Application of propofol-remifentanil intravenous general anesthesia combined with regional block in pediatric ophthalmic surgery.

OBJECTIVE: The aim of this study is to observe the anesthetic effect and safety of intravenous anesthesia without muscle relaxant with propofol-remifentanil combined with regional block under laryngeal mask airway in pediatric ophthalmologic surgery. METHODS: A total of 90 undergoing ophthalmic surgery were anesthetized with general anesthesia using the laryngeal mask airway without muscle relaxant. They were randomly divided into two groups: 45 children who received propofol-remifentanil intravenous anesthesia combined with regional block (LG group), and 45 children who received total intravenous anesthesia (G group). The peri-operative circulatory indicators, awakening time after general anesthesia, postoperative analgesic effect and the incidence of anesthesia-related adverse events were respectively compared between the two groups. RESULTS: All the children successfully underwent the surgical procedure. The awakening time after general anesthesia and removal time of laryngeal mask were significantly shorter in the LG group than in the G group (P < 0.05). There was no statistically significant difference in the heart rates in the perioperative period between the two groups (P > 0.05). There was no statistically significant difference in the incidence of intraoperative physical response, respiratory depression, postoperative nausea and vomiting (PONV) and emergence agitation (EA) between the two groups (P > 0.05). The pain score at the postoperative hour 2 was lower in the LG group than in the G group (P < 0.05). CONCLUSION: Propofol-remifentanil intravenous anesthesia combined with long-acting local anesthetic regional block anesthesia, combined with laryngeal mask ventilation technology without muscle relaxants, can be safely used in pediatric eye surgery to achieve rapid and smooth recovery from general anesthesia and better postoperative analgesia. This anesthesia scheme can improve the comfort and safety of children in perioperative period, and has a certain clinical popularization value.

Engrailed 2 serves as a master regulator of the super-enhancer in the TNC gene locus in non-small cell lung cancer.

Engrailed 2 (EN2) is a homeodomain-containing protein that is dysregulated in many types of cancer. However, the role of EN2 in non-small cell lung cancer (NSCLC) and the mechanism underlying its biological function are largely unclear. Here, we showed that EN2 played an oncogenic function in NSCLC and greatly enhanced the malignant phenotype of NSCLC cells. Meanwhile, EN2 was able to boost the expression of a well-studied oncogenic Tenascin-C (TNC) gene, which in turn activated the AKT signaling pathway. Interestingly, we found that EN2 directly bound to the super-enhancer (SE) region in the TNC locus. The histone marker H3K27ac was also enriched in the region, indicating the activation of the SE. Treatment of the cells with JQ1, an inhibitor of SE activity, abrogated the effect of EN2 on the expression of TNC and phosphorylation of AKT-Ser473. Collectively, our work unveils a novel mode of EN2 function, in which EN2 governs the SE in the TNC locus, consequently activating the oncogenic TNC-AKT axis in NSCLC.

Engrailed 2 triggers the activation of multiple phosphorylation-induced signaling pathways in both transcription-dependent and -independent manners.

Homeodomain (HD)-containing proteins are typically recognized as transcription factors. Engrailed 2 (EN2) is an HD-containing protein that is highly expressed in various types of cancers, however, the mechanism underlying the biological function of EN2 is not fully understood. Here, we report a transcription-independent function of EN2 in addition to its role as a transcription factor. EN2 expression leads to the activation of multiple signaling pathways mediated by phosphorylation cascades. A phosphoproteomic analysis revealed that the phosphorylation status of numerous protein sites was altered after EN2 is expressed. Notably, EN2 was shown to interact with a myriad of proteins implicated in phosphorylation signaling cascades, as determined by immunoprecipitation-mass spectrometry (IP-MS). We validated the interaction between EN2 and B55α, the regulatory subunit of the PP2A-B55α complex, and confirmed that the phosphatase activity of the complex was suppressed by EN2 binding. To target EN2-induced malignancy, two kinds of small molecules were utilized to inhibit the EN2-activated NF-κB and AKT signaling pathways. A clear synergistic effect was observed when the activation of the two pathways was simultaneously blocked. Collectively, the data show that EN2 functions in a transcription-independent manner in addition to its role as a transcription factor. This finding may have therapeutic implications in treating esophageal squamous cell carcinoma (ESCC).

