Disease-controlled multiple myeloma in a patient with 17p gain and t(4;14): A case report.

Cytogenetic karyotypes such as t(4; 14), del(17p), t(14; 16), t(14; 20), and TP53 mutations are associated with high-risk multiple-myeloma (MM) and indicate poor prognosis. Therefore, cytogenetic testing is extremely important for determining prognosis of MM. However, the aberrant karyotypes reported in the current literature are incomplete. The cytogenetic karyotype 17p gain has not received widespread attention, and its relationship with MM prognosis is unknown; additionally, the prognosis of 17p gain associated with t(4; 14) has not been studied in depth. Therefore, we introduce a special case in which a patient had both 17p gain and t(4; 14). An 81-year-old woman was admitted to the Affiliated Hospital of Shandong University of Traditional Chinese Medicine for stomach discomfort. The patient had no relevant medical history. Laboratory tests, immunophenotyping, and haematological results suggested MM, and cytogenetic tests indicated 17p gain and t(4; 14) with no other abnormalities. She was treated with two different chemotherapeutic regimens and achieved very good partial response, but eventually experienced biochemical relapses after discontinuing therapy. However, she eventually achieved good disease control with a bortezomib, lenalidomide, and dexamethasone-based regimen; she has survived longer than 5 years, much longer than the 1 year reported for MM patients with t(4:14), and been progression-free more than 3 years. We use this case to explore the possible relationship between the 17p gain and prognosis of patients with MM, as well as the treatment of MM with high-risk cytogenetic karyotypes. This case enriches the clinical application of cytogenetic analysis and adds important indicators for the prognosis of MM patients.

Selenium deficiency exacerbated Bisphenol A-induced intestinal toxicity in chickens: Apoptosis and cell cycle arrest mediated by ROS/P53.

Bisphenol A (BPA) is a phenolic organic synthetic compound that is used as the raw material of polycarbonate plastics, and its safety issues have recently attracted wide attention. Selenium (Se) deficiency has gradually developed into a global disease affecting intestinal function via oxidative stress and apoptosis. However, the toxic effects and potential mechanisms of BPA exposure and Se deficiency in the chicken intestines have not been studied. In this study, BPA exposure and/or Se deficiency models were established in vivo and in vitro to investigate the effects of Se deficiency and BPA on chicken jejunum. The results showed that BPA exposure and/or Se deficiency increased jejunum oxidative stress and DNA damage, activated P53 pathway, led to mitochondrial dysfunction, and induced apoptosis and cell cycle arrest. Using protein-protein molecular docking, we found a strong binding ability between P53 and peroxisome proliferator-activated receptor γ coactivator-1, thereby regulating mitochondrial dysfunctional apoptosis. In addition, we used N-acetyl-L-cysteine and pifithrin-α for in vitro intervention and found that N-acetyl-L-cysteine and pifithrin-α intervention reversed the aforementioned adverse effects. This study clarified the potential mechanism by which Se deficiency exacerbates BPA induced intestinal injury in chickens through reactive oxygen species/P53, which provides a new idea for the study of environmental combined toxicity of Se deficiency, and insights into animal intestinal health from a new perspective.

Seasonal Factors Are Associated with Activities of Enzymes Involved in High-Density Lipoprotein Metabolism among Pregnant Females in Ghana.

