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Aims: To investigate tertiary lymphoid structures (TLSs) in ductal carcinoma in situ (DCIS) of the breast and their correlation with pathological features, immune cell markers and clinical outcomes. Methods and results: Morphological identification of TLSs in 198 DCIS cases incorporated B and T cell zones with high endothelial venules. TLS positivity was defined as ≥ 1 TLSs in lesional areas, while TLS area percentage was divided into two categories: low (TLSs < 5%) and high (TLSs ≥ 5%). Previously reported biomarkers included ER, PR, HER2, CD68, CD163, CD4, CD8 and PD‐L1. TLSs were observed in 24.7% (49 of 198) of cases, with a mean diameter of 0.44 mm (median = 0.4 mm, range = 0.12–1.43 mm). TLSs were significantly associated with higher nuclear grade, presence of necrosis, hormone receptor negativity/HER2 positivity, triple negativity, tumour infiltrating lymphocytes (TILs) and immune related biomarkers such as FOXP3, CD163, CD4 and CD4/CD8 ratio (all P < 0.05). There were no significant associations between TLSs and recurrence, but a combination of TLSshigh with FOXP3+, CD4high, CD4/CD8 ratiohigh and CD68high individually, compared with all other combinations, disclosed significantly poorer disease‐free survival (DFS) for ipsilateral invasive recurrence (IIR) on both Kaplan–Meier and multivariable Cox regression analyses (all P < 0.05). Conclusions: TLSs in DCIS were associated with unfavourable prognostic features, TILs and immune cell markers in our study. TLSshigh/FoxP3+, TLSshigh/CD4high, TLSshigh/(CD4/CD8) ratiohigh and TLSshigh/CD68high were independent factors for poorer DFS for IIR. Further exploration of the pathological significance of TLSs may provide a clinical basis for their recognition as an important structure and functional unit in the tumour immune microenvironment. [ABSTRACT FROM AUTHOR]

Background The clinical relevance of arachidonic acid (AA) metabolites in chronic kidney disease (CKD) progression is poorly understood. We aimed to compare the concentrations of 85 enzymatic pathway products of AA metabolism in patients with CKD who progressed to end-stage kidney disease (ESKD) versus patients who did not in a subcohort of Chronic Renal Insufficiency Cohort (CRIC) and to estimate the risk of CKD progression and major cardiovascular events by levels of AA metabolites and their link to enzymatic metabolic pathways. Methods A total 123 patients in the CRIC study who progressed to ESKD were frequency matched with 177 nonprogressors and serum eicosanoids were quantified by mass spectrometry. We applied serum collected at patients' Year 1 visit and outcome of progression to ESKD was ascertained over the next 10 years. We used logistic regression models for risk estimation. Results Baseline 15-hydroxyeicosatetraenoate (HETE) and 20-HETE levels were significantly elevated in progressors (false discovery rate Q  ≤ 0.026). The median 20-HETE level was 7.6 pmol/mL [interquartile range (IQR) 4.2–14.5] in progressors and 5.4 pmol/mL (IQR 2.8–9.4) in nonprogressors (P < 0.001). In an adjusted model, only 20-HETE independently predicted CKD progression. Each 1 standard deviation increase in 20-HETE was independently associated with 1.45-fold higher odds of progression (95% confidence interval 1.07–1.95; P = 0.017). Principal components of lipoxygenase (LOX) and cytochrome P450 (CYP450) pathways were independently associated with CKD progression. Conclusions We found higher odds of CKD progression associated with higher 20-HETE, LOX and CYP450 metabolic pathways. These alterations precede CKD progression and may serve as targets for interventions aimed at halting progression. [ABSTRACT FROM AUTHOR]