Light Chain Q166C Mutation Permits One-step Site Specific Conjugation on Monoclonal Antibodies.

Engineered cysteines are frequently used for site-specific conjugation in antibody-drug conjugate (ADC) development. When cysteine-engineered mAbs are produced in the cell culture process, the sulfhydryl groups on the engineered cysteines are mostly in an oxidized form. The oxidized cysteines require multiple steps (such as reduction, reoxidation, and buffer exchanges) to reactivate for bioconjugation, which complicates the ADC production process and reduces yields. In this study, we identified a Q166C mutation in the light chain that allows the presence of free sulfhydryl groups during cell culture and purification process. This mutation is in the constant region and away from sites involved in antigen binding or Fc-mediated functions. The free sulfhydryl reacts readily with maleimide in a mild solution at a high conjugation rate. This is only the second such site reported (the first one is Q124C in the light chain). Using the Q166C mutation, we conjugated an anti-angiopoietin-2 (Ang-2) peptide on bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, to construct a peptide antibody conjugate, Ava-Plus, which could block two pro-angiogenic factors simultaneously. Ava-Plus showed high affinity for both VEGF and Ang-2 and demonstrated higher activity than bevacizumab in in vitro cell migration and in vivo mouse xenograft models.

Lumbar spine segmentation method based on deep learning.

Aiming at the difficulties of lumbar vertebrae segmentation in computed tomography (CT) images, we propose an automatic lumbar vertebrae segmentation method based on deep learning. The method mainly includes two parts: lumbar vertebra positioning and lumbar vertebrae segmentation. First of all, we propose a lumbar spine localization network of Unet network, which can directly locate the lumbar spine part in the image. Then, we propose a three-dimensional XUnet lumbar vertebrae segmentation method to achieve automatic lumbar vertebrae segmentation. The method proposed in this paper was validated on the lumbar spine CT images on the public dataset VerSe 2020 and our hospital dataset. Through qualitative comparison and quantitative analysis, the experimental results show that the method proposed in this paper can obtain good lumbar vertebrae segmentation performance, which can be further applied to detection of spinal anomalies and surgical treatment.

Lkb1 aggravates diffuse large B-cell lymphoma by promoting the function of Treg cells and immune escape.

BACKGROUND: Regulatory T cells (Tregs) induce immune responses and may contribute to immune escape in tumors. Accumulation of Tregs in tumors represents a critical barrier to anti-tumor immunity and immunotherapy. However, conflicting results describing the role of Tregs in lymphoma warrant further investigation. The precise features and mechanisms underlying the alteration in Tregs in diffuse large B-cell lymphoma (DLBCL) are not well understood yet. In this study, we analyzed the mechanism underlying the observed alterations in Tregs in DLBCL and examined the effect of Lkb1 expression on the immunosuppressive function of human Tregs. METHODS: Flow cytometry and immunofluorescence were used to analyze the proportion of Tregs and effector Tregs in the peripheral blood and lymph nodes of patients with DLBCL and control group. In vitro culture assays were used to analyze the immunosuppressive function of Tregs in the two groups. Transcriptome sequencing was performed to analyze the differentially expressed genes in the two groups, and the transcription level and protein expression of Lkb1 in the two groups were detected using RT-PCR and WES microprotein technology. Lentiviral vectors were constructed to explore the functional changes of Tregs with stable upregulation and downregulation of Lkb1. Finally, a humanized murine lymphoma model was established to study the function of Lkb1 in Tregs in the pathogenesis of DLBCL. RESULTS: The number of Tregs was found to be dramatically increased in peripheral blood and tumor tissue in DLBCL patients compared with that in healthy controls, and decreased after treatment. Tregs from DLBCL patients exhibited multiple enhanced functions, including increased inhibition of CD8+cytotoxic T cells (CTL) against tumor cells, enhanced suppression of CD8+CTL secretion of granular enzyme, and suppression of CD8+CTL degranulation. Lkb1 was found to be upregulated in Tregs of DLBCL patients. Furthermore, Lkb1 contributes to Treg immunosuppressive function in DLBCL by regulating the mevalonate pathway. Finally, deletion of Lkb1 in Tregs suppressed tumor growth and promoted anti-tumor immunity in a DLBCL murine model. CONCLUSIONS: These findings confirmed that Lkb1-regulated Tregs are critical for immune escape in DLBCL, which emphasizes that Lkb1 is a potential target for the immunotherapy of DLBCL.

