Hair dye use and prostate cancer risk: A prospective analysis in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort.

BACKGROUND: According to the International Agency for Research on Cancer, some hair dye chemicals are considered mutagenic and carcinogenic in humans. One hospital-based study reported a positive association between hair dye use and prostate cancer risk, but no prospective analyses have been conducted. METHODS: This study investigated the association between hair dye use and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort, a large, well-characterized cohort of 29,133 male Finnish smokers. Participants completed questionnaires regarding lifestyle, medical, and risk factor information, including the use of hair dye, which was available for 98.8% of the cohort (28,795 men). Prostate cancer cases were identified through linkage with the Finnish Cancer Registry and the Finnish Mortality Register. Hazard ratios (HRs) and confidence intervals (CIs) were estimated via multivariable Cox proportional hazards regression. RESULTS: During a 28-year period of observation, 2703 incident prostate cancer cases were diagnosed. As reported at the baseline, 75 men used hair dye, and 13 of these men were subsequently diagnosed with prostate cancer. After adjustments for potential confounders, men who used hair dyes experienced substantially higher prostate cancer risk than men who did not (HR, 1.77; 95% CI, 1.03-3.05). CONCLUSIONS: This first prospective investigation of hair dye use and prostate cancer suggests that personal hair dye use may be related to increased risk. The findings warrant re-examination in other prospective cohorts along with studies evaluating specific hair dyes and possible underlying biological mechanisms.

Multivitamin Use and Overall and Site-Specific Cancer Risks in the National Institutes of Health-AARP Diet and Health Study.

BACKGROUND: Multivitamins are among the most commonly used supplements in the United States, but their effectiveness in preventing cancer remains unclear. OBJECTIVES: We prospectively examined the association between multivitamin use and risks of overall and site-specific cancer in a large, well-characterized cohort to ascertain potential preventive or harmful relationships. METHODS: We examined 489,640 participants ages 50-71 in the NIH-American Association of Retired Persons (AARP) Diet and Health Study who were enrolled from 1995 to 1998. We linked to 11 state cancer registries in order to identify incident cancers. Multivitamin use was assessed by a baseline questionnaire. Cox proportional hazards regression models of multivitamin use were used to estimate HRs and 95% CIs for cancer risks in men and women, adjusted for potential confounders, including age, BMI, smoking, physical activity, the Healthy Eating Index 2015 score, and use of single-vitamin/-mineral supplements. RESULTS: A slightly higher overall cancer risk was observed in men (but not women) who consumed 1 or more multivitamins daily compared to nonusers [HRs, 1.02 (95% CI: 1.01-1.04) and 1.03 (95% CI: 1.00-1.07), respectively; P-trend = 0.002]. The latter reflected higher risks for prostate cancer (HR, 1.04; 95% CI: 0.98-1.10; P-trend = 0.005), lung cancer (HR, 1.07; 95% CI: 0.96-1.20; P-trend = 0.003), and leukemia (HR, 1.26; 95% CI: 1.02-1.57; P-trend = 0.003). Taking more than 1 multivitamin daily was also strongly positively associated with the risk of oropharyngeal cancer in women (HR, 1.53, 95% CI: 1.04-2.24; P-trend < 0.0001). By contrast, daily multivitamin use was inversely associated with the colon cancer risk in both sexes (HR, 0.82; 95% CI: 0.73-0.93; P-trend = 0.0003). CONCLUSIONS: We found little evidence to support a cancer-preventive role for multivitamin use, with the exception of colon cancer, in both sexes in the NIH-AARP Diet and Health Study. In addition, slightly higher risks of overall, prostate, and lung cancer, as well as leukemia, were observed for greater multivitamin use in men, with a higher oropharyngeal cancer risk in women.

Assessment of the feasibility of developing a clinical pathway using a clinical order log.

A clinical pathway (CP) is a tool for effectively managing a care process. There are several research efforts on developing clinical pathways (CPs) in the process mining domain. However, the nature of the data affects data analysis results, and patient clinical variability makes it challenging to develop CPs. Thus, it is crucial to determine candidate care processes that can be standardized as CPs before applying process mining techniques. This paper proposed a method for assessing CP feasibility regarding clinical complexity using clinical order logs from electronic health records. The proposed method consists of data preparation, activity & trace homogeneity evaluations, and process inspection using process mining. Each step consists of metrics to measure the homogeneity of processes and a visualization method to demonstrate the diversity of processes based on the log. The case study was conducted with five surgical groups of patients from a tertiary hospital in South Korea to validate the proposed method. The five groups of patients were successfully assessed. In addition, the visualization methods helped clinical experts grasp the diversity of care processes.

