SEEI: spherical evolution with feedback mechanism for identifying epistatic interactions.

BACKGROUND: Detecting epistatic interactions (EIs) involves the exploration of associations among single nucleotide polymorphisms (SNPs) and complex diseases, which is an important task in genome-wide association studies. The EI detection problem is dependent on epistasis models and corresponding optimization methods. Although various models and methods have been proposed to detect EIs, identifying EIs efficiently and accurately is still a challenge. RESULTS: Here, we propose a linear mixed statistical epistasis model (LMSE) and a spherical evolution approach with a feedback mechanism (named SEEI). The LMSE model expands the existing single epistasis models such as LR-Score, K2-Score, Mutual information, and Gini index. The SEEI includes an adaptive spherical search strategy and population updating strategy, which ensures that the algorithm is not easily trapped in local optima. We analyzed the performances of 8 random disease models, 12 disease models with marginal effects, 30 disease models without marginal effects, and 10 high-order disease models. The 60 simulated disease models and a real breast cancer dataset were used to evaluate eight algorithms (SEEI, EACO, EpiACO, FDHEIW, MP-HS-DHSI, NHSA-DHSC, SNPHarvester, CSE). Three evaluation criteria (pow1, pow2, pow3), a T-test, and a Friedman test were used to compare the performances of these algorithms. The results show that the SEEI algorithm (order 1, averages ranks = 13.125) outperformed the other algorithms in detecting EIs. CONCLUSIONS: Here, we propose an LMSE model and an evolutionary computing method (SEEI) to solve the optimization problem of the LMSE model. The proposed method performed better than the other seven algorithms tested in its ability to identify EIs in genome-wide association datasets. We identified new SNP-SNP combinations in the real breast cancer dataset and verified the results. Our findings provide new insights for the diagnosis and treatment of breast cancer. AVAILABILITY AND IMPLEMENTATION: https://github.com/scutdy/SSO/blob/master/SEEI.zip .

Combinational therapy of CAR T-cell and HDT/ASCT demonstrates impressive clinical efficacy and improved CAR T-cell behavior in relapsed/refractory large B-cell lymphoma.

BACKGROUND: Approximately two-thirds of patients with relapsed or refractory large B-cell lymphoma (R/R LBCL) do not respond to or relapse after anti-CD19 chimeric antigen receptor T (CAR T)-cell therapy, leading to poor outcomes. Previous studies have suggested that intensified lymphodepletion and hematological stem cell infusion can promote adoptively transferred T-cell expansion, enhancing antitumor effects. Therefore, we conducted a phase I/II clinical trial in which CNCT19 (an anti-CD19 CAR T-cell) was administered after myeloablative high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT) in patients with R/R LBCL. METHODS: Transplant-eligible patients with LBCL who were refractory to first-line immunochemotherapy or experiencing R/R status after salvage chemotherapy were enrolled. The study aimed to evaluate the safety and efficacy of this combinational therapy. Additionally, frozen peripheral blood mononuclear cell samples from this trial and CNCT19 monotherapy studies for R/R LBCL were used to evaluate the impact of the combination therapy on the in vivo behavior of CNCT19 cells. RESULTS: A total of 25 patients with R/R LBCL were enrolled in this study. The overall response and complete response rates were 92.0% and 72.0%, respectively. The 2-year progression-free survival rate was 62.3%, and the overall survival was 68.5% after a median follow-up of 27.0 months. No unexpected toxicities were observed. All cases of cytokine release syndrome were of low grade. Two cases (8%) experienced grade 3 or higher CAR T-cell-related encephalopathy syndrome. The comparison of CNCT19 in vivo behavior showed that patients in the combinational therapy group exhibited enhanced in vivo expansion of CNCT19 cells and reduced long-term exhaustion formation, as opposed to those receiving CNCT19 monotherapy. CONCLUSIONS: The combinational therapy of HDT/ASCT and CNCT19 demonstrates impressive efficacy, improved CNCT19 behavior, and a favorable safety profile. TRIAL REGISTRATION NUMBERS: ChiCTR1900025419 and NCT04690192.

