Unveiling novel insights into human IL-6 - IL-6R interaction sites through 3D computer-guided docking and systematic site mutagenesis.

The cytokine interleukin-6 (IL-6) plays a crucial role in autoimmune and inflammatory diseases. Understanding the precise mechanism of IL-6 interaction at the amino acid level is essential to develop IL-6-inhibiting compounds. In this study, we employed computer-guided drug design tools to predict the key residues that are involved in the interaction between IL-6 and its receptor IL-6R. Subsequently, we generated IL-6 mutants and evaluated their binding affinity to IL-6R and the IL-6R - gp130 complex, as well as monitoring their biological activities. Our findings revealed that the R167A mutant exhibited increased affinity for IL-6R, leading to enhanced binding to IL-6R - gp130 complex and subsequently elevated intracellular phosphorylation of STAT3 in effector cells. On the other hand, although E171A reduced its affinity for IL-6R, it displayed stronger binding to the IL-6R - gp130 complex, thereby enhancing its biological activity. Furthermore, we identified the importance of R178 and R181 for the precise recognition of IL-6 by IL-6R. Mutants R181A/V failed to bind to IL-6R, while maintaining an affinity for the IL-6 - gp130 complex. Additionally, deletion of the D helix resulted in complete loss of IL-6 binding affinity for IL-6R. Overall, this study provides valuable insights into the binding mechanism of IL-6 and establishes a solid foundation for future design of novel IL-6 inhibitors.

Isobavachin induces autophagy-mediated cytotoxicity in AML12 cells via AMPK and PI3K/Akt/mTOR pathways.

Isobavachin (IBA) is a dihydroflavonoid compound with various pharmacological effects. However, further investigation into the hepatotoxicity of IBA is necessary. This study aims to identify the hepatotoxic effects of IBA and explore its potential mechanisms. The study assessed the impact of IBA on the viability of AML12, HepG2, LO2, rat, and mouse primary hepatocytes using MTT and LDH assays. Autophagy was detected in AML12 cells after IBA treatment using electron microscopy, MDC, and Ad-mCherry-GFP-LC3B fluorescence. The effect of IBA on autophagy-related proteins was examined using Western blot. The results showed that IBA had dose-dependent inhibitory effects on five cells, induced autophagy in AML12 cells, and promoted autophagic flux. The study found that IBA treatment inhibited phosphorylation of PI3K, Akt, and mTOR, while increasing phosphorylation levels of AMPK and ULK1. Treatment with both AMPK and PI3K inhibitors reversed the expression of AMPK and PI3K-Akt-mTOR signaling pathway proteins. These results suggest that IBA may have hepatocytotoxic effects but can also prevent IBA hepatotoxicity by inhibiting the AMPK and PI3K/Akt/mTOR signaling pathways. This provides a theoretical basis for preventing and treating IBA hepatotoxicity in clinical settings.

An N-terminal heptad repeat trimer-based peptide fusion inhibitor exhibits potent anti-H1N1 activity.

Influenza viruses are susceptible to seasonal influenza, which has repeatedly caused global pandemics and jeopardized human health. Vaccines are only used as preventive medicine due to the extreme mutability of influenza viruses, and antiviral medication is the most significant clinical treatment to reduce influenza morbidity and mortality. Nevertheless, the clinical application of anti-influenza virus agents is characterized by the narrow therapeutic time window, the susceptibility to drug resistance, and relatively limited effect on severe influenza. Therefore, it is of great significance to develop novel anti-influenza virus drugs to fulfill the urgent clinical needs. Influenza viruses enter host cells through the hemagglutinin (HA) mediated membrane fusion process, and fusion inhibitors function antivirally by blocking hemagglutinin deformation, promising better therapeutic efficacy and resolving drug resistance, with targets different from marketed medicines. Previous studies have shown that unnatural peptides derived from Human Immunodeficiency Virus Type 1 (HIV-1) membrane fusion proteins exhibit anti-HIV-1 activity. Based on the similarity of the membrane fusion protein deformation process between HIV-1 and H1N1, we selected sequences derived from the gp41 subunit in the HIV-1 fusion protein, and then constructed N-trimer spatial structure through inter-helical isopeptide bond modification, to design the novel anti-H1N1 fusion inhibitors. The results showed that the novel peptides could block 6-HB formation during H1N1 membrane fusion procedure, and thus possessed significant anti-H1N1 activity, comparable to the positive control oseltamivir. Our study demonstrates the design viability of peptide fusion inhibitors based on similar membrane fusion processes among viruses, and furthermore provides an important idea for the novel anti-H1N1 inhibitors development.

