Predictive DNA damage signaling for low­dose ionizing radiation.

Numerous studies have attempted to develop biological markers for the response to radiation for broad and straightforward application in the field of radiation. Based on a public database, the present study selected several molecules involved in the DNA damage repair response, cell cycle regulation and cytokine signaling as promising candidates for low­dose radiation­sensitive markers. The HuT 78 and IM­9 cell lines were irradiated in a concentration­dependent manner, and the expression of these molecules was analyzed using western blot analysis. Notably, the activation of ataxia telangiectasia mutated (ATM), checkpoint kinase 2 (CHK2), p53 and H2A histone family member X (H2AX) significantly increased in a concentration­dependent manner, which was also observed in human peripheral blood mononuclear cells. To determine the radioprotective effects of cinobufagin, as an ATM and CHK2 activator, an in vivo model was employed using sub­lethal and lethal doses in irradiated mice. Treatment with cinobufagin increased the number of bone marrow cells in sub­lethal irradiated mice, and slightly elongated the survival of lethally irradiated mice, although the difference was not statistically significant. Therefore, KU60019, BML­277, pifithrin­α, and nutlin­3a were evaluated for their ability to modulate radiation­induced cell death. The use of BML­277 led to a decrease in radiation­induced p­CHK2 and γH2AX levels and mitigated radiation­induced apoptosis. On the whole, the present study provides a novel approach for developing drug candidates based on the profiling of biological radiation­sensitive markers. These markers hold promise for predicting radiation exposure and assessing the associated human risk.

Associations of meal timing and sleep duration with incidence of obesity: a prospective cohort study.

OBJECTIVES: Late mealtime and short sleep are known to be associated with obesity risk due to a misaligned circadian rhythm. This study aimed to investigate the relationship between obesity and mealtime and sleep duration using the Korean Genome and Epidemiology Study (KoGES) data. DESIGN: Longitudinally prospective cohort study. SETTING: Population-based. PARTICIPANTS: KoGES analysed data from 9,474 Korean adults with an average age of 54- years old at baseline. MEASUREMENTS: Meal timing was defined as the eating occasions of the day reported by the participant eating a 24-h dietary recall method. Sleep duration was categorized as <6, 6-7, 7-8, and ≥8 h. The Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident obesity according to meal timing, sleep duration, and nightly fasting duration. RESULTS: During a mean follow-up of 3.5 years, 826 participants developed obesity. In the multivariable-adjusted analysis, midnight snack eating (HR, 1.20; 95% CI, 1.02-1.41) and higher energy intake from midnight snacks (HR, 1.26; 95% CI, 1.06-1.49) were associated with a higher risk of obesity. Sleeping 8 h or more (HR, 0.67; 95% CI, 0.53-0.85) was associated with a lower risk of obesity. CONCLUSIONS: Our findings highlight the importance of meal and sleep times and suggest that healthy eating habits related to the time of day.

The Associations between Intakes of One-Carbon Metabolism-Related Vitamins and Breast Density among Young Women.

BACKGROUND: Folate is the primary methyl donor and B vitamins are cofactors for one-carbon metabolism that maintain DNA integrity and epigenetic signatures implicated in carcinogenesis. Breast tissue is particularly susceptible to stimuli in early life. Only limited data are available on associations of one-carbon metabolism-related vitamin intake during youth and young adulthood with breast density, a strong risk factor for breast cancer. METHODS: Over 18 years in the DISC and DISC06 Follow-up Study, diets of 182 young women were assessed by three 24-hour recalls on five occasions at ages 8 to 18 years and once at 25 to 29 years. Multivariable-adjusted linear mixed-effects regression was used to examine associations of intakes of one-carbon metabolism-related vitamins with MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at ages 25 to 29 years. RESULTS: Folate intake in youth was inversely associated with %DBV (Ptrend = 0.006) and ADBV (Ptrend = 0.02). These inverse associations were observed with intake during post-, though not premenarche. In contrast, premenarche vitamin B2 intake was positively associated with ADBV (Ptrend < 0.001). Young adult folate and vitamin B6 intakes were inversely associated with %DBV (all Ptrend ≤ 0.04), whereas vitamins B6 and B12 were inversely associated with ADBV (all Ptrend ≤ 0.04). CONCLUSIONS: Among these DISC participants intakes of one-carbon metabolism-related vitamins were associated with breast density. Larger prospective studies among diverse populations are needed to replicate these findings. IMPACT: Our results suggest the importance of one-carbon metabolism-related vitamin intakes early in life with development of breast density and thereby potentially breast cancer risk later in life.