Is a low dose of dexamethasone sufficient to prevent paclitaxel-related hypersensitivity reactions? A retrospective study in patients with gynecologic malignancy.

BACKGROUND: Paclitaxel hypersensitivity reactions (HSRs) are prevalent, especially in females. The common paclitaxel pretreatment, dexamethasone, may inhibit chemotherapy efficacy and accelerate tumor progression. We aimed to balance paclitaxel HSRs and the lowest dexamethasone dose for gynecologic malignancies. METHODS: We retrospectively examined 1,074 cycles of 3-weekly paclitaxel-containing treatment for 231 gynecologic malignancies at Xiangya Hospital. HSR incidence with different dexamethasone regimens was the primary outcome. Risk factors were examined in all cycles using univariate and multivariate models with generalized estimating equations. A subgroup analysis of initial exposure to paclitaxel was also conducted. RESULTS: HSR occurred in 33 patients (14.29%) and 49 cycles (4.56%), including 69.39% in cycles 1-2. There were no severe HSRs (grade ≥3). Different premedication regimens, including dexamethasone dosage and route, ranitidine presence or absence, didn't affect HSR incidence in univariate and multivariate analyzes (p > 0.05). Premenopausal women exerted fewer HSRs (ORadj 0.22, 95%CI 0.08-0.58; p = 0.002). At the first exposure to paclitaxel, more than 10 mg of dexamethasone didn't diminish HSRs (OR 0.83, 95%CI 0.27-2.59; p = 0.753). CONCLUSIONS: In gynecologic malignancies, 10 mg dexamethasone along with 20 mg diphenhydramine may be adequate to prevent paclitaxel HSRs without ranitidine. It is necessary to reevaluate paclitaxel premedication regimens.

Shared genetic basis and causality between schizophrenia and inflammatory bowel disease: evidence from a comprehensive genetic analysis.

BACKGROUND: The comorbidity between schizophrenia (SCZ) and inflammatory bowel disease (IBD) observed in epidemiological studies is partially attributed to genetic overlap, but the magnitude of shared genetic components and the causality relationship between them remains unclear. METHODS: By leveraging large-scale genome-wide association study (GWAS) summary statistics for SCZ, IBD, ulcerative colitis (UC), and Crohn's disease (CD), we conducted a comprehensive genetic pleiotropic analysis to uncover shared loci, genes, or biological processes between SCZ and each of IBD, UC, and CD, independently. Univariable and multivariable Mendelian randomization (MR) analyses were applied to assess the causality across these two disorders. RESULTS: SCZ genetically correlated with IBD (rg = 0.14, p = 3.65 × 10−9), UC (rg = 0.15, p = 4.88 × 10−8), and CD (rg = 0.12, p = 2.27 × 10−6), all surpassed the Bonferroni correction. Cross-trait meta-analysis identified 64, 52, and 66 significantly independent loci associated with SCZ and IBD, UC, and CD, respectively. Follow-up gene-based analysis found 11 novel pleiotropic genes (KAT5, RABEP1, ELP5, CSNK1G1, etc) in all joint phenotypes. Co-expression and pathway enrichment analysis illustrated those novel genes were mainly involved in core immune-related signal transduction and cerebral disorder-related pathways. In univariable MR, genetic predisposition to SCZ was associated with an increased risk of IBD (OR 1.11, 95% CI 1.07­1.15, p = 1.85 × 10−6). Multivariable MR indicated a causal effect of genetic liability to SCZ on IBD risk independent of Actinobacteria (OR 1.11, 95% CI 1.06­1.16, p = 1.34 × 10−6) or BMI (OR 1.11, 95% CI 1.04­1.18, p = 1.84 × 10−3). CONCLUSIONS: We confirmed a shared genetic basis, pleiotropic loci/genes, and causal relationship between SCZ and IBD, providing novel insights into the biological mechanism and therapeutic targets underlying these two disorders.

AEBP1 upregulation contributes to cervical cancer progression by facilitating cell proliferation, migration, and invasion.

