Serum Concentrations Research Articles

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) from contaminated water and risk of childhood cancer in California, 2000-2015.

Few studies have investigated associations between per- and polyfluoroalkyl substances (PFAS) and childhood cancers. Detectable levels of PFAS in California water districts were reported in the Third Unregulated Contaminant Monitoring Rule for 2013-2015. Geocoded residences at birth were linked to corresponding water district boundaries for 10,220 California-born children (aged 0-15 years) diagnosed with cancers (2000-2015) and 29,974 healthy controls. A pharmacokinetic model was used to predict average steady-state maternal serum concentrations of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) from contaminated drinking water. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) per doubling of background exposure were calculated for cancers with at least 90 cases. Predicted PFOS and PFOA maternal serum concentrations ranged from background (5 ng/ml PFOS and 2 ng/ml PFOA) to 22.89 ng/ml and 6.66 ng/ml, respectively. There were suggestive associations between PFOS and nonastrocytoma gliomas (n = 268; AOR = 1.26; 95% CI: 0.99, 1.60), acute myeloid leukemia (n = 500; AOR = 1.14; 95% CI: 0.94, 1.39), Wilms tumors (n = 556, AOR = 1.15; 95% CI: 0.96, 1.38), and noncentral system embryonal tumors (n = 2,880; AOR = 1.07; 95% CI: 0.98, 1.17), and between PFOA and non-Hodgkin lymphoma (n = 384; AOR = 1.19; 95% CI: 0.95, 1.49). Among children of Mexico-born mothers, there was increased risk of Wilms tumor (n = 101; AORPFOS = 1.52; 95% CI: 1.06, 2.18; AORPFOA = 1.59, 95% CI: 1.12, 2.24) and noncentral system embryonal tumors (n = 557; AORPFOS = 1.24, 95% CI: 1.03, 1.50; AORPFOA = 1.19, 95% CI: 0.98, 1.45). Results suggest associations between predicted prenatal maternal PFAS serum concentrations and some childhood cancers. Future analyses are warranted.

Chronic cadmium exposure to minimal-risk doses causes dysfunction of epididymal adipose tissue and metabolic disorders.

Cadmium (Cd) is among the top seven most hazardous environmental contaminants. Minimal risk levels for daily exposure have been established, such as no observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL). Chronic exposure to Cd, at both NOAEL and LOAEL doses, causes toxicity in diverse tissues. However, Cd toxicity in adipose tissue, an endocrine and metabolic organ, remains relatively understudied. We aimed to investigate the potentially toxic effects of chronic Cd exposure (at NOAEL and LOAEL doses) on epidydimal adipose tissue of adult male Wistar rats. Ninety male Wistar rats were divided into three groups (n=30): Control Cd-free, NOAEL, and LOAEL that received CdCl2 in drinking water for 15days to 5months. We evaluated over time zoometry, serum and adipose Cd concentration, redox balance, GLUT4 and Nrf2 expression, histology, leptin, adiponectin, adipose insulin resistance index, free fatty acids, and glucose tolerance. The higher dose group showed a more pronounced and sustained increase in serum and adipose tissue of Cd concentration. Zoometry was similarly affected in both Cd-exposed groups with adipocyte hypertrophy. The redox balance was maintained due to the augmenting of Nrf2 expression. Leptin concentration augmented, while adiponectin diminished. Adipose insulin resistance increased simultaneously to lipolysis and glucose intolerance despite high GLUT4 expression. In conclusion, this study provides strong evidence that chronic Cd exposure, even at minimal risk levels (LOAEL and NOAEL doses), has toxic effects, disrupting the function of epididymal adipose tissue and contributing to metabolic disorders.

Iron Chelation Prevents Age-Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging.

A decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age-related sarcopenia in mice. We investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (kl/kl), an established mouse model for aging. Four weeks old Klotho -/- male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8-14 weeks (n = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods. Treatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (p < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both p < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (p = 0.019) and serum (p = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, p = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (p < 0.0001, p = 0.005), respectively, and elevated insulin-like growth factor levels (p = 0.472). This was associated with reduced DNA damage and reduced 8-hydroxy 2 deoxyguanosine in muscle and HO-1 protein (p < 0.001, p = 079), respectively. Significant weight loss (p < 0.001) and decreased water intake (p = 0.012) were observed in untreated mice compared to treatment group. Kaplan-Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (p = 0.0002). In summary, our research findings indicate that deferiprone reduced age-related sarcopenia in the muscles of Klotho-/- mice. Our finding suggests chelation of excess iron could be an effective therapy to counter sarcopenia. However, additional studies are needed to evaluate and determine the efficacy in humans.