Untargeted serum metabolomic profiles and breast density in young women.

PURPOSE OF THE STUDY: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. METHODS: In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). RESULTS: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. CONCLUSION: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.

Association between use of vitamin and mineral supplement and non-alcoholic fatty liver disease in hypertensive adults.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic metabolic disorder in hypertensive adults. Impaired metabolism of micronutrients may increase NAFLD risk by exacerbating oxidative stress, insulin resistance, and inflammation among hypertensive adults. In this first cross-sectional analysis of 7,376 hypertensive adults with 2,015 NAFLD cases in the Korea National Health and Nutrition Examination Survey, vitamin and mineral supplements (VMS) use was identified via questionnaire. NAFLD was defined by a hepatic steatosis index > 36. Multivariable-adjusted odds ratios (MVOR) and 95% confidence intervals (CIs) were calculated using logistic regression models. In our study, 18.6% were current users of VMS; of these, 76.7% used multi-vitamin/mineral supplements. Current VMS users had significantly lower odds of NAFLD, compared with non-users (MVOR [95% CI]: 0.73 [0.58-0.92]). The inverse association became attenuated and non-significant among those consuming VMS at higher frequency (≥ 2 times/day), for longer duration (> 16 months), and taking ≥ 2 VMS products. The inverse association with current use of VMS was only evident in those aged < 56 years (MVOR [95% CI]: 0.54 [0.40-0.72]) and men (MVOR [95% CI]: 0.56 [0.40-0.80])(Pinteraction ≤ 0.04). Our results suggest that VMS use may lower NAFLD risk, particularly among younger or male hypertensive adults, if taken in moderation.

Early childhood eating behaviors associated with risk of overweight and its socio-ecological determinants in Korean preschool children.

BACKGROUND/OBJECTIVES: This study aimed to identify preschool children's eating behaviors associated with early childhood obesity and its multi-level, socio-ecological determinants. SUBJECTS/METHODS: In a cross-sectional study of 364 mothers of preschool children aged 3-5 years, these children's healthy eating behaviors were assessed using a validated preschool nutrition quotient (NQ-P) questionnaire. The children's overweight or obesity statuses were determined based on body mass index percentiles from the 2017 Korean National Growth Chart. The associations between the NQ-P score and risk of overweight or obesity were examined using multivariable logistic regression. The associations of individual, maternal, physical, and media environmental factors with the NQ-P score were also examined using multivariable linear regression. RESULTS: Preschool children with greater NQ-P scores were at a significantly lower risk of overweight or obesity (P < 0.01). The NQ-P score had a significantly positive association with maternal body mass index and an inverse association with household income (all P < 0.05). Maternal parenting and feeding practices exhibited associations with the NQ-P score. Positive associations were observed with "warm," "structured," and "autonomy-supportive" parenting as well as monitoring feeding practices (all P < 0.05). In addition, the NQ-P score had a significantly positive association with the childcare center's anti-obesogenic environment, such as the provision of nutritional and physical-activity support and vicinity of the built food environment to the home, including access to good-quality food, fruits and vegetables, and low-fat foods (all P < 0.05). Regarding media environments, the NQ-P score demonstrated more significant associations with viewing and eating and/or cooking content displayed on online video platforms (all P < 0.05) than with that on television. CONCLUSIONS: Our findings confirm the significance of healthy eating behaviors in early-childhood-obesity prevention and underscore the importance of multilevel maternal, physical, and media environmental interventions that effectively guide eating behaviors in preschool children.

Associations of Food Insecurity with Dietary Inflammatory Potential and Risk of Low Muscle Strength.