BACKGROUND: Aberrant expression of adipocyte enhancer-binding protein 1 (AEBP1) has been demonstrated to be involved in the tumorigenesis and progression of numerous cancers. This study was aimed to investigate the mechanism of AEBP1 in the development of cervical cancer. METHODS: The expression of AEBP1 in cervical cancer was assessed by immunohistochemistry. The function of AEBP1 on cell proliferation, migration, and invasion was determined by methyl thiazolyl tetrazolium assay, colony formation, and transwell assay. The activation of related signaling pathway was determined by western blot. The bioinformatics analysis was performed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: Higher protein expression of AEBP1 was observed in patients with cervical cancer. Overexpressed AEBP1 promoted cell proliferation, migration, and invasion abilities in cervical cancer cells. Moreover, the research manifested that AEBP1 activated the phosphorylation of STAT3. GO and KEGG analysis showed that genes positively related to AEBP1 were highly enriched in functions like epithelial cell proliferation, muscle cell migration, myoblast migration, smooth muscle tissue development, ECM-receptor interaction, transcriptional misregulation in cancer, and proteoglycans in cancer. While genes negatively related to AEBP1 were associated with immunity, including inflammatory response, external-stimulus response, neutrophil, granulocyte, and macrophage chemotaxis. CONCLUSIONS: This study suggested that AEBP1 acts as an oncogened and might be a potential therapeutic target for the treatment of cervical cancer.

Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling.

Protein phosphatases are primarily responsible for dephosphorylation modification within signal transduction pathways. Phosphatase of regenerating liver-3 (PRL-3) is a dual-specific phosphatase implicated in cancer pathogenesis. Understanding PRL-3's intricate functions and developing targeted therapies is crucial for advancing cancer treatment. This review highlights its regulatory mechanisms, expression patterns, and multifaceted roles in cancer progression. PRL-3's involvement in proliferation, migration, invasion, metastasis, angiogenesis, and drug resistance is discussed. Regulatory mechanisms encompass transcriptional control, alternative splicing, and post-translational modifications. PRL-3 exhibits selective expressions in specific cancer types, making it a potential target for therapy. Despite advances in small molecule inhibitors, further research is needed for clinical application. PRL-3-zumab, a humanized antibody, shows promise in preclinical studies and clinical trials. Our review summarizes the current understanding of the cancer-related cellular function of PRL-3, its prognostic value, and the research progress of therapeutic inhibitors.

In-Operando Spatiotemporal Imaging of Coupled Film-Substrate Elastodynamics During an Insulator-to-Metal Transition.

The drive toward non-von Neumann device architectures has led to an intense focus on insulator-to-metal (IMT) and the converse metal-to-insulator (MIT) transitions. Studies of electric field-driven IMT in the prototypical VO2 thin-film channel devices are largely focused on the electrical and elastic responses of the films, but the response of the corresponding TiO2 substrate is often overlooked, since it is nominally expected to be electrically passive and elastically rigid. Here, in-operando spatiotemporal imaging of the coupled elastodynamics using X-ray diffraction microscopy of a VO2 film channel device on TiO2 substrate reveals two new surprises. First, the film channel bulges during the IMT, the opposite of the expected shrinking in the film undergoing IMT. Second, a microns thick proximal layer in the substrate also coherently bulges accompanying the IMT in the film, which is completely unexpected. Phase-field simulations of coupled IMT, oxygen vacancy electronic dynamics, and electronic carrier diffusion incorporating thermal and strain effects suggest that the observed elastodynamics can be explained by the known naturally occurring oxygen vacancies that rapidly ionize (and deionize) in concert with the IMT (MIT). Fast electrical-triggering of the IMT via ionizing defects and an active "IMT-like" substrate layer are critical aspects to consider in device applications.

GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer.

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS-STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination.

Genetic Links Between Metabolic Syndrome and Osteoarthritis: Insights from Cross-Trait Analysis.