Spatial Variations in Per- and Polyfluoroalkyl Substance Concentrations in Pooled Sera from Inland, Coastal, and Island Populations

Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitously detected chemicals, some of which are highly persistent and bioaccumulative in humans. Within the general population, dietary ingestion is considered a primary pathway for PFAS exposure, and seafood consumption specifically has been associated with higher serum PFAS concentrations. Proximity of residence to the ocean may influence dietary habits, particularly seafood consumption, and exposure to geographically specific PFAS sources such as sea spray aerosols (SSA). The objective of this study was to evaluate potential spatial trends in serum PFAS concentrations between Australian coastal and island populations compared to those with inland residency. Human sera were obtained from deidentified surplus pathology samples and pooled with respect to geographical location, sex (male or female), and age group (males: ≥15-<45 years, ≥45 years; females: ≥15-<45 years, ≥45-<60 years, ≥60 years) stratification criteria. Serum samples were then analysed for PFAS using High Performance Liquid Chromatography-Mass Spectrometry (HP LC-MS). A total of 13 of the 45 targeted PFAS were quantifiable in at least one pooled sample, including the detection of perfluorooctane sulfonate (PFOS) replacement compounds 5:3 fluorotelomer carboxylic acid (5:3 FTCA) and potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (9Cl-F53B). Significant spatial trends were observed in males aged ≥45 years, with serum concentrations of PFOS, perfluorobutanoic acid (PFBA), perfluorodecanoic acid (PFDA) and perfluoroheptane sulfonic acid (PFHpS) demonstrated to be 32-77% higher in pooled samples from island locations compared with inland. A similar trend was observed for PFHpS in coastal locations. Whilst deidentification of samples limited inferences about exposure pathways associated with the observed trends, this study indicated the feasibility of utilising pooled samples for assessing spatial variations in serum PFAS concentrations between geographically distinct subpopulations.

An oat fiber intervention for reducing PFAS body burden: A pilot study in male C57Bl/6J mice.

Perfluoroalkyl substances (PFAS) are a major public health concern, in part because several PFAS have elimination half-lives on the order of years and are associated with adverse health outcomes. While PFAS can be transported into bile, their efficient reuptake by intestinal transporter proteins results in minimal fecal elimination. Here, we tested the hypothesis that consumption of oat β-glucan, a dietary supplement known to disrupt the enterohepatic recirculation of bile acids, will reduce PFAS body burdens. Male C57Bl/6J mice were fed diets based on the "What we eat in America" analysis that were supplemented with inulin or oat β-glucan and exposed via drinking water to a seven PFAS mixture (PFHpA, PFOA, PFNA, Nafion Byproduct-2, PFHxS and PFOS) for 6weeks. One cohort of mice was euthanized at the end of the exposure, and one cohort continued on the experimental diets for 4 more weeks without additional PFAS exposure. The β-glucan fed mice drank significantly more water than the inulin fed mice, resulting in a significantly higher dose of PFAS. Relative to overall exposure, we observed lower serum concentration trends (p<0.1) in β-glucan fed mice for PFHpA, PFOA and PFOS. Additionally, β-glucan fed mice had lower adipose:body weight ratios and liver and jejunum triglyceride concentrations. Hepatic mRNA expression of Cyp4a10, Cyp2b10 and Cyp3a11 were elevated in PFAS exposed mice, with only the expression of Cyp3a11 decreasing following depuration. This pilot study generates support for the hypothesis that oat β-glucan supplementation can reduce PFAS body burdens and stimulate healthful effects on lipid homeostasis.

