaction between electrons and the lattice. While polarons are ubiquitous in insulators, how they evolve in transitions to metallic and superconducting states in quantum materials remains an open question. Here, we use resonant inelastic x-ray scattering to track the electron-lattice coupling in the colossal magneto-resistive bi-layer manganite La_{1.2}Sr_{1.8}Mn_{2}O_{7} across its metal-to-insulator transition. The response in the insulating high-temperature state features harmonic emissions of a dispersionless oxygen phonon at small energy transfer. Upon cooling into the metallic state, we observe a drastic redistribution of spectral weight from the region of these harmonic emissions to a broad high energy continuum. In concert with theoretical calculations, we show that this evolution implies a shift in electron-lattice coupling from static to dynamic lattice distortions that leads to a distinct polaronic ground state in the low temperature metallic phase-a dynamic polaron liquid.

[A sericin hydrogel scaffold for sustained dexamethasone release modulates macrophage polarization to promote mandibular bone defect repair in rats].

OBJECTIVE: To evaluate the efficacy of a modified sericin hydrogel scaffold loaded with dexamethasone (SMH-CD/DEX) scaffold for promoting bone defect healing by stimulating anti-inflammatory macrophage polarization. METHODS: The light-curable SMH-CD/DEX scaffold was prepared using dexamethasone-loaded NH2-ß-cyclodextrin (NH2-ß-CD) and sericin hydrogel and characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), biocompatibility assessment and drug release test. THP-1 macrophages incubated with the scaffold were examined for protein expressions of iNOS and Arg-1, mRNA expressions of IL-6, Il-10, Arg-1 and iNOS, and surface markers CD86 and CD206 using Western blotting, RT-qPCR, and flow cytometry. In a co-culture system of human periodontal ligament stem cells (HPDLSCs) and THP-1 macrophages, the osteogenic ability of the stem cells incubated with the scaffold was evaluated by detecting protein expressions of COL1A1 and Runx2 and expressions of ALP, Runx2, OCN and BMP2 mRNA, ALP staining, and alizarin red staining. In a rat model of mandibular bone defect, the osteogenic effect of the scaffold was assessed by observing bone regeneration using micro-CT and histopathological staining. RESULTS: In THP-1 macrophages, incubation with SMH-CD/DEX scaffold significantly enhanced protein expressions of Arg-1 and mRNA expressions of IL-10 and Arg-1 and lowered iNOS protein expression and IL-6 and iNOS mRNA expressions. In the co-culture system, SMH-CD/DEX effectively increased the protein expressions of COL1A1 and Runx2 and mRNA expressions of ALP and BMP2 in HPDLSCs and promoted their osteogenic differentiation. In the rat models, implantation of SMH-CD/DEX scaffold significantly promoted bone repair and bone regeneration in the bone defect. CONCLUSION: The SMH-CD/DEX scaffold capable of sustained dexamethasone release promotes osteogenic differentiation of stem cells and bone defect repair in rats by regulating M2 polarization.

[Colorectal adenocarcinoma with enteroblastic differentiation: a clinicopathological analysis of eight cases].