Clinical efficacy of upper limb robotic therapy in people with tetraplegia: a pilot randomized controlled trial.

STUDY DESIGN: A pilot randomized controlled trial. OBJECTIVES: To evaluate the clinical efficacy of upper limb robotic therapy in people with tetraplegia. SETTING: Inpatient rehabilitation hospital in Seoul, Korea. METHODS: Participants were randomly allocated to a robotic therapy (RT) or occupational therapy (OT) group. Both groups received usual care plus 30 min of additional therapy per day for 4 weeks. The additional therapy provided to the OT group was OT, and the additional therapy provided to RT group was RT using the Armeo Power. Primary outcomes were the Medical Research Council scale of each key muscle and Upper Extremity Motor Score (UEMS) for the trained arm. Secondary outcomes were the Spinal Cord Independence Measurement version III (SCIM-III) subscale and total score. Evaluations were performed at baseline and 4 weeks. RESULTS: A total of 34 individuals with tetraplegia were included; 17 in each group. At 4 weeks, the median (IQR) change in UEMS in the RT group was 1/25 (0 to 3) points compared with 0/25 (-1 to 1) points in the OT group (p = 0.03). The median (IQR) change in total SCIM-III score in the RT group was 7/100 (1.5 to 11) points compared with 0/100 (-8 to 4) points in the OT group (p < 0.01). CONCLUSIONS: There were small improvements in motor strength and SCIM-III scores in the RT group, but there were no statistically significant differences between the groups. Further studies are required for a better understanding of the effects of RT for people with tetraplegia.

Correction: Clinical efficacy of upper limb robotic therapy in people with tetraplegia: a pilot randomized controlled trial.

In the original version of the article the authors incorrectly stated that: "One case study provided evidence of some improvements in motor performance and spasticity [19], while several other studies only provided evidence on the feasibility of UER as an assessment tool; however, the fact that the manufacturer funded these studies lessens their objectivity [15, 20-24]." This is not correct as the manufacturers did not fund the studies. The correct phrase therefore should have read: "One case study provided evidence of some improvements in motor performance and spasticity [19], while several other studies provided evidence focusing more on the feasibility of UER rather than the clinical efficacy [15, 20-24]." The authors would like to apologise for this error.This has been corrected in both the PDF and HTML versions of the Article.

Menopausal hormone therapy and the risk of breast cancer by histological type and race: a meta-analysis of randomized controlled trials and cohort studies.

PURPOSE: This meta-analysis investigated the association between the risk of breast cancer and hormone replacement therapy (HRT). Various stratified analyses were performed according to race (Asian/Westerner), HRT type [all hormone therapies, estrogen-only therapy (ET), or combined estrogen-progestin therapy (EPT)], histological breast cancer type (ductal/lobular/mixed ductal-lobular), and estrogen receptor status (ER-positive/ER-negative). METHODS: A literature search was performed using Pubmed, Embase, and KoreaMed. Twenty-five epidemiological studies including 23 cohort studies and two randomized controlled trials were included in this meta-analysis. RESULTS: Using a random-effects model, HRT use was found to be positively associated with the risk of breast cancer with a pooled hazard ratio (HR) of 1.33 [95% confidence interval (CI) 1.24, 1.44]. Compared with ET, EPT was more strongly associated with breast cancer risk. EPT was associated with both ductal and lobular breast cancer risks [for ductal breast cancer, HR = 1.51 (95% CI 1.28, 1.78); for lobular breast cancer, HR = 1.38 (95% CI 1.20, 1.60)]. According to ER status, all HRTs were associated with the risk of ER-positive breast cancer, but not with that of ER-negative breast cancer. CONCLUSIONS: Asian HRT users had a higher risk of breast cancer than western HRT users. Both ET and EPT were significantly associated with the risk of all breast cancer histological types and ER-positive breast cancer.

Bisphenol A exposure and type 2 diabetes mellitus risk: a meta-analysis.