[Display omitted] • An efficient unreported ultrasound-assisted enzymatic method was used for the extraction of AIMP. • AIMP as a modifier can significantly adjust the particle size of SeNPs. • The gastrointestinal stability of AIMP-SeNPs is significantly better than that of SeNPs. • AIMP-SeNPs have a significant inhibitory effect on bacteria by destroying their structure. A new type of uniformly dispersed selenium nanoparticles (SeNPs) was prepared using Antarctic ice microalgae polypeptides (AIMP) as the stabilizer and dispersant. Different characterization techniques and tests show that the SeNPs are effectively combined with AIMP through physical adsorption and hydrogen bonding to form a more stable structure. Orange-red, zero-valence, amorphous, and spherical AIMP-SeNPs with a diameter of 52.07 ± 1.011 nm and a zeta potential of −41.41 ± 0.882 mV were successfully prepared under the optimal conditions. The AIMP-SeNPs had significantly higher DPPH, ABTS and hydroxyl radicals scavenging abilities compared with AIMP and Na 2 SeO 3 , and prevented the growth of both Gram-negative and Gram-positive bacteria by disrupting the integrity of cell walls, cell membranes and mitochondrial membranes. The AIMP-SeNPs had higher gastrointestinal stability compared with SeNPs. Thus, this research highlights the crucial role of AIMP as a biopolymer framework in the dispersion, stabilization, and size management of SeNPs and concludes that AIMP-SeNPs can be exploited as a potent antioxidant supplement and antibacterial substance in foods and medicine. [ABSTRACT FROM AUTHOR]

We have measured the electron and X-ray emission of tungsten bombarded with proton in the energy range of 50–250 keV. It is found that the total electron yield mainly consists of kinetic electron emission, which results from the excited valence electrons, and presents a similar trend to the curve of stopping power. The ratio between electron yield and electronic energy loss is not constant, but decreases with increasing incident energy. The behavior is interpreted by an expected competitive mechanism of ionization between different shell electrons of target atom. The explanation is verified by the experimental increase of M-shell X-ray emission yield, and the measured and calculated ionization cross section of core and valence electrons. [ABSTRACT FROM AUTHOR]

• The inclusion complex of essential oil from wampee fruit pericarp and β-CD were prepared for the first time. • The aqueous solubility of wampee essential oil after encapsulation was enhanced significantly. • Different analyses (XRD, SEM, FTIR) confirmed the formation of the inclusion compound. • The antioxidant capacity of encapsulated wampee essential oil was well preserved. The essential oil of wampee [ Clausena lansium (Lour.) Skeels] fruit pericarp (WEO) has excellent biological activities. However, it is highly volatile and in poor solubility, limiting its application in the food and pharmaceutical industries. This study aimed to synthesize the inclusion complex of WEO and β-cyclodextrin (WEO–β-CD-IC) to overcome its shortcomings. Prepared by using the freeze-drying method, the obtained inclusion complex was characterized by several analytical methods: FT-IR, SEM, TG-DSC, and XRD. Effects of three elements on the WEO extraction yield using the ultrasound-assisted hydrodistillation (UAHD) method were also measured. The results of FT-IR and XRD demonstrated the encapsulation of WEO into β-CD. TG-DSC was used to probe the thermostability of WEO obviously improved and the water-solubility of WEO was distinctly enhanced by 14 times after complexing. DPPH and ABTS radical scavenging ability of encapsulated WEO demonstrated that the antioxidant capacity was well preserved. These data support further development of making better use of wampee fruit peel essential oil. [ABSTRACT FROM AUTHOR]

