Immunogenicity of Pfizer mRNA COVID-19 vaccination followed by J&J adenovirus COVID-19 vaccination in two CLL patients

ImportanceIndividuals with Chronic Lymphocytic Leukemia have significant immune disfunction, often further disrupted by treatment. While currently available COVID-19 vaccinations are highly effective in immunocompetent individuals, they are often poorly immunogenic in CLL patients. It is important to understand the role heterologous boost would have in patients who did not respond to the recommended two-dose mRNA vaccine series with a SARS-CoV-2 specific immune response ObjectiveTo characterize the immune response of two CLL patients who failed to seroconvert after initial mRNA vaccine series following a third, heterologous, COVID-19 vaccination with Ad26.COV2.S. DesignTwo subjects with CLL were enrolled in an IRB-approved observational longitudinal cohort study of the immune response to COVID-19 vaccination. After enrollment, they received a third vaccination with Ad26.COV2.S. Blood was drawn prior to original vaccination series, four weeks after mRNA vaccination, and again four weeks after third vaccination. SettingEligible subjects were approached by oncologist overseeing CLL treatment and informed about study, at time of enrollment subjects consented to join the cohort study. ParticipantsSixteen subjects enrolled in the larger CLL cohort study, of whom two subjects received a third COVID-19 vaccination and were included in this analysis. Subject 1 is CLL treatment naive, while Subject 2 is currently on active treatment. Main Outcome(s) and Measure(s)SARS-CoV-2 specific immune response, including plasma antibodies, memory B-cells, CD4 and CD8 T-cells were assessed prior to vaccination (baseline) as well as post vaccination series and post third dose. ResultsOf the two subjects who received Ad26.COV2.S doses, Subject 1 seroconverted, had RBD-specific memory B-cells as well as spike-specific CD4 T-cells while Subject 2 did not. Both subjects had a spike-specific CD8 T-cell response after original mRNA vaccination series that was further boosted after third dose (Subject 1), or remained stable (Subject 2). Conclusions and RelevanceThe results of this study, however small, is especially promising to CLL individuals who did not seroconvert following initial mRNA vaccination series. Especially those that are treatment naive, not currently in active treatment, or who may consider vaccination before beginning active treatment.

Traditional Korean diet can alter the urine organic acid profile, which may reflect the metabolic influence of the diet / 한국영양학회지

Purpose@#To determine the metabolic influence of the traditional Korean diet (K-diet), which has been regarded as a healthy diet, we investigated the profile of urine organic acids that are intermediates of various types of metabolism including energy metabolism. @*Methods@#Ten women aged 50–60 years were recruited and randomly divided into 2 diet groups, K-diet and control diet, the latter of which is a Westernized Korean diet that is commonly consumed by Koreans nowadays. Before and after the 2-week intervention, 46 urine organic acids were determined using LC/MS/MS, along with clinical parameters. @*Results@#The average concentrations of succinate (4.14 ± 0.84 μg/mg creatinine vs. 1.49 ± 0.11, p = 0.0346) and hydroxymethylglutarate (3.67 ± 0.36 μg/mg creatinine vs. 2.97 ± 0.29, p = 0.0466), both of which are intermediates of energy metabolism, decreased in the K-diet group after the 2-week intervention, but these were not observed in the control diet group. In particular, the average concentration of succinate in the K-diet group was lower than that in the control group (3.33 ± 0.56 μg/mg creatinine vs. 1.49 ± 0.11, p = 0.0284) after 2 weeks. The concentrations of two tryptophan metabolites, 5-hydroxyindolacetate (3.72 ± 0.22 μg/mg creatinine vs. 3.14 ± 0.21, p = 0.0183) and indican (76.99 ± 8.35 μg/mg creatinine vs. 37.89 ± 10.06, p = 0.0205) also decreased only in the K-diet group. After the 2-week intervention, the concentration of kynurenate, another tryptophan metabolite, was lower in the K-diet group than that in the control diet group (3.96 ± 0.51 μg/mg creatinine vs. 2.90 ± 0.22, p = 0.0356). Interestingly, the urine level of kynurenate was positively correlated with BMI (r = 0.61424, p = 0.0003) and total cholesterol (r = 0.46979, p = 0.0088), which decreased only in the K-diet group (239.40 ± 15.14 mg/dL vs. 198.20 ± 13.25, p = 0.0163). @*Conclusion@#The K-diet alters the urinary excretion of organic acids involved in energy metabolism and tryptophan metabolism, suggesting the influence of the K-diet on these types of metabolism. Urine organic acids changed by the K-diet may serve as biomarkers in future studies.