Association between priori and posteriori dietary patterns and gastric cancer risk: an updated systematic review and meta-analysis of observational studies.

An increasing number of epidemiological studies have explored the relationship between the risk of gastric cancer and specific dietary patterns, but the findings remain inconclusive. We, therefore, performed this comprehensive systematic review and meta-analysis to analyze the available evidence regarding the associations between a priori and a posteriori dietary patterns and the risk of gastric cancer. A systematic search of six electronic databases, including PubMed, Web of Science, EBSCO, Scopus, China National Knowledge Infrastructure (CNKI), and Wanfang Data, was carried out to retrieve the relevant articles published up to March 2024. Thirty-six studies (10 cohort and 26 case-control studies) with a total of 2 181 762 participants were included in the final analyses. Combining 15 effect sizes extracted from 12 articles, we observed a reduced risk of gastric cancer in the highest versus the lowest categories of the Mediterranean diet [relative risk (RR), 0.72; 95% confidence interval (CI), 0.61-0.85; P < 0.001]. Combining 11 effect sizes from 10 articles (involving 694 240 participants), we found that the highest Dietary Inflammatory Index scores were significantly associated with an increased risk of gastric cancer (RR, 1.32; 95% CI, 1.11-1.57; P < 0.001). A reduced risk of gastric cancer was shown for the highest compared with the lowest categories of healthy dietary pattern (RR, 0.78; 95% CI, 0.67-0.91; P = 0.002). Conversely, the highest adherence to the Western dietary pattern was associated with an increased risk of gastric cancer (RR, 1.33; 95% CI, 1.19-1.49; P < 0.001). Our study demonstrated that the Mediterranean diet and a healthy dietary pattern were associated with a decreased risk of gastric cancer. Conversely, the Dietary Inflammatory Index and Western dietary pattern were associated with an increased risk of gastric cancer.

Comparison and Evaluation of the Accuracy for Thoracic and Lumbar Pedicle Screw Fixation in Early-Onset Congenital Scoliosis Children.

BACKGROUND: Compared to adult scoliosis, correcting scoliosis in children often presents greater challenges. This is attributed to two key factors. Firstly, it involves accounting for the growth potential of children. Secondly, the thinner pedicles in children can complicate screw insertion, particularly when dealing with existing deformities. The utilization of intraoperative navigation technology offers a modest improvement in the precision of screw placement but does come with the drawback of increased radiation exposure. The aim of this study is to investigate and assess the accuracy of manually inserting pedicle screws in the thoracic and lumbar spine to rectify deformities in children with early-onset congenital scoliosis. METHODS: In this retrospective study, 26 hospitalized patients diagnosed with early-onset congenital scoliosis between December 2014 and December 2019 were selected. The cohort comprised 16 boys and 10 girls, aged between 2 and 10 years, with an average age of 4.68 ± 2.42 years. Pedicle screw fixation was applied in the segment spanning from T1 to L5. Pedicle screws were inserted manually, guided by the positioning of the C-arm and anatomical markers. The assessment of pedicle screw placement was based on the distance of penetration into the medial, lateral, or anterior bone cortex of the vertebral body, including the pedicle, categorized into three grades: Grade 1 (placement <2 mm), Grade 2 (placement between 2-4 mm), and Grade 3 (placement >4 mm). Grade 1 indicates accurate pedicle screw placement, while Grades 2 and 3 signify abnormal pedicle screw placement. Complications related to pedicle screw insertion were also recorded, both during and after the surgical procedure. RESULTS: A total of 173 pedicle screws were inserted in this study, with an average of 6.65 screws per patient. Accurate screw placement was achieved in 143 cases (82.7%), while 30 pedicle screws were found to be abnormal. Among the abnormal screws, 24 were categorized as Grade 2 (13.9%), and 6 as Grade 3 (3.5%). Grade 2 abnormalities were distributed across 20 thoracic vertebrae and 4 lumbar vertebrae, while Grade 3 abnormalities affected 5 thoracic vertebrae and 1 lumbar vertebra. When comparing the lumbar and thoracic vertebral regions, a significant difference in the rate of abnormal screw placement was observed (χ2 = 5.801, p < 0.05). The rate of abnormal screw placement was higher in the thoracic vertebral region with abnormal vertebral bodies than in the lumbar vertebral regions. Furthermore, a statistically significant difference in the rate of abnormal screw placement was found between the concave and convex sides (χ2 = 23.047, p < 0.05). The concave side of the abnormal vertebral body had a higher rate of abnormal screw placement (55.6%, 15/27) compared to the convex side (20.1%, 7/34), and this difference was statistically significant (p < 0.05). Throughout the intraoperative and postoperative follow-up period, spanning from 12 to 56 months, only one patient experienced issues with wound healing, and no complications related to pedicle screw placement occurred, such as hemopneumothorax, pedicle fracture, nerve root injury, aortic injury, screw loosening, pullout or breakage, or spinal cord injury. CONCLUSIONS: In children under 10 years of age with early-onset congenital scoliosis, the freehand placement of thoracic and lumbar pedicle screws demonstrates a high level of accuracy. Moreover, complications associated with pedicle screw insertion are infrequent following surgery. It is advisable to exercise caution when placing pedicle screws in thoracic vertebral bodies and morphologically abnormal vertebral bodies, with particular attention to the concave side when screw placement is required in these regions.