Objective: To investigate the clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation (CAED). Methods: Eight cases of CAED diagnosed at the Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China from January 2017 to August 2023 were collected. The histopathological, immunohistochemical, molecular and prognostic features of 8 CAED cases were analyzed. The relevant studies were also reviewed. Results: Among the eight patients, there were six males and two females, with an average age of 58 years (range: 29-77 years, median age: 61.5 years). Preoperative serum alpha-fetoprotein levels were elevated in five patients (14.0-286.6 µg/L). Four tumors were located in the colon, and four tumors in the rectum. Two patients were clinically staged as advanced stage (stage Ⅳ), and distant metastasis occurred at the initial diagnosis (one case had liver metastasis, and the other had lung, bone and multiple lymph nodes metastases). Six patients were clinically staged as locally-advanced stage (Stage Ⅱ-Ⅲ). Three of them developed distant metastases after surgery (one case had liver metastasis, one case had lung metastasis, and one case had peritoneal metastasis). Additionally, two patients died at 9 months and 24 months after surgery, respectively. The tumors were composed of various proportions of adenocarcinoma components with enteroblastic differentiation (30%-100%) and classical tubular adenocarcinoma components. The component with enteroblastic differentiation exhibited morphology similar to embryonic intestinal epithelium: cuboidal or columnar tumor cells arranged in tubular, papillary, cribriform, or solid nest patterns, with clear cytoplasm. Immunohistochemical studies showed that tumor cells expressed at least one oncofetal protein (SALL4, Glypican-3, and AFP). In addition, focal squamous differentiation was observed in 3 cases (3/8). Compared to the primary tumor, both CAED and squamous differentiation components were increased in the metastatic tumors. Based on the sequencing results of KRAS, NRAS and BRAF of the primary and/or metastatic tumors, 5 cases were wild-type, while KRAS exon 2 (G13D) mutations were identified in 2 cases. Conclusions: CAED is a rare colorectal malignancy with a dismal prognosis. Accurate pathological diagnosis is prognostically valuable. The histological features of enteroblastic differentiation, elevated serum AFP levels, and the expression of oncofetal proteins play an important role in the tumor diagnosis.

Machine learning framework develops neutrophil extracellular traps model for clinical outcome and immunotherapy response in lung adenocarcinoma.

Neutrophil extracellular traps (NETs) are novel inflammatory cell death in neutrophils. Emerging studies demonstrated NETs contributed to cancer progression and metastases in multiple ways. This study intends to provide a prognostic NETs signature and therapeutic target for lung adenocarcinoma (LUAD) patients. Consensus cluster analysis performed by 38 reported NET-related genes in TCGA-LUAD cohorts. Then, WGCNA network was conducted to investigate characteristics genes in clusters. Seven machine learning algorithms were assessed for training of the model, the optimal model was picked by C-index and 1-, 3-, 5-year ROC value. Then, we constructed a NETs signature to predict the overall survival of LUAD patients. Moreover, multi-omics validation was performed based on NETs signature. Finally, we constructed stable knockdown critical gene LUAD cell lines to verify biological functions of Phospholipid Scramblase 1 (PLSCR1) in vitro and in vivo. Two NETs-related clusters were identified in LUAD patients. Among them, C2 cluster was provided as "hot" tumor phenotype and exhibited a better prognosis. Then, WGCNA network identified 643 characteristic genes in C2 cluster. Then, Coxboost algorithm proved its optimal performance and provided a prognostic NETs signature. Multi-omics revealed that NETs signature was involved in an immunosuppressive microenvironment and predicted immunotherapy efficacy. In vitro and in vivo experiments demonstrated that knockdown of PLSCR1 inhibited tumor growth and EMT ability. Besides, cocultural assay indicated that the knockdown of PLSCR1 impaired the ability of neutrophils to generate NETs. Finally, tissue microarray (TMA) for LUAD patients verified the prognostic value of PLSCR1 expression. In this study, we focus on emerging hot topic NETs in LUAD. We provide a prognostic NETs signature and identify PLSCR1 with multiple roles in LUAD. This work can contribute to risk stratification and screen novel therapeutic targets for LUAD patients.

[Adeno-associated virus-mediated hepatocyte-specific NDUFA13 overexpression protects against CCl4-induced liver fibrosis in mice by inhibiting hepatic NLRP3 activation].