Associations between Per- and Polyfluoroalkyl Substances (PFAS) and Female Sexual Function in a Preconception Cohort

Female sexual function is important for sexual well-being, general health, fertility, and relationship satisfaction. Distressing impairments in sexual function, clinically recognized as female sexual dysfunction (FSD), can manifest as issues with interest/desire, arousal, orgasm, and pain during vaginal penetration. Some evidence suggests that exposure to endocrine-disrupting chemicals may adversely affect female sexual function, but associations for per- and polyfluoroalkyl substances (PFAS) have not been previously evaluated. We investigated associations between serum PFAS concentrations and female sexual function among U.S. pregnancy planners. We used cross-sectional data from participants from Pregnancy Study Online (PRESTO), a prospective preconception cohort study. Participants reported sexual function at baseline on two validated measures: a modified version of the Female Sexual Function Index-6 (FSFI-6) and Female Sexual Distress Scale (FSDS). We quantified PFAS serum concentrations in samples collected in the preconception period (i.e., at baseline) using solid phase extraction-high performance liquid chromatography-isotope-dilution-mass spectrometry. Participants reported sociodemographic information on structured baseline questionnaires. We included 78 participants with complete PFAS and sexual function data and fit multivariable linear regression models to estimate mean differences in FSFI-6 scores (β) or percent differences (%) in FSDS scores per interquartile range (IQR) increase in PFAS concentrations, adjusting for age, annual household income, years of education, parity, and body mass index. We further investigated effect measure modification by parity (parous vs. nulliparous) in stratified models. An IQR increase in perfluorohexanesulfonic acid was associated with a 1.0-point decrease (95% CI=-1.8, -0.1) in reported FSFI-6 scores, reflecting poorer sexual function. PFAS were consistently associated with lower FSFI-6 scores among parous participants. PFAS were also associated, though imprecisely, with greater sexual distress. Some PFAS were associated with poorer sexual function among parous U.S. pregnancy planners, but future studies are needed to clarify the extent to which PFAS influences female sexual health.

Intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic sub-study of the TIGeR-PaC phase 3 clinical trial.

719 Background: Localized, dual balloon catheter-mediated, intra-arterial delivery of gemcitabine (IAG) targeted to tumors/tissue can provide higher local drug potency (1). Furthermore, IAG may result in a decreased systemic drug concentration and associated side effects. In patients with locally advanced pancreatic cancer (LAPC), this approach is currently being tested in the TIGeR-PaC Phase 3 clinical trial. Herein we report the results of a 19-patient pharmacokinetics (PK) sub-study analysis within TIGeR-PaC. Methods: PK analyses were performed for a total of 19 participants across 6 TIGeR-PaC study sites; 11 participants received IAG with the RenovoCath dual balloon catheter at 1000 mg/m 2 over 20 minutes and 8 participants received intravenous gemcitabine (IVG) (5 at 1000 mg/m 2 , 2 at 800 mg/m 2 , 1 at 500 mg/m 2 ) over 30 minutes. IAG target treatment arteries were either the superior mesenteric artery (SMA) (n=5) or branches of the celiac axis (n=6). At T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion, 2 mL of blood was collected in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. Plasma from each sample was frozen and shipped to a reference lab for gemcitabine assays. Maximum plasma drug concentration (C max ) and the area under the drug plasma concentration curve (AUC) based on the terminal phase were compared between the two groups; for these dose-dependent parameters, only participants who received 1000 mg/m 2 gemcitabine (IAG, N=11; IVG, N=5) were included in the comparison analysis. Results: As shown in the table, AUC was significantly lower with IAG (4.99) compared to IVG (9.97) ( P = 0.019). Peak plasma gemcitabine concentrations were also lower with IAG (12.9 mcg/mL) vs. IVG (14.6 mcg/mL) despite a 50% higher drug concentration during IAG vs. IVG (1000 mg/m 2 infused over 20 minutes vs. 30 minutes, respectively). There was no difference in plasma levels between IAG treatment sites (SMA vs. celiac axis). Conclusions: In this analysis, localized, dual-balloon catheter-mediated IAG resulted in decreased systemic levels of gemcitabine compared to IVG. Thus, in addition to providing increased local potency, the IAG approach may also be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 2024. JVIR 35:1043-48 e3. Clinical trial information: NCT03257033 . Effects of treatment mode on mean pharmacokinetic parameters for gemcitabine. PK parameter IAG Group(N=11) IVG Group(N=5) C max (mcg/mL), Mean (SE) 12.9 (±2.4) 14.6 (±1.2) AUC (hr ⋅ mcg/mL), Mean (SE) 4.99 (±0.96) 9.97 (±1.9) AUC = area under the curve; C max = maximum serum concentration; IAG = intra-arterial gemcitabine; IVG = intravenous gemcitabine; PK = pharmacokinetic; SE = standard error.

