Overexpressed Trophoblast Glycoprotein Contributes to Preeclampsia Development by Inducing Abnormal Trophoblast Migration and Invasion Toward the Uterine Spiral Artery.

BACKGROUND: Preeclampsia is a significant pregnancy disorder with an unknown cause, mainly attributed to impaired spiral arterial remodeling. METHODS: Using RNA sequencing, we identified key genes in placental tissues from healthy individuals and preeclampsia patients. Placenta and plasma samples from pregnant women were collected to detect the expression of TPBG (trophoblast glycoprotein). Pregnant rats were injected with TPBG-carrying adenovirus to detect preeclamptic features. HTR-8/SVneo cells transfected with a TPBG overexpression lentiviral vector were used in cell function experiments. The downstream molecular mechanisms of TPBG were explored using RNA sequencing and single-cell RNA sequencing data. TPBG expression was knocked down in the lipopolysaccharide-induced preeclampsia-like rat model to rescue the preeclampsia features. We also assessed TPBG's potential as an early preeclampsia predictor using clinical plasma samples. RESULTS: TPBG emerged as a crucial differentially expressed gene, expressed specifically in syncytiotrophoblasts and extravillous trophoblasts. Subsequently, we established a rat model with preeclampsia-like phenotypes by intravenously injecting TPBG-expressing adenoviruses, observing impaired spiral arterial remodeling, thus indicating a causal correlation between TPBG overexpression and preeclampsia. Studies with HTR-8/SVneo cells, chorionic villous explants, and transwell assays showed TPBG overexpression disrupts trophoblast/extravillous trophoblast migration/invasion and chemotaxis. Notably, TPBG knockdown alleviated the lipopolysaccharide-induced preeclampsia-like rat model. We enhanced preeclampsia risk prediction in early gestation by combining TPBG expression with established clinical predictors. CONCLUSIONS: These findings are the first to show that TPBG overexpression contributes to preeclampsia development by affecting uterine spiral artery remodeling. We propose TPBG levels in maternal blood as a predictor of preeclampsia risk. The proposed mechanism by which TPBG overexpression contributes to the occurrence of preeclampsia via its disruptive effect on trophoblast and extravillous trophoblast migration/invasion on uterine spiral artery remodeling, thereby increasing the risk of preeclampsia.

Four-years change of BMI and waist circumference are associated with metabolic syndrome in middle-aged and elderly Chinese.

The purpose of the study was to determine whether changes in body mass index (BMI) and waist circumference (WC) in middle-aged and elderly Chinese are associated with metabolic syndrome. In this cohort investigation, 3697 middle-aged and elderly people aged 45 or over were recruited from the China Health and Retirement Longitudinal Study (CHARLS). The National Cholesterol Education Program Adult Treatment Panel III (2005) defined metabolic syndrome (MetS). With Cox regression analysis, we calculated hazard ratio (HR) and 95% confidence intervals (CIs) for MetS based on BMI-WC change categories. To assess the prevalence of MetS, the changes in BMI and WC levels were classified into four quartiles based on their relative and absolute changes. In subjects whose BMI and WC decreased (HR = 0.338; 95% CIs 0.264, 0.433) as well as those whose BMI increased and their WC decreased (HR = 0.375; 95% CIs 0.228, 0.499), metabolic syndrome risk was significantly lower compared with those with increases in both BMI and WC. Regarding the absolute changes in BMI, the lowest percentile of BMI was significantly lower in both males (HR = 0.302; 95% CIs 0.204, 0.448) and females (HR = 0.486; 95% CIs 0.354, 0.667) for the risk of metabolic syndrome. Similar results were observed in the absolute changes in WC, with the lowest quantile of WC having a significant impact on MetS risk in males (HR = 0.170; 95% CIs 0.107, 0.270) and females (HR = 0.303; 95% CIs 0.217, 0.424). The risk of metabolic syndrome was significantly associated with changes in BMI and WC in middle-aged and elderly Chinese. A reduced BMI and WC are associated with lower metabolic syndrome risks in middle-aged and elderly people.

Hernandezine promotes cancer cell apoptosis and disrupts the lysosomal acidic environment and cathepsin D maturation.