BACKGROUND: Previous observational studies have indicated a bidirectional association between metabolic syndrome (MetS) and osteoarthritis (OA). However, it remains unclear whether these bidirectional associations reflect causal relationships or shared genetic factors, and the underlying biological mechanisms of this association are not fully understood. METHODS: Leveraging summary statistics from genome-wide association studies (GWASs) conducted by the UK Biobank and the Glucose and Insulin-related Traits Consortium (MAGIC), we performed global genetic correlation analyses, genome-wide cross-trait meta-analyses, and a bidirectional two-sample Mendelian randomization analyses using summary statistics from GWASs to comprehensively assess the relationship of MetS and OA. RESULTS: We first detected an extensive genetic correlation between MetS and OA (rg=0.393, P=1.52×10-18), which was consistent in four MetS components, including waist circumference, triglycerides, hypertension and high-density lipoprotein cholesterol and OA with rg ranging from -0.229 to 0.490. We then discovered 32 variants jointly associated with MetS and OA through multi-trait Analysis of GWAS. Co-localization analysis founded 12 genes shared between MetS and OA, with functional implications in several biological pathways. Finally, MR analysis suggested genetic liability to MetS significantly increased the risk of OA, but no reverse causality was found. CONCLUSION: Our results illustrate a common genetic architecture, pleiotropic loci, as well as causality between MetS and OA, potentially enhancing our knowledge of high comorbidity and genetic processes that overlap between the two disorders.

Distilling lessons from home hospital implementation: a narrative scoping review.

INTRODUCTION: Multiple Cochrane Reviews have demonstrated 'hospital at home' (HaH) as a promising healthcare model to be explored, with benefits such as higher care quality, reduced readmissions, shorter lengths of stay, lower cost and greater patient satisfaction. While there have been many reviews focusing on the quantitative clinical outcomes of HaH, there is generally a lack of collation of qualitative insights from stakeholders and lessons learnt from past HaH implementation. METHODS: We performed a systematic literature search on four databases and included 17 papers involving the provision of acute and/or subacute care by healthcare professionals in patients' homes. Review characteristics and relevant outcomes were extracted from the reported findings and tables in the reviews, and these included stakeholder attitudes and factors contributing to the success of HaH implementation. RESULTS: Factors relating to patients and caregivers included home setup, preference for care and death settings, and support for caregiver. Factors involving the healthcare professionals and intervention included a multidisciplinary care team, accessibility to emergency care and support, training of providers and patients, adequate manpower allocation, robust eligibility and referral criteria, sufficient awareness of the HaH referral pathway, communication and medication management. CONCLUSION: HaH presents a promising alternative care model, and many of the success factors identified, including the strong push for multidisciplinary single care teams, existing frameworks for data sharing and strong community network, are already present today. As such, Singapore appears to be well positioned to adopt a new care model like HaH.

Cost-effectiveness of tumor-treating fields plus standard therapy for advanced non-small cell lung cancer progressed after platinum-based therapy in the United States.

Background: Tumor treating fields (TTF) was first approved for treatment of glioblastoma. Recently, the LUNAR study demonstrated that TTF + standard therapy (ST) extended survival in patients with advanced non-small cell lung cancer (NSCLC). This primary objective of this study is to analyze the cost-effectiveness of this treatment from the United States healthcare payers' perspective. Methods: A 3-health-state Markov model was established to compare the cost-effectiveness of TTF + ST and that of ST alone. Clinical data were extracted from the LUNAR study, supplemented by additional cost and utility data obtained from publications or online sources. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted. The willingness-to-pay (WTP) threshold per quality-adjusted life-years (QALYs) gained was set to $150,000. The main results include total costs, QALYs, incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB). Subgroup analyses were conducted for two types of ST, including immune checkpoint inhibitor, and docetaxel. Results: During a 10-year time horizon, the costs of TTF + ST and ST alone were $431,207.0 and $128,125.9, and the QALYs were 1.809 and 1.124, respectively. The ICER of TTF + ST compared to ST was $442,732.7 per QALY, and the INMB was -$200,395.7 at the WTP threshold. The cost of TTF per month was the most influential factor in cost-effectiveness, and TTF + ST had a 0% probability of being cost-effective at the WTP threshold compared with ST alone. Conclusion: TTF + ST is not a cost-effective treatment for advanced NSCLC patients who progressed after platinum-based therapy from the perspective of the United States healthcare payers.