Walnut phenolic extracts reduce telomere length and telomerase activity in a colon cancer stem cell model

BACKGROUND/OBJECTIVES: Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by hTERT and c-MYC, maintains telomeric DNA sequences. Especially, telomerase is active in cancer and stem cells to maintain telomere length for replicative immortality. Recently we reported that walnut phenolic extract (WPE) can reduce cell viability in a colon cancer stem cell (CSC) model. We, therefore, investigated the effect of WPE on telomere maintenance in the same model. MATERIALS/METHODS: CD133+CD44+ cells from HCT116, a human colon cancer cell line, were sorted by Fluorescence-activated cell sorting (FACS) and treated with WPE at the concentrations of 0, 10, 20, and 40 µg/mL for 6 days. Telomere lengths were assessed by quantitative real-time PCR (qRT-PCR) using telomere specific primers and DNA extracted from the cells, which was further adjusted with single-copy gene and reference DNA (ddCt ). Telomerase activity was also measured by qRT-PCR after incubating the PCR mixture with cell protein extracts, which was adjusted with reference DNA (dCt ). Transcriptions of hTERT and c-MYC were determined using conventional RT-PCR. RESULTS: Telomere length of WPE-treated cells was significantly decreased in a dose-dependent manner (5.16 ± 0.13 at 0 µg/mL, 4.79 ± 0.12 at 10 µg/mL, 3.24 ± 0.08 at 20 µg/mL and 3.99 ± 0.09 at 40 µg/mL; P = 0.0276). Telomerase activities concurrently decreased with telomere length (1.47 ± 0.04, 1.09 ± 0.01, 0.76 ± 0.08, and 0.88 ± 0.06; P = 0.0067). There was a positive correlation between telomere length and telomerase activity (r = 0.9090; P < 0.0001). Transcriptions of both hTERT and c-MYC were also significantly decreased in the same manner. CONCLUSIONS: In the present cell culture model, WPE reduced telomere maintenance, which may provide a mechanistic link to the effect of walnuts on the viability of colon CSCs.

The association between dietary pattern and depression in middle-aged Korean adults

BACKGROUND/OBJECTIVES: The association between dietary patterns and depression has been reported but the results have been inconsistent. This study was conducted to investigate the association between dietary patterns and depression in middle-aged Korean adults. SUBJECTS/METHODS: The participants were selected from a community-based cohort, a subset of the Korean Genome and Epidemiology Study. Depression was assessed using the Korean version of the Beck Depression Inventory (BDI) and those with a BDI score ≥ 16 were defined as having depression. The subjects' food intakes over the year preceding the survey were estimated by using a validated semi-quantitative food frequency questionnaire. Dietary patterns were identified by using factor analysis. Multiple logistic regression was used to assess the association of dietary pattern with depression. RESULTS: Among 3,388 participants, 448 (13.2%) were identified as having depression. We identified two major dietary patterns: ‘Healthy’ dietary pattern was characterized by high intakes of vegetables, soybeans, mushroom, seaweeds, white fish, shellfish and fruits and a low intake of white rice. ‘Unhealthy’ dietary pattern was characterized by high intakes of white rice, meats, ramen, noodles, bread and coffee and a low intake of rice with other grains. Compared with subjects in the lowest quartiles, those in the highest quartiles of the healthy dietary pattern had a significantly lower odds ratio (OR = 0.59, 95% CI: 0.42–0.82, P for trend = 0.0037) after adjusting for potential confounders. In contrast, the unhealthy dietary pattern was negatively associated with depression (OR = 1.65, 95% CI: 1.19–2.28, P for trend = 0.0021). CONCLUSION: This results suggest that a healthy dietary pattern (rich in vegetables, soybeans, mushroom, seaweeds, white fish, shellfish, and fruits) is associated with low risk of depression. Whereas an unhealthy dietary pattern (rich in white rice, meats, ramen, noodles, bread, and coffee) is associated with a high risk of depression in middle-aged Korean adults.