BACKGROUND: This meta-analytic study explored the relationship between the risk of type 2 diabetes mellitus (T2DM) and bisphenol A concentrations. METHODS: The Embase and Medline (PubMed) databases were searched, using relevant keywords, for studies published between 1980 and 2018. A total of 16 studies, twelve cross-sectional, two case-control and one prospective, were included in the meta-analysis. The odds ratio (OR) and its 95% confidence interval (CI) were determined across the sixteen studies. The OR and its 95% CI of diabetes associated with bisphenol A were estimated using both fixed-effects and random-effects models. RESULTS: A total of 41,320 subjects were included. Fourteen of the sixteen studies included in the analysis provided measurements of urine bisphenol A levels and two study provided serum bisphenol A levels. Bisphenol A concentrations in human bio-specimens showed positive associations with T2DM risk (OR 1.28, 95% CI 1.14, 1.44). A sensitivity analysis indicated that urine bisphenol A concentrations were positively associated with T2DM risk (OR 1.20, 95% CI 1.09, 1.31). CONCLUSIONS: This meta-analysis indicated that Bisphenol A exposure is positively associated with T2DM risk in humans.

Association between serum persistent organic pollutants and DNA methylation in Korean adults.

BACKGROUND: Exposure to persistent organic pollutants (POPs) has been associated with epigenetic changes such as DNA methylation, which can influence human health. However, the association between POPs and DNA methylation by sex was not shown in previous studies. OBJECTIVES: We investigated the association between POPs and DNA methylation in men and women using a larger population. METHODS: A cross-sectional study was conducted using the data of 444 Koreans (253 men and 191 women). Measurements for sixteen different POPs, including six organochlorine pesticides (OCPs) and ten polychlorinated biphenyls (PCBs) were taken in serum. DNA methylation via Alu and LINE-1 in peripheral leukocytes was measured by pyrosequencing. To evaluate the association between POPs and DNA methylation, the Pearson's correlation and multiple linear regression analyses were performed. RESULTS: Except for PCB52 and PCB101, we found significant inverse associations between p,p'-DDE, cis-Heptachlor epoxide, and PCBs and Alu assay in men after adjusting for age, BMI, smoking status, and alcohol consumption (ß = -0.67 for p,p'-DDE; -0.28 for cis-Heptachlor epoxide; in the range from -0.43 to -1.60 for PCBs). In women, PCB153 and PCB180 showed statistically significant inverse association with Alu assay (ß = -0.22 for PCB153; -0.22 for PCB180). Except for PCB101, p,p'-DDE and PCBs were positively associated with LINE-1 assay in women (ß = 0.48 for p,p'-DDE; in the range from 0.40-0.89 for PCBs) while p,p'-DDE, PCB153, and PCB180 showed positive associations with LINE-1 assay in men (ß = 0.55 for p,p'-DDE; 0.65 for PCB153; 1.02 for PCB180). CONCLUSIONS: We found that several POPs were associated with global DNA hypomethylation in the Alu assay for men and global DNA hypermethylation in the LINE-1 assay for women.

Association between serum concentrations of persistent organic pollutants and smoking in Koreans: A cross-sectional study.

BACKGROUND: Studies on the associations between persistent organic pollutants (POPs) and smoking according to gender and smoking amount (cigarettes/day) are limited, and the results regarding the relationship between POPs and smoking are not completely consistent across studies. OBJECTIVES: The smoking rate in Korea is one of the highest among the Organization for Economic Cooperation and Development (OECD) countries. We investigated the association between serum concentrations of POPs and cigarette smoking in Koreans by smoking status (never-smoker/ever-smoker) and smoking amount (cigarettes/day) according to gender. METHODS: Serum concentrations of 32 polychlorinated biphenyls (PCBs) and 19 organochlorine pesticides (OCPs) were measured in 401 participants (232 men and 169 women) who received health examinations during the Korean Cancer Prevention Study-II. We compared POP levels in ever-smokers and never-smokers and conducted multivariate logistic regression analyses to identify associations between POPs and smoking. RESULTS: Among women, the concentrations of PCB 156, PCB 167, and PCB 180 were significantly higher in ever-smokers than in never-smokers. After adjustments for age, body mass index, gamma-glutamyl transpeptidase, and alcohol intake, serum PCB 157 concentration was positively associated with male ever-smokers (OR 2.26; 95% CI, 1.01-5.04). In addition, trans-nonachlordane in OCPs as well as PCBs was significantly positively related with female ever-smokers (OR 3.21; 95% CI, 1.04-9.86). We found that subjects who smoked fewer than 15 cigarettes/day had a higher risk of having high POP concentrations than never-smokers. CONCLUSIONS: These results indicate that smoking may be associated with human serum POPs levels.

Pre-diagnostic free androgen and estradiol levels influence heart failure risk in both women and men: A prospective cohort study in the UK Biobank.