Epigenetic and genetic analysis of p16 in dermal fibroblasts from type 1 diabetic patients with nephropathy. Background. Several studies have shown that cultured skin fibroblasts from patients with diabetic nephropathy (DN) exhibit a hyperplastic growth phenotype. Increased DNA synthesis in cells from patients with DN may ultimately involve alterations in cell cycle regulatory proteins. p16 protein is a member of INK4 family of cyclin-dependent kinase inhibitors, which plays an important role in cell cycle regulation. In this study, we examined the correlation between p16 protein expression in cultured dermal fibroblasts from type 1 diabetic patients and the presence of DN. Method. Western blot analysis was performed to compare p16 protein expression in skin fibroblasts from patients with DN as compared to control subjects, diabetic patients without DN, and nondiabetic patients with nephropathy. Transcriptional regulation of the p16 gene was assessed using competitive reverse transcription-polymerase chain reaction (RT-PCR). Methylation status of the promoter region of p16 was examined using methylation-specific PCR, and we used single-stranded conformational polymorphism (SSCP)-PCR to assess p16 single-nucleotide polymorphism. Results. Cells from diabetic patients with DN had nondetectable to significantly lower protein expression of p16. Similarly, mRNA expression of p16 was significantly lower in diabetic patients with DN. No hypermethylation of p16 gene was detected, and no abnormal migrating bands were noticed on SSCP-PCR analysis in cells from patients with DN. Conclusion. Our data indicate that cells from patients with DN exhibit significantly lower protein and mRNA expression of p16. This study could have not only important implications for the understanding of the pathogenesis of DN, but also the absence of p16 may ultimately serve as an early marker for DN. [ABSTRACT FROM AUTHOR]

The L-shell x-rays of Te have been measured for the impact of protons with energies from 100 to 300 keV, and He2+ ions in the energy range of 300–600 keV. The new experimental data of Te for individual L-subshell and total L x-ray production cross sections were extracted from the thick-target analysis of x-ray yields. This is significant for updating the existing database. The cross sections were also compared with theoretical calculations of BEA, PWBA, ECPSSR and ECUSAR along with various atomic parameter databases and including modification of multiple ionization. On the whole, The ECUSAR-MI predictions using Campbell's atomic parameters present a best agreement to the experimental data. [ABSTRACT FROM AUTHOR]

Mg K-shell x-ray production cross sections have been investigated for the impact of H+, He2+ and highly charged heavy ions Xe20+ and Eu20+ in the energy range near the Bohr velocity. The x-ray production cross sections were extracted from the yield and compared with various theoretical calculations. It is found that, with the same incident energy per nucleon, the cross section induced by light ions is lower than that produced by highly charged heavy ions by a factor of about 104. With the impact of H+ and He2+ ions, the x-ray emission cross section can be well predicted by ECPSSR theory. However, for the bombardment of highly charged heavy ions, the BEA calculation, corrected both by Coulomb repulsion and effective nuclear charge, results in a good estimation to the experimental data. [ABSTRACT FROM AUTHOR]

Gestational Bisphenol A (BPA) exposure is associated with low birth weight. We hypothesized that the low birth weight is the consequence of reduced placental efficiency and a function of BPA-induced inflammatory, oxidative, lipotoxic, angiogenic, steroidal and fibrotic changes involving epigenetic alterations. Placentomes were collected during early (day 65) and mid (day 90) gestation (term ∼147 days) from control and BPA (gestational day 30–90)-treated pregnant sheep. BPA treatment: reduced placental efficiency and fetal weight; increased interleukin 8, lipid peroxidation marker, antioxidants, aromatase, 17 alpha-hydroxylase, estrogen receptor 2, insulin like growth factor (IGF) 2 receptor and IGF binding proteins (IGFBP), and histone deacetylase 1 and 2; reduced tumor necrosis factor alpha and IGF1 receptor at early gestation (Day 65). Gestational BPA-induced mid-gestational changes include: reduced angiogenic factor hypoxia inducible factor 1 alpha; increased IL1beta, oxidative stress markers, triglyceride, 17alpha hydroxylase, IGFBP 1, DNA methyltransferase 3 A and histone deacetylase 1. These findings indicate that gestational BPA, either acting directly or by altering steroidal input, produces early/mid-gestational-specific epigenetic changes culminating in placental disruptions at several levels, in keeping with time-specific/time-lagged pregnancy-associated changes in placental efficiency and fetal weight. The reduced early-gestational placental efficiency may be a function of increased inflammation/oxidative stress and reduced IGF bioavailability with the mid-gestational restoration of placental efficiency likely driven by improved IGF bioavailability and the time-lagged response to antioxidant increase. This compensation, the result of time-lagged response to increases in negative mediators of placental function must have failed with pregnancy advancement to explain the low birthweight outcome. • Exposure to BPA compromises early pregnancy placental efficiency. • Gestational BPA exposure disrupts several mediators of placental function. • BPA-induced effects on placental mediators differ between early and mid-gestation. • Gestational BPA exposure induces pregnancy stage-specific epigenetic alterations. • Effects of gestational BPA may involve changes in placental steroid milieu. [ABSTRACT FROM AUTHOR]