High dairy products intake reduces osteoporosis risk in Korean postmenopausal women: A 4 year follow-up study

BACKGROUND/OBJECTIVES: The aim of this study was to identify the effect of dairy products, milk and yogurt on osteoporosis incidence among Korean postmenopausal women using prospective cohort data. MATERIALS/METHODS: Between 2001 and 2003, 10,038 participants were recruited in rural and urban areas for a baseline examination of a community-based cohort study. Of those, 1,573 postmenopausal women (aged 40–69 years at baseline) were eligible for the present study. Intakes of dairy products, milk, and yogurt were assessed using a validated semi-quantitative food frequency questionnaire. The speed of sound at the radius and tibia were measured using a quantitative ultrasound device and osteoporosis was defined based on the WHO criteria (T-score ≤−2.5). RESULTS: During the 4-years follow-up study, the cumulative incidence of osteoporosis was 18.4% (273 cases) in the radius and 33.6% (407 cases) in the tibia. The subjects with higher frequency of dairy product consumption showed a decreased risk of radius osteoporosis after adjusting for potential confounders [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.33–0.80 for >1 time/day vs. non consumer; P for trend = 0.0027]. Similarly, high frequency of milk and yogurt consumption had a protective effect on radius osteoporosis risk [milk: HR = 0.60, 95% CI: 0.42–0.87 for >5–6 times/week vs. non consumer (P for trend = 0.0130), yogurt: HR = 0.51, 95% CI: 0.30–0.85 for > 5–6 times/week vs. non consumer (P for trend = 0.0167)]. However, high dairy products consumption was not related with tibia osteoporosis. CONCLUSIONS: This study suggests that daily intake of dairy products could potentially reduce radius osteoporosis incidence among Korean postmenopausal women.

Managing Chronic Kidney Disease and Chemotherapy-Induced Peripheral Neuropathy with Acupuncture and Herbal Medicine: A Case Study.

This case study details the treatment of a 59-year-old male with Stage 3B chronic kidney disease (CKD) and chemotherapy-induced peripheral neuropathy of the left limbs using acupuncture and bulk herbs. After 6 weeks of combined acupuncture and herbal treatments, glomerular filtration rate increased significantly from 37 mL/min to 51 mL/min and serum creatinine level decreased from 1.85 mg/dL to 1.41 mg/dL. After a course of 15 acupuncture treatments over 4 months with some appointments in closer proximity, the patient additionally reported increased sensation of his left limbs. Since there are limited treatments for CKD, others with CKD may benefit from acupuncture and herbal treatments. This study offers an approach to managing CKD and chemotherapy-induced peripheral neuropathy more effectively using herbs and acupuncture supported by biomedical verification results.

Genome-wide association study for the interaction between BMR and BMI in obese Korean women including overweight