Hernandezine (Her), a bisbenzylisoquinoline alkaloid extracted from Thalictrum flavum, is recognized for its range of biological activities inherent to this herbal medicine. Despite its notable properties, the anti-cancer effects of Her have remained largely unexplored. In this study, we elucidated that Her significantly induced cytotoxicity in cancer cells through the activation of apoptosis and necroptosis mechanisms. Furthermore, Her triggered autophagosome formation by activating the AMPK and ATG5 conjugation systems, leading to LC3 lipidation. Our findings revealed that Her caused damage to the mitochondrial membrane, with the damaged mitochondria undergoing mitophagy, as evidenced by the elevated expression of mitophagy markers. Conversely, Her disrupted autophagic flux, demonstrated by the upregulation of p62 and accumulation of autolysosomes, as observed in the RFP-GFP-LC3 reporter assay. Initially, we determined that Her did not prevent the fusion of autophagosomes and lysosomes. However, it inhibited the maturation of cathepsin D and increased lysosomal pH, indicating an impairment of lysosomal function. The use of the early-stage autophagy inhibitor, 3-methyladenine (3-MA), did not suppress LC3II, suggesting that Her also induces noncanonical autophagy in autophagosome formation. The application of Bafilomycin A1, an inhibitor of noncanonical autophagy, diminished the recruitment of ATG16L1 and the accumulation of LC3II by Her, thereby augmenting Her-induced cell death. These observations imply that while autophagy initially plays a protective role, the disruption of the autophagic process by Her promotes programmed cell death. This study provides the first evidence of Her's dual role in inducing apoptosis and necroptosis while also initiating and subsequently impairing autophagy to promote apoptotic cell death. These insights contribute to a deeper understanding of the mechanisms underlying programmed cell death, offering potential avenues for enhancing cancer prevention and therapeutic strategies.

Modulation of neuroinflammation and oxidative stress by targeting GPR55 - new approaches in the treatment of psychiatric disorders.

Pharmacological treatment of psychiatric disorders remains challenging in clinical, pharmacological, and scientific practice. Even if many different substances are established for treating different psychiatric conditions, subgroups of patients show only small or no response to the treatment. The neuroinflammatory hypothesis of the genesis of psychiatric disorders might explain underlying mechanisms in these non-responders. For that reason, recent research focus on neuroinflammatory processes and oxidative stress as possible causes of psychiatric disorders. G-protein coupled receptors (GPCRs) form the biggest superfamily of membrane-bound receptors and are already well known as pharmacological targets in various diseases. The G-protein coupled receptor 55 (GPR55), a receptor considered part of the endocannabinoid system, reveals promising modulation of neuroinflammatory and oxidative processes. Different agonists and antagonists reduce pro-inflammatory cytokine release, enhance the synthesis of anti-inflammatory mediators, and protect cells from oxidative damage. For this reason, GPR55 ligands might be promising compounds in treating subgroups of patients suffering from psychiatric disorders related to neuroinflammation or oxidative stress. New approaches in drug design might lead to new compounds targeting different pathomechanisms of those disorders in just one molecule.

Construction and significance of a breast cancer prognostic model based on cuproptosis-related genotyping and lncRNAs.

BACKGROUND: /Purpose: Cuproptosis may play a significant role in breast cancer (BC). We aimed to investigate the prognostic impact of cuproptosis-related lncRNAs in BC. METHODS: Consensus clustering analysis categorized TCGA-BRCA samples into 3 clusters, followed by survival and immune analyses of the 3 clusters. LASSO-COX analysis was performed on cuproptosis-related lncRNAs differentially expressed in BC to construct a BC prognostic model. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment, immune, and drug prediction analyses were performed on the high-risk and low-risk groups. Cell experiments were conducted to analyze the results of drug prediction and two cuproptosis-related lncRNAs (AC104211.1 and LINC01863). RESULTS: Significant differences were observed in survival outcomes and immune infiltration levels among the three clusters (p < 0.05). The validation of the model showed significant differences in survival outcomes between the high-risk and low-risk groups in both the training and validation sets (p < 0.05). Differential mRNAs between the two groups were significantly enriched in the Neuroactive ligand-receptor interaction and cAMP signaling pathway. Additionally, significant differences were found in immune infiltration levels, human leukocyte antigen (HLA) expression, Immunophenoscore (IPS) scores, and Tumor Immune Dysfunction and Exclusion (TIDE) scores between the two groups (p < 0.05). Drug prediction and corresponding cell experimental results showed that Trametinib, 5-fluorouracil, and AICAR significantly inhibited the viability of MCF-7 cells (p < 0.05). AC104211.1 and LINC01863 were found to impact the proliferation of BC cells. CONCLUSION: The risk-scoring model obtained in this study may serve as a robust prognostic biomarker, potentially aiding in clinical decision-making for BC patients.

Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200 mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400 mg (n = 12); group 3-single dose study with pivmecillinam 600 mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24 h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600 mg) or multiple-dose (400 mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

Role of tcaA, a potential target as a ceftobiprole resistance breaker, in MRSA ß-lactam resistance.

OBJECTIVES: Using a random forest algorithm, we previously found that teicoplanin-associated gene A (tcaA) might play a role in resistance of methicillin-resistant Staphylococcus aureus (MRSA) to ß-lactams, which we have investigated further here. METHODS: Representative MRSA strains of prevalent clones were selected to identify the role of tcaA in the MRSA response to ß-lactams. tcaA genes were deleted by homologous recombination in the selected MRSA strains, and antibiotic susceptibility tests were applied to evaluate the effect of tcaA on the minimum inhibitory concentrations (MICs) of glycopeptides and ß-lactams. Scanning electron microscopy, RNA sequencing, and quantitative reverse transcription-polymerase chain reaction were performed to explore the mechanism of tcaA in MRSA resistance to ß-lactams. RESULTS: The MIC of penicillin plus clavulanate decreased from 3 mg/L to 0.064 mg/L and that of oxacillin decreased from 16 to 0.5 mg/L when tcaA was knocked out in the LAC strain. Compared with wild-type MRSA isolates, when tcaA was deleted, all selected strains were more susceptible to ß-lactams. Susceptibility to ceftobiprole was restored in the ceftobiprole-resistant strain when tcaA was deleted. tcaA knockout caused "log-like" abnormal division of MRSA, and tcaA deficiency mediated low expression of mecA, ponA, and murA2. CONCLUSIONS: Machine learning is a reliable tool for identifying drug resistance-related genes. tcaA may be involved in S. aureus cell division and may affect mecA, ponA, and murA2 expression. Furthermore, tcaA is a potential resistance breaker target for ß-lactams, including ceftobiprole, in MRSA.

Macrophages and tumor-associated macrophages in the senescent microenvironment: From immunosuppressive TME to targeted tumor therapy.

In-depth studies of the tumor microenvironment (TME) have helped to elucidate its cancer-promoting mechanisms and inherent characteristics. Cellular senescence, which acts as a response to injury and can the release of senescence-associated secretory phenotypes (SASPs). These SASPs release various cytokines, chemokines, and growth factors, remodeling the TME. This continual development of a senescent environment could be associated with chronic inflammation and immunosuppressive TME. Additionally, SASPs could influence the phenotype and function of macrophages, leading to the recruitment of tumor-associated macrophages (TAMs). This contributes to tumor proliferation and metastasis in the senescent microenvironment, working in tandem with immune regulation, angiogenesis, and therapeutic resistance. This comprehensive review covers the evolving nature of the senescent microenvironment, macrophages, and TAMs in tumor development. We also explored the links between chronic inflammation, immunosuppressive TME, cellular senescence, and macrophages. Moreover, we compiled various tumor-specific treatment strategies centered on cellular senescence and the current challenges in cellular senescence research. This study aimed to clarify the mechanism of macrophages and the senescent microenvironment in tumor progression and advance the development of targeted tumor therapies.

Optimal obesity- and lipid-related indices for predicting type 2 diabetes in middle-aged and elderly Chinese.

