Search

Study Question: What is the transcriptome signature associated with poor performance of rescue IVM (rIVM) oocytes and how can we rejuvenate them?Summary Answer: The GATA-1/CREB1/WNT signalling axis was repressed in rIVM oocytes, particularly those of poor quality; restoration of this axis may produce more usable rIVM oocytes.What Is Known Already: rIVM aims to produce mature oocytes (MII) for IVF through IVM of immature oocytes collected from stimulated ovaries. It is not popular due to limited success rate in infertility treatment. Genetic aberrations, cellular stress and the absence of cumulus cell support in oocytes could account for the failure of rIVM.Study Design, Size, Duration: We applied single-cell RNA sequencing (scRNA-seq) to capture the transcriptomes of human in vivo oocytes (IVO) (n = 10) from 7 donors and rIVM oocytes (n = 10) from 10 donors. The effects of maternal age and ovarian responses on rIVM oocyte transcriptomes were also studied. In parallel, we studied the effect of gallic acid on the maturation rate of mouse oocytes cultured in IVM medium with (n = 84) and without (n = 85) gallic acid.Participants/materials, Setting, Methods: Human oocytes were collected from donors aged 28-41 years with a body mass index of <30. RNA extraction, cDNA generation, library construction and sequencing were performed in one preparation. scRNA-seq data were then processed and analysed. Selected genes in the rIVM versus IVO comparison were validated by quantitative real-time PCR. For the gallic acid study, we collected immature oocytes from 5-month-old mice and studied the effect of 10-μM gallic acid on their maturation rate.Main Results and the Role Of Chance: The transcriptome profiles of rIVM/IVO oocytes showed distinctive differences. A total of 1559 differentially expressed genes (DEGs, genes with at least 2-fold change and adjusted P < 0.05) were found to be enriched in metabolic processes, biosynthesis and oxidative phosphorylation. Among these DEGs, we identified a repression of WNT/β-catenin signalling in rIVM when compared with IVO oocytes. We found that oestradiol levels exhibited a significant age-independent correlation with the IVO mature oocyte ratio (MII ratio) for each donor. rIVM oocytes from women with a high MII ratio were found to have over-represented cellular processes such as anti-apoptosis. To further identify targets that contribute to the poor clinical outcomes of rIVM, we compared oocytes collected from young donors with a high MII ratio with oocytes from donors of advanced maternal age and lower MII ratio, and revealed that CREB1 is an important regulator. Thus, our study identified that GATA-1/CREB1/WNT signalling was repressed in both rIVM oocytes versus IVO oocytes and in rIVM oocytes of lower versus higher quality. Consequently we investigated gallic acid, as a potential antioxidant substrate in human rIVM medium, and found that it increased the mouse oocyte maturation rate by 31.1%.Large Scale Data: Raw data from this study can be accessed through GSE158539.Limitations, Reasons For Caution: In the rIVM oocytes of the high- and low-quality comparison, the number of samples was limited after data filtering with stringent selection criteria. For the oocyte stage identification, we were unable to predict the presence of oocyte spindle, so polar body extrusion was the only indicator.Wider Implications Of the Findings: This study showed that GATA-1/CREB1/WNT signalling was repressed in rIVM oocytes compared with IVO oocytes and was further downregulated in low-quality rIVM oocytes, providing us the foundation of subsequent follow-up research on human oocytes and raising safety concerns about the clinical use of rescued oocytes.Study Funding/competing Interest(s): This work was supported by the Collaborative Research Fund, Research Grants Council, C4054-16G, and Research Committee Funding (Research Sustainability of Major RGC Funding Schemes), The Chinese University of Hong Kong. The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