Determination of oxidative stress and copeptin levels of COVID-19 according to the clinical course.

COVID-19, caused by the novel coronavirus SARS-CoV-2, is characterized by hyperinflammation, which can trigger oxidative stress. At the same time, COVID-19 is accompanied by both psychological and physical stress. Copeptin, a novel stress marker, has been shown to predict disease outcomes in stress-induced diseases. In this study, we aimed to explore the potential of copeptin, with inflammatory and oxidative stress markers, in distinguishing between different clinical courses of COVID-19. This case-control study included 75 participants: 25 COVID-19 patients hospitalized in the intensive care unit (ICU), 25 non-ICU COVID-19 patients, and 25 healthy individuals. 64% of the ICU patients received corticosteroid treatment for 4-10 days before sampling. Serum concentrations of the study parameters were assessed by enzyme-linked immunosorbent assay (ELISA) and compared between the study groups. Serum IL-6 levels (p<0.001) were significantly higher in ICU patients compared to non-ICU patients and the control group. Serum MDA (p<0.001) and 4-HNE (p=0.027) concentrations were significantly lower in the ICU group in comparison with the other groups. Copeptin was not statistically significant. MDA (p=0.040) and 4-HNE (p=0.017) levels were significantly lower in the treated ICU group than the untreated one. Serum IL-6 levels were noticeably associated with COVID-19 severity. Corticosteroid therapy administration seemed to influence MDA and 4-HNE levels in the treated group, with no obvious influence on IL-6 and copeptin in the same cohort. This data suggests that in SARS-CoV-2 infection, corticosteroids may act through a rapid non-genomic mechanism.

Modifying effects of prenatal exposure to rare earth elements on birth outcomes through maternal thyroid function in early pregnancy.

The potential health effects of exposure to rare earth elements (REEs) remain largely unexplored. This prospective cohort study aimed to elucidate the association between early pregnancy REE exposure and maternal thyroid function, as well as neonatal birth outcomes, in a cohort of pregnant women in Beijing, China. Additionally, the study explored the mediating role of thyroid homeostasis in the effects of REE exposure. Serum concentrations of fifteen REEs, along with Free Thyroxine (FT4), Thyroid Stimulating Hormone (TSH), and Thyroid Peroxidase Antibodies (TPOAb), were measured in 195 pregnant women. Multivariable linear regression analyses identified significant correlations between REE exposure and disruptions in maternal thyroid homeostasis. Specifically, Praseodymium (Pr) and Lutetium (Lu) were positively associated with FT4 levels, while Gadolinium (Gd) showed a positive correlation with TSH levels. Conversely, Thulium (Tm) was negatively associated with FT4 levels, and Yttrium (Y) was negatively correlated with TSH levels, indicating distinct interactions of specific REEs with thyroid regulation. Notably, Lu remained positively correlated with FT4 levels (β=1.39, 95% CI=0.55, 2.22) after adjusting for multiple comparisons. Regarding neonatal birth outcomes, Dysprosium (Dy) was found to be negatively associated with infant birth weight (β=-0.09, 95% CI=-0.170, -0.002). Furthermore, gender-specific analyses revealed significant associations between REE exposure and TPOAb levels among female neonates. Mediation analyses indicated that TSH significantly mediated the relationships between Terbium (Tb) and Y exposure and neonatal birth outcomes. The study suggests that REEs may disrupt endocrine function, particularly thyroid hormones, which could adversely affect neonatal growth, highlighting the need for further research on their impact in vulnerable populations.

Electrochemical capacitance-based aptasensor for HER2 detection.

The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) protein is specifically related to tumor cell proliferation in breast cancers. Its presence in biological serum samples indicates presence or progression of cancer, becoming a promise biomarker. However, their detection needs a simple and high accuracy platform. In this study, we report the develop and optimization of a simple highly sensitive electrochemical platform for HER2. Gold electrode surface was modified with a self-assembled monolayer composed by DNA aptamer, 6-(ferrocenyl) hexanethiol and 6-mercapto-1-hexanethiol. Electrochemical impedance spectroscopy was used to quantify the changes in capacitance on the interface due to the presence ferrocene, whether acting as a redox charge or its behavior under different HER2 concentration in PBS and undiluted human serum. As a result, the approach allows detection of HER2 with a limit of detection of 3.61 pg/mL, 12.28 nF sensitivity per decade and a linear range from 1 pM to 1 [Formula: see text]M in serum. This electrochemical aptasensor can be applied to different arrays for aptamer screening and has a significant importance to interaction study of biological systems.