OBJECTIVE: To investigate the protective effect of NDUFA13 protein against acute liver injury and liver fibrosis in mice and explore the possible mechanisms. METHODS: BALB/C mice (7 to 8 weeks old) were divided into normal group, CCl4 group, CCl4+AAV-NC group and CCl4+AAV-NDU13 group (n=18). Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 twice a week for 3, 5 or 7 weeks, and the recombinant virus AAV8-TBG-NC or AAV8-TBG-NDUFA13 was injected via the tail vein 7-10 days prior to CCl4 injection. After the treatments, pathological changes in the liver of the mice were observed using HE and Masson staining. Hepatic expression levels of NDUFA13 and α-SMA were detected with Western blotting, and the coexpression of NDUFA13 and NLRP3, TNF-α and IL-1ß, and α-SMA and collagen Ⅲ was analyzed with immunofluorescence assay. RESULTS: HE and Masson staining showed deranged liver architecture, necrotic hepatocytes and obvious inflammatory infiltration and collagen fiber deposition in mice with CCl4 injection (P < 0.001). NDUFA13 expression markedly decreased in CCl4-treated mice (P < 0.001), while a significant reduction in inflammatory aggregation and fibrosis was observed in mice with AAV-mediated NDUFA13 overexpression (P < 0.001). In CCl4+AAV-NDU13 group, immunofluorescence assay revealed markedly weakened activation of NLRP3 inflammasomes (P < 0.001), significantly decreased TNF-α and IL-1ß secretion (P < 0.001), and inhibited hepatic stellate cell activation (P < 0.05) and collagen formation in the liver (P < 0.001). CONCLUSION: Mitochondrial NDUFA13 overexpression in hepatocytes protects against CCl4- induced liver fibrosis in mice by inhibiting activation of NLRP3 signaling.

Efficacy and safety of intrathecal pemetrexed for TKI-failed leptomeningeal metastases from EGFR+ NSCLC: an expanded, single-arm, phase II clinical trial.

BACKGROUND: This study aimed to evaluate the efficacy and safety of intrathecal pemetrexed (IP) for treating patients with leptomeningeal metastases (LM) from non-small-cell lung cancer (NSCLC) who progressed from epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment in an expanded, prospective, single-arm, phase II clinical study (ChiCTR1800016615). PATIENTS AND METHODS: Patients with confirmed NSCLC-LM who progressed from TKI received IP (50 mg, day 1/day 5 for 1 week, then every 3 weeks for four cycles, and then once monthly) until disease progression or intolerance. Objectives were to assess overall survival (OS), response rate, and safety. Measurable lesions were assessed by investigator according to RECIST version 1.1. LM were assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: The study included 132 patients; 68% were female and median age was 52 years (31-74 years). The median OS was 12 months (95% confidence interval 10.4-13.6 months), RANO-assessed response rate was 80.3% (106/132), and the most common adverse event was myelosuppression (n = 42; 31.8%), which reversed after symptomatic treatment. The results of subgroup analysis showed that absence of brain parenchymal metastasis, good Eastern Cooperative Oncology Group score, good response to IP treatment, negative cytology after treatment, and patients without neck/back pain/difficult defecation had longer survival. Gender, age, previous intrathecal methotrexate/cytarabine, and whole-brain radiotherapy had no significant influence on OS. CONCLUSIONS: This study further showed that IP is an effective and safe treatment method for the EGFR-TKI-failed NSCLC-LM, and should be recommended for these patients in clinical practice and guidelines.

[Different methods in predicting mortality of pediatric intensive care units sepsis in Southwest China].