Food insecurity refers to the uncertain availability of or limited access to nutritious food. Poor diets prevalent among food insecure populations may incite an inflammatory state and subsequently negatively affect skeletal muscle metabolism. To examine the inflammatory mechanistic potential of the association between food insecurity and the risk of low muscle strength, we analyzed cross-sectional data from 8624 adults aged ≥20 years from the Korean National Health and Nutrition Examination Survey 2014-2015. Household food security status was assessed using an 18-item food security survey module. The inflammatory potential of diets was estimated by the dietary inflammation index (DII). Low muscle strength was ascertained using hand grip strength. In the multivariable-adjusted model, greater food insecurity was significantly associated with a higher DII score and risk of low muscle strength. The multivariable-adjusted mean difference (95% confidence interval) on the DII, comparing the "moderate-to-severe" food insecurity group with the "food secure" group, was 0.43 (0.06-0.80) (P-trend: <0.001) and the odds ratio (95% confidence intervals) of low muscle strength for the same comparison groups was 2.06 (1.07-3.96) (P-trend: 0.005). Our results suggest that individuals with greater food insecurity may be susceptible to diets with greater inflammatory potential, which may contribute to a loss of muscle strength.

BMI trajectory and inflammatory effects on metabolic syndrome in adolescents.

BACKGROUND: Various life course factors can affect susceptibility to diseases during adolescence and adulthood, and those relationships are complex. However, few studies have assessed the potential mediating factors. Therefore, we assessed the mediating effects of factors related to growth and inflammation between perinatal factors and metabolic syndrome risk during adolescence. METHODS: The study was conducted on adolescents who participated in the follow-up in the Ewha Birth and Growth Cohort. We considered the ponderal index (PI) as a perinatal factor and the continuous metabolic syndrome score (cMetS) as the outcome and confirmed the mediating effects of body mass index (BMI) trajectory pattern in childhood and inflammation levels by using the PROCESS macro for SAS. RESULTS: Although the direct effect of BMI trajectory on the relationship between PI and cMetS was not significant (0.545), the indirect effect was significant (1.044). In addition, the indirect effect was statistically significant in the pathways mediating the BMI trajectory pattern and inflammation (ß = 1.456). CONCLUSIONS: The direct and indirect effects on the relationship between PI and cMetS suggest that childhood factors related to growth may be involved in disease susceptibility. Therefore, appropriate interventions for the management of obesity during the growth phase are necessary. IMPACT: Unlike other existing studies, this study assessed multiple mediating effects by considering the BMI trajectory pattern and inflammatory indexes as mediating factors between the ponderal index and the continuous metabolic syndrome score during adolescence. We found significant indirect effects of the BMI trajectory between PI and cMetS, and also significant indirect effects in the pathways mediating the BMI trajectory and hs-CRP. The significant indirect mediating effects support that childhood factors related to growth may be involved in disease susceptibility.

A comparison of associations of body mass index and dual-energy x-ray absorptiometry measured percentage fat and total fat with global serum metabolites in young women.

OBJECTIVE: Body mass index (BMI) does not directly measure adiposity, whereas dual-energy x-ray absorptiometry (DXA) provides valid direct estimates of adiposity. Therefore, this study evaluated usefulness of BMI as a measure of adiposity in serum metabolomics studies. METHODS: A cross-sectional analysis was conducted of 202 women aged 25 to 29 years in the Dietary Intervention Study in Children Follow-Up Study. Heights and weights were measured, and body composition was quantified using clinical DXA protocols. Serum metabolomic profiling was performed by liquid chromatography-tandem mass spectrometry. Partial correlations of BMI, percentage fat (%FAT), and total fat (TOTFAT) with log transformed serum metabolites were calculated. RESULTS: There was significant overlap in the 93 metabolites that correlated with BMI, %FAT, and/or TOTFAT; 9 differently correlated with BMI and %FAT, whereas 15 differently correlated with BMI and TOTFAT. Even for these metabolites, absolute differences were modest. Metabolite set enrichment analysis identified diacylglycerol and sphingolipid metabolism as overrepresented among metabolites significantly correlated with all three measures of adiposity. CONCLUSIONS: BMI can be a good proxy for DXA measured %FAT and TOTFAT in descriptive metabolomic studies of healthy, young White women. Larger studies in more diverse populations are needed to endorse more generalized conclusions.