Liver kinase B1 overexpression controls mycobacterial infection in macrophages via FOXO1/Wnt5a signaling.

Mycobacterium tuberculosis (Mtb) is a primary cause of tuberculosis (TB), which has infected more than one-third of the world's population. Mtb survival and subsequent inflammation in macrophages are important components of TB. Liver kinase B1 (LKB1) has demonstrated anti-inflammation effects, but its function and underlying mechanism in mycobacteria-infected macrophages remains unknown. In the current study, we discovered that LKB1 was markedly decreased in Mtb-infected THP-1 and U937 macrophages. Moreover, LKB1 overexpression inhibited Mtb survival in macrophages. Mtb infection increased expression of nitric oxide, inducible nitric oxide synthase, and inflammation-related cytokines interleukin (IL)-6, tumor necrosis factor-α, and IL-1ß, whereas pcDNA3-LKB1 transfection inhibited the release of these cytokines in THP-1 and U937 cells. Furthermore, LKB1 overexpression significantly decreased protein expression of Wnt5a, which is dependent on the elevation of forkhead box protein O1 (FOXO1). Generally, we show that interruption of FOXO1 or overexpression of Wnt5a can reverse the effects of LKB1 on mycobacterial intracellular survival, nitric oxide, inducible nitric oxide synthase expression, and inflammatory cytokine release. These findings indicate important roles for LKB1, FOXO1, and Wnt5a in controlling mycobacteria and cell inflammation.

Long non-coding PCED1B-AS1 regulates macrophage apoptosis and autophagy by sponging miR-155 in active tuberculosis.

Macrophages play a major role in the control and elimination of invading Mycobacterium tuberculosis (Mtb). Emerging studies have demonstrated that long non-coding RNAs (lncRNAs) are involved in resident macrophages in Mtb. However, the regulatory mechanism between lncRNAs and macrophages in tuberculosis (TB) remains unclear. In this study, we sought to investigate the effect of Mtb-associated lncRNA PCED1B-AS1 on macrophage apoptosis and autophagy. Our study first evaluated PCED1B-AS1 expression in the CD14+ monocytes from patients with active tuberculosis and from healthy individuals. It was found that PCED1B-AS1 expression was down-regulated in patients with active tuberculosis, accompanied by significant attenuated monocyte apoptosis and enhanced autophagy. In vitro, knockdown of PCED1B-AS1 reduced macrophage apoptosis and promoted autophagy. PCED1B-AS1 serves as an endogenous sponge to block miR-155 expression in macrophages by directly binding to miR-155. Furthermore, we demonstrated that overexpression of FOXO3/Rheb, target genes of miR-155, reversed the PCED1B-AS1-mediated effects on macrophage apoptosis and autophagy. Altogether, our data indicate that PCED1B-AS1 modulates macrophage apoptosis and autophagy by targeting the miR-155 axis in active TB.

Recombinant Domain V of beta (2)-Glycoprotein I Inhibits OxLDL-induced TF Expression in Macrophages.