Objective: To investigate the value of systemic inflammatory response syndrome (SIRS), pediatric sequential organ failure assessment (pSOFA) and pediatric critical illness score (PCIS) in predicting mortality of pediatric sepsis in pediatric intensive care units (PICU) from Southwest China. Methods: This was a prospective multicenter observational study. A total of 447 children with sepsis admitted to 12 PICU in Southwest China from April 2022 to March 2023 were enrolled. Based on the prognosis, the patients were divided into survival group and non-survival group. The physiological parameters of SIRS, pSOFA and PCIS were recorded and scored within 24 h after PICU admission. The general clinical data and some laboratory results were recorded. The area under the curve (AUC) of the receiver operating characteristic curve was used to compare the predictive value of SIRS, pSOFA and PCIS in mortality of pediatric sepsis. Results: Amongst 447 children with sepsis, 260 patients were male and 187 patients were female, aged 2.5 (0.8, 7.0) years, 405 patients were in the survival group and 42 patients were in the non-survival group. 418 patients (93.5%) met the criteria of SIRS, and 440 patients (98.4%) met the criteria of pSOFA≥2. There was no significant difference in the number of items meeting the SIRS criteria between the survival group and the non-survival group (3(2, 4) vs. 3(3, 4) points, Z=1.30, P=0.192). The pSOFA score of the non-survival group was significantly higher than that of the survival group (9(6, 12) vs. 4(3, 7) points, Z=6.56, P<0.001), and the PCIS score was significantly lower than that of the survival group (72(68, 81) vs. 82(76, 88) points, Z=5.90, P<0.001). The predictive value of pSOFA (AUC=0.82) and PCIS (AUC=0.78) for sepsis mortality was significantly higher than that of SIRS (AUC=0.56) (Z=6.59, 4.23, both P<0.001). There was no significant difference between pSOFA and PCIS (Z=1.35, P=0.176). Platelet count, procalcitonin, lactic acid, albumin, creatinine, total bilirubin, activated partial thromboplastin time, prothrombin time and international normalized ratio were all able to predict mortality of sepsis to a certain degree (AUC=0.64, 0.68, 0.80, 0.64, 0.68, 0.60, 0.77, 0.75, 0.76, all P<0.05). Conclusion: Compared with SIRS, both pSOFA and PCIS had better predictive value in the mortality of pediatric sepsis in PICU.

[Preliminary study on the effect of Echinococcus multilocaris on phenotypic transformations of glucose metabolism and polarization types in macrophages].

OBJECTIVE: To investigate the effects of Echinococcus multilocularis on the phenotypic transformations of glucose metabolism, polarization types and inflammatory responses in macrophages, so as to provide insights into elucidation of echinococcosis pathogenesis. METHODS: Bone marrow cells were isolated from C57BL/6J mice at ages of 6 to 8 weeks, and induced into bone marrow-derived macrophages (BMDMs) with mouse macrophage colony-stimulating factor (M-CSF), which served as controls (BMDMs-M0). BMDMs-M0 induced M2 macrophages by interleukin-4 for 24 hours served as the IL-4 induction group, and BMDMs-M0 co-cultured with 2.4 ng/mL E. multilocularis cystic fluid (CF) served as the BMDM-CF co-culture group, while BMDMs-M0 co-cultured with E. multilocularis protoscolex (PSC) at a ratio of 500:1 served as the BMDM-PSC co-culture group. The types of polarization of BMDMs co-cultured with E. multilocularis CF and PSC were analyzed using flow cytometry, and the expression of macrophage markers, inflammatory factors, and glucose metabolism-related enzymes was quantified using fluorescent quantitative real-time PCR (qPCR) and Western blotting assays. RESULTS: There were significant differences among the four groups in terms of Arginase-1 (Arg1) (F = 1 457.00, P < 0.000 1), macrophages-derived C-C motif chemokine 22 (Ccl22) (F = 22 203.00, P < 0.000 1), resistin-like α (Retnla) (F = 151.90, P < 0.000 1), inducible nitric oxide synthase (iNOS) (F = 107.80, P < 0.001), hexokinase (HK) (F = 9 389.00, P < 0.000 1), pyruvate kinase (PK) (F = 641.40, P < 0.001), phosphofructokinase 1 (PFK1) (F = 43.97, P < 0.01), glucokinase (GK) (F = 432.50, P < 0.000 1), pyruvate dehydrogenase kinases1 (PDK1) (F = 737.30, P < 0.000 1), lactic dehydrogenase (LDH) (F = 3 632.00, P < 0.000 1), glucose transporter 1 (GLUT1) (F = 532.40, P < 0.000 1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (F = 460.00, P < 0.000 1), citrate synthase (CS) (F = 5 642.00, P < 0.01), glycogen synthase1 (GYS1) (F = 273.30, P < 0.000 1), IL-6 (F = 1 823.00, P < 0.000 1), IL-10 (F = 291.70, P < 0.000 1), IL-1ß (F = 986.60, P < 0.000 1), and tumor necrosis factor (TNF)-α (F = 334.80, P < 0.000 1) and transforming growth factor (TGF)-ß mRNA expression (F = 163.30, P < 0.001). The proportion of M2 macrophages was significantly higher than that of M1 macrophages in the BMDM-PSC co-culture group [(22.87% ±1.48%) vs. (1.70% ±0.17%); t = 24.61, P < 0.001], and the proportion of M2 macrophages was significantly higher than that of M1 macrophages in the BMDM-CF co-culture group [(20.07% ±0.64%) vs. (1.93% ±0.25%); t = 45.73, P < 0.001]. The mRNA expression of M2 macrophages markers Arg1, Ccl22 and Retnla was significantly higher in the BMDM-CF and BMDM-PSC co-culture groups than in the control group (all P values < 0.01), and no significant difference was seen in the mRNA expression of the M1 macrophage marker iNOS among the three groups (P > 0.05), while qPCR assay quantified higher mRNA expression of key glycolytic enzymes HK, PK and PFK, as well as inflammatory factors IL-10, IL-1ß, TNF-α and TGF-ß in the BMDM-CF and BMDM-PSC co-culture groups than in the control group (all P values < 0.01). Western blotting assay determined higher HK, PK and PFK protein expression in the BMDM-PSC co-culture group than in the control group (all P values < 0.05), and qPCR quantified higher GLUT1, GAPDH and IL-6 mRNA expression in the BMDM-CF co-culture group than in the control group (all P values < 0.05), while higher HK, PK and PFK protein and mRNA expression (all P values < 0.01), as well as lower IL-6 and TNF-α and higher TGF-ß mRNA expression (both P values < 0.05) was detected in the IL-4 induction group than in the control group. Glycolytic stress test showed no significant difference in the extracellular acidification rate (ECAR) of mouse BMDM among the control group, IL-4 induction group and BMDM-PSC co-culture group (F = 124.4, P < 0.05), and a higher ECAR was seen in the BMDM-PSC co-culture group and a lower ECAR was found in the IL-4 induction group than in the control group (both P values < 0.05). CONCLUSIONS: Treatment of E. multilocularis CF or PSC mainly causes polarization of BMDM into M2 macrophages, and phenotypic transformation of glucose metabolism into high-energy and high-glycolytic metabolism, and affects inflammatory responses in BMDM.