To investigate the screening and predicting functions of obesity- and lipid-related indices for type 2 diabetes (T2D) in middle-aged and elderly Chinese, as well as the ideal predicted cut-off value. This study's data comes from the 2011 China Health and Retirement Longitudinal Study (CHARLS). A cross-sectional study design was used to investigate the relationship of T2D and 13 obesity- and lipid-related indices, including body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), lipid accumulation product (LAP), conicity index (CI), Chinese visceral adiposity index (CVAI), triglyceride- glucose index (TyG index) and its correlation index (TyG-BMI, TyG-WC, TyG-WHtR). The unadjusted and adjusted correlations between 13 indices and T2D were assessed using binary logistic regression analysis. The receiver operating characteristic curve (ROC) was used to determine the usefulness of anthropometric indices for screening for T2D and determining their cut­off value, sensitivity, specificity, and area under the curve (AUC). The study comprised 9488 people aged 45 years or above in total, of whom 4354 (45.89%) were males and 5134 (54.11%) were females. Among them were 716 male cases of T2D (16.44%) and 870 female cases of T2D (16.95%). A total of 13 obesity- and lipid-related indices were independently associated with T2D risk after adjusted for confounding factors (P < 0.05). According to ROC analysis, the TyG index was the best predictor of T2D among males (AUC = 0.780, 95% CI 0.761, 0.799) and females (AUC = 0.782, 95% CI 0.764, 0.799). The AUC values of the 13 indicators were higher than 0.5, indicating that they have predictive values for T2D in middle-aged and elderly Chinese. The 13 obesity- and lipid-related indices can predict the risk of T2D in middle­aged and elderly Chinese. Among 13 indicators, the TyG index is the best predictor of T2D in both males and females. TyG-WC, TyG-BMI, TyG-WHtR, LAP, and CVAI all outperformed BMI, WC, and WHtR in predicting T2D.

The bidirectional relationship between activities of daily living and frailty during short-and long-term follow-up period among the middle-aged and older population: findings from the Chinese nationwide cohort study.

Objective: Frailty and activities of daily living (ADL) disability are common conditions among older population. Studies on the bidirectional relationship between frailty and ADL are limited. The current study examined the cross-sectional and longitudinal associations between frailty and ADL in middle-aged and older Chinese individuals. Methods: The data was collected through the China Health and Retirement Longitudinal Study (CHARLS), conducted in 2011, 2013, and 2015, encompassing 17,284 individuals aged ≥45 years. We excluded individuals without follow-up data. 2,631 participants finished the baseline survey. The definition of ADL disability encompasses difficulty in engaging in either basic activities of daily living (BADL) or instrumental activities of daily living (IADL). Frailty was assessed according to the Fried criteria. Logistic regression was utilized to examine odds ratios (ORs) and 95% confidence intervals (CIs) for assessing the cross-sectional relationships between ADL with frailty at baseline. The prediction effects were explored using Cox proportional hazards analysis, testing hazard ratios (HRs) and 95%CIs. Results: In cross-sectional analysis, BADL [OR = 6.660 (4.519-9.815)], IADL [OR = 5.950 (4.490-7.866)], and ADL [OR = 5.658 (4.278-7.483)] exhibited significant associations with frailty; frailty demonstrated significant associations with BADL [OR = 6.741 (4.574-9.933)], IADL [OR = 6.042 (4.555-8.016)] and ADL [OR = 5.735 (4.333-7.591)]. In longitudinal analysis, IADL and ADL were significantly associated with frailty in participants without baseline frailty in the short-term period [IADL: HR = 1.971 (1.150-3.379), ADL: HR = 1.920 (1.146-3.215)], IADL exhibited a significant association with frailty in the long-term period [HR = 2.056 (1.085-3.895)]. There was no significant link observed between frailty and an elevated risk of disability onset in BADL, IADL and ADL during the short-term period. When considering the long-term perspective, frailty exhibited a significant association with an elevated risk of disability onset in BADL [HR= 1.820 (1.126-2.939)] and IADL [HR = 1.724 (1.103-2.694)]. Conclusion: In middle-aged and older adults, ADL and IADL disability predicted frailty after 2-year follow-up, IADL disability predicted frailty after 4-year follow-up. Moreover, frailty did not predict BADL, IADL and ADL disability after 2-year follow-up. However, frailty predicted BADL and IADL disability after 4-year follow-up.

Calcium signaling crosstalk between the endoplasmic reticulum and mitochondria, a new drug development strategies of kidney diseases.