The Diagnostic Performance of Fibroblast Growth Factor-21 during Early Stage of Missed Miscarriage

Abstract Background: Missed miscarriages (MMs) occur when an embryo without a cardiac pulse or gestational sac is not expelled from the uterus. Fibroblast growth factor-21 (FGF-21), a member of the fibroblast growth factor family, plays an important regulatory role in metabolism, primarily in glucose and lipid metabolism. Objective: The aim of this study is to investigate whether serum levels of FGF-21 are associated with MM in 8–14 weeks of gestation. Materials and Methods: This case–control study consisted of 88 pregnant women; they were divided into two groups: healthy pregnant (HP), composed of 40 women with a normal viable pregnancy at 8–14 weeks of gestation with mean age (29.07 ± 6.96 years); and study group that included 40 women with MM diagnosed by ultrasound at the same gestational age (GA) with mean age (28.27 ± 7.74 years). Demographic criteria and maternal serum FGF-21 levels were recorded for comparison. ELISA technique was used to measure FGF-21 in circulation. Results: This study revealed a statistically significant increase in serum levels of FGF-21 in MMs (142.47 ± 48.036 pg/ml) compared to normal pregnant women (87.9 ± 30.86). The cutoff point was ≥149.97, with high sensitivity (73.2%) and specificity (97.9%). There was no significant correlation between FGF-21 levels and age, GA, body mass index, or gravidity. Conclusion: The MM group’s serum concentrations of FGF-21 were markedly elevated within a time frame of 8–14 weeks compared to the HP group, suggesting its involvement in the development of MM. Based on the findings, FGF21 demonstrates a remarkable capacity for diagnosing MM.

O-11 IDIOPATHIC HYPERANDROGENAEMIA

Abstract Introduction Increased serum concentrations of androgens in women are referred to as hyperandrogenaemia. The most common cause is polycystic ovary syndrome. Clinical Case We report the case of a 38-year-old female patient who was referred to our clinic because of biochemical hyperandrogenemia. The first examination was initiated by her gynecologist because of weight gain. The patient had gained 15 kg over the last four years without changing her diet. Among the laboratory findings, we highlight a significantly elevated testosterone level that was 4x above the upper limit of normal (ULN), in addition to a slightly elevated dehydroepiandrosterone sulfate (DHEAs) level that was 1.5x above the ULN, with normal gonadotropin levels. Clinically, she had regular menstrual cycles and showed no signs of hyperandrogenism or cushingoid features. A transvaginal ultrasound revealed no abnormalities. To determine the source of the elevated testosterone, we performed a gonadotropin-releasing hormone analogue stimulation test (GAST) with goserelin. Testosterone levels remained unchanged before and after the test and were 2.5x above the ULN, suggesting an adrenal origin. However, an MSCT of the adrenal glands showed no abnormalities. Although the patient had no clinical symptoms related to elevated androgen levels, we measured 17-hydroxyprogesterone (17-OHP) at the beginning of her menstrual cycle, which was within the normal range. Conclusion During the follow-up examinations, her testosterone levels were consistently 3 to 4 times above the ULN, with no clinically recognizable signs of androgen excess. To date, the cause of the androgen excess has not been identified.

Cord blood metabolite profiles and childhood cardio-metabolic outcomes in a population-based cohort.

Adverse exposures in utero might cause adaptations of cardiovascular and metabolic organ development, predisposing individuals to an adverse cardio-metabolic risk profile from childhood onwards. We hypothesized that adaptations in metabolic pathways underlie these associations and examined associations of metabolite profiles at birth with childhood cardio-metabolic risk factors. The study included 763 mother-child pairs participating in an ongoing population-based prospective cohort study with an overall low disease risk. Cord blood serum concentrations of amino acids (AA), non-esterified fatty acids (NEFA), phospholipids (PL) and carnitines (Carn) were obtained using a liquid chromatography coupled with tandem mass-spectrometry. We measured android/gynoid fat mass ratio, blood pressure, insulin, and lipid concentrations at the children's age of 5.9 (0.3) and 9.8 (0.9) years. We did not observe associations of cord blood metabolites with systolic or diastolic blood pressure, insulin, triglycerides and android/gynoid fat mass ratio at both ages and cardio-metabolic risk clustering at age 10 years. Five short- and medium-chain Carn.a metabolites were positively associated with cardio-metabolic risk clustering at age 6 but did not survive more stringent confounder adjustment. No consistent associations between cord blood metabolites and cardiovascular risk factors at school age were observed.

