Authors: O'Brien KM, Sandler DP, Taylor JA, Weinberg CR
Journal: Environ Health Perspect. 2017 Jul 6;125(7):077004. doi: 10.1289/EHP943.
BACKGROUND: Vitamin D is an environmental and dietary agent with known anticarcinogenic effects, but protection against breast cancer has not been established.
OBJECTIVE: We evaluated the association between baseline serum 25-hydroxyvitamin D [25(OH)D] levels, supplemental vitamin D use, and breast cancer incidence over the subsequent 5 y of follow-up.
METHODS: From 2003-2009, the Sister Study enrolled 50,884 U.S. women 35-74 y old who had a sister with breast cancer but had never had breast cancer themselves. Using liquid chromatography-mass spectrometry, we measured 25(OH)D in serum samples from 1,611 women who later developed breast cancer and from 1,843 randomly selected cohort participants. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of developing breast cancer using Cox proportional hazards models.
RESULTS: We found that 25(OH)D levels were associated with a 21% lower breast cancer hazard (highest versus lowest quartile: adjusted ; CI: 0.63, 0.98). Analysis of the first 5 y of follow-up for all 50,884 Sister Study participants showed that self-reported vitamin D supplementation was associated with an 11% lower hazard [ (CI: 0.81, 0.99)]. These associations were particularly strong among postmenopausal women [ (CI: 0.57, 0.93) and (CI: 0.74, 0.93), respectively].
CONCLUSIONS: In this cohort of women with elevated risk, high serum 25(OH)D levels and regular vitamin D supplement use were associated with lower rates of incident, postmenopausal breast cancer over 5 y of follow-up. These results may help to establish clinical benchmarks for 25(OH)D levels; in addition, they support the hypothesis that vitamin D supplementation is useful in breast cancer prevention.
Authors: Whitehead GS, Thomas SY, Shalaby KH, Nakano K, Moran TP, Ward JM, Flake GP, Nakano H, Cook DN
Journal: J Clin Invest. 2017 Jul 31. pii: 90890. doi: 10.1172/JCI90890.
Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNFsignaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergicairway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.
Authors: Choi K, Sabado M, El-Toukhy S, Vogtmann E, Freedman ND, Hatsukami DK
Journal: Cancer Epidemiol Biomarkers Prev. 2017 Jul 14. pii: cebp.0338.2017. doi: 10.1158/1055-9965.EPI-17-0338.
BACKGROUND: Few studies have examined differences in product consumption patterns and nicotine and tobacco-specific nitrosamines (TSNAs) exposure between single versus dual and poly-tobacco users. We applied the Tobacco Product Use Patterns (T-PUPs) model to fill this gap in the literature.
METHODS: Data from adults (aged >18 years) who used any tobacco products during the five days prior to participating in the 1999-2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Participants were classified into seven T-PUPs: (1) cigarettes only, (2) non-cigarette combustibles only, (3) non-combustibles only, (4) dual non-cigarette combustibles and non-combustibles, (5) dual cigarettes and non-combustibles, (6) dual cigarettes and non-cigarette combustibles, and (7) poly-tobacco use. Weighted regression models were used to compare product consumption, serum cotinine, and urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL) levels between single, dual, and poly-tobacco T-PUPs.
RESULTS: Dual and poly-tobacco T-PUPs were associated with lower product consumption compared to single product T-PUPs only in some cases (e.g., dual cigarette and non-combustible users smoked cigarettes on 0.6 fewer days in the past five days compared to cigarette-only users; p<0.05). Dual and poly-tobacco T-PUPs had either non-distinguishable or higher levels of serum cotinine and urinary total NNAL than corresponding single product T-PUPs.
CONCLUSION: Product consumption, and nicotine and TSNAs exposure of dual and poly-tobacco product category users somewhat differ from those of single product category users as defined by the T-TUPs model.
IMPACT: Higher levels of cotinine and NNAL among dual- and poly-tobacco T-TUPs users compared to the single product T-TUPs users may indicate health concerns.
Authors: Zheng W, Wu Y, Winter P, Fischer R, Nogare DD, Hong A, McCormick C, Christensen R, Dempsey WP, Arnold DB, Zimmerberg J, Chitnis A, Sellers J, Waterman C, Shroff H
Journal: Nat Methods. 2017 Jun 19. doi: 10.1038/nmeth.4337.
We improve multiphoton structured illumination microscopy using a nonlinear guide star to determine optical aberrations and a deformable mirror to correct them. We demonstrate our method on bead phantoms, cells in collagen gels, nematode larvae and embryos, Drosophila brain, and zebrafish embryos. Peak intensity is increased (up to 40-fold) and resolution recovered (up to 176 ± 10 nm laterally, 729 ± 39 nm axially) at depths ∼250 μm from the coverslip surface.
Authors: Tarasenko TN, Pacheco SE, Koenig MK, Gomez-Rodriguez J, Kapnick SM, Diaz F, Zerfas PM, Barca E, Sudderth J, DeBerardinis RJ, Covian R, Balaban RS, DiMauro S, McGuire PJ
Journal: Cell Metab. 2017 Jun 6;25(6):1254-1268.e7. doi: 10.1016/j.cmet.2017.05.007.
T cells undergo metabolic reprogramming with major changes in cellular energy metabolism during activation. In patients with mitochondrial disease, clinical data were marked by frequent infections and immunodeficiency, prompting us to explore the consequences of oxidative phosphorylation dysfunction in T cells. Since cytochrome c oxidase (COX) is a critical regulator of OXPHOS, we created a mouse model with isolated dysfunction in T cells by targeting a gene, COX10, that produces mitochondrial disease in humans. COX dysfunction resulted in increased apoptosis following activation in vitro and immunodeficiency in vivo. Select T cell effector subsets were particularly affected; this could be traced to their bioenergetic requirements. In summary, the findings presented herein emphasize the role of COX particularly in T cells as a metabolic checkpoint for cell fate decisions following T cell activation, with heterogeneous effects in T cell subsets. In addition, our studies highlight the utility of translational models that recapitulate human mitochondrial disease for understanding immunometabolism.
Authors: Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, Reynolds PR, Lyons JJ, Nelson CG, Ruffo E, Dorjbal B, Glauzy S, Yamakawa N, Arjunaraja S, Voss K, Stoddard J, Niemela J, Zhang Y, Rosenzweig SD, McElwee JJ, DiMaggio T, Matthews HF, Jones N, Stone KD, Palma A, Oleastro M, Prieto E, Bernasconi AR, Dubra G, Danielian S, Zaiat J, Marti MA, Kim B, Cooper MA, Romberg ND, Meffre E, Gelfand EW, Snow AL, Milner JD