CSNK2A1 confers gemcitabine resistance to pancreatic ductal adenocarcinoma via inducing autophagy.

Gemcitabine, a pivotal chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC), frequently encounters drug resistance, posing a significant clinical challenge with implications for PDAC patient prognosis. In this study, employing an integrated approach involving bioinformatic analyses from multiple databases, we unveil CSNK2A1 as a key regulatory factor. The patient-derived xenograft (PDX) model further substantiates the critical role of CSNK2A1 in gemcitabine resistance within the context of PDAC. Additionally, targeted silencing of CSNK2A1 expression significantly enhances sensitivity of PDAC cells to gemcitabine treatment. Mechanistically, CSNK2A1's transcriptional regulation is mediated by H3K27 acetylation in PDAC. Moreover, we identify CSNK2A1 as a pivotal activator of autophagy, and enhanced autophagy drives gemcitabine resistance. Silmitasertib, an established CSNK2A1 inhibitor, can effectively inhibit autophagy. Notably, the combinatorial treatment of Silmitasertib with gemcitabine demonstrates remarkable efficacy in treating PDAC. In summary, our study reveals CSNK2A1 as a potent predictive factor for gemcitabine resistance in PDAC. Moreover, targeted CSNK2A1 inhibition by Silmitasertib represents a promising therapeutic strategy to restore gemcitabine sensitivity in PDAC, offering hope for improved clinical outcomes.

Curcumin nicotinate increases LDL cholesterol uptake in hepatocytes through IDOL/LDL-R pathway regulation.

BACKGROUND: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid-lowering effects. OBJECTIVE: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes. METHODS: Differential metabolites in Curtn-treated HepG2 cells were identified via LC-MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high-fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes. RESULTS: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors. CONCLUSION: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy.

High-density lipoprotein cholesterol subfraction HDL2 is associated with improved endothelial function in systemic lupus erythematosus.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have increased risk of premature atherosclerosis but the exact mechanisms remains unclear. Flow-mediated dilatation (FMD) is an established non-invasive assessment of vascular endothelial function. Lipoprotein subfractions may be better predictors of FMD than conventional cholesterol measurements. We tested the hypothesis that lipoprotein subfractions are independently associated with FMD. METHODS: Forty-one consecutive adult patients with SLE without known cardiovascular risk factors or disease were recruited in this cross-sectional study. Endothelial function and early atherosclerosis were assessed by brachial FMD and common carotid artery (CCA) intima-media thickness (IMT). High-density lipoprotein (HDL)/low-density lipoprotein (LDL) subfractions were measured. Machine learning models were also constructed to predict FMD and CCA IMT. RESULTS: Median FMD was 4.48% (IQR 5.00%) while median IMT was 0.54 mm (IQR 0.12 mm). Univariate analysis showed lower LDL1 (r=-0.313, p<0.05) and higher HDL2 subfractions (r=0.313, p<0.05) were significantly associated with higher log-transformed FMD. In a multiple linear regression model, HDL2 (ß=0.024, SE=0.012, p<0.05) remained an independent predictor of higher FMD after adjusting for age, body mass index, LDL1 and systolic blood pressure. The machine learning model included parameters such as HDL2 (positive association), prednisolone dose, LDL cholesterol and LDL1 for prediction of FMD (r=0.433, p<0.01). Age, LDL cholesterol and systolic blood pressure were independently associated with higher CCA IMT after adjusting for body mass index and HDL2. CONCLUSIONS: HDL 2, a large HDL particle, was independently associated with greater FMD and may be a biomarker of vascular health in SLE.

Age-related digital disparities, functional limitations, and social isolation: unraveling the grey digital divide between baby boomers and the silent generation in senior living facilities.