An Integrating Microfluidic System for Concentration Gradient Generation of Exosomes and Exosome-Assisted Single-Cell-Derived Tumor-Sphere Formation.

To enhance exploration on tumor stem-like cells (TSCs) without altering their cellular biological characteristics, researchers advocate for application of single-cell-derived tumor-spheres (STSs). TSCs are regulated by their surrounding microenvironment, making it crucial to simulate a tumor microenvironment to facilitate STS formation. Recently, exosomes that originated from the tumor microenvironment have emerged as a promising approach for mimicking the tumor microenvironment. In the tumor microenvironment, various associated cells (such as fibroblasts, endothelial cells, and immune cells) play crucial roles. Utilizing exosomes derived from these cells enabled us to simulate the tumor microenvironment and promote STS formation. Herein, we have developed an integrated microfluidic platform to generate serial concentration gradients and evaluate the effects of multiple exosomes on STS formation. To demonstrate the feasibility of our approach, we generated serial concentration gradients of exosomes derived from two different cell types (HUVEC and NIH/3T3 cells) and assessed their effects on STS formation. Subsequently, we investigated the drug resistance of STSs treated with free doxorubicin and doxorubicin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles. Our findings revealed that the serial concentration gradients of mixed exosomes could be successfully generated, leading to an enhanced formation rate and size of STSs. Compared to exosomes derived from one cell type, the mixed exosomes exhibited superior promotion of STS formation. Additionally, nanomedicines demonstrated a reduction in the drug resistance of TSCs compared to free drug treatment, particularly in smaller and/or more deformable TSCs. This platform provides an innovative approach for STS formation enhancement and tumor microenvironment simulation.

A Bayesian Joint Model of Multiple Nonlinear Longitudinal and Competing Risks Outcomes for Dynamic Prediction in Multiple Myeloma: Joint Estimation and Corrected Two-Stage Approaches.

Predicting cancer-associated clinical events is challenging in oncology. In Multiple Myeloma (MM), a cancer of plasma cells, disease progression is determined by changes in biomarkers, such as serum concentration of the paraprotein secreted by plasma cells (M-protein). Therefore, the time-dependent behavior of M-protein and the transition across lines of therapy (LoT), which may be a consequence of disease progression, should be accounted for in statistical models to predict relevant clinical outcomes. Furthermore, it is important to understand the contribution of the patterns of longitudinal biomarkers, upon each LoT initiation, to time-to-death or time-to-next-LoT. Motivated by these challenges, we propose a Bayesian joint model for trajectories of multiple longitudinal biomarkers, such as M-protein, and the competing risks of death and transition to the next LoT. Additionally, we explore two estimation approaches for our joint model: simultaneous estimation of all parameters (joint estimation) and sequential estimation of parameters using a corrected two-stage strategy aiming to reduce computational time. Our proposed model and estimation methods are applied to a retrospective cohort study from a real-world database of patients diagnosed with MM in the US from January 2015 to February 2022. We split the data into training and test sets in order to validate the joint model using both estimation approaches and make dynamic predictions of times until clinical events of interest, informed by longitudinally measured biomarkers and baseline variables available up to the time of prediction.

Acute Effects of a Single Bout of Strength and Endurance Exercise on Vitamin D Metabolites in Young Adults.