BACKGROUND/OBJECTIVES: This is the first study to identify common genetic factors associated with the basal metabolic rate (BMR) and body mass index (BMI) in obese Korean women including overweight. This will be a basic study for future research of obese gene-BMR interaction. SUBJECTS/METHODS: The experimental design was 2 by 2 with variables of BMR and BMI. A genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) was conducted in the overweight and obesity (BMI > 23 kg/m2) compared to the normality, and in women with low BMR (< 1426.3 kcal/day) compared to high BMR. A total of 140 SNPs reached formal genome-wide statistical significance in this study (P < 1 x 10(-4)). Surveys to estimate energy intake using 24-h recall method for three days and questionnaires for family history, a medical examination, and physical activities were conducted. RESULTS: We found that two NRG3 gene SNPs in the 10q23.1 chromosomal region were highly associated with BMR (rs10786764; P = 8.0 x 10(-7), rs1040675; 2.3 x 10(-6)) and BMI (rs10786764; P = 2.5 x 10(-5), rs10786764; 6.57 x 10(-5)). The other genes related to BMI (HSD52, TMA16, MARCH1, NRG1, NRXN3, and STK4) yielded P <10 x 10-4. Five new loci associated with BMR and BMI, including NRG3, OR8U8, BCL2L2-PABPN1, PABPN1, and SLC22A17 were identified in obese Korean women (P < 1 x 10(-4)). In the questionnaire investigation, significant differences were found in the number of starvation periods per week, family history of stomach cancer, coffee intake, and trial of weight control in each group. CONCLUSION: We discovered several common BMR- and BMI-related genes using GWAS. Although most of these newly established loci were not previously associated with obesity, they may provide new insights into body weight regulation. Our findings of five common genes associated with BMR and BMI in Koreans will serve as a reference for replication and validation of future studies on the metabolic rate.

TT Mutant Homozygote of Kruppel-like Factor 5 Is a Key Factor for Increasing Basal Metabolic Rate and Resting Metabolic Rate in Korean Elementary School Children

We investigated the contribution of genetic variations of KLF5 to basal metabolic rate (BMR) and resting metabolic rate (RMR) and the inhibition of obesity in Korean children. A variation of KLF5 (rs3782933) was genotyped in 62 Korean children. Using multiple linear regression analysis, we developed a model to predict BMR in children. We divided them into several groups; normal versus overweight by body mass index (BMI) and low BMR versus high BMR by BMR. There were no differences in the distributions of alleles and genotypes between each group. The genetic variation of KLF5 gene showed a significant correlation with several clinical factors, such as BMR, muscle, low-density lipoprotein cholesterol, and insulin. Children with the TT had significantly higher BMR than those with CC (p = 0.030). The highest muscle was observed in the children with TT compared with CC (p = 0.032). The insulin and C-peptide values were higher in children with TT than those with CC (p= 0.029 vs. p = 0.004, respectively). In linear regression analysis, BMI and muscle mass were correlated with BMR, whereas insulin and C-peptide were not associated with BMR. In the high-BMR group, we observed that higher muscle, fat mass, and C-peptide affect the increase of BMR in children with TT (p < 0.001, p < 0.001, and p = 0.018, respectively), while Rohrer's index could explain the usual decrease in BMR (adjust r2 = 1.000, p < 0.001, respectively). We identified a novel association between TT of KLF5 rs3782933 and BMR in Korean children. We could make better use of the variation within KLF5 in a future clinical intervention study of obesity.

Role of Morphine in the Glutamate-Induced Oxidative Damage of C6 Glial Cells / 대한마취과학회지

BACKGROUND: Although many studies regarding several neurotransmitters and receptors have been conducted to define the mechanism involved in the development of dependence on opioids, definitive evidence has still not been presented. This study was designed to investigate the effect of morphine on glutamate-induced cytotoxicity of rat C6 glial cells. METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used for cell viability. Morphology of nuclei was observed by fluorescent microscopy. Reduced glutathione (GSH) contents were measured in acid-soluble cell fractions. Generation of hydrogen peroxide (H2O2) was measured from the cultured supernatant of C6 glial cells using the scopoletin-horseradish peroxidase (HRP) assay. RESULTS: Glutamate induced the death of C6 glial cells in a time- and dose-dependent manner. Glutamate-induced cytotoxicity was protected by morphine and antioxidants, such as GSH and N-acetyl-L-cysteine (NAC). However, morphine antagonist, naloxone did not inhibit the protective effect of morphine on glutamate-induced cytotoxicity. In addition, the specific agonists, [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin acetate salt (DAMGO), [D-Pen2,5]-Enkephalin (DPDPE) and U69593 did not protect C6 glial cells from glutamate-induced cytotoxicity. Furthermore, morphine recovered the depletion of GSH by glutamate and inhibited the generation of H2O2 by glutamate in C6 glial cells. CONCLUSIONS: We suggest that morphine protects C6 glial cells from glutamate-induced cytotoxicity via the inhibition of GSH depletion and the generation of H2O2 by glutamate.