OBJECTIVE: To investigate if lectin-like oxidised low density lipoprotein receptor is implicated in oxidised low density lipoprotein induced up regulation of tissue factor and whether recombinant domain V of beta (2)-Glycoprotein I expressed in Pichia pastoris inhibits the binding of oxidised and lectin-like low density lipoprotein. METHODS: The expression of tissue factor and lectin-like oxidised low density lipoprotein receptor was detected using Western blot methods. Small interference ribonucleic acid of lectin-like oxidised low density lipoprotein receptor was used to block lectin-like oxidised low density lipoprotein receptor expression. Flow cytometry was used to test the effect of beta (2)-Glycoprotein I expressed in Pichia pastoris on the binding of oxidised low density lipoprotein with lectin-like oxidised low density lipoprotein receptor by using the lectin-like oxidised low density lipoprotein receptor-expressing 293T cells. RESULTS: Oxidised low density lipoprotein at 5-10 g/mL increased tissue factor and lectin-like oxidised low density lipoprotein receptor expression, whereas 20-50 g/mL oxidised low density lipoprotein attenuated tissue factor expression. Inhibiting lectin-like oxidised low density lipoprotein receptor expression by small interference ribonucleic acid of lectin-like oxidised low density lipoprotein receptor impaired oxidised low density lipoprotein-induced tissue factor over expression in macrophages. Pretreatment with beta (2)-Glycoprotein I expressed in Pichia pastoris led to a strong inhibition of tissue factor and lectin-like oxidised low density lipoprotein receptor expression in a dose-dependent manner in macrophages. Flow cytometry analysis showed that beta (2)-Glycoprotein I expressed in Pichia pastoris attenuated the interaction of oxidised low density lipoprotein with lectin-like oxidised low density lipoprotein receptor in lectin-like oxidised low density lipoprotein receptor-expressing 293T cells. CONCLUSIONS: Lectin-like oxidised low density lipoprotein receptor was implicated in the expression of tissue factor induced by oxidised low density lipoprotein, and beta (2)-Glycoprotein I expressed in Pichia pastoris inhibited oxidised low density lipoprotein-induced tissue factor and lectin-like oxidised low density lipoprotein receptor expression, at least in part, via inhibition of the interaction between oxidised low density lipoprotein and lectin-like oxidised low density lipoprotein receptor.

Human papillomavirus type 16 E6 oncoprotein promotes proliferation and invasion of non-small cell lung cancer cells through Toll-like receptor 3 signaling pathway.

Human papillomavirus (HPV) oncoproteins play vital roles in non-small cell lung cancer (NSCLC) pathogenesis, and Toll-like receptors (TLRs) contribute to tumor progression. However, interaction between HPV oncoproteins and TLR signaling in NSCLC progression remains unclear. Thus, the aim of the study was to explore effects of HPV16 E6 oncoprotein-induced TLRs pathway on growth and invasion of NSCLC cells and to examine potential mechanisms being involved. Recombinant plasmid (pcDNA-HPV16 E6) expressing HPV16 E6 protein was constructed. The expression prolife of TLRs was measured in NSCLC cell line A549 with or without pcDNA-HPV16 E6 transfection by real-time reverse polymerase chain reaction and Western blot. Cellular proliferation, invasion, cytokine productions, and downstream signaling pathways were also examined in TLR3-silencing/pcDNA-HPV16 E6 transfect A549 cells. Overexpression of HPV16 E6 increased proliferation, invasion, proliferation cytokine secretion, and TLR3 expression of A549 cells, while TLR3 silence inhibited HPV16 E6-induced tumor bioactivities of A549 cells. Down-regulation of TLR3 suppressed HPV16 E6-induced phosphorylation of Src, but did not affect TRIF expression. Moreover, inhibition of Src pathway also suppressed proliferation and invasion of A549 cells. In conclusion, HPV16 E6 oncoprotein promoted the bioactivities of NSCLC cells. TLR3-Src signaling pathway might be involved in this procession by up-regulation of cytokine production. The interaction between HPV16 E6 protein and TLR3 might contribute to the poor prognosis of NSCLC.

Eimeria tenella: a novel dsRNA virus in E. tenella and its complete genome sequence analysis.