Calcium (Ca2+) acts as a second messenger and constitutes a complex and large information exchange system between the endoplasmic reticulum (ER) and mitochondria; this process is involved in various life activities, such as energy metabolism, cell proliferation and apoptosis. Increasing evidence has suggested that alterations in Ca2+ crosstalk between the ER and mitochondria, including alterations in ER and mitochondrial Ca2+ channels and related Ca2+ regulatory proteins, such as sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), inositol 1,4,5-trisphosphate receptor (IP3R), and calnexin (CNX), are closely associated with the development of kidney disease. Therapies targeting intracellular Ca2+ signaling have emerged as an emerging field in the treatment of renal diseases. In this review, we focused on recent advances in Ca2+ signaling, ER and mitochondrial Ca2+ monitoring methods and Ca2+ homeostasis in the development of renal diseases and sought to identify new targets and insights for the treatment of renal diseases by targeting Ca2+ channels or related Ca2+ regulatory proteins.

Formation and Fluorescent Mechanism of Multiple Color Emissive Carbon Dots from o-Phenylenediamine.

Carbon dots (CDs) have received considerable attention in many application areas owing to their unique optical properties and potential applications; however, the fluorescent mechanism is an obstacle to their applications. Herein, three-color emissive CDs are prepared from single o-phenylenediamine (oPD) by regulating the ratio of ethanol and dimethylformamide (DMF). Fluorescent mechanism of these CDs is proposed as molecular state fluorescence. Reaction intermediates are identified using liquid chromatrography-mass spectroscopy (LC-MS) and 1H nuclear magnetic resonance (NMR) spectra. 1H-Benzo[d]imidazole (BI), 2,3-diaminophenazine (DAP), and 5,14-dihydroquinoxalino[2,3-b] phenazine (DHQP) are proposed to be the fluorophores of blue, green, and red emissive CDs by comparing their optical properties. As per the LC-MS and 1H-NMR analysis, DHQP with red emission tends to form from DAP and oPD in pure ethanol. By adding DMF, BI formation is enhanced and DHQP formation is suppressed. The prepared CDs exhibit green emission with DAP. When the DMF amount is >50%, BI formation is considerably promoted, resulting in DAP formation being suppressed. BI with blue emission then turns into the fluorophore of CDs. This result provides us an improved understanding of the fluorescent mechanism of oPD-based CDs, which guides us in designing the structure and optical properties of CDs.

Development and validation of nomograms to predict survival and recurrence after hepatectomy for intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma.

BACKGROUND: Despite the Barcelona Clinic Liver Cancer system discouraging hepatectomy for intermediate/advanced hepatocellular carcinoma, the procedure is still performed worldwide, particularly in Asia. This study aimed to develop and validate nomograms for predicting survival and recurrence for these patients. METHODS: We analyzed patients who underwent curative-intent hepatectomy for intermediate/advanced hepatocellular carcinoma between 2010 and 2020 across 3 Chinese hospitals. The Eastern Hepatobiliary Surgery Hospital cohort was used as the training cohort for the nomogram construction, and the Jilin First Hospital and Fujian Mengchao Hepatobiliary Hospital cohorts served as the external validation cohorts. Independent preoperative predictors for survival and recurrence were identified through univariable and multivariable Cox regression analyses. Predictive accuracy was measured using the concordance index and calibration curves. The predictive performance between nomograms and conventional hepatocellular carcinoma staging systems was compared. RESULTS: A total of 1,328 patients met the inclusion criteria. The nomograms for predicting survival and recurrence were developed using 10 and 6 independent variables, respectively. Nomograms' concordance indices in the training cohort were 0.777 (95% confidence interval 0.759-0.800) and 0.719 (95% confidence interval 0.697-0.742) for survival and recurrence, outperforming 4 conventional staging systems (P < .001). Nomograms accurately stratified risk into low, intermediate, and high subgroups. These results were validated well by 2 external validation cohorts. CONCLUSION: We developed and validated nomograms predicting survival and recurrence for patients with intermediate/advanced hepatocellular carcinoma, contradicting Barcelona Clinic Liver Cancer surgical guidelines. These nomograms may facilitate clinicians to formulate personalized surgical decisions, estimate long-term prognosis, and strategize neoadjuvant/adjuvant anti-recurrence therapy.