Summary: Following 150 mg of oral ibandronate, Taiwanese females have greater serum and urine levels of this drug and bone resorption marker suppression than Caucasian women. These inter-ethnic differences seems to be partly explained by a 2.48-fold higher bioavailability of ibandronate in Taiwanese postmenopausal women. Introduction: Interethnic differences in the pharmacokinetics of oral ibandronate for osteoporosis are unknown. We compared the disposition of oral ibandronate between Caucasian and Taiwanese postmenopausal women. Methods: Ibandronate 150 mg was administered to 35 Caucasian and 16 Taiwanese postmenopausal women in two separate phase 1 studies. Interethnic comparisons were performed to assess pharmacokinetic properties, including the area under the concentration-time curve (AUC), peak concentration (Cmax), elimination half-life, urinary drug recovery (Ae%), renal clearance (CLr), apparent total clearance (CL/F), and apparent volume of distribution (Vd/F). Results: The mean AUC, Cmax, and Ae% were 2.41-, 1.69-, and 2.95-fold greater in the Taiwanese than in the Caucasian subjects, and the average CL/F and Vd/F were 2.48- and 2.46-fold smaller. There were no significant differences in mean CLr and half-life between both groups. As bisphosphonates are not biotransformed but are mainly excreted in the urine, the total body clearance is close to the CLr. These results suggested a larger bioavailability in the Taiwanese group which resulted in the differences in the CL/F and Vd/F. Multiple linear regression analysis demonstrated ethnicity influences of the pharmacokinetic properties after adjusting for the other variables. Conclusions: Bioavailability was largely responsible for the interethnic pharmacokinetic differences following oral administration of 150 mg ibandronate and seemed greater in the Taiwanese compared with the Caucasian subjects. Further dose-ranging studies are warranted to determine the optimal dosages of oral ibandronate in patients of Asian or Taiwanese ethnicity [ABSTRACT FROM AUTHOR]

Background: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions.Methods: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes.Results: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so.Conclusions: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs. [ABSTRACT FROM AUTHOR]

Objective: Uterine artery occlusion is often used to treat symptomatic uterine myomas, as this is a minimally invasive approach. However, alternative methods for uterus-sparing therapy are in development. This study aimed to compare the clinical effects of laparoscopic uterine artery occlusion (LUAO) in combination with laparoscopic myomectomy (LM) with LM alone for the management of symptomatic uterine leiomyomas.Study Design: This multicentre study was a retrospective controlled investigation. In total, 618 patients with symptomatic uterine myomas from six hospitals in Eastern China underwent LUAO+LM or LM alone between June 2011 and December 2012. Operative time, blood loss, transfusion, highest temperature, postoperative hospital stay, complications and follow-up results were compared between the two groups.Results: Complete clinical data were available for 504 patients. Among these, 324 patients underwent LUAO+LM and 180 patients underwent LM alone. Mean±standard deviation blood loss, transfusion, highest peri-operative temperature and duration of hospital stay were significantly lower in the LUAO+LM group compared with the LM group (83.61±53.70ml vs 109±58.43ml, 1.85% vs 6.11%, 37.6±0.40°C vs 37.9±0.45°C and 5.11±0.62 days vs 6.10±0.83 days, respectively). The mean duration of follow-up was 38.97±5.82 months in the LUAO+LM group and 37.30±2.25 months in the LM group (p>0.05). The relief of abnormal uterine bleeding, reduction of uterine volume and recurrence of myomas were more remarkable in the LUAO+LM group than the LM group (97.22% vs 83.75%, 62.42% vs 51.83% and 3.47% vs 10.63%, respectively).Conclusions: LUAO in combination with LM was associated with higher surgical quality, greater relief of abnormal symptoms and less recurrence of myomas compared with LM alone. LUAO in combination with LM is recommended for women with symptomatic uterine myomas who wish to preserve their uterus. [ABSTRACT FROM AUTHOR]

This study compared the performance between membrane-coupled moving bed biofilm reactor (MMBBR) and a conventional membrane bioreactor (MBR) in parallel. Extensive tests were conducted in three pilot-scale experimental units over 6 months. Emphasis was placed on the factors that would affect the performance of membrane filtration. The results showed that the concentrations of soluble microbial product (SMP), colloidal total organic carbon and transparent exopolymer particles in the M-MBBR systems were not significantly different from those in the control MBR system. However, the fouling rates were much higher in the M-MBBR systems as compared to the conventional MBR systems. This indicates membrane fouling potential was related not only to the concentration of SMP, but also to their sources and characteristics. The addition of polyaluminum chloride could reduce the fouling rate of the moving bed biofilm reactor unit by 56.4-84.5% at various membrane fluxes. [ABSTRACT FROM AUTHOR]