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes. In human umbilical vein endothelial cells (HUVECs), the risk allele "C" is associated with lower expression of the adjacent gene GLUL encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and the γ-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17-58% increase/allele copy, P = 0.046-0.002), including five γ-glutamyl amino acids, β-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate-a marker of γ-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione-to-glutamate ratio (-9%, P = 0.012), decreased S-lactoylglutathione (-41%, P = 0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, P = 0.008). GLUL downregulation by shRNA caused a 40% increase in the methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the γ-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers. [ABSTRACT FROM AUTHOR]

In element analysis of materials, whether the X-ray emission is isotropic plays an import role in the technique of Particle Induced X-ray Emission (PIXE). Thus, it is meaningful to investigate the alignment of vacancy states produced by impact ionization. In this work, the emission of L X-rays for Ag has been measured by electrons at 20–40 keV. In order to study the angular distribution, the characteristic spectra are detected at different emission angles (from 5° to 25° with intervals of 5°). It is found that the emission of L β1 (L 2 M 4) and L γ1 (L 2 N 4) X-rays exhibits isotropic distribution, while the emission of L α (L 3 M 4,5) and L β2 (L 3 N 5) X-rays is anisotropic. With the increase of impact energy, the intensity ratios of L α /L β1 and L β2 /L β1 increase significantly. While the slopes of intensity ratios for L α /L β1 and L β2 /L β1 on emission angle do not change significantly at different impact energy. It indicates that the alignment degree A 20 is independent on incident energy from 20 to 40 keV. Consequently, the alignment degree A 20 for L 3 subshell is deduced to be 0.63 ± 0.10 experimentally. [ABSTRACT FROM AUTHOR]

Highlights • Prenatal BPA disrupts mediators of insulin sensitivity in female sheep. • Prenatal BPA induces oxidative stress status in metabolic tissues. • Prenatal BPA induces dyslipidemia and lipotoxicity in the liver and muscle. • Elevated negative mediators of insulin sensitivity underlie prenatal BPA effects. Abstract Developmental exposure to endocrine disruptor bisphenol A (BPA) is associated with metabolic defects during adulthood. In sheep, prenatal BPA treatment causes insulin resistance (IR) and adipocyte hypertrophy in the female offspring. To determine if changes in insulin sensitivity mediators (increase in inflammation, oxidative stress, and lipotoxicity and/or decrease in adiponectin) and the intracrine steroidal milieu contributes to these metabolic perturbations, metabolic tissues collected from 21-month-old female offspring born to mothers treated with 0, 0.05, 0.5, or 5 mg/kg/day of BPA were studied. Findings showed prenatal BPA in non-monotonic manner (1) increased oxidative stress; (2) induced lipotoxicity in liver and muscle; and (3) increased aromatase and estrogen receptor expression in visceral adipose tissues. These changes are generally associated with the development of peripheral and tissue level IR and may explain the IR status and adipocyte hypertrophy observed in prenatal BPA-treated female sheep. [ABSTRACT FROM AUTHOR]