An anoikis-related lncRNA signature is a useful tool for predicting the prognosis of patients with lung adenocarcinoma.

Background: Anoikis-related long non-coding RNAs (ARLs) play a critical role in tumor metastasis and progression, suggesting that they may serve as risk markers for cancer. This study aimed to investigate the prognostic value of ARLs in patients with lung adenocarcinoma (LUAD). Methods: Clinical data, RNA sequencing (RNA-seq) data, and mutation data from the LUAD project were obtained from The Cancer Genome Atlas (TCGA) database. The Molecular Signatures Database (MSigDB) and the GeneCard database were used to collect an anoikis-related gene (ARG) set. Pearson correlation analysis was performed to identify ARLs. LASSO and Cox regression were then used to establish a prognostic risk signature for ARLs. The median risk score served as the basis for categorizing patients into high and low-risk groups. Kaplan-Meier analysis was utilized to compare the prognosis between these two groups. The study also examined the associations between risk scores and prognosis, clinicopathological characteristics, immune status, tumor mutation burden (TMB), and chemotherapeutic agents. LncRNA expression was assessed using quantitative real-time PCR (qRT-PCR). Results: A total of 480 RNA expression profiles, 501 ARGs, and 2698 ARLs were obtained from the database. A prognostic ARL signature for LUAD was established, consisting of 9 lncRNAs. Patients in the low-risk group exhibited significantly better prognosis compared to those in the high-risk group (P < 0.001). The 9 lncRNAs from the ARL signature were identified as independent prognostic factors (P < 0.001). The signature demonstrated high accuracy in predicting LUAD prognosis, with area under the curve values exceeding 0.7. The risk scores for ARLs showed strong negative correlations with stroma score (P = 5.9E-07, R = -0.23), immune score (P = 9.7E-09, R = -0.26), and microenvironment score (P = 8E-11, R = -0.29). Additionally, the low-risk group exhibited significantly higher TMB compared to the high-risk group (P = 4.6E-05). High-risk status was significantly associated with lower half-maximal inhibitory concentrations for most chemotherapeutic drugs. Conclusion: This newly constructed signature based on nine ARLs is a useful instrument for the risk stratification of LUAD patients. The signature has potential clinical significance for predicting the prognosis of LUAD patients and guiding personalized immunotherapy.

Analysis of the factors affecting the loss of correction effect in patients with congenital scoliosis after one stage posterior hemivertebrae resection and orthosis fusion.