Poliovirus receptor inhibition in breast cancer cells induces antitumor immunity via T cell activation.

Radiotherapy (RT) is a commonly used treatment option for patients with cancer because it can effectively control tumor growth and kill tumor cells. However, the impact of RT goes beyond direct tumor cell killing because it can change the tumor microenvironment by altering surrounding tissues and infiltrating cells and modulating the expression of immune checkpoints. Poliovirus receptor (PVR, cluster of differentiation (CD)155), a member of the nectin-like molecule family, is overexpressed in many human cancers. However, its role in the tumor growth and T-cell immune responses of triple-negative breast cancer (TNBC) remains unclear. In the present study, we observe that radiation exposure increases PVR expression in MDA-MB-231 and BT549 cells. Silencing PVR not only inhibited the proliferation of breast cancer cells but also significantly enhanced the cytotoxicity of cytotoxic T lymphocytes (CTLs) compared with the control or RT groups. Treatment of T cells with PVR decreased CD8+ T cells, increased CD4+ T cells, and induced PVR ligands such as T cell immunoreceptor with immunoglobulin and ITIM domain, CD226, and CD96. However, after treatment with PVR, CTL responses decreased and secretion of interferon-γ, tumor necrosis factor-α, interleukin (IL)-2, IL-6, and IL-10 was significantly inhibited. In contrast, PVR knockdown increased the production of these cytokines, illustrating the immunosuppressive function of PVR. Suppression of PVR using an anti-PVR antibody inhibited 4T1 tumor growth by increasing immune cell infiltration. These results provide new insights into the role of PVR in TNBC and highlight its potential as a target for T cell-mediated immunotherapy in breast cancer.

Childhood adiposity, serum metabolites and breast density in young women.

BACKGROUND: Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density. METHODS: Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25-29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation. RESULTS: Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity-%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV. CONCLUSIONS: Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk.

Receptor interacting protein 1 knockdown induces cell death in liver cancer by suppressing STAT3/ATR activation in a p53-dependent manner.

The survival and death of eukaryotic cells are tightly controlled by a variety of proteins in response to the cellular environment. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a receptor-interacting Ser/Thr kinase that has recently been reported as an important regulator of cell survival, apoptosis, and necroptosis; however, its role in liver cancer remains unclear. In this study, we examined the effect of siRNA-mediated RIPK1 knockdown on the survival and death of liver cancer cells. Treatment with siRIPK1 decreased the growth rate of liver cancer cells and increased apoptotic, but not necrotic cell death, which was higher in wild-type p53 (wt-p53) cells than in mutant-type p53 (mt-p53) cells. In addition, RIPK1 knockdown increased p53 expression and G1 phase arrest in wt-p53 cells. Although suppressing p53 did not alter RIPK1 expression, it did attenuate siRIPK1-induced cell death. Interestingly, RIPK1 knockdown also increased the generation of reactive oxygen species and DNA damage by inhibiting signal transduced and activator of transcription 3 (STAT3) and ATM and RAD3-related (ATR) in wt-p53 cells but not in mt-p53 cells. Moreover, STAT3 or ATR inhibition in p53 mutant cells restored siRIPK1-mediated cell death. Together, the results of this study suggest that RIPK1 suppression induces apoptotic cell death by inhibiting the STAT3/ATR axis in a p53-dependent manner. Furthermore, these findings suggest that RIPK1, alone or in combination, may be a promising target for treating liver cancer.

The Mediating Effect of Inflammation between the Dietary and Health-Related Behaviors and Metabolic Syndrome in Adolescence.