The effect of exercise on serum concentration of vitamin D metabolites remains inconclusive, with studies reporting deviating results. This study evaluated the acute effect of a single session of two specific exercise forms; strength training (ST) and high-intensity interval training (HIIT), on circulating 25-hydroxyvitamin D (25(OH)D), free25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)2D), and skeletal muscle vitamin D receptor (VDR) gene expression, in healthy adults. Thirty-nine participants (19 women and 20 men, age 21-30 years) completed a single bout of ST and HIIT exercise, separated by two weeks. Serum concentration of total 25(OH)D, free25(OH)D and 1,25(OH)2D were assessed before exercise, immediately after, and 3 hours and 24 hours after each session. Muscle biopsies were obtained at rest (1st visit), and at 3 hours and 24 hours post ST and HIIT, and analyzed for VDR gene expression. Repeated measures ANOVA was used to assess serum concentration across time, while paired samples t-test was used for muscle VDR gene expression analyses. Serum concentration of 25(OH)D or free 25(OH)D did not change after either exercise mode when correcting for plasma volume alterations. 1,25(OH)2D was reduced by 13.1 ± 18.3 pmol/L and 7.1 ± 9.6 pmol/L immediately after ST and HIIT, respectively (P < 0.001). Muscle VDR mRNA expression increased after ST by 3.1 ± 1.8 (3 hr) and 2.2 ± 1.7 (24 hr) fold change (P < 0.05). One single session of ST or HIIT did not alter serum concentration of 25(OH)D and free 25(OH)D when correcting for plasma volume changes. Both exercise modes caused a transient reduction in 1,25(OH)2D suggesting utilization of 1,25(OH)2D by muscle cells following exercise. Elevated VDR gene expression following ST suggests a functional role of VDR in fast-twitch muscle fibers.

Association of interictal epileptiform discharges and serum concentration of levetiracetam and lamotrigine

BackgroundInterictal epileptiform discharges (IEDs) are an electrographic biomarker of epilepsy. Despite their crucial role in diagnosing epilepsy, heterogeneous findings exist on the mechanisms underlying their occurrence and the effects of anti-seizure medications (ASMs) on IEDs.MethodsWe conducted a study to investigate the association between IED frequency and the serum concentration of two commonly used ASMs, levetiracetam (LEV) and lamotrigine (LTG). We included 56 patients undergoing a continuous video EEG monitoring in our center with tapering of ASM. IED frequency was analyzed using automated and semiautomated methods and serum samples were collected sequentially throughout the stay.ResultsThe cohort consisted of 41 patients (23 female, 18 male), between 19 and 64 years (mean 37.42 years), most of which were diagnosed with focal epilepsy (93%). IED frequency increased after ASM reduction revealing a negative correlation similarly with LEV and LTG serum concentrations (p = 0.0057 and p = 0.0426, respectively).DiscussionNotably, we observed a significant increase in IED frequency following dose reduction or discontinuation of both medications. This effect was reversed after ASM were re-dosed. This may indicate the suppressive properties of LEV and LTG against epileptic seizures. Furthermore, our study highlights the importance of ASM discontinuation, which may be required for capturing IEDs during diagnostic continuous EEG monitoring, and not be fully explained by circadian or ultradian rhythms alone.ConclusionOur findings contribute to the understanding of ASM effects on IED frequency dynamics and suggest seizure suppressive properties of LEV and LTG.

Sex-specific association of immunological markers in CS-delivered newborns with pre-pregnancy body mass index and gestational weight gain of mothers

Just as overweight and obesity may impair immunity, excessive body weight-related parameters of women in the pre-conception period and during pregnancy are possible detrimental factors for fetal programming of the immune system in their offspring. We investigated the relationship of pre-pregnancy body mass index (pBMI) and gestational weight gain (GWG) of mothers with the placental transport rate (PTR) of IgG antibodies and antineutrophil cytoplasmatic antibodies against lactoferrin (Lf-ANCA) and their concentration in umbilical cord blood serum (UCS), verifying the sex-specificity of this relationship. The examined group of this cross-sectional pilot study consisted of 101 pregnant women and their healthy CS-delivered newborn children. The concentration of antibodies in maternal serum (MS) and UCS were determined by ELISA method. PTR was assessed as a ratio of the concentration of antibodies in the UCS and MS. A significantly lower PTR of IgG and their concentration in the UCS were demonstrated in newborns of mothers with an excessive pBMI compared to those with pBMI < 25 and the association was more pronounced in male newborns. The lowest PTR of beneficial IgG and their concentration in the UCS as well as the highest PTR of detrimental Lf-ANCA and their concentration in UCS were observed in newborns born to mothers with co-occurrence of both an excessive pBMI and GWG. It seems that maternal preconception overweight and obesity along with an excessive GWG can be a predictor of unfavorable immune effects in fetuses. Further studies are needed to explain the role of maternal weight-related parameters in the development of immunological health of their offspring.