BACKGROUND: To analyze the factors affecting the loss of correction effect in patients with congenital scoliosis after one stage posterior hemivertebra resection, orthosis, fusion and internal fixation. METHODS: Thirty-nine patients with congenital scoliosis (CS) who underwent one-stage posterior hemivertebra resection, orthosis, fusion and internal fixation were retrospectively included in Hebei Children's Hospital General demographic information of patients was collected. Preoperative and postoperative imaging indicators were compared, Including cobb Angle of the main curvature of the spine, segmental Cobb Angle, compensatory cephalic curve, compensatory curve on the caudal side, segmental kyphosis, coronal balance, sagittal balance, thoracic kyphosis, lumbar lordosis, and apical vertebra translation. Correlation analysis is used to evaluate the factors affecting the loss of judgment and correction effect, and the correlation indicators are included in the multi-factor Logistics regression. RESULTS: In terms of radiographic indicators in the coronal plane, compared to preoperative values, significant improvements were observed in postoperative Cobb Angle of main curve (8.00°±4.62° vs. 33.30°±9.86°), Segmental Cobb angle (11.87°±6.55° vs. 31.29°±10.03°), Compensatory cephalic curve (6.22°±6.33° vs. 14.75°±12.50°), Compensatory curve on the caudal side (5.58°±3.43° vs. 12.61°±8.72°), coronal balance (10.95 mm ± 8.65 mm vs. 13.52 mm ± 11.03 mm), and apical vertebra translation (5.96 mm ± 5.07 mm vs. 16.55 mm ± 8.39 mm) (all P < 0.05). In the sagittal plane, significant improvements were observed in Segmental kyposis Angle (7.60°±9.36° vs. 21.89°±14.62°, P < 0.05) as compared to preoperative values. At the last follow-up, Segmental kyphosis Angle (6.09°±9.75° vs. 21.89°±14.62°, P < 0.05), Thoracic kyphosis (26.57°±7.68° vs. 24.06°±10.49°, P < 0.05) and Lumbar lordosis (32.12°±13.15° vs. 27.84°±16.68°, P < 0.05) had statistical significance compared with the preoperative department. The correlation analysis showed that the correction effect of the main curve Cobb angle was correlated with fixed segment length (rs=-0.318, P = 0.048), postoperative segment Cobb angle (rs=-0.600, P < 0.001), preoperative apical vertebra translation (rs = 0.440, P = 0.005), and spinal cord malformation (rs=-0.437, P = 0.005). The correction effect of segmental kyphosis was correlated with age (rs = 0.388, P = 0.037). The results of the multivariate logistic regression analysis revealed that postoperative segmental Cobb angle > 10° (OR = 0.011, 95%CI:0.001-0.234, P = 0.004), associated spinal cord anomalies (OR = 24.369, 95%CI:1.057-561.793, P = 0.046), and preoperative apical translation > 10 mm (OR = 0.012, 95%CI:0.000-0.438, P = 0.016) were influential factors in the progression of the main curve Cobb angle. CONCLUSION: The one-stage posterior hemivertebra resection and short-segment corrective fusion with internal fixation are effective means to treat congenital scoliosis. However, attention should be paid to the loss of correction and curve progression during follow-up. Patients with spinal cord malformation and a large preoperative apical vertebra translation have a greater risk of losing the correction after surgery.

Application of DKI and IVIM imaging in evaluating histologic grades and clinical stages of clear cell renal cell carcinoma.

Purpose: To evaluate the value of quantitative parameters derived from diffusion kurtosis imaging (DKI) and intravoxel incoherent motion (IVIM) in differentiating histologic grades and clinical stages of clear cell renal cell carcinoma (ccRCC). Materials and methods: A total of 65 patients who were surgically and pathologically diagnosed as ccRCC were recruited in this study. In addition to routine renal magnetic resonance imaging examination, all patients underwent preoperative IVIM and DKI. The corresponding diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), mean diffusivity (MD), kurtosis anisotropy (KA), and mean kurtosis (MK) values were obtained. Independent-samples t-test or Mann-Whitney U test was used for comparing the differences in IVIM and DKI parameters among different histologic grades and clinical stages. The diagnostic efficacy of IVIM and DKI parameters was evaluated using the receiver operating characteristic (ROC) curve. Spearman's correlation analysis was used to separately analyze the correlation of each parameter with histologic grades and stages of ccRCC. Results: The D and MD values were significantly higher in low-grade ccRCC than high-grade ccRCC (all p < 0.001) and in low-stage than high-stage ccRCC (all p < 0.05), and the f value of high-stage ccRCC was lower than that of low-stage ccRCC (p = 0.007). The KA and MK values were significantly higher in low-grade than high-grade ccRCC (p = 0.000 and 0.000, respectively) and in low-stage than high-stage ccRCC (p = 0.000 and 0.000, respectively). The area under the curve (AUC) values of D, D*, f, MD, KA, MK, DKI, and IVIM+DKI values were 0.825, 0.598, 0.626, 0.792, 0.750, 0.754, 0.803, and 0.857, respectively, in grading ccRCC and 0.837, 0.719, 0.710, 0.787, 0.796, 0.784, 0.864, 0.823, and 0.916, respectively, in staging ccRCC. The AUC of IVIM was 0.913 in staging ccRCC. The D, D*, and MD values were negatively correlated with the histologic grades and clinical stages (all p < 0.05), and the KA and MK values showed a positive correlation with histologic grades and clinical stages (all p < 0.05). The f value was also negatively correlated with the ccRCC clinical stage (p = 0.008). Conclusion: Both the IVIM and DKI values can be used preoperatively to predict the degree of histologic grades and stages in ccRCC, and the D and MD values have better diagnostic performance in the grading and staging. Also, further slightly enhanced diagnostic efficacy was observed in the model with combined IVIM and DKI parameters.