OBJECTIVES: The onset of the digital age has sparked a significant age-related digital divide, detrimentally affecting older adults. The age-related digital disparities and the gray digital divide between the Baby Boomers and the Silent Generation in senior living facilities remains an exigent issue. This study explored the lived experiences of older adults as they confront the challenges posed by age-related digital disparities inherent in the gray digital divide in senior living facilities. METHODS: In-depth, semi-structured interviews and observations were conducted with 28 older adults living in six senior living facilities in three urban locations. Moustakas's transcendental phenomenology was employed, and the Modified Stevick-Colaizzi-Keen method was used to analyze the data. RESULTS: This study identified six main themes: barriers to connectivity, digital literacy, generational-rooted perceptions, navigating technology with functional limitations, social isolation, and end-of-life planning. CONCLUSION: The gray digital divide disproportionately affects older adults in senior living facilities. The study emphasizes the need for tailored interventions and targeted support to address the specific needs of each cohort and reduce age-related disparities. Addressing these disparities has significant implications for academics, policy-makers, senior living accommodations, and technology developers.

"Savoring the Past, Nourishing the Present": Uncovering the Essence of Multicultural Mealtime Experiences in Senior Living Facilities.

Mealtimes are crucial markers of daily schedules and hold significant meaning for older adults in senior living facilities worldwide, extending beyond the food served. Utilizing Moustakas' transcendental phenomenological approach, this study explores the lived experiences and multifaceted meanings of mealtimes for older adults from multicultural backgrounds in senior living facilities in Malaysia. In six urban senior living facilities, 28 older adults from Malaysia's three major ethnic groups, namely Bumiputera Malays, Chinese, and Indians were interviewed through semi-structured one-on-one interviews. Five discernible themes beyond tangible aspects emerged: mealtimes as cultural bridges, memories and palate, emotional bonds through food, quality control and consumption, and comfort through personalized dining experience. This study raises awareness among senior-living facilitators, family caregivers, academics, and policymakers to acknowledge the evident complexities of mealtimes for older adults living away from the comfort of familiarity. Future research should consider the active involvement of all stakeholders in co-creating and implementing interventions that enhance older adults' mealtime experiences in senior-friendly establishments.

Correlation analysis between the in vivo bioavailability and in vitro bioaccessibility of nitro PAHs in soil: Application of simplified FOREhST in vitro methods based on the Chinese pharmacopoeia.

In this study, the relative bioavailability (RBA) of nitrated polycyclic aromatic hydrocarbons (NPAHs) in soil samples (n = 30) was assessed using an in vivo mouse model. Based on the correlation between the bioaccessibility data obtained from the Tenax improved traditional Fed ORganic Estimation human Simulation Test (FOREhST) in vitro method (TITF) and the bioavailability data obtained from in vivo experiments, the TITF method was further optimized and simplified by referring to the "Pharmacopoeia of the People's Republic of China: Volume IV, 2020" to adjust the formulation and parameters of the gastrointestinal fluid (GIF) in order to establish a simpler and lower cost in vitro method for the determination of the bioaccessibilities of NPAHs. The dose-accumulation relationship of the in vivo experiment showed that the linear dose-response was better in adipose tissue (R2 = 0.77-0.93), and the accumulation of NPAHs in adipose tissue was higher than that in kidney or liver tissue. Depending on the mouse adipose model, the NPAHs-RBA ranged from 1.88 % to 73.92 %, and a strongly significant negative relationship (R2 = 0.94, p < 0.05) was found between the NPAHs-RBA and Log Kow. The simplified experiment of the TITF showed that the composition of the GIF medium had a significant effect on the bioaccessibilities of NPAHs. The NPAH bioaccessibilities measured by the Tenax improved simplified FOREhST method (TISF) (9.0-36.5 %) were higher than that of the traditional FOREhST method (6.8-22.8 %) but significantly lower than that of the TITF method (16.8-55.2 %). With an increase in the bile concentration in the GIF (from 6 to 10 g/L), the bioaccessibilities of NPAHs increased from 9.0 to 36.5 % to 12.9-42.4 %. The accuracies of the four in vitro methods for predicting the bioavailabilities of NPAHs was in the following order: Tenax improved simplified FOREhST method with increased bile concentration (TITF-IB) (R2 = 0.54-0.87) ≈ TITF (R2 = 0.55-0.85) > TISF (R2 = 0.41-0.77) > FOREhST (R2 = 0.02-0.68). These results indicated that the simple in vitro method could also effectively predict the bioavailabilities of NPAHs.