Protozoa double-stranded (ds) RNA viruses have been described in Trichomonas, Giardia, and Leishmania. In this study, dsRNA and virus-like particles (approximately 30 nm in diameter) were discovered in Eimeria tenella sporulated oocysts. The complete genome of this novel dsRNA virus was sequenced using a three-step strategy. The sequencing results showed that the complete genome sequence was 6006 bp containing two open reading frames (ORFs) (2367 bp for ORF1 and 3216 bp for ORF2) with a five-nucleotide overlap (UGA/UG). The predicted ORF1 and ORF2 encoded a putative capsid protein of 788 amino acids (84.922 kDa) and a putative RNA-dependent RNA polymerase (RdRp) protein of 1071 amino acids (118.190 kDa). BLASTp analysis showed that the amino acid sequences for the E. tenella virus shared similarity with the E. brunetti RNA virus, with 29% homology in capsid proteins and 36% in RDRP proteins. The two untranslated regions were 349 bp (5' UTR) and 78 bp (3' UTR). The complete genome sequence of the E. tenella virus resembled characteristics of the Totiviridae family, indicating that this virus was a novel member of Totiviridae. Surprisingly, phylogenetic analysis showed that the E. tenella virus, E. brunetti RNA virus 1, and Mycoviruses were clustered into the genus Victorivirus and separated from the reported protozoa viruses, strongly suggesting a novel Eimeriaviruses subgenus. To the best of our knowledge, this is the first report for the complete genome sequence of the E. tenella virus. Using the nomenclature generally adopted for viruses, this new isolate was named E. tenella RNA virus 1. This study provides a foundation basis for further research on the biological characteristics of Eimeriaviruses.

Preliminary application of high-definition computed tomographic Gemstone Spectral Imaging in lung cancer.

RATIONALE AND OBJECTIVES: To evaluate the feasibility of multiparameter quantitative measurement lung cancer by Gemstone Spectral Imaging (GSI) high-definition computed tomography. MATERIALS AND METHODS: Seventy-seven patients who were found to have a lung mass or a nodule by CT plain scan for the first time received chest contrast CT scan with GSI mode on high-definition computed tomography. The GSI viewer was used to display the spectral curve, iodine-based images, water-based images, and 101 sets of monochromatic images of a selected region of interest from the relative homogeneous area of the mass or nodule. Iodine concentration, water concentration, spectral curve slope, and CT values at 40 keV of the region of interest were measured. Finally, 68 eligible patients were divided into a pneumonia group (n = 24) and a malignant tumor group (n = 44, including squamous carcinoma, n = 29, and adenocarcinoma, n = 15). RESULTS: Significant differences existed in iodine concentration (t = 6.459), spectral curve slope (t = 6.276), and CT values at 40 keV (t = 6.698) between the pneumonia group and the malignant tumor group (P < 0.05), as well as between squamous carcinoma and adenocarcinoma (t = 6.494, 5.634, 6.091, respectively, P < 0.05), whereas water concentrations were found to have no difference between the 2 groups (t = 0.082, P > 0.05) and between the 2 types of malignant tumors (t = 1.234, P > 0.05). CONCLUSIONS: High-definition computed tomographic GSI technique might be helpful to differentiate lung cancer from lung benign lesions by providing qualitative and quantitative information.

[Reducing the pain of intravenous injections in preschool children].

BACKGROUND & PROBLEMS: Peripheral intravenous catheter insertion is a significant source of stress for preschoolers during hospitalization. An average of about 85% of pediatric patients at our general pediatric unit are preschoolers. An average 71% of these exhibit severe pain-related behavior during intravenous insertions. The factors influencing this pain experience may include inappropriate administration of analgesics by nurses, non-pharmacologic pain management, and inappropriate clinical settings. PURPOSE: This project worked to develop a strategy to reduce the incidence of severe injection pain in preschool children from 71.0% to 36.0% and to achieve a capacity improvement target of 50%. RESOLUTIONS: We implemented the following: 1) arranged a relevant training program for pediatric nurses; 2) revised hospital standards for pediatric intravenous insertions; and 3) enhanced analgesic administration and non-pharmacologic pain management through creating child-friendly clinical settings and providing interactive toys. RESULTS: After implementing the above mentioned interventions, the incidence of severe pain-related behavior in pediatric patients decreased from 71.0% to 19.7%, a result that greatly exceeded expectations. CONCLUSIONS: This project demonstrated an effective approach to reducing severe intravenous-insertion pain in preschoolers and increasing pediatric care quality.