Multifunctional gene delivery vectors containing different liver-targeting fragments for specifically transfecting hepatocellular carcinoma (HCC) cells.

Gene therapy is a promising strategy for HCC treatment, but it commonly faces the problem of low specificity in gene transfection. In this study, we designed and synthesized a series of peptide-based gene delivery vectors (H-01 to H-18) containing varied HCC cell-targeting fragments for specifically binding different receptors highly expressed on HCC cell membranes. The physicochemical properties of peptide vectors or peptide/DNA complexes were characterized, and the gene delivery abilities of peptide vectors were evaluated in HepG2 cell lines. The results showed that peptide vectors H-02 and H-09, which contained targeted fragments for ACE2 and c-Met receptors, respectively, could specifically transfect HCC cells in a highly -efficient manner in vitro. Furthermore, the liver-targeting function in vivo of Cy5.5 labeled H-02 (H-17) and H-09 (H-18) was investigated by fluorescence imaging.

Selective Fluorescent Sensing for Iron in Aqueous Solution by A Novel Functionalized Pillar[5]arene.

Iron ion is one of the most physiologically important elements in metabolic processes, indispensable for all living systems. Since its excess can lead to severe diseases, new approaches for its monitoring in water samples are urgently needed to meet requirements. Here, we firstly report a novel and universal route for the synthesis of a series of pillar[n]arene derivates containing one benzoquinone unit by photocatalysis. With this in hand, an anthracene - appended water - soluble pillar[5]arene (H) with excellent fluorescence sensing potency was prepared. H enabled the ultrasensitive detection of iron ions in aqueous solution with limits of detection of 10-8  M. Over a wide range of metal ions, H exhibited specific selectivity toward Fe3+ . More importantly, H could still properly operate in a simulated sewage sample, coexisting with multiple interference ions.

Cigarette Smoking Contributes to Th1/Th2 Cell Dysfunction via the Cytokine Milieu in Chronic Obstructive Pulmonary Disease.

Background: Dysregulation and pyroptosis of T-helper (Th) cells and inflammatory cytokines have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the immune response mechanisms as a consequence of tobacco smoke exposure are not fully understood. We hypothesized that cigarette smoke-induced inflammation could be modulated through the cytokine milieu and T-cell nicotinic acetylcholine receptors (nAChRs). Methods: The proportions of peripheral blood Th1 and Th2 cells from patients with COPD, smokers without airway obstruction and healthy nonsmokers were analyzed using flow cytometry. The levels of plasma proinflammatory cytokines and their potential association with pulmonary function were also measured. The influence of cigarette smoke extract (CSE) on the conditioned differentiation of T helper cell subsets was further examined in vitro. Results: Significantly higher Th1 cell and plasma IFN-γ and IL-18 levels but lower levels of Th2 cells were found in the peripheral blood from patients with COPD. The increased plasma levels of IFN-γ and IL-18 were negatively correlated with pulmonary function (FEV1% predicted value). Pyroptosis participates in COPD development probably through the activation of the NLRP3 inflammasome upon exposure to CSE. CSE does not directly induce the differentiation of T helper cells; however, under conditioned medium, CSE promotes Th1 development through α7 nAChR modification, while it does not substantially interfere with Th2 differentiation. Conclusion: The differences in the cytokine milieu play a key role in the effects of CSE on the immune response in patients with COPD.

Endoscopic Submucosal Dissection Versus Surgery or Endoscopic Mucosal Resection for Metachronous Early Gastric Cancer: a Meta-analysis.