Background: Small-quantity lipid-based nutrient supplements (SQ-LNS) during pregnancy and postnatally were previously shown to improve high-density lipoprotein (HDL) cholesterol efflux capacity (CEC) and length in the children of supplemented mothers at 18 mo of age in the International Lipid-Based Nutrient Supplements (iLiNS) DYAD trial in Ghana. However, the effects of SQ-LNS on maternal HDL functionality during pregnancy are unknown. Objective: The goal of this cross-sectional, secondary outcome analysis was to compare HDL function in mothers supplemented with SQ-LNS vs. iron and folic acid (IFA) during gestation. Methods: HDL CEC and the activities of 3 HDL-associated enzymes were analyzed in archived plasma samples (N = 197) from a subsample of females at 36 weeks of gestation enrolled in the iLiNS-DYAD trial in Ghana. Correlations between HDL function and birth outcomes, inflammatory markers C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP), and the effects of season were explored to determine the influence of these factors on HDL function in this cohort of pregnant females. Results: There were no statistically significant differences in HDL CEC, plasma lecithin-cholesterol acyltransferase (LCAT) activity, cholesteryl ester transfer protein (CETP) activity, or phospholipid transfer protein (PLTP) activity between mothers supplemented with SQ-LNS compared with IFA control, and no statistically significant relationships between maternal HDL function and childbirth outcomes. LCAT activity was negatively correlated with plasma AGP (R = -0.19, P = 0.007) and CRP (R = -0.28, P < 0.001), CETP and LCAT activity were higher during the dry season compared to the wet season, and PLTP activity was higher in the wet season compared to the dry season. Conclusions: Mothers in Ghana supplemented with SQ-LNS compared with IFA during gestation did not have measurable differences in HDL functionality, and maternal HDL function was not associated with childbirth outcomes. However, seasonal factors and markers of inflammation were associated with HDL function, indicating that these factors had a stronger influence on HDL functionality than SQ-LNS supplementation during pregnancy. Clinical Trial Registry number: The study was registered as NCT00970866. https://clinicaltrials.gov/study/NCT00970866.

An enhanced three-stage design with trend analysis for allergen immunotherapy trials.

We previously introduced a three-stage design and associated end-of-stage analyses for allergen immunotherapy (AIT) trials. End-of-stage differences alone may not provide a fuller picture of Stages 2 and 3 effects because they may depend upon stage-specific durations. Therefore, we introduce an additional trend analysis to evaluate the difference in progression curves of two groups over the entire stage. Results from such analysis are used to inform persistence of end-of-stage benefit and thus provide evidence for stagewise effects beyond the study periods. We jointly apply end-of-stage and trend analyses to support the enhanced three-stage design to determine treatment response over time and sustained response to AIT. A simulation study was performed to illustrate the statistical properties (bias and power) of trend analyses under varying statistical missing mechanisms and effect sizes. The extent of bias depended on the missing mechanism and magnitude. Powers were largely driven by effect and sample sizes as well as pre-specified success margins, particularly of relative trend. As an illustration, assuming relative treatment differences of 25-30%, stagewise dropout rate of 15%, and parallel outcome progressions, a sample size of 200 per group may achieve 97% power to demonstrate a treatment effect and 53% power to demonstrate a sustained effect post-treatment. Trend analysis supplements the end-of-stage analysis to enhance the statistical claims of stagewise effects. Inferential statistics support our proposed trend analysis for evaluating benefits of AIT over time and inform clinical understanding and decisions.

Gene-Folic Acid Interactions and Risk of Conotruncal Heart Defects: Results from the National Birth Defects Prevention Study.

Conotruncal heart defects (CTDs) are heart malformations that affect the cardiac outflow tract and typically cause significant morbidity and mortality. Evidence from epidemiological studies suggests that maternal folate intake is associated with a reduced risk of heart defects, including CTD. However, it is unclear if folate-related gene variants and maternal folate intake have an interactive effect on the risk of CTDs. In this study, we performed targeted sequencing of folate-related genes on DNA from 436 case families with CTDs who are enrolled in the National Birth Defects Prevention Study and then tested for common and rare variants associated with CTD. We identified risk alleles in maternal MTHFS (ORmeta = 1.34; 95% CI 1.07 to 1.67), maternal NOS2 (ORmeta = 1.34; 95% CI 1.05 to 1.72), fetal MTHFS (ORmeta = 1.35; 95% CI 1.09 to 1.66), and fetal TCN2 (ORmeta = 1.38; 95% CI 1.12 to 1.70) that are associated with an increased risk of CTD among cases without folic acid supplementation. We detected putative de novo mutations in genes from the folate, homocysteine, and transsulfuration pathways and identified a significant association between rare variants in MGST1 and CTD risk. Results suggest that periconceptional folic acid supplementation is associated with decreased risk of CTD among individuals with susceptible genotypes.