Use of Bilateral Rectus Sheath Blocks in Open Umbilical Hernia Repair.

BACKGROUND: In recent years, the rectus sheath block (RSB) has become increasingly prevalent in laparoscopic surgery. However, there is currently no definitive research on its use in the open repair of umbilical hernias with cirrhotic ascites. OBJECTIVE: In this study, we assessed the safety and clinical efficacy of ultrasound-guided (US-guided) bilateral RSBs in open umbilical hernia repair for patients diagnosed with cirrhotic ascites. STUDY DESIGN: Seventy-two patients diagnosed with umbilical hernias that presented with cirrhotic ascites and who were admitted to our hospital were randomly divided into 2 groups. These categories were labeled the RSB group (Group R) and the local infiltration group (Group L); we used US-guided RSBs in Group R and local infiltration in Group L. SETTING: The clinical outcomes of the patients in each group were compared to one another. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded at various time points in both groups. METHODS: Measurements of the patients' outcomes were taken before anesthesia (T0), at the beginning of surgery (T1), at the time of the separation of the hernia sac (T2), at the end of surgery (T3), 6 hours postoperatively (T4), and 24 hours postoperatively (T5). On the Visual Analog Scale (VAS), pain scores at rest (T1-T3) and during activity (T4-T5) were recorded, as were the incidence of perioperative remedial analgesia and adverse effects. RESULTS: Compared to T0, both groups' HR was significantly higher at T1-T3 (P < 0.05). The SBP and DBP were also significantly higher (P < 0.05). At T1-T3, the HR of Group R was significantly slower than that of Group L (P < 0.05), and at T4-T5, the VAS score for activity in Group R was significantly lower than that of Group L (P < 0.05). Group R had a significantly lower incidence of intraoperative remedial analgesia and postoperative nausea and vomiting than did Group L (P < 0.05). Neither group required postoperative remedial analgesia, and no patient experienced adverse reactions during the perioperative period. LIMITATIONS: This study has limitations in its sample size, lack of blood ammonia levels, and absence of data on patient satisfaction, necessitating future studies to address these issues. CONCLUSION: US-guided RSBs are an efficient method of anesthesia for open umbilical hernia repair in patients diagnosed with cirrhosis. This technique not only provides precise anesthesia and appropriate analgesia but also results in a low incidence of postoperative nausea and vomiting.

Nrf2 activation by pyrroloquinoline quinone inhibits natural aging-related intervertebral disk degeneration in mice.

Age-related intervertebral disk degeneration (IVDD) involves increased oxidative damage, cellular senescence, and matrix degradation. Pyrroloquinoline quinone (PQQ) is a water-soluble vitamin-like compound with strong anti-oxidant capacity. The goal of this study was to determine whether PQQ can prevent aging-related IVDD, and the underlying mechanism. Here, we found that dietary PQQ supplementation for 12 months alleviated IVDD phenotypes in aged mice, including increased disk height index and reduced histological scores and cell loss, without toxicity. Mechanistically, PQQ inhibited oxidative stress, cellular senescence, and senescence-associated secretory phenotype (SASP) in the nucleus pulposus and annulus fibrosus of aged mice. Similarly, PQQ protected against interleukin-1ß-induced matrix degradation, reactive oxygen species accumulation, and senescence in human nucleus pulposus cells (NPCs) in vitro. Molecular docking predicted and biochemical assays validated that PQQ interacts with specific residues to dissociate the Keap1-Nrf2 complex, thereby increasing nuclear Nrf2 translocation and activation of Nrf2-ARE signaling. RNA sequencing and luciferase assays revealed Nrf2 can transcriptionally upregulate Wnt5a by binding to its promoter, while Wnt5a knockdown prevented PQQ inhibition of matrix metalloproteinase-13 in NPCs. Notably, PQQ supplementation failed to alleviate aging-associated IVDD phenotypes and oxidative stress in aged Nrf2 knockout mice, indicating Nrf2 is indispensable for PQQ bioactivities. Collectively, this study demonstrates Nrf2 activation by PQQ inhibits aging-induced IVDD by attenuating cellular senescence and matrix degradation. This study clarifies Keap1-Nrf2-Wnt5a axis as the novel signaling underlying the protective effects of PQQ against aging-related IVDD, and provides evidence for PQQ as a potential agent for clinical prevention and treatment of natural aging-induced IVDD.