BACKGROUND: Resection options for early gastric cancer (EGC) include endoscopic submucosal dissection (ESD), endoscopic mucosal resection (EMR), and surgery. In patients with metachronous EGC following previous resection, the optimal resection technique is not well elucidated. We conducted a systematic review and meta-analysis of studies comparing ESD to EMR, or ESD to surgery, in patients with metachronous EGC. METHODS: We conducted an electronic search of studies reporting on outcomes and AEs following ESD versus either EMR or surgery for patients with metachronous EGC. Pooled odds ratios (OR) of included studies were obtained using DerSimonian and Laird random effects models. Funnel plots were produced and visually inspected for evidence of publication bias. The quality of the evidence was assessed using GRADE. RESULTS: A total of 9367 abstracts were screened and 10 observational studies were included. The odds of complete resection were higher amongst patients undergoing ESD compared to EMR (OR 5.88, 95% confidence intervals, CI, 1.79-19.35), whereas the odds of complete resection were no different between ESD and surgery (OR 0.57, 95% CI 0.04-8.24). There were no differences in the odds of local recurrence with ESD versus surgery (OR 5.01, 95% CI 0.86-29.13). Post-procedural bleeding did not differ significantly between ESD and EMR (OR 0.70, 95% CI 0.16-3.00). There was no evidence of publication bias. DISCUSSION: For metachronous EGC, ESD or surgery is preferred over EMR depending on local expertise and patient preferences, largely due to a higher risk of incomplete resection with EMR. REVIEW REGISTRATION: PROSPERO CRD42021270445.

[Mechanism of Marsdenia tenacissima against ovarian cancer based on network pharmacology and experimental verification].

The present study aimed to explore the main active components and underlying mechanisms of Marsdenia tenacissima in the treatment of ovarian cancer(OC) through network pharmacology, molecular docking, and in vitro cell experiments. The active components of M. tenacissima were obtained from the literature search, and their potential targets were obtained from SwissTargetPrediction. The OC-related targets were retrieved from Therapeutic Target Database(TTD), Online Mendelian Inheritance in Man(OMIM), GeneCards, and PharmGKB. The common targets of the drug and the disease were screened out by Venn diagram. Cytoscape was used to construct an "active component-target-disease" network, and the core components were screened out according to the node degree. The protein-protein interaction(PPI) network of the common targets was constructed by STRING and Cytoscape, and the core targets were screened out according to the node degree. GO and KEGG enrichment analyses of potential therapeutic targets were carried out with DAVID database. Molecular docking was used to determine the binding activity of some active components to key targets by AutoDock. Finally, the anti-OC activity of M. tenacissima extract was verified based on SKOV3 cells in vitro. The PI3K/AKT signaling pathway was selected for in vitro experimental verification according to the results of GO function and KEGG pathway analyses. Network pharmacology results showed that 39 active components, such as kaempferol, 11α-O-benzoyl-12ß-O-acetyltenacigenin B, and drevogenin Q, were screened out, involving 25 core targets such as AKT1, VEGFA, and EGFR, and the PI3K-AKT signaling pathway was the main pathway of target protein enrichment. The results of molecular docking also showed that the top ten core components showed good binding affinity to the top ten core targets. The results of in vitro experiments showed that M. tenacissima extract could significantly inhibit the proliferation of OC cells, induce apoptosis of OC cells through the mitochondrial pathway, and down-regulate the expression of proteins related to the PI3K/AKT signaling pathway. This study shows that M. tenacissima has the characteristics of multi-component, multi-target, and multi-pathway synergistic effect in the treatment of OC, which provides a theoretical basis for in-depth research on the material basis, mechanism, and clinical application.

Effect of intraoperative remimazolam on postoperative sleep quality in elderly patients after total joint arthroplasty: a randomized control trial.

PURPOSE: To investigate the effect of intraoperative remimazolam sedation on postoperative sleep quality in elderly patients after total joint arthroplasty. METHODS: Between May 15, 2021 and March 26, 2022, 108 elderly patients (age ≥ 65 years) who received total joint arthroplasty under neuraxial anesthesia were randomized into remimazolam group (a loading dose of 0.025-0.1 mg/kg and followed by an infusion rate of 0.1-1.0 mg/kg/h till end of surgery) or routine group (sedation was given on patient's requirement by dexmedetomidine 0.2-0.7 µg/kg/h). Primary outcome was the subjective sleep quality at surgery night which was evaluated by Richards Campbell Sleep Questionnaire (RCSQ). Secondary outcomes included RCSQ scores at postoperative first and second nights and numeric rating scale pain intensity within first 3 days after surgery. RESULTS: RCSQ score at surgery night was 59 (28, 75) in remimazolam group which was comparable with 53 (28, 67) in routine group (median difference 6, 95% CI - 6 to 16, P = 0.315). After adjustment of confounders, preoperative high Pittsburg sleep quality index was associated worse RCSQ score (P = 0.032), but not remimazolam (P = 0.754). RCSQ score at postoperative first night [69 (56, 85) vs. 70 (54, 80), P = 0.472] and second night [80 (68, 87) vs. 76 (64, 84), P = 0.066] were equivalent between two groups. Safety outcomes were comparable between the two groups. CONCLUSIONS: Intraoperative remimazolam did not significantly improve postoperative sleep quality in elderly patients undergoing total joint arthroplasty. But it is proved to be effective and safe for moderate sedation in these patients. CLINICAL TRIAL NUMBER AND REGISTRY URL: ChiCTR2000041286 ( www.chictr.org.cn ).