Chronic diseases develop via complex pathways, depending on the degree of exposure to risk factors from early in life and childhood onward. Metabolic syndrome has multiple risk factors, including genetic factors, inappropriate diet, and insufficient physical activity. This study classified health-related behavior classes in childhood and adolescents and analyzed the direct and indirect effects of each class on the metabolic risk in inflammation-mediated pathways. We identified the health-related lifestyle classes based on health-related behavior indicators in subjects aged 3-15 years who participated in the Ewha Birth and Growth Cohort Study by using a latent class analysis. A mediation analysis was performed to access the direct and indirect effects of each class on the continuous metabolic syndrome score (cMetS), with the inflammatory index used as a mediating factor. Subjects were classified into inactive and positive lifestyle classes according to their characteristics. In the inactive lifestyle class, interleukin (IL)-6 and cMetS had a significant association. The study confirmed that IL-6 exerts a significant indirect effect between inactive lifestyle and cMetS. This result supports previous studies. Since the health behaviors of children and adolescents can affect the likelihood of subsequent metabolic syndrome, appropriate health behavior interventions for this period are needed.

Association between Use of Nutrition Labels and Risk of Chronic Kidney Disease: The Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2019.

Nutrition labeling on food packages is increasingly found to promote healthier food choices associated with lower risk of chronic kidney disease (CKD). To examine associations between nutrition labels use and CKD risk, we conducted a nationally representative cross-sectional study of 32,080 adults from the 2008−2019 Korean National Health and Nutrition Examination Survey. Nutrition labels use was collected via self-reported questionnaires. Ascertainment and severity of CKD was determined by estimated glomerular filtration rate or proteinuria. In multivariable-adjusted (MV) logistic regression models, increasing awareness and use of nutrition labels was significantly associated with lower CKD risk (MV-adjusted OR "nutrition labels aware and use" group vs. "nutrition labels unaware" group [95% CIs]: 0.75 [0.59−0.95], Ptrend:0.03). This inverse association varied with CKD's risk of progression, with 21% and 42% reduced risk observed for CKD subtypes with "moderate" and "high" risk of progression, respectively (all Ptrend ≤ 0.04). Furthermore, the nutrition labels use and CKD risk association significantly differed by age, with 35% reduced risk observed in the older group aged 49 years or older, but not in the younger group (Pinteraction < 0.001). Our results suggest increasing perception and use of nutrition labels may contribute to CKD prevention and its early asymptomatic progression, especially in older adults.

BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion.

Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis.

Evaluation of Anti-Tumor Effects of Whole-Body Low-Dose Irradiation in Metastatic Mouse Models.

Low-dose irradiation (LDI) has recently been shown to have various beneficial effects on human health, such as on cellular metabolic activities, DNA repair, antioxidant activity, homeostasis potency, and immune activation. Although studies on the immunogenic effects of LDI are rapidly accumulating, clinical trials for cancer treatment are considered premature owing to the lack of available preclinical results and protocols. Here, we aim to investigate anti-tumor and anti-metastatic effects of whole-body LDI in several tumor-bearing mouse models. Mice were exposed to single or fractionated whole-body LDI prior to tumor transplantation, and tumor growth and metastatic potential were determined, along with analysis of immune cell populations and expression of epithelial-mesenchymal transition (EMT) markers. Whole-body fractionated-LDI decreased tumor development and lung metastasis not only by infiltration of CD4+, CD8+ T-cells, and dendritic cells (DCs) but also by attenuating EMT. Moreover, a combination of whole-body LDI with localized high-dose radiation therapy reduced the non-irradiated abscopal tumor growth and increased infiltration of effector T cells and DCs. Therefore, whole-body LDI in combination with high-dose radiation therapy could be a potential therapeutic strategy for treating cancer.

A new FGFR inhibitor disrupts the TGF-ß1-induced fibrotic process.

Pulmonary fibrosis (PF) is chronic and irreversible damage to the lung characterized by fibroblast activation and matrix deposition. Although recently approved novel anti-fibrotic agents can improve the lung function and survival of patients with PF, the overall outcomes remain poor. In this study, a novel imidazopurine compound, 3-(2-chloro-6-fluorobenzyl)-1,6,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (IM-1918), markedly inhibited transforming growth factor (TGF)-ß-stimulated reporter activity and reduced the expression of representative fibrotic markers, such as connective tissue growth factor, fibronectin, collagen and α-smooth muscle actin, on human lung fibroblasts. However, IM-1918 neither decreased Smad-2 and Smad-3 nor affected p38MAPK and JNK. Instead, IM-1918 reduced Akt and extracellular signal-regulated kinase 1/2 phosphorylation increased by TGF-ß. Additionally, IM-1918 inhibited the phosphorylation of fibroblast growth factor receptors 1 and 3. In a bleomycin-induced murine lung fibrosis model, IM-1918 profoundly reduced fibrotic areas and decreased collagen and α-smooth muscle actin accumulation. These results suggest that IM-1918 can be applied to treat lung fibrosis.