The objective of this study was to compare the diets with and without supplemental protein or protein sources on ruminai degradability, duodenal flows, and intestinal digestibility of protein and AA in growing heifers; supplemental protein included canola meal (CM) or dried distillers grains with solubles (DDGS) that varied in grain source and milling process. Five ruminally and duodenally cannulated Angus heifers (initial BW, 386 kg ± 20 kg) were assigned to a 5 x 5 Latin square with 21-d experimental periods. The diets consisted of 60% barley silage and 40% barley grain-based concentrate (DM basis) varying in protein source: CON (no protein supplement), CM, wheat DDGS (wDDGS), com DDGS (cDDGS), or fractionated com DDGS (fDDGS) plus urea N. Dietary CP concentrations were 11.9, 14.4, 14.4, 14.3, and 14.3% (DM basis), respectively, for CON-, CM-, wDDGS-, cDDGS-, and fDDGS-based diets. Intake of DM was less (P < 0.02) for heifers fed CON than those fed protein-supplemented diets (PSD), which did not differ. Intake of N followed the same pattern as DMI with less (P < 0.01) N intake by heifers fed CON than those fed PSD. Flows of OM, NDF, and starch to duodenum, and their digestibility in the rumen and in the total digestive tract did not differ among treatments. Flows of nonammonia N (NAN) and microbial N to the duodenum were greater (P < 0.05) for heifers fed PSD than those fed CON. Furthermore, heifers fed fDDGS had greater (P < 0.05) duodenal flow of NAN than those fed CM or cDDGS. Ruminai degradability of protein did not differ among diets, whereas digestibility of protein in the intestine was greater (P < 0.04) for fDDGS than CON. Overall, flows of essential AA, nonessential AA, and total AA were greatest (P < 0.05) for wDDGS and fDDGS, intermediate for CM and cDDGS, and least (P < 0.01) for CON diets. Ruminai total VFA concentration was greater for wDDGS (P <0.01) and fDDGS (P < 0.05) than CON and cDDGS with no differences in molar proportion of individual VFA. Ruminai NH3 N was greater for CM {P <0.01) and wDDGS (P < 0.02) than CON, which was not different from cDDGS and fDDGS diets. These results indicate that wDDGS and fDDGS supplemented backgrounding diets delivered greater amounts of protein and AA at the small intestine compared to CM and cDDGS diets when formulated to be isonitrogenous. Supplemental protein increased the supply of protein and AA at the small intestine of cattle fed backgrounding diets comprised of barley silage and barley grain. [ABSTRACT FROM AUTHOR]

Abstract: Background: To validate the clinical value of the One-Step Nucleic Acid Amplification (OSNA) Breast Cancer System for the intraoperative detection of sentinel lymph node (SLN) metastases in early-stage breast cancer patients in a Chinese population, a prospective, multicenter trial, the China Breast Cancer Clinical Study Group (CBCSG)-001c trial, was conducted. The present study focused on the prospective comparison of the performance between OSNA and touch imprint cytology (TIC). Methods: The retrieved SLNs were divided into sections. Alternate slices from the tissue blocks were subjected either to OSNA analysis or to postoperative histopathology evaluation through serial sectioning. TIC was performed on every sample surface of each tissue block and was used by the surgeon to determine whether to perform an immediate ALND. Results: A total of 552 patients qualified for the analysis. The sensitivity, specificity, and overall accuracy of OSNA were 87.8%, 89.6%, and 88.4%, respectively, on a per-patient basis compared with those of TIC, which were 81.3%, 96.9%, and 92.0%, respectively. OSNA detected more micrometastasis-involved nodes than TIC (52.8% vs. 25.0%; p = 0.029) on a per-node basis. Tissue allocation bias (TAB) was the main cause of discordant results. The performance of TIC varied significantly among the institutes, while the performance of OSNA was steady. Conclusions: Both OSNA and TIC can serve as qualified intraoperative assessments of SLNs. For institutes lacking the support of experienced cytopathologists, OSNA can be the first choice for the intraoperative assessment. In addition, OSNA can be applied as a complement to histopathology assessment. However, the results of the present study do not support the routine application of OSNA in the entire SLNs in place of pathology with serial sectioning. [Copyright &y& Elsevier]

Abstract: For the study of ground-borne vibration from surface sources, it is commonly assumed that soil properties remain constant with depth. However, various studies in the field of geotechnical engineering have shown that soil properties (stiffness and damping) change with depth due to the effect of increasing confining stress. Ground-borne vibration is hence unrealistically simulated if constant soil properties are assumed throughout a half space or a soil layer. This paper presents a study of the effect of the variation of soil properties with depth, referred to as soil non-homogeneity, on ground-borne vibrations induced by surface sources. The study involved physical modelling using a geotechnical centrifuge and numerical modelling using EDT and FLAC to gain further understanding of experimental results. In the centrifuge model, a dynamic excitation was applied to a rigid foundation resting on the surface of sand within a cylindrical container. Dynamic soil response was measured using accelerometers on the surface and within the soil. Comparison of the experimental and numerical results demonstrated that it is important to account for the variation of soil properties with depth when studying ground-borne vibration from surface sources. [Copyright &y& Elsevier]