AIMS: Serum sex hormones have been linked to cardiovascular disease risk. However, their roles in the pathogenesis of heart failure (HF) in both men and women are unclear. We investigated the associations between free androgen, testosterone, and estradiol, and future risk of HF. METHODS AND RESULTS: This prospective cohort study evaluated UK Biobank participants free of prevalent cardiovascular disease and HF at baseline. Unitless free androgen, testosterone, and estradiol indices were generated using serum concentrations of total testosterone (nmol/L), estradiol (pmol/L), sex hormone binding globulin (SHBG, nmol/L), and albumin (g/L) in blood collected at enrolment. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF in relation to quartiles (Q) of free androgen (FAI), testosterone (FTI), estradiol (FEI) indices, and potential confounders. There were 180 712 men (including 5585 HF cases with FAI and 571 HF cases with FEI), and 177 324 women (including 2858 HF cases with FAI and 314 HF cases with FEI) with complete data. Increased FAI was associated with decreased HF risk in both men (HRQ4 vs. Q1: 0.86, 95% CI 0.79-0.94, p-trendcontinuous < 0.0001) and post-menopausal women (HRQ4 vs. Q1: 0.83, 95% CI 0.73-0.95). Similar inverse associations were observed for FTI only in men (HRQ4 vs. Q1: 0.91, 95% CI 0.83-0.98). Higher FEI was significantly associated with decreased HF risk among men (HRQ4 vs. Q1: 0.76, 95% CI 0.59-0.98), but was positively associated among pre-menopausal women (HRQ4 vs. Q1: 2.16, 95% CI 1.11-4.18). CONCLUSIONS: Sex hormones potentially influence HF pathogenesis and may offer pathways for interventions.

Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom.

Background: Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear. Methods: We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190,613 men and 224,853 women with genotyping data from the UK Biobank. Among these participants, we analyzed 37,037 men with mLOY and 13,978 women with mLOX detected using Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization (MR) was conducted to estimate causal associations. Results: Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR=1.06, 95%CI:1.03-1.11). The associations were apparent in both never-smokers (HR=1.07, 95%:1.01-1.14) and ever-smokers (HR=1.05, 95%CI:1.01-1.11) as well as men > and ≤60 years of age. MR analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO=1.15, 95%CI:1.13-1.18). Among post-menopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR=0.90, 95%CI:0.83-0.98). However, associations with mLOY and mLOX were not found for other heart diseases. Conclusions: Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

Do expressive writing interventions have positive effects on Koreans?: a meta-analysis.

Introduction: Expressive Writing (EW) is an intervention that focuses on individuals' writing down their thoughts and feelings about trauma or stressful events. Meta-analyses on EW studies have confirmed that EW has a positive effect. However, the heterogeneity of studies is high, so many studies have investigated boundary conditions and moderators. One of these moderators is the cultural difference in emotional suppression. Since EW focuses on the expression of suppressed thoughts and emotions, its effect might be slightly different for people in Asian cultures who show a high tendency to suppress their emotions. This study attempted to confirm the effect size of the EW interventions in Korea and examine whether these studies have different effect size from those based on Western cultures. Method: A total of 29 studies published in Korea until 2021 were analyzed. The effect size was calculated using the "dmetar," "meta," and "metafor" packages of the statistical program R 4.0.4. Results: The results were as follows. First, the effect size of EW intervention was 0.16, and we found that studies in the Korean context showed no significant difference from studies based on western meta-analysis. Second, the moderating variables that influenced the EW intervention were the writing type, the number of sessions, the time per session, and the measurement time. Discussion: The results of this study suggest that EW interventions benefit Koreans. And it is at least harmless and has a positive effect considering the efficiency and conciseness of interventions. Furthermore, the finding shows that EW interventions can be helpful even in the general population without apparent psychological problems. By considering moderators, we could structure more effective form of EW interventions for Koreans.

Serum metabolomic profile of hair dye use.

The International Agency for Research on Cancer reported that some chemicals in hair dyes are probably carcinogenic to those exposed to them occupationally. Biological mechanisms through which hair dye use may be related to human metabolism and cancer risk are not well-established. We conducted the first serum metabolomic examination comparing hair dye users and nonusers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Metabolite assays were conducted using ultrahigh performance liquid chromatography-tandem mass spectrometry. The association between metabolite levels and hair dye use was estimated using linear regression, adjusting for age, body mass index, smoking, and multiple comparisons. Among the 1,401 detected metabolites, 11 compounds differed significantly between the two groups, including four amino acids and three xenobiotics. Redox-related glutathione metabolism was heavily represented, with L-cysteinylglycine disulfide showing the strongest association with hair dye (effect size (ß) = - 0.263; FDR adjusted p-value = 0.0311), along with cysteineglutathione disulfide (ß = - 0.685; FDR adjusted p-value = 0.0312). 5alpha-Androstan-3alpha,17beta-diol disulfate was reduced in hair dye users (ß = - 0.492; FDR adjusted p-value = 0.077). Several compounds related to antioxidation/ROS and other pathways differed significantly between hair dye users and nonusers, including metabolites previously associated with prostate cancer. Our findings suggest possible biological mechanisms through which the use of hair dye could be associated with human metabolism and cancer risk.