Alcohol consumption and serum metabolite concentrations in young women.

PURPOSE: Alcohol consumption is an established breast cancer risk factor, though further research is needed to advance our understanding of the mechanism underlying the association. We used global metabolomics profiling to identify serum metabolites and metabolic pathways that could potentially mediate the alcohol-breast cancer association. METHODS: A cross-sectional analysis of reported alcohol consumption and serum metabolite concentrations was conducted among 211 healthy women 25-29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-Up Study (DISC06). Alcohol-metabolite associations were evaluated using multivariable linear mixed-effects regression. RESULTS: Alcohol was significantly (FDR p < 0.05) associated with several serum metabolites after adjustment for diet composition and other potential confounders. The amino acid sarcosine, the omega-3 fatty acid eicosapentaenoate, and the steroid 4-androsten-3beta,17beta-diol monosulfate were positively associated with alcohol intake, while the gamma-tocopherol metabolite gamma-carboxyethyl hydroxychroman (CEHC) was inversely associated. Positive associations of alcohol with 2-methylcitrate and 4-androsten-3beta,17beta-diol disulfate were borderline significant (FDR p < 0.10). Metabolite set enrichment analysis identified steroids and the glycine pathway as having more members associated with alcohol consumption than expected by chance. CONCLUSIONS: Most of the metabolites associated with alcohol in the current analysis participate in pathways hypothesized to mediate the alcohol-breast cancer association including hormonal, one-carbon metabolism, and oxidative stress pathways, but they could also affect risk via alternative pathways. Independent replication of alcohol-metabolite associations and prospective evaluation of confirmed associations with breast cancer risk are needed.

Pubertal timing and breast density in young women: a prospective cohort study.

BACKGROUND: Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk. METHODS: From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006-2008, 182 participants then aged 25-29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV. RESULTS: The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2-86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2-26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9-17.5%)). CONCLUSIONS: Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

Tumor-Treating Fields Induce RAW264.7 Macrophage Activation Via NK-κB/MAPK Signaling Pathways.

OBJECTIVE: Tumor-treating fields are currently used to successfully treat various cancers; however, the specific pathways associated with its efficacy remain unknown in the immune responses. Here, we evaluated tumor-treating fields-mediated initiation of the macrophage-specific immune response. MATERIALS AND METHODS: We subjected RAW 264.7 mouse macrophages to clinically relevant levels of tumor-treating fields (0.9 V/cm, 150 kHz) and evaluated alterations in cytokine expression and release, as well as cell viability. Additionally, we investigated the status of immunomodulatory pathways to determine their roles in tumor-treating fields-mediated immune activation. RESULTS AND DISCUSSION: Our results indicated that tumor-treating fields treatment at 0.9 V/cm decreased cell viability and increased cytokine messenger RNA/protein levels, as well as levels of nitric oxide and reactive oxygen species, relative to controls. The levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 were markedly increased in tumor-treating fields-treated RAW 264.7 cells cocultured with 4T1 murine mammary carcinoma cells compared with those in 4T1 or RAW 264.7 cells with or without tumor-treating fields treatment. Moreover, the viability of 4T1 cells treated with the conditioned medium of tumor-treating fields-stimulated RAW 264.7 cells decreased, indicating that macrophage activation by tumor-treating fields effectively killed the tumor cells. Moreover, tumor-treating fields treatment activated the nuclear factor κB and mitogen-activated protein kinase pathways involved in immunomodulatory signaling. CONCLUSION: These results provide critical insights into the mechanisms through which tumor-treating fields affect macrophage-specific immune responses and the efficacy of this method for cancer treatment.