High carrier-mobility organic field-effect transistors are developed employing high-k gate dielectrics so that unprecedentedly high transconductance is realized. 2,9-didecyl-dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene (C10-DNTT) solution-crystallized films are coated on hybrid gate insulators of silane self-assembled monolayers and high-k Al2O3 formed by atomic-layer-deposition. Intrinsically high carrier mobility exceeding 10 cm2/Vs in the crystalline C10-DNTT is preserved even on the high-k gate insulators because of suppressed coupling of the field-induced carriers to the polarization of the dielectrics. [ABSTRACT FROM AUTHOR]

Enhanced emission of high energy ions is measured from sub-wavelength metallic grating targets under irradiation by intense (1015-1016 W cm-2), p-polarized, 50 fs, 800 nm laser pulses. The maximum ion energy is 55% higher and the ion flux is 60% higher for the modulated surface in comparison with polished surfaces of the same atomic composition. The ion emission, a result of enhanced light coupling and hot electron production in the grating targets, is correlated with enhancement in hard x-ray bremsstrahlung emission. The results are well reproduced by particle-in-cell simulations. The study reveals that the enhanced laser coupling by surface plasmon excitation on metallic gratings is directly responsible for the enhancement of ion energies. [ABSTRACT FROM AUTHOR]

Abstract: Applying the melt-fluxing method, rapid solidifications of undercooled Cu50Co50 immiscible and Cu70Ni30 solid solution alloys were performed to investigate the grain refinement regularity at moderate undercooling. Due to the essential distinction of physical properties between these alloys, grain refinement phenomenon was detected in Cu50Co50 alloy with a tendency of liquid separation, while dendrite structure appears for Cu70Ni30 alloy. The association of microstructure morphology to non-equilibrium solidification process was constructed with the description of recalescence degree as a function of undercooling. Quantitative thermodynamic calculation for the undercooled liquid of the researched systems was carried out to elucidate the influence of liquid separation on the variation of Gibbs free energy for the subsequent rapid solidification, which gives a better understanding of the as-observed experimental results. [Copyright &y& Elsevier]

Combustion in a furnace equipped with two HiTAC burner pairs, with a thermal power of 100 kWth each, has been investigated experimentally and computationally. The objective of this study is (1) to observe differences in the performance of the furnace operating in two different firing modes, parallel and staggered, and (2) to explain these differences using detailed CFD simulations. Besides the permanent measurements of temperature, flow and pressure, in-furnace probe measurements of temperature, oxygen and emissions (NO and CO) have been performed. Experimental results show that the efficiency of the furnace was higher in parallel mode compared to staggered mode, 48% and 41% respectively. The values of CO emitted were equal for both firing modes. However, in parallel mode the NOx production was 39 ppmv@3%O2, whereas in staggered mode 53 ppmv@3%O2 NOx was produced. Considering both efficiency and emissions, parallel firing mode performs better than staggered mode. Next, CFD simulations of the furnace were performed in order to explain the observed differences. The simulations were validated with the in-furnace measurements. It was confirmed that the furnace firing in parallel mode achieved a higher efficiency. The radiative heat transfer was higher due to formation of a larger zone with gases with improved radiative properties. In addition, higher velocities along the cooling tubes, due to lower momentum destruction, led to higher convective heat transfer. Also, the lower production of NOx in parallel mode was reproduced by the simulations. This is due to the fact that in parallel mode the fuel jets are merging slower with the combustion air jet, leading to less intense combustion zones. Thus, lower peak temperatures and radical concentrations are achieved, and the NOx production via the thermal and N2O pathways was lower. [ABSTRACT FROM AUTHOR]

Background: Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti-inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer.Method: We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo.Results: Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein δ-catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity.Conclusion: Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3. [ABSTRACT FROM AUTHOR]