HIF-1α inhibitor YC-1 suppresses triple-negative breast cancer growth and angiogenesis by targeting PlGF/VEGFR1-induced macrophage polarization.

Triple negative breast cancer (TNBC) is an invasive and metastatic phenotype of breast cancer with limited treatment options. Published studies have demonstrated an inhibitory effect of HIF-α inhibition by its inhibitor YC-1 (lificiguat) on growth and angiogenesis of TNBC. However, the underlying mechanism remains poorly understood. In the current paper, our results show that HIF-1α inhibitor significantly inhibited TNBC growth by increasing cellular apoptosis and decreasing MVD, independent of a cell-autonomous mechanism in both endothelial and tumor cells. Genetic screening and in vivo experiments showed that a large number of M2-polarized TAMs accumulated in the hypoxic peri-necrotic region (PNR), where placental growth factor (PlGF) and its ligand, vascular endothelial growth factor receptor-1 (VEGFR-1) were upregulated. Furthermore, YC-1 skewed the polarization of TAMs away from M2 to M1 phenotype, therefore inhibiting TNBC angiogenesis and growth. This effect was further abrogated by VEGFR-1 neutralization and TAM depletion following clodronate liposome injection. These findings provide preclinical evidence for an indirect mechanism underlying YC-1-induced suppression of TNBC growth and angiogenesis, thereby offering a treatment option for TNBC.

Combining Serum Procalcitonin Level, Thromboelastography, and Platelet Count to Predict Short-term Development of Septic Shock in Intensive Care Unit.

OBJECTIVE: Despite the recent advances in diagnosis and treatment, sepsis continues to lead to high morbidity and mortality. Early diagnosis and prompt treatment are essential to save lives. However, most biomarkers can only help to diagnose sepsis, but cannot predict the development of septic shock in high-risk patients. The present study determined whether the combined measurement of procalcitonin (PCT), thromboelastography (TEG) and platelet (PLT) count can predict the development of septic shock. METHODS: A retrospective study was conducted on 175 septic patients who were admitted to the intensive care unit between January 2017 and February 2021. These patients were divided into two groups: 73 patients who developed septic shock were assigned to the septic shock group, while the remaining 102 patients were assigned to the sepsis group. Then, the demographic, clinical and laboratory data were recorded, and the predictive values of PCT, TEG and PLT count for the development of septic shock were analyzed. RESULTS: Compared to the sepsis group, the septic shock group had statistically lower PLT count and TEG measurements in the R value, K value, α angle, maximum amplitude, and coagulation index, but had longer prothrombin time (DT), longer activated partial thromboplastin time (APTT), and higher PCT levels. Furthermore, the Sequential Organ Failure Assessment (SOFA) score was higher in the septic shock group. The multivariate logistic regression analysis revealed that PCT, TEG and PLT count were associated with the development of septic shock. The area under the curve analysis revealed that the combined measurement of PCT, TEG and PLT count can be used to predict the development of septic shock with higher accuracy, when compared to individual measurements. CONCLUSION: The combined measurement of PCT, TEG and PLT count is a novel approach to predict the development of septic shock in high-risk patients.

Highly localized, efficient, and rapid photothermal therapy using gold nanobipyramids for liver cancer cells triggered by femtosecond laser.

In this study, the photothermal effect and up-conversion florescence imaging effect of gold nanobipyramids in liver cancer cells are investigated theoretically and experimentally to explore the photothermal ablation tumor therapy with higher photothermal conversion efficiency, shorter laser action time, smaller action range and lower laser power. The small-size gold nanobipyramids with good biocompatibility and infrared absorption peak located in the first biological window are synthesized. Femtosecond laser is focused on the nanobipyramids clusters in cells and the cells die after being irradiated for 20 s at a power as low as 3 mW. In contrast, the control cells die after irradiation with 30 mW laser for 3 min. The theoretical simulation results show that: under femtosecond laser irradiation, the local thermal effect of gold nanoclusters is produced in the range of hundreds of square nanometers and the temperature rises by 516 °C in 106 picoseconds. This therapy reduces the treatment time to seconds level, and the treatment range to square micrometer level, the power to milliwatt level. In this treatment, cells die by apoptosis rather than necrosis, which reduces inflammation. This result opens up a new way to develop photothermal ablation therapy with less side effects and more minimally invasive.