Selenium Deficiency Induces Inflammatory Response and Decreased Antimicrobial Peptide Expression in Chicken Jejunum Through Oxidative Stress.

Selenium deficiency can affect the level of selenoprotein in organs and tissues and cause inflammation. However, the mechanism of selenium deficiency on jejunal injury in chickens remains unclear. In this study, we established a selenium deficiency model in chickens by feeding a low selenium diet and observed ultrastructural and pathological changes in the jejunum. The expression levels of 25 selenoproteins, the levels of oxidative stress, tight junction (TJ) proteins, and antimicrobial peptides (AMP), as well as the expression levels of factors related to inflammatory signaling pathways, were examined in the intestine and analyzed using principal component analysis (PCA). The results of PCA and quantitative real-time PCR (qRT-PCR) showed that selenium deficiency mainly affected the expression of antioxidant selenoproteins in chicken jejunum, especially glutathione peroxidases, thioredoxin reductase, and iodothyronine deiodinase, thus weakening the antioxidant function in the intestine and inducing oxidative stress. We also found disruption of intestinal TJ structures, a significant reduction in TJ protein expression, and downregulation of antimicrobial peptide levels, suggesting that selenium deficiency led to damage of the intestinal barrier. In addition, a significant increase in inflammatory cell infiltration and expression of inflammatory factors was observed in the jejunum, indicating that selenium deficiency induces inflammatory injury. In conclusion, selenium deficiency downregulates antioxidant selenoproteins levels, induces oxidative stress, decreases intestinal AMP levels, and leads to inflammatory injury and disruption of the intestinal barrier in the jejunum. These results shed new light on the molecular mechanisms of intestinal damage caused by selenium deficiency.

Multi-Omic Analyses Reveal Bifidogenic Effect and Metabolomic Shifts in Healthy Human Cohort Supplemented With a Prebiotic Dietary Fiber Blend.

Dietary fiber, a nutrient derived mainly from whole grains, vegetables, fruits, and legumes, is known to confer a number of health benefits, yet most Americans consume less than half of the daily recommended amount. Convenience and affordability are key factors determining the ability of individuals to incorporate fiber-rich foods into their diet, and many Americans struggle to access, afford, and prepare foods rich in fiber. The objective of this clinical study was to test the changes in microbial community composition, human metabolomics, and general health markers of a convenient, easy to use prebiotic supplement in generally healthy young participants consuming a diet low in fiber. Twenty healthy adults participated in this randomized, placebo-controlled, double-blind, crossover study which was registered at clinicaltrials.gov as NCT03785860. During the study participants consumed 12 g of a prebiotic fiber supplement and 12 g of placebo daily as a powder mixed with water as part of their habitual diet in randomized order for 4 weeks, with a 4-week washout between treatment arms. Fecal microbial DNA was extracted and sequenced by shallow shotgun sequencing on an Illumina NovaSeq. Plasma metabolites were detected using liquid chromatography-mass spectrometry with untargeted analysis. The phylum Actinobacteria, genus Bifidobacterium, and several Bifidobacterium species (B. bifidum, B. adolescentis, B. breve, B. catenulatum, and B. longum) significantly increased after prebiotic supplementation when compared to the placebo. The abundance of genes associated with the utilization of the prebiotic fiber ingredients (sacA, xfp, xpk) and the production of acetate (poxB, ackA) significantly changed with prebiotic supplementation. Additionally, the abundance of genes associated with the prebiotic utilization (xfp, xpk), acetate production (ackA), and choline to betaine oxidation (gbsB) were significantly correlated with changes in the abundance of the genus Bifidobacterium in the prebiotic group. Plasma concentrations of the bacterially produced metabolite indolepropionate significantly increased. The results of this study demonstrate that an easy to consume, low dose (12 g) of a prebiotic powder taken daily increases the abundance of beneficial bifidobacteria and the production of health-promoting bacteria-derived metabolites in healthy individuals with a habitual low-fiber diet. Clinical Trial Registration: www.clinicaltrials.gov/, identifier: NCT03785860.