Asparaginase is an important component for treatment of childhood acute lymphoblastic leukemia (ALL). The basis for interindividual differences in asparaginase sensitivity remains unclear. To comprehensively identify genetic variants important in the cytotoxicity of asparaginase, we used a genome-wide association approach using the HapMap lymphoblastoid cell lines (87 CEU trio members) and 54 primary ALL leukemic blast samples at diagnosis. Asparaginase sensitivity was assessed as the drug concentration necessary to inhibit 50% of growth (inhibitory concentration (IC)(50)). In CEU lines, we tested 2,390,203 single-nucleotide polymorphism (SNP) genotypes at the individual SNP (P<0.001) and gene level (P<0.05), and identified 329 SNPs representing 94 genes that were associated with asparaginase IC(50). The aspartate metabolism pathway was the most overrepresented among 199 pathways evaluated (P=8.1 × 10(-3)), with primary involvement of adenylosuccinate lyase and aspartyl-tRNA synthetase genes. We validated that SNPs in the aspartate metabolism pathway were also associated with asparaginase sensitivity in primary ALL leukemic blast samples (P=5.5 × 10(-5)). Our genome-wide interrogation of CEU cell lines and primary ALL blasts revealed that inherited genomic interindividual variation in a plausible candidate pathway can contribute to asparaginase sensitivity. [ABSTRACT FROM AUTHOR]

Background and Purpose: The cannabinoid CB(1) receptor is primarily thought to be functionally coupled to the G(i) form of G proteins, through which it negatively regulates cAMP accumulation. Here, we investigated the dual coupling properties of CB(1) receptors and characterized the structural determinants that mediate selective coupling to G(s) and G(i).Experimental Approach: A cAMP-response element reporter gene system was employed to quantitatively analyze cAMP change. CB(1)/CB(2) receptor chimeras and site-directed mutagenesis combined with functional assays and computer modelling were used to determine the structural determinants mediating selective coupling to G(s) and G(i).Key Results: CB(1) receptors could couple to both G(s)-mediated cAMP accumulation and G(i)-induced activation of ERK1/2 and Ca(2+) mobilization, whereas CB(2) receptors selectively coupled to G(i) and inhibited cAMP production. Using CB(1)/CB(2) chimeric receptors, the second intracellular loop (ICL2) of the CB(1) receptor was identified as primarily responsible for mediating G(s) and G(i) coupling specificity. Furthermore, mutation of Leu-222 in ICL2 to either Ala or Pro switched G protein coupling from G(s) to G(i), while to Ile or Val led to balanced coupling of the mutant receptor with G(s) and G(i) .Conclusions and Implications: The ICL2 of CB(1) receptors and in particular Leu-222, which resides within a highly conserved DRY(X)(5) PL motif, played a critical role in G(s) and G(i) protein coupling and specificity. Our studies provide new insight into the mechanisms governing the coupling of CB(1) receptors to G proteins and cannabinoid-induced tolerance. [ABSTRACT FROM AUTHOR]

This study was carried out to develop a two-layered finite element model of the oesophagus. The outer muscle and inner mucosal layer were constructed individually with different mechanical properties and zero-stress opening angles. With the model, two simulations were performed. First, the distention of oesophageal wall under the pressurized state was investigated, from which the effects of residual strains on the stress distribution were evaluated. Second, the buckling modes were determined using a linear eigenvalue analysis. The self-contact capability in ABAQUS was applied to simulate the folding of mucosa under the muscle contraction. The first simulation indicated that, by taking the residual strains into account, the mucosa undertook a very small portion of stress and the luminal pressure almost transmitted completely to the outer muscle layer. On the other hand, the folding of mucosa was shown to be able to reduce the contractile force of circular muscle to maintain the lumen closure. In conclusion, the preliminary study demonstrated the feasibility of simulating the oesophageal peristaltic transport using finite element analysis. [ABSTRACT FROM AUTHOR]

Though the concentration of serum lipoprotein(a) [Lp(a)] is mostly determined by genetic factors, secondary factors such as acute-phase response (APR) and end-stage renal disease (ESRD) also contribute to its increase. Lp(a) is known to be one of the acute-phase reactants and interleukin-6 (IL-6) is the key cytokine in the hepatic synthesis of acute-phase proteins. The serum concentrations of Lp(a) and IL-6 were measured in patients with APR and in patients with ESRD to investigate the relationship between Lp(a) and IL-6. A total of 180 patients were selected for the study: 60 patients were normal controls, 60 were patients with renal disease who had been on hemodialysis for more than 6 months [C-reactive protein (CRP)<4.0 mg/L], and 60 were APR patients who had a erythrocyte sedimentation rate (ESR) of over 50 mm/h. The three groups were age- and sex matched. The serum concentrations of Lp(a) and IL-6 were measured by ELISA. The serum concentrations of Lp(a) [median (interquartile range)] in normal controls, ESRD patients, and APR patients were 0.222 (0.103-0.364) g/L, 0.511 (0.308-0.755) g/L, and 0.546 (0.234-0.747) g/L, respectively; those of IL-6 were 1.0 (0.7-1.3) pg/mL, 2.1 (1.4-3.3) pg/mL, and 26.2 (15.2-35.6) pg/mL. The concentration of IL-6, which increases Lp(a) synthesis, was much lower in ESRD patients than in APR patients (p<0.001). However, there were no significant differences in Lp(a) concentration between the two groups (p=0.88). In APR patients, the increase in Lp(a) synthesis seems to play a significant role in the increase in blood Lp(a), but there might be different mechanisms that regulate the increment of serum Lp(a) concentrations in ESRD patients other than synthesis of Lp(a). [ABSTRACT FROM AUTHOR]