• Largest study to examine phthalate and eicosanoid associations in single and multipollutant frameworks. • First study to investigate the impact of a recent phthalate replacement on altered levels of eicosanoids during pregnancy. • Metabolites of low molecular phthalates and a recent replacement became prominent in multipollutant analysis. • Weighted sum of phthalate exposure positively associated with multiple eicosanoids, particularly those from the Cytochrome P450 pathway. Humans are exposed to complex mixtures of phthalates. Gestational exposure to phthalates has been linked to preeclampsia and preterm birth through potential pathways such as endocrine disruption, oxidative stress, and inflammation. Eicosanoids are bioactive signaling lipids that are related to a variety of homeostatic and inflammatory processes. We investigated associations between urinary phthalates and their mixtures with plasma eicosanoid levels during pregnancy using the PROTECT cohort in Puerto Rico (N = 655). After adjusting for covariates, we estimated pair-wise associations between the geometric mean of individual phthalate metabolite concentrations across pregnancy and eicosanoid biomarkers using multivariable linear regression. We used bootstrapping of adaptive elastic net regression (adENET) to evaluate phthalate mixtures associated with eicosanoids and subsequently create environmental risk scores (ERS) to represent weighted sums of phthalate exposure for each individual. After adjusting for false-discovery, in single-pollutant analysis, 14 of 20 phthalate metabolites or parent compound indices showed significant and primarily negative associations with multiple eicosanoids. In our mixture analysis, associations with several metabolites of low molecular weight phthalates – DEP, DBP, and DIBP – became prominent. Additionally, MEHHTP and MECPTP, metabolites of a new phthalate replacement, DEHTP, were selected as important predictors for determining the concentrations of multiple eicosanoids from different pathway groups. A unit increase in phthalate ERS derived from bootstrapping of adENET was positively associated with several eicosanoids mainly from Cytochrome P450 pathway. For example, an increase in ERS was associated with 11(S)-HETE (β = 1.6, 95% CI: 0.020, 3.180), (±)11,12-DHET (β = 2.045, 95% CI: 0.250, 3.840), 20(S)-HETE (β = 0.813, 95% CI: 0.147, 1.479), and 9 s-HODE (β = 2.381, 95% CI: 0.657, 4.104). Gestational exposure to phthalates and phthalate mixtures were associated with eicosanoid levels during pregnancy. Results from the mixture analyses underscore the complexity of physiological impacts of phthalate exposure and call for further in-depth studies to examine these relationships. [ABSTRACT FROM AUTHOR]

Environmental contamination with hexavalent chromium (CrVI) is a growing problem both in the United States and developing countries. Hexavalent chromiumis widely used in numerous industries. Environmental exposure to CrVI adversely affects pregnancy outcomes and subsequent health of 2 generations, resulting in higher pregnancy loss, spontaneous abortion and low birth rate. Pregnant women exposed to CrVI through occupational settings experience increased risk of spontaneous abortion, stillbirth, preterm birth, and neonatal death. Children of the CrVI exposed women experience respiratory problems, perinatal jaundice, and increased birth defects. Because placental dysfunction may have a role in such adverse pregnancy outcome, we tested the hypothesis that environmental Cr exposure in pregnant women results in Cr accumulation in the human placenta, which could increase placental oxidative stress by disrupting antioxidant machinery and inducing apoptosis. Studies using frozen, deidentified human term placenta samples indicated that: (1) Cr accumulates in human term placenta tissues and (2) increase in Cr accumulation is positively correlated with oxidative stress and apoptotic markers, and altered antioxidants levels. Interestingly, there was a sexual dimorphism in the correlation between Cr accumulation and oxidative stress, and expression of apoptotic and antioxidant markers. Mechanistic in vitro studies using human trophoblast cells BeWo confirmed the detrimental effects of Cr in altering antioxidant genes. For the first time, this study provides evidence in support of a positive correlation between Cr accumulation in the human placenta and accelerated oxidative stress, with a gender bias toward the male sex. [ABSTRACT FROM AUTHOR]