Obesity and lipid indices as predictors of depressive symptoms in middle-aged and elderly Chinese: insights from a nationwide cohort study.

BACKGROUND: Depressive symptoms are one of the most common psychiatric disorders, with a high lifetime prevalence rate among middle-aged and elderly Chinese. Obesity may be one of the risk factors for depressive symptoms, but there is currently no consensus on this view. Therefore, we investigate the relationship and predictive ability of 13 obesity- and lipid-related indices with depressive symptoms among middle-aged and elderly Chinese. METHODS: The data were obtained from The China Health and Retirement Longitudinal Study (CHARLS). Our analysis includes individuals who did not have depressive symptoms at the baseline of the CHARLS Wave 2011 study and were successfully follow-up in 2013 and 2015. Finally, 3790 participants were included in the short-term (from 2011 to 2013), and 3660 participants were included in the long-term (from 2011 to 2015). The average age of participants in short-term and long-term was 58.47 years and 57.88 years. The anthropometric indicators used in this analysis included non-invasive [e.g. waist circumference (WC), body mass index (BMI), and a body mass index (ABSI)], and invasive anthropometric indicators [e.g. lipid accumulation product (LAP), triglyceride glucose index (TyG index), and its-related indices (e.g. TyG-BMI, and TyG-WC)]. Receiver operating characteristic (ROC) analysis was used to examine the predictive ability of various indicators for depressive symptoms. The association of depressive symptoms with various indicators was calculated using binary logistic regression. RESULTS: The overall incidence of depressive symptoms was 20.79% in the short-term and 27.43% in the long-term. In males, WC [AUC = 0.452], LAP [AUC = 0.450], and TyG-WC [AUC = 0.451] were weak predictors of depressive symptoms during the short-term (P < 0.05). In females, BMI [AUC = 0.468], LAP [AUC = 0.468], and TyG index [AUC = 0.466] were weak predictors of depressive symptoms during the long-term (P < 0.05). However, ABSI cannot predict depressive symptoms in males and females during both periods (P > 0.05). CONCLUSION: The research indicates that in the middle-aged and elderly Chinese, most obesity- and lipid-related indices have statistical significance in predicting depressive symptoms, but the accuracy of these indicators in prediction is relatively low and may not be practical predictors.

TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

A new integrative analysis of histopathology and single cell RNA-seq reveals the CCL5 mediated T and NK cell interaction with vascular cells in idiopathic pulmonary arterial hypertension.

BACKGROUND: Inflammation and dysregulated immunity play vital roles in idiopathic pulmonary arterial hypertension (IPAH), while the mechanisms that initiate and promote these processes are unclear. METHODS: Transcriptomic data of lung tissues from IPAH patients and controls were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, protein-protein interaction (PPI) and functional enrichment analysis were combined with a hemodynamically-related histopathological score to identify inflammation-associated hub genes in IPAH. The monocrotaline-induced rat model of pulmonary hypertension was utilized to confirm the expression pattern of these hub genes. Single-cell RNA-sequencing (scRNA-seq) data were used to identify the hub gene-expressing cell types and their intercellular interactions. RESULTS: Through an extensive bioinformatics analysis, CXCL9, CCL5, GZMA and GZMK were identified as hub genes that distinguished IPAH patients from controls. Among these genes, pulmonary expression levels of Cxcl9, Ccl5 and Gzma were elevated in monocrotaline-exposed rats. Further investigation revealed that only CCL5 and GZMA were highly expressed in T and NK cells, where CCL5 mediated T and NK cell interaction with endothelial cells, smooth muscle cells, and fibroblasts through multiple receptors. CONCLUSIONS: Our study identified a new inflammatory pathway in IPAH, where T and NK cells drove heightened inflammation predominantly via the upregulation of CCL5, providing groundwork for the development of targeted therapeutics.

Integrative multi-omics characterization of hepatocellular carcinoma in Hispanic patients.

Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions: Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.

Platelet-Rich Plasma in Young and Elderly Humans Exhibits a Different Proteomic Profile.