Background: Human cancer cell lines grown in the presence of the cytotoxic agent mitoxantrone frequently develop resistance associated with a reduction in intracellular drug accumulation without increased expression of the known drug resistance transporters P-glycoprotein and multidrug resistance protein (also known as multidrug resistance-associated protein). Breast cancer resistance protein (BCRP) is a recently described adenosine triphosphate-binding cassette transporter associated with resistance to mitoxantrone and anthracyclines. This study was undertaken to test the prevalence of BCRP overexpression in cell lines selected for growth in the presence of mitoxantrone.Methods: Total cellular RNA or poly A+ RNA and genomic DNA were isolated from parental and drug-selected cell lines. Expression of BCRP messenger RNA (mRNA) and amplification of the BCRP gene were analyzed by northern and Southern blot hybridization, respectively.Results: A variety of drug-resistant human cancer cell lines derived by selection with mitoxantrone markedly overexpressed BCRP mRNA; these cell lines included sublines of human breast carcinoma (MCF-7), colon carcinoma (S1 and HT29), gastric carcinoma (EPG85-257), fibrosarcoma (EPF86-079), and myeloma (8226) origins. Analysis of genomic DNA from BCRP-overexpressing MCF-7/MX cells demonstrated that the BCRP gene was also amplified in these cells.Conclusions: Overexpression of BCRP mRNA is frequently observed in multidrug-resistant cell lines selected with mitoxantrone, suggesting that BCRP is likely to be a major cellular defense mechanism elicited in response to exposure to this drug. It is likely that BCRP is the putative "mitoxantrone transporter" hypothesized to be present in these cell lines. [ABSTRACT FROM AUTHOR]

This study assessed the association between adverse childhood experiences (ACEs) and clustering of high-risk behaviors in a sample of high school students. This was a cross-sectional study. A sample of students who attended randomly selected classes in 99 high schools completed the 2019 Nevada Youth Risk Behavior Survey (N = 4959). The survey included six ACE measures: (1) physical abuse, (2) sexual abuse, (3) verbal abuse, (4) household physical abuse, (5) household mental illness, and (6) household substance abuse. Students were assigned a cumulative ACE score (range = 0–6). A count of high-risk behavior domains was created using multiple questions across the following domains: (1) violence behaviors, (2) suicidal indicators, (3) non-suicidal self-injury, (4) substance use, (5) high-risk sexual behaviors, (6) poor diet, (7) physical inactivity, and (8) high screen time (range = 0–8). The relationship between ACEs and the count of high-risk behavior domains was assessed using weighted negative binomial regression; incidence rate ratios (IRRs) were calculated adjusting for sociodemographic characteristics. More than 40% of the sampled students reported high-risk behaviors across two or more domains. There was a strong, graded relationship between cumulative ACE score and the count of high-risk behavior domains. Compared with students who experienced zero ACEs, there was an increase in the count of high-risk behavior domains among students who experienced one ACE (adjusted IRR [aIRR] = 1.22, 95% confidence interval [CI] = 1.12–1.33), two ACEs (aIRR = 1.57, 95% CI = 1.42–1.73), three ACEs (aIRR = 1.73, 95% CI = 1.54–1.94), four ACEs (aIRR = 2.07, 95% CI = 1.84–2.33), five ACEs (aIRR = 2.69, 95% CI = 2.34–3.10), and six ACEs (aIRR = 2.91, 95% CI = 2.34–3.62). Trauma-informed prevention efforts may be an efficient way to address multiple adolescent risk behaviors that cluster. [ABSTRACT FROM AUTHOR]