Simple Summary: Type 1 and type 2 diabetes can lead to serious health problems that affect many organs including the nerve, the eye, and the kidney. These health problems can be disabling or even life-threatening, and to date, there are no effective therapies that can slow or prevent their development. We studied the effect of empagliflozin, a medication that reduces blood sugar levels and the risk of cardiovascular disease, on the nerve, eye, and kidney in a side-by-side comparison of type 1 and type 2 mouse models. Empagliflozin had no beneficial effects on disease progression in type 2 diabetic mice, but improved nerve function in the type 1 diabetic model, an effect that was accompanied by reduced markers of oxidative injury. These findings support the concept that different mechanisms contribute to nerve damage in type 1 and type 2 diabetes. Our results further support our view that the concept of one therapy will benefit all complications should be abandoned as we pursue more personalized, tissue-specific, diabetes type-specific treatments. Microvascular complications account for the significant morbidity associated with diabetes. Despite tight glycemic control, disease risk remains especially in type 2 diabetes (T2D) patients and no therapy fully prevents nerve, retinal, or renal damage in type 1 diabetes (T1D) or T2D. Therefore, new antidiabetic drug classes are being evaluated for the treatment of microvascular complications. We investigated the effect of empagliflozin (EMPA), an inhibitor of the sodium/glucose cotransporter 2 (SGLT2), on diabetic neuropathy (DPN), retinopathy (DR), and kidney disease (DKD) in streptozotocin-induced T1D and db/db T2D mouse models. EMPA lowered blood glycemia in T1D and T2D models. However, it did not ameliorate any microvascular complications in the T2D model, which was unexpected, given the protective effect of SGLT2 inhibitors on DKD progression in T2D subjects. Although EMPA did not improve DKD in the T1D model, it had a potential modest effect on DR measures and favorably impacted DPN as well as systemic oxidative stress. These results support the concept that glucose-centric treatments are more effective for DPN in T1D versus T2D. This is the first study that provides an evaluation of EMPA treatment on all microvascular complications in a side-by-side comparison in T1D and T2D models. [ABSTRACT FROM AUTHOR]

Endogenous signaling molecules derived from lipids, peptides, and DNA, are important regulators of physiological processes during pregnancy. The effect of their collective impact on preterm birth (delivery < 37 weeks gestation) is understudied. We aimed to characterize the associations and predictive capacity of an extensive panel of eicosanoids, immune biomarkers, oxidative stress markers, and growth factors towards preterm birth and its subtypes. We conducted a cross-sectional study of pregnant women (recruited < 15 weeks gestation) in the LIFECODES birth cohort, which included 58 cases of preterm birth and 115 controls that delivered term. Among the cases there were 31 cases who had a spontaneous preterm birth (cases who had spontaneous preterm labor and/or preterm premature rupture of membranes) and 25 that had preterm birth associated with aberrant placentation (cases who had preeclampsia and/or intrauterine growth restriction) and 2 cases that could not be sufficiently categorized as either. We analyzed single biomarker associations with each preterm birth outcome using multiple logistic regression. Adaptive elastic-net was implemented to perform a penalized multiple logistic regression on all biomarkers simultaneously to identify the most predictive biomarkers. We then organized biomarkers into biological groups and by enzymatic pathways and applied adaptive elastic-net and random forest to evaluate the accuracy of each group for predicting preterm birth cases. The majority of associations we observed were for spontaneous preterm birth, and adaptive elastic-net identified 5-oxoeicosatetraenoic acid, resolvin D1, 5,6-epoxy-eicsatrienoic acid, and 15-deoxy-12,14-prostaglandin J2 as most predictive. Overall, lipid biomarkers performed the best at separating cases from controls compared to other biomarker categories (adaptive elastic-net AUC = 0.78 [0.62, 0.94], random forest AUC = 0.84 [0.72, 0.96]). Among the enzymatic pathways that differentiate eicosanoid metabolites, we observed the highest prediction of overall preterm birth by lipoxygenase metabolites using random forest (AUC = 0.83 [0.69, 0.96]), followed by cytochrome p450 metabolites using adaptive elastic-net (AUC = 0.74 [0.52, 0.96]). In this study we translate biological hypothesis into the language of modern machine learning. Many lipid biomarkers were highly associated with overall and spontaneous preterm birth. Among eicosanoids, lipoxygenase and cytochrome p450 products performed best in identifying overall and spontaneous preterm birth. The combination of lipid biomarkers may have good utility in clinical settings to predict preterm birth. [ABSTRACT FROM AUTHOR]