Luteoloside Prevents Sevoflurane-induced Cognitive Dysfunction in Aged Rats via Maintaining Mitochondrial Function and Dynamics in Hippocampal Neurons.

Postoperative cognitive dysfunction (POCD) is characterized by impaired cognitive function, such as decreased learning and memory after anesthesia and surgery. This study aimed to explore the effect of luteoloside, a flavonoid extracted from natural herbs, on sevoflurane-induced cognitive dysfunction. Aged Sprague-Dawley male rats (20 months old) were treated with luteoloside for 7 days prior to sevoflurane exposure. After evaluation using an open field, novel object recognition, and Y-maze tests, it was determined that luteoloside effectively prevented sevoflurane-induced cognitive dysfunction. Sevoflurane exposure led to hippocampal neuron apoptosis in vivo (n = 6) and in vitro (n = 3), while this injury was prevented by luteoloside in a dose-dependent manner. Mechanistically, luteoloside maintained mitochondrial function and dynamics, as evidenced by the restored adenosine triphosphate (ATP) production and mitochondrial membrane potential as well as the upregulated levels of mitochondrial fission (optic atrophy protein 1 (Opa1) and mitofusin1 (Mfn1)) and downregulated mitochondrial fusion (mitochondrial fission 1 (Fisl) and dynamin-related protein 1 (Drp1)) factors. Notably, silencing Opa1 blocked the protective effect of luteoloside on hippocampal neurons and mitochondrial function. In summary, luteoloside prevented sevoflurane-induced cognitive dysfunction in aged rats, which may be achieved by regulating mitochondrial dynamics. Our study reveals the potential of luteoloside in preventing POCD in aged patients.

KLK2 single-nucleotide polymorphism rs198977 is associated with increased susceptibility and hyperleukocytosis in AML.

Introduction: Acute myeloid leukemia (AML) is a heterogeneous myeloid malignancy with abnormal molecular diversity. Tissue kallikrein 2 (KLK2) is a kind of serine protease, and has a close relationship with the occurrence and development of malignant tumors. Single nucleotide polymorphism (SNP) of various genes are associated with susceptibility, treatment and survival of AML. Methods: We investigated the association of KLK2 SNPs rs198977 and rs2664155 with AML. We recruited 284 AML patients and 280 healthy controls from the Han population and genotyping KLK2 SNPs rs198977 and rs2664155 by MassARRAY system. Results: Using clinical data from AML patients and controls, including AML susceptibility, blood count, risk stratification, response to induced chemotherapy and survival, our results showed an increased risk of AML susceptibility with KLK2 rs198977 TT genotype in the recessive model. Regarding white blood cell counts in AML patients, the results showed an increased risk of hyperleukocytosis with the TT genotype of KLK2 rs198977 in a codominant model. Moreover, in the recessive model, AML with KLK2 SNPs rs198977 TT genotype had an increased risk of hyperleukocytosis. No significant correlation was found between KLK2 rs2664155 and AML. Discussion: This study suggests that KLK2 rs198977 may be an important genetic factor in the occurrence of AML and hyperleukocytosis in AML, providing a new perspective for disease progression and new therapeutic targets.

Establishing a Predictive Model to Predict Survival of de Novo Metastatic HER2-Low Breast Cancer: A National Cancer Database Analysis.