Metabolomic Analysis of Vitamin E Supplement Use in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C22 lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C22 lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C22 lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases.

Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis.

The human brain choroid plexus (ChP) is a highly organized secretory tissue with a complex vascular system and epithelial layers in the ventricles of the brain. The ChP is the body's principal source of cerebrospinal fluid (CSF); it also functions as a barrier to separate the blood from CSF, because the movement of CSF through the body is pulsatile in nature. Thus far, it has been challenging to recreate the specialized features and dynamics of the ChP in a physiologically relevant microenvironment. In this study, we recapitulated the ChP structure by developing a microfluidic chip in accordance with established design rules. Furthermore, we used image processing and analysis to mimic CSF flow dynamics within a rlcking system; we also used a hydrogel containing laminin to mimic brain extracellular matrix (ECM). Human ChP cells were cultured in the ChP-on-a-chip with in vivo-like CSF dynamic flow and an engineered ECM. The key ChP characteristics of capillaries, the epithelial layer, and secreted components were recreated in the adjusted microenvironment of our human ChP-on-a-chip. The drug screening capabilities of the device were observed through physiologically relevant drug responses from breast cancer cells that had spread in the ChP. ChP immune responses were also recapitulated in this device, as demonstrated by the motility and cytotoxic effects of macrophages, which are the most prevalent immune cells in the ChP. Our human ChP-on-a-chip will facilitate the elucidation of ChP pathophysiology and support the development of therapeutics to treat cancers that have metastasized into the ChP.

3D microengineered vascularized tumor spheroids for drug delivery and efficacy testing.

Tumor angiogenesis is regarded as a promising target for limiting cancer progression because tumor-associated vasculature supplies blood and provides a path for metastasis. Thus, in vitro recapitulation of vascularized tumors is critical to understand the pathology of cancer and identify the mechanisms by which tumor cells proliferate, metastasize, and respond to drugs. In this study, we microengineered a vascularized tumor spheroid (VTS) model to reproduce the pathological features of solid tumors. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Notably, the hybrid spheroids also exhibited expression profiles associated with aggressive behavior. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. With the VTS chip showing a progressive tumor phenotype, we validated the suppressive effects of axitinib on tumor growth and angiogenesis, which depended on exposure dose and time, highlighting the significance of tumor vascularization to predict the efficacy of anticancer drugs. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow. Thus, our VTS model is a valuable platform with which to investigate the interactions between tumor microenvironments and explore therapeutic strategies in cancer. STATEMENT OF SIGNIFICANCE: We conducted an integrative study within a vascularized tumor spheroid (VTS) model. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Through RNA sequencing, we elucidated that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behavior such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow.

A 28-year prospective analysis of serum vitamin E, vitamin E-related genetic variation and risk of prostate cancer.

OBJECTIVE: Investigate the relationship between serum α-tocopherol concentration and long-term risk of prostate cancer, and evaluate the interaction with vitamin E-related genetic variants and their polygenic risk score (PRS). METHODS: We conducted a biochemical analysis of 29,102 male Finnish smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and 2724 prostate cancer cases were identified during 28 years of follow-up. Cox proportional hazards models examined whether serum α-tocopherol concentrations were associated with prostate cancer risk. Among 8383 participants, three SNPs related to vitamin E status (rs964184, rs2108622, and rs11057830) were examined to determine whether they modified the relationship between serum α-tocopherol concentrations and prostate cancer risk, both individually and as a PRS using logistic regression models. RESULTS: No association was observed between serum α-tocopherol and prostate cancer risk (fifth quintile (Q5) vs. Q1 hazard ratio (HR) = 0.87, 95% confidence interval (95% CI) 0.75, 1.02; P-trend = 0.57). Though no interactions were seen by population characteristics, high α-tocopherol concentration was associated with reduced prostate cancer risk among the trial α-tocopherol supplementation group (Q5 quintile vs. Q1 HR = 0.79, 95% CI 0.64, 0.99). Finally, no associated interaction between the three SNPs or their PRS and prostate cancer risk was observed. CONCLUSION: Although there was a weak inverse association between α-tocopherol concentration and prostate cancer risk over nearly three decades, our findings suggest that men receiving the trial α-tocopherol supplementation who had higher baseline serum α-tocopherol concentration experienced reduced prostate cancer risk. Vitamin E-related genotypes did not modify the serum α-tocopherol-prostate cancer risk association.