An elastase-inhibiting, plaque-targeting and neutrophil-hitchhiking liposome against atherosclerosis.

Neutrophil extracellular traps (NETs) play a crucial role in the formation of vulnerable plaques and the development of atherosclerosis. Alleviating the pathological process of atherosclerosis by efficiently targeting neutrophils and inhibiting the activity of neutrophil elastase to inhibit NETs is relatively unexplored and is considered a novel therapeutic strategy with clinical significance. Sivelestat (SVT) is a second-generation competitive inhibitor of neutrophil elastase with high specificity. However, therapeutic effect of SVT on atherosclerosis is restricted because of the poor half-life and the lack of specific targeting. In this study, we construct a plaque-targeting and neutrophil-hitchhiking liposome (cRGD-SVT-Lipo) to improve the efficacy of SVT in vivo by modifying the cRGD peptide onto SVT loaded liposome, which was based on the interaction between cRGD peptide and integrin ανß3 on the surface of cells in blood and plaque, including epithelial cell, macrophage and neutrophils. The cRGD-SVT-Lipo could actively tend to or hitchhike neutrophils in situ to reach atherosclerotic plaque, which resulted in enhanced atherosclerotic plaque delivery. The cRGD-SVT-Lipo could also reduce plaque area, stabilize plaque, and ultimately alleviate atherosclerosis progression through efficiently inhibiting the activity of neutrophil elastase in atherosclerotic plaque. Therefore, this study provides a basis and targeting strategy for the treatment of neutrophil-related diseases. STATEMENT OF SIGNIFICANCE: Neutrophil extracellular traps (NETs)-inhibiting is a prospective therapeutic approach for atherosclerosis but has received little attention. The NETs can be inhibited by elastase-restraining. In this work, an intriguing system that delivers Sivelestat (SVT), a predominantly used neutrophil elastase inhibitor with poor targeting capability, is designed to provide the drug with plaque-targeting and neutrophil-hitchhiking capability. The result suggests that this system can effectively hinder the formation of NETs and delay the progression of atherosclerosis.

Peptidomic analysis of follicular fluid in patients with polycystic ovarian syndrome.

Objective: The aim of this study was to analyze and compare the differential expression of peptides within the follicular fluid of polycystic ovary syndrome (PCOS) patients versus normal women by using peptidomics techniques. The underlying mechanisms involved in PCOS pathogenesis will be explored, together with screening and identification of potential functional peptides via bioinformatics analysis. Materials and methods: A total of 12 patients who underwent in vitro fertilization and embryo transfer (IVF-ET) at the Reproductive Medicine Center of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from 1 September 2022 to 1 November 2022 were included in this study. The follicular fluid of PCOS patients (n = 6) and normal women (n = 6) were collected. The presence and concentration differences of various peptides were detected by the LC-MS/MS method. GO and KEGG analysis were performed on the precursor proteins of the differentially-expressed peptides, and protein network interaction analysis was carried out to identify functionally-relevant peptides among the various peptides. Results: A variety of peptides within the follicular fluid of PCOS versus normal patients were detected by peptidomics techniques. Altogether, 843 upregulated peptides and 236 downregulated peptides were detected (absolute fold change ≥2 and p < 0.05). Of these, 718 (718 = 488 + 230) peptides were only detected in the PCOS group, while 205 (205 = 174 + 31) were only detected in the control group. Gene Ontology enrichment and pathway analysis were performed to characterize peptides through their precursor proteins. We identified 18 peptides from 7 precursor proteins associated with PCOS, and 4 peptide sequences were located in the functional domains of their corresponding precursor proteins. Conclusion: In this study, differences in the follicular development of PCOS versus normal patients were revealed from the polypeptidomics of follicular development, which thus provided new insights for future studies on the pathological mechanisms of PCOS development.