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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

PTSD prevalence and factors in intern nursing students after COVID-19 full liberalization in China: a cross-sectional study.

Objective: This study aimed to assess the prevalence of post-traumatic stress disorder (PTSD) and its influencing factors among intern nursing students after the full liberalization of the COVID-19 prevention and control policy in China. Methods: Participants completed the online survey from January 14 to January 19, 2023. A demographic questionnaire, COVID-19 and internship-related questionnaire, the Fear of COVID-19 scale, the Primary Care PTSD Screen, and the Connor-Davidson Resilience Scale were used to conduct the online survey. Results: Of 438 participants, 88.4% tested positive for COVID-19 in the last 6 months. The prevalence of fear, resilience, and PTSD was 16.9, 15.5, and 11.2%, respectively. Direct care of COVID patients in hospital (OR = 2.084, 95%CI 1.034 ~ 4.202), the experience of occupational exposure (OR = 2.856, 95%CI 1.436 ~ 5.681), working with an experienced team (OR = 2.120, 95%CI 1.070 ~ 4.198), and fear COVID-19 (OR = 8.269, 95%CI 4.150 ~ 16.479) were significantly and positively associated with PTSD in nursing internship students. Conclusion: After COVID-19 full liberalization in China, intern nursing students still experienced pandemic-related mental distress, which can bring PTSD. Adequate support and counseling should be provided, as needed, to intern nursing students who are about to enter the workforce and have experienced severe PTSD symptoms related to COVID-19. Our findings indicated that should understand the importance of screening, formulate intervention strategies and preventive measures to address psychosocial problems, and provide coping skills training to intern nursing students.

Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells.

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression.

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.

Platelet-derived TGF-ß1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia.

Platelet α-granules are rich in TGF-ß1 which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and re-balancing T cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-ß/Smad pathways in TPO-RA-corrected-MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-ß1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that ITP patients achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-ß1 induces the expansion and functional reprogramming of MDSCs via the TGF-ß/Smad pathway. These data indicate that platelet recovery not only serves as an endpoint of treatment response, but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.

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.

Proteinase 3 depletion attenuates leukemia by promoting myeloid differentiation.

Hematopoietic stem and progenitor cells (HSPCs) that have impaired differentiation can transform into leukemic blasts. However, the mechanism that controls differentiation remains elusive. Here, we show that the genetic elimination of Proteinase 3 (PRTN3) in mice led to spontaneous myeloid differentiation. Mechanistically, our findings indicate that PRTN3 interacts with the N-terminal of STAT3, serving as a negative regulator of STAT3-dependent myeloid differentiation. Specifically, PRTN3 promotes STAT3 ubiquitination and degradation, while simultaneously reducing STAT3 phosphorylation and nuclear translocation during G-CSF-stimulated myeloid differentiation. Strikingly, pharmacological inhibition of STAT3 (Stattic) partially counteracted the effects of PRTN3 deficiency on myeloid differentiation. Moreover, the deficiency of PRTN3 in primary AML blasts promotes the differentiation of those cells into functional neutrophils capable of chemotaxis and phagocytosis, ultimately resulting in improved overall survival rates for recipients. These findings indicate PRTN3 exerts an inhibitory effect on STAT3-dependent myeloid differentiation and could be a promising therapeutic target for the treatment of acute myeloid leukemia.

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.

Simultaneous Determination of Ibrutinib, Dihydroxydiol Ibrutinib, and Zanubrutinib in Human Plasma by Liquid Chromatography-Mass Spectrometry/Mass Spectrometry.

BACKGROUND: Ibrutinib and zanubrutinib are Bruton tyrosine kinase inhibitors used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Dihydroxydiol ibrutinib (DHI) is an active metabolite of the drug. A liquid chromatography-tandem mass spectrometry method was developed to detect ibrutinib, DHI, and zanubrutinib in human plasma. METHODS: The method involved a protein precipitation step, followed by chromatographic separation using a gradient of 10 mM ammonium acetate (containing 0.1% formic acid)-acetonitrile. Ibrutinib-d5 was used as an internal standard. Analytes were separated within 6.5 minutes. The optimized multiple reaction monitoring transitions of m/z 441.1 → 304.2, 475.2 → 304.2, 472.2 → 455.2, and 446.2 → 309.2 were selected to inspect ibrutinib, DHI, zanubrutinib, and the internal standards in positive ion mode. RESULTS: The validated curve ranges included 0.200-800, 0.500-500, and 1.00-1000 ng/mL for ibrutinib, DHI, and zanubrutinib, respectively. The precisions of the lower limit of quantification of samples were below 15.5%, the precisions of the other level samples were below 11.4%, and the accuracies were between -8.6% and 8.4%. The matrix effect and extraction recovery of all compounds ranged between 97.6%-109.0% and 93.9%-105.2%, respectively. The selectivity, accuracy, precision, matrix effect, and extraction recovery results were acceptable according to international method validation guidelines. CONCLUSIONS: A simple and rapid method was developed and validated in this study. This method was used to analyze plasma concentrations of ibrutinib and zanubrutinib in patients with mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, or diffuse large B-cell lymphoma. The selected patients were aged between 44 and 74 years.