Metabolomic analysis of serum alpha-tocopherol among men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

BACKGROUND/OBJECTIVES: The role of vitamin E in chronic disease risk remains incompletely understood, particularly in an un-supplemented state, and evidence is sparse regarding the biological actions and pathways involved in its influence on health outcomes. Identifying vitamin-E-associated metabolites through agnostic metabolomics analyses can contribute to elucidating the specific associations and disease etiology. This study aims to investigate the association between circulating metabolites and serum α-tocopherol concentration in an un-supplemented state. SUBJECTS/METHODS: Metabolomic analysis of 4,294 male participants was conducted based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The associations between 1,791 known metabolites measured by ultra-high-performance LC-MS/GC-MS and HPLC-determined α-tocopherol concentration were estimated using multivariable linear regression. Differences in metabolite levels per unit difference in α-tocopherol concentration were calculated as standardized ß-coefficients and standard errors. RESULTS: A total of 252 metabolites were associated with serum α-tocopherol at the Bonferroni-corrected p value (p < 2.79 × 10-5). Most of these metabolites were of lipid and amino acid origin, with the respective subclasses of dicarboxylic fatty acids, and valine, leucine, and isoleucine metabolism, being highly represented. Among lipids, the strongest signals were observed for linoleoyl-arachidonoyl-glycerol (18:2/20:4)[2](ß = 0.149; p = 8.65 × 10-146) and sphingomyelin (D18:2/18:1) (ß = 0.035; p = 1.36 × 10-30). For amino acids, the strongest signals were aminoadipic acid (ß = 0.021; p = 5.01 × 10-13) and l-leucine (ß = 0.007; p = 1.05 × 10-12). CONCLUSIONS: The large number of metabolites, particularly lipid and amino acid compounds associated with serum α-tocopherol provide leads regarding potential mechanisms through which vitamin E influences human health, including its role in cardiovascular disease and cancer.

Human bone marrow-derived mesenchymal stem cells play a role as a vascular pericyte in the reconstruction of human BBB on the angiogenesis microfluidic chip.

A blood-brain barrier (BBB) on a chip similar to the in vivo BBB is important for evaluating the efficacy of reparative cell therapeutics for ischemic stroke in vitro. In this study, we established human BBB-like microvasculature on an angiogenesis microfluidic chip and analyzed the role of human pericytes (hPCs) and human astrocytes (hACs) on the architecture of human brain microvascular endothelial cells (hBMEC)-derived microvasculature on a chip. We found that human bone marrow mesenchymal stem cells (hBM-MSCs) play a role as perivascular pericytes in tight BBB reformation with a better vessel-constrictive capacity than that of hPCs, providing evidence of reparative stem cells on BBB repair rather than a paracrine effect. We also demonstrated that pericytes play an important role in vessel constriction, and astrocytes may induce the maturation of a capillary network. Higher expression of VEGF, SDF-1α, PDGFRß, N-cadherin, and α-SMA in hBM-MSCs than in hPCs and their subsequent downregulation with hBMEC co-culture suggest that hBM-MSCs may be better recruited and engaged in the BBB-microvasculature than hPCs. Collectively, the human BBB on a chip may be adopted as an alternative to evaluate in vitro cellular behavior and the engagement of cell therapeutics in BBB regeneration and may also be used for studying stroke.

Microvascularized tumor organoids-on-chips: advancing preclinical drug screening with pathophysiological relevance.

Recent developments of organoids engineering and organ-on-a-chip microfluidic technologies have enabled the recapitulation of the major functions and architectures of microscale human tissue, including tumor pathophysiology. Nevertheless, there remain challenges in recapitulating the complexity and heterogeneity of tumor microenvironment. The integration of these engineering technologies suggests a potential strategy to overcome the limitations in reconstituting the perfusable microvascular system of large-scale tumors conserving their key functional features. Here, we review the recent progress of in vitro tumor-on-a-chip microfluidic technologies, focusing on the reconstruction of microvascularized organoid models to suggest a better platform for personalized cancer medicine.