A Parotid Gland Mammary Analogue Secretory Carcinoma in a 4-Year-Old Boy: Case Report and Literature Review.

Background: Mammary analogue secretory carcinoma (MASC) is characterized by similar histologic, immunohistochemical, and molecular features with breast secretory carcinoma. MASC usually occurs in adults. Case report: A 4-year-old boy presented with a right infra-auricular mass. Features of the tumor include solid, tubular, and papillary growth patterns, with homogenous eosinophilic secretions inside microcystic structures. Immunohistochemical stains showed strong, diffuse staining for CK7, S100, pan-TRK protein. P63 was positive in a peripheral pattern. Fluorescence in situ hybridization (FISH) analysis showed the characteristic ETV6-NTRK3 gene fusion. Conclusion: Typical histological, immunohistochemical, and molecular features are present in MASC occurring early in childhood.

Robotic-assisted vs non-robotic traction techniques in endoscopic submucosal dissection for malignant gastrointestinal lesions.

Endoscopic submucosal dissection is an effective approach with higher en bloc resection and complete resection rate for superficial gastrointestinal (GI) lesions. However, endoscopic submucosal dissection is technically challenging and associated with several adverse events, such as bleeding or perforations. The single channel flexible endoscope's intrinsic limitations in preserving visualization of the submucosal dissection plane as compared to laparoscopic surgery are the most common cause of complications during the endoscopic submucosal dissection technique. As a result, traction techniques were created as the endoscope's second helping hand in order to improve the effectiveness of the endoscopic submucosal dissection method. Trainees can master endoscopic submucosal dissection methods more quickly by using traction techniques. The anatomical location of the lesion plays a major role in determining which traction technique should be employed. An appealing way of traction is robot-assisted endoscopic submucosal dissection, and various types of endoscopic robots that allow bimanual operation are currently being developed. The advent of robot-assisted endoscopic technology ushers in a new era of endoscopic submucosal dissection, and with it come its own unique challenges that remain to be elucidated. Future research and development efforts are needed to focus on pathways and curriculums for trainees to master the currently available traction techniques and provide avenues for the development of newer traction modalities. In this article, we discuss evolution, characteristics, technological improvements and clinical comparisons of both robotic and non-robotic endoscopic traction techniques used in endoscopic submucosal dissection.

The changes of hepatic bile acid synthesis and transport and bile acids profiles in isopsoralen-induced liver injury C57BL/6J mice.

CONTEST: Isopsoralen, one of the main active and quality-control compounds in Psoralea corylifolia L. (Fabaceae), has antitumor and oestrogen-like effects. Previous studies demonstrated that isopsoralen induced hepatotoxicity and its long-term exposure led to cholestatic liver injury. OBJECTIVE: This study investigates the effect of three- or seven-day exposure of low dose isopsoralen (80 mg/kg) on bile acid homeostasis in C57BL/6J mice. MATERIALS AND METHODS: Forty-two C57BL/6J mice were randomly divided into control, three- and seven-day groups (n = 14 per group, half female and half male). Isopsoralen suspension was administrated intragastrically at 80 mg/kg once a day. Blood and liver samples were collected to measure biochemical indices and transport of BAs. The histopathology of the liver was also observed. HPLC-MS/MS was also used to measure the BAs profiles and transport activity. RESULTS: In the study, isopsoralen increased the levels of serum AST, ALT in three- and seven-day groups, and caused vacuolar degeneration and swelling in the liver. Canalicular efflux transporters BSEP, OSTα, MRP2, MRP3, and basolateral uptake transporters NTCP, OATP4 were inhibited after seven-day-administration. Moreover, amino acid binding enzymes (BAAT and BACS) were also inhibited after seven-day-administration. The composition of BAs changed greatly and the concentration of some unconjugated-BAs which have stronger hydrophobicity, such as CA, CDCA, was significantly increased. CONCLUSIONS: Isopsoralen (80 mg/kg) caused hepatotoxicity after short-term exposure by inhibiting the expression of efflux transporters, amino acid binding enzymes, and disrupting BAs spectrum.