[C/EBPß mediates expressions of downstream inflammatory factors of the tumor necrosis factor-α signaling pathway in renal tubular epithelial cells with NPHP1 knockdown].

OBJECTIVE: To explore the activation of tumor necrosis factor-α (TNF-α) signaling pathway and the expressions of the associated inflammatory factors in NPHP1-defective renal tubular epithelial cells. METHODS: A human proximal renal tubular cell (HK2) model of lentivirus-mediated NPHP1 knockdown (NPHP1KD) was constructed, and the expressions of TNF-α, p38, and C/EBPß and the inflammatory factors CXCL5, CCL20, IL-1ß, IL-6 and MCP-1 were detected using RT-qPCR, Western blotting or enzyme-linked immunosorbent assay. A small interfering RNA (siRNA) was transfected in wild-type and NPHP1KDHK2 cells, and the changes in the expressions of TNF-α, p38, and C/EBPß and the inflammatory factors were examined. RESULTS: NPHP1KDHK2 cells showed significantly increased mRNA expressions of TNF-α, C/EBPß, CXCL5, IL-1ß, and IL-6 (P < 0.05), protein expressions of phospho-p38 and C/EBPß (P < 0.05), and IL-6 level in the culture supernatant (P < 0.05), and these changes were significantly blocked by transfection of cells with siRNA-C/EBPß (P < 0.05). CONCLUSION: TNF-α signaling pathway is activated and its associated inflammatory factors are upregulated in NPHP1KDHK2 cells, and C/EBPß may serve as a key transcription factor to mediate these changes.