Innovative approach to identify multigenomic and environmental interactions associated with birth defects in family-based hybrid designs.

Genes, including those with transgenerational effects, work in concert with behavioral, environmental, and social factors via complex biological networks to determine human health. Understanding complex relationships between causal factors underlying human health is an essential step towards deciphering biological mechanisms. We propose a new analytical framework to investigate the interactions between maternal and offspring genetic variants or their surrogate single nucleotide polymorphisms (SNPs) and environmental factors using family-based hybrid study design. The proposed approach can analyze diverse genetic and environmental factors and accommodate samples from a variety of family units, including case/control-parental triads, and case/control-parental dyads, while minimizing potential bias introduced by population admixture. Comprehensive simulations demonstrated that our innovative approach outperformed the log-linear approach, the best available method for case-control family data. The proposed approach had greater statistical power and was capable to unbiasedly estimate the maternal and child genetic effects and the effects of environmental factors, while controlling the Type I error rate against population stratification. Using our newly developed approach, we analyzed the associations between maternal and fetal SNPs and obstructive and conotruncal heart defects, with adjustment for demographic and lifestyle factors and dietary supplements. Fourteen and 11 fetal SNPs were associated with obstructive and conotruncal heart defects, respectively. Twenty-seven and 17 maternal SNPs were associated with obstructive and conotruncal heart defects, respectively. In addition, maternal body mass index was a significant risk factor for obstructive defects. The proposed approach is a powerful tool for interrogating the etiological mechanism underlying complex traits.

The parthenolide derivative ACT001 synergizes with low doses of L-DOPA to improve MPTP-induced Parkinson's disease in mice.

L-3,4-dihydroxyphenylalanine (L-DOPA) is currently the main drug used to treat Parkinson's disease (PD). However, long-term use of l-DOPA causes substantial side effects, and we hope to find a biological active ingredient that synergizes with a low-dose of l-DOPA to achieve the same therapeutic effect as that of a high-dose of l-DOPA. The natural product parthenolide (PTL) is the active ingredient in the medicinal plant feverfew (Tanacetum parthenium) and has antioxidant and anti-inflammatory properties. ACT001, a fumarate salt form of dimethylaminomicheliolide (DMAMCL), is a derivative of parthenolide and has comparable effects to those of PTL but exhibits higher stability in the plasma and is available at a lower cost. In our study, we used ACT001 in combination with l-DOPA to treat 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. Specifically, ACT001 significantly reduced motor dysfunction and dopaminergic neurodegeneration in MPTP-treated mice. Furthermore, ACT001 abolished MPTP-induced α-synuclein overexpression, astrocyte activation and interleukin-1ß (IL-1ß) production in the substantia nigra and striatum of the mouse brain. In addition, ACT001 increased the levels of the anti-apoptotic signalling molecule Bcl-2 and the pAkt/Akt ratio and reduced the levels of the pro-apoptotic signalling molecule Bax and the activation of Caspase3 in the substantia nigra and striatum. We found that the effects of the co-administration of ACT001 and l-DOPA (5 mg/kg) were equivalent to those of the administration of 8 mg/kg l-DOPA in MPTP-induced Parkinson's disease in mice. Then, this evidence suggests that l-DOPA + ACT001 may be used for the treatment of PD.

Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation.

Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity.

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways.

BACKGROUND: We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs METHODS: Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental triads affected by CTDs and 1645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDs RESULTS: Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest Bayesian false-discovery probability (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and nine fetal SNPs had a Bayesian false-discovery probability <0.8 for gene-by-environment (G × E) interactions with maternal folic acid supplementation. CONCLUSION: These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine, and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.