BACKGROUND: Breast cancer with low human epidermal growth factor receptor (HER2) expression is increasingly considered as a distinct subtype which consists of types of HER2 immunohistochemistry (IHC) 1+ and HER2 IHC 2+/in-situ hybridization (ISH)-negative. We aim to assess the survival difference between HER2 IHC 1+ and HER2 IHC 2+/ISH-negative breast cancer patients with metastasis at presentation and construct a prognostic nomogram for HER2-low patients. METHOD: Patients diagnosed with de novo metastatic HER2-low breast cancer from 2010 to 2015 were included and analyzed using the National Cancer Database (NCDB). Cox proportional hazards regression model and Kaplan-Meier (KM) method were used for survival analysis. Nomograms were built to predict survival. RESULT: A total of 7897 patients were included in the final analysis, among which 5458 (69.1%) patients were HER2 IHC 1+ and 2439 (30.9%) were HER2 IHC 2+/ISH-negative. Although the Kaplan-Meier survival analysis showed difference in survival, this survival difference was lost in the multivariate Cox analysis (multivariate: HR (hazard ratio) = 0.97; 95% CI (confidence interval) [0.92-1.03]). A prognostic nomogram was successfully constructed for individually predicting the long-term survival rate of HER2-low patients, which exhibited an acceptable predictive capability in training (C index: 0.719) and validation cohort (C index: 0.706). This nomogram could easily divide patients into high and low-risk subgroups with distinct prognoses. CONCLUSIONS: Our data suggest no statistical survival differences between HER2 1+ and HER2 2+ breast cancer. Additionally, a nomogram was constructed with an acceptable capacity to individually predict the long-term outcome of HER2-low metastatic breast cancer patients.

Spatial single cell analysis of tumor microenvironment remodeling pattern in primary central nervous system lymphoma.

To determine the overall tumor microenvironment (TME), characteristics, and transition mechanisms in primary central nervous system lymphoma (PCNSL), we performed spatial transcriptomics and matched the corresponding single-cell sequencing data of PCNSL patients. We found that tumor cells may achieve a "TME remodeling pattern" through an "immune pressure-sensing model", in which they could choose to reshape the TME into a barrier environment or a cold environment according to the immune pressure. A key FKBP5+ tumor subgroup was found to be responsible for pushing tumors into the barrier environment, which provides a possible way to evaluate the stage of PCNSL. The specific mechanism of the TME remodeling pattern and the key molecules of the immune pressure-sensing model were identified through the spatial communication analysis. Finally, we discovered the spatial and temporal distributions and variation characteristics of immune checkpoint molecules and CAR-T target molecules in immunotherapy. These data clarified the TME remodeling pattern of PCNSL, provided a reference for its immunotherapy, and provided suggestions for the TME remodeling mechanism of other cancers.

Immune checkpoint-related gene polymorphisms are associated with acute myeloid leukemia.

BACKGROUND: Chemotherapy is still the standard regimen for treating acute myeloid leukemia (AML) and its disappointing efficacy requires the urgent need for new therapeutic targets. It is well known that immune response plays an increasingly significant role in the pathogenesis of AML. METHODS: We detected nine single nucleotide polymorphisms (SNPs) in immune checkpoint-related genes, including PD1, LAG3, TIM3, and TIGIT in 285 AML inpatients and 324 healthy controls. SNP genotyping was performed on the MassARRAY platform. Furthermore, we analyzed the relationship between the susceptibility and prognosis of AML and the selected SNPs. RESULTS: Our results showed that rs2227982 and rs10204525 in PD1 were significantly associated with susceptibility to AML after false discovery rate correction. PD1 rs10204525 also showed a significant correlation with the response to chemotherapy and risk stratification of AML. Importantly, the AA genotype of PD1 (rs2227982) under the recessive model showed a negative impact on AML prognosis independently. CONCLUSIONS: Our results indicate that PD1 SNPs are important for susceptibility and prognosis in AML, which may provide a new therapeutic target for AML patients.