Morphine Protects Peroxynitrite-induced Cell Death in Primary Rat Neonatal Astrocytes / 대한마취과학회지

BACKGROUND: Astrocytes, representing a major non-neuronal cell population in the central nervous system (CNS), contain opioid receptors and are actively involved in several brain functions. This study is designed to evaluate the effects by which morphine contributes to cytotoxicity of nitric oxide (NO) species including NO and peroxynitrite (ONOO(-)) in primary astrocytes isolated from the cerebral cortexes of 1 - 2 day Sprague-Dawley rats. METHODS: The cultured cells were pretreated with morphine and exposed to 3-morpholinosydnonimine (SIN-1) which simultaneously generates NO and superoxide, thus possibly forming peroxynitrite. The cell damage was assessed by using an MTT (methylthizol-2-yl-2, 5-diphenyl, tetrazolium bromide) assay. Morphological nuclear changes of the cells after exposure to SIN-1 for 24 hours was evaluated by using 4', 6-diamidino-2-phenylindole (DAPI) staining. RESULTS: Morphine significantly protected primary rat astrocytes in a dose-dependent manner from the death mediated by sodium nitroprusside (SNP), a donor of nitric oxide, and SIN-1. Moreover, it was found that naloxone antagonized the protective effect of morphine on SIN-1-induced cell death, revealed as apoptosis by the occurrence of morphological nuclear changes characteristic of apoptosis. Morphine also inhibited the nuclear condensation of SIN-1-treated cells, however the action of morphine was antagonized by pretreatment of naloxone. The protective role of morphine on SIN-1-induced cytotoxicity was inhibited by DL-Buthionine-[S, R]-sulfoximine (BSO). Furthermore, the effects of morphine on SIN-1-induced cytotoxicity were blocked by pretreatment of Gi protein inhibitor, pertussis toxin, and phosphoinositide 3-kinase (PI3 kinase) inhibitors, Wortmannin and LY294002. CONCLUSIONS: These results suggest that morphine may protect primary rat astrocytes from NO species via the signaling cascades involving G-protein and PI3-kinase, and possibly regulates the anti-oxidant, glutathione (GSH).

Bacterial Lipopolysaccharide - Induced Generation of Nitric Oxide is Mediated by ERK1 and JNK1 / SAPK in Primary Rat Neonatal Astrocytes / 대한면역학회지

No abstract available.

The Protective Mechanism of Zinc in Fungal Metabolte Gliotoxin - induced Apoptosis

Gliotoxin, a fungal metabolite, is one of the epipolythiodioxopiperazine classes and has a variety of effects including imrnunomodulatory and apoptotic agents. This study is designed to evaluate the effect of zinc on gliotoxin-induced death of HL-60 cells. Here, we demonstrated that treatment of gliotoxin decreased cell viability in a dose and time-dependent manner. Gliotoxin-induced cell death was confirtned as apoptosis characterized by chromatin marginafion, fragmentation and ladder-pattern digestion of genomic DNA. Gliotoxin increased the proteolytic activities of caspase 3, 6, 8, and 9. Caspase-3 activation was further confirmed by the degradation of procaspase-3 and PARP in gliotoxin-treated HL-60 cells. Zinc compounds including ZnC12 and ZnSO4 markedly inhibited gliotoxin-induced apoptosis in HL-60 cells (from 30% to 90%). Consistent with anti- apoptotic effects, zinc also suppressed the enzymatic activities of caspase-3 and -9 proteases. In addition, cleavage of both PARP and procaspase 3 in gliotoxin-treated HL-60 cells was inhibited by the addition of zinc compounds. We further demonstrated that expression of Fas ligand by gliotoxin was suppressed by zinc compounds. These data suggest that zinc may prevent gliotoxin- induced apoptosis via inhibition of Fas ligand expression as well as suppression of caspase family cysteine proteases-3 and -9 in HL-60 cells.