As people age, their ability to resist injury and repair damage decreases significantly. Platelet-rich plasma (PRP) has demonstrated diverse therapeutic effects on tissue repair. However, the inconsistency of patient outcomes poses a challenge to the practical application of PRP in clinical practice. Furthermore, a comprehensive understanding of the specific impact of aging on PRP requires a systematic investigation. We derived PRP from 6 young volunteers and 6 elderly volunteers, respectively. Subsequently, 95% of high-abundance proteins were removed, followed by mass spectrometry analysis. Data are available via ProteomeXchange with the identifier PXD050061. We detected a total of 739 proteins and selected 311 proteins that showed significant differences, including 76 upregulated proteins in the young group and 235 upregulated proteins in the elderly group. Functional annotation and enrichment analysis unveiled upregulation of proteins associated with cell apoptosis, angiogenesis, and complement and coagulation cascades in the elderly. Conversely, IGF1 was found to be upregulated in the young group, potentially serving as the central source of enhanced cell proliferation ability. Our investigation not only provides insights into standardizing PRP preparation but also offers novel strategies for augmenting the functionality of aging cells or tissues.

Identification of the novel fosfomycin resistance gene fosSC in Staphylococcus capitis.

OBJECTIVES: Fosfomycin has regained attention for treating infections caused by methicillin-resistant Staphylococcus aureus and multidrug-resistant coagulase-negative staphylococci. In this research, our objective was to investigate the mechanisms underlying fosfomycin resistance in Staphylococcus capitis. METHODS: The minimum inhibitory concentrations (MICs) of fosfomycin were assessed in 109 clinical S. capitis isolates by the agar dilution method. By cloning the fos-like genes into the shuttle vector, pTSSCm-Pcap, and observing the change in fosfomycin MICs, the gene function was verified. Core genome multilocus sequence typing and comparative genomics analysis were conducted to determine the population characteristics of S. capitis isolates and analyse the genetic environment of the fos-like genes. RESULTS: We identified a novel fosfomycin resistance gene, fosSC, on the chromosome in 58 out of 109 (53.2%) S. capitis isolates. The deduced products of the fosSC genes shared 67.15-67.88% amino acid sequence identity with FosB. The RN-pT-fosSC transformants carrying fosSC showed a 512-fold increase in the fosfomycin MICs. The fosSC gene was embedded in a conserved genetic context, but IS431mec was located to the left of the fosSC gene in cluster L due to the insertion of staphylococcal cassette chromosome mec. CONCLUSIONS: The chromosomal fosSC genes in some lineages of S. capitis explained their high-level fosfomycin resistance. Ongoing surveillance is crucial for monitoring the potential threat of horizontal transfer, which could be facilitated by the presence of mobile genetic elements surrounding the fosSC gene.

Protective effects of sodium butyrate on fluorosis in rats by regulating bone homeostasis and serum metabolism.

Fluorosis due to high fluoride levels in drinking water profoundly affects the development of human skeletal and dental structures. Sodium butyrate (NaB) has been found to regulate overall bone mass and prevent pathological bone loss. However, the mechanism of NaB action on fluorosis remains unclear. In this study, a rat model of fluorosis induced by 100 mg/L sodium fluoride was used to investigate the impact of NaB on bone homeostasis and serum metabolomics. It was found that NaB significantly reduced the levels of bone resorption markers CTX-Ⅰ and TRACP-5B in fluorosis rats. Moreover, NaB increased calcium and magnesium levels in bone, while decreasing phosphorus levels. In addition, NaB improved various bone microstructure parameters, including bone mineral density (BMD), trabecular thickness (Tb. Th), trabecular bone separation (Tb. SP), and structural model index (SMI) in the femur. Notably, NaB intervention also enhanced the antioxidant capacity of plasma in fluorosis rats. Furthermore, a comprehensive analysis of serum metabolomics by LC-MS revealed a significant reversal trend of seven biomarkers after the intervention of NaB. Finally, pathway enrichment analysis based on differential metabolites indicated that NaB exerted protective effects on fluorosis by modulating arginine and proline metabolic pathways. These findings suggest that NaB has a beneficial effect on fluorosis and can regulate bone homeostasis by ameliorating metabolic disorders.