Construction of the cancer patients’ database based on the US National Health and Nutrition Examination Survey (NHANES) datasets for cancer epidemiology research

BackgroundThe US National Health and Nutrition Examination Survey (NHANES) dataset does not include a specific question or laboratory test to confirm a history of cancer diagnosis. However, if straightforward variables for cancer history are introduced, US NHANES could be effectively utilized in future cancer epidemiology studies. To address this gap, the authors developed a cancer patient database from the US NHANES datasets by employing multiple R programming codes.MethodsTo illustrate the practical application of this methodology to a real-world problem, the authors extracted the R codes applied in an academic paper published in another journal on January 30th, 2024 (https://doi.org/10.1016/j.heliyon.2024.e24337). This paper will focus on the construction of the database and analysis using R codes. Entire.ResultsIn the first example, the urine concentration of monocarboxynonyl phthalate, monocarboxyoctyl phthalate, mono-2-ethyl-5-carboxypentyl phthalate, and mono-2-hydroxy-iso-butyl phthalate (all ng/mL) were used as the independent variable, instead of the serum concentration of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), respectively. In the second example, the serum concentration of 2,3,3’,4,4’-Pentachlorobiphenyl (PCB105), 2,3,4,4´,5-Pentachlorobiphenyl (PCB114), 2,3’,4,4’,5-Pentachlorobiphenyl (PCB118), and 2,2’,3,4,4’,5’- and 2,3,3’,4,4’,6-Hexachlorobiphenyl (PCB138) were used as the independent variable, instead of the serum concentration of PFOA, PFOS, PFHxS, and PFNA, respectively.DiscussionThis research offers a comprehensive set of R codes aimed at creating a single, user-friendly variable that encapsulates the history of each type of cancer while also considering the age at which the diagnosis was made. The US NHANES provides a wealth of critical data on environmental toxicant exposures. By employing these R codes, researchers can potentially discover numerous new associations between environmental toxicant exposures and cancer diagnoses. Ultimately, these codes could significantly advance the field of cancer epidemiology in relation to environmental toxicant exposure.

Elevated glycocalyx shedding components as the early predictors of unfavorable outcomes in patients after cardiac arrest: A single-center observational study.

To assess the association of serum glycocalyx shedding components (Heparan sulfate, HS; Hyaluronic acid, HA; Syndecan-1, Sdc-1) with outcomes after CA. Patients who were comatose for >24h after CA in the intensive care unit (ICU) of the Affiliated Hospital of Xuzhou Medical University from 9/2021 to 04/2023 were enrolled. Serum samples were collected 24h after CA to measure the concentrations of glycocalyx shedding components. The outcomes were the 30-day Cerebral Performance Categories (CPC) scale and 30-day mortality. The association of glycocalyx shedding with outcomes was examined by regression analysis. The area under the curve was used to evaluate the value of glycocalyx shedding for predicting outcomes. Sensitivity analysis and subgroup analysis were conducted. 111 patients were enrolled. The unfavorable group (CPC 3-5, n=69) had significantly higher serum concentrations of HA and Sdc-1 than the favorable group (CPC 1-2, n=42) (HA:149.7ng/ml vs. 824.8ng/ml, P<0.001; Sdc-1: 303.8ng/L vs. 447.0ng/L, P=0.026)but not HS. Elevated serum HA concentrations was an independent risk factor for unfavorable 30-day neurological function (OR=2.485, 95% CI=1.656-3.729). For the 30-day mortality, the nonsurvivor group (n=53) had significantly higher serum concentrations of HA, HS and Sdc-1 (HA: 177.3ng/ml vs. 1106.7ng/ml, P<0.001; HS: 2403.7ng/ml vs. 3383.3ng/ml P=0.030; Sdc-1: 352.1ng/L vs. 487.8ng/L, P=0.005) than the survivor group (n=58). However, only elevated serum HA and Sdc-1 concentrations are independent risk factors for 30-day mortality (HA: HR=2.321, 95% CI=1.776-3.035; Sdc-1: HR=1.702, 95% CI=1.038-2.792). Elevated serum HA at 24h after CA is an independent risk factor for 30-day unfavorable neurological function or mortality and elevated serum Sdc-1 concentrations is an independent risk factor for 30-day mortality. Our results suggested the potential value of serum glycocalyx shedding components as predictors for the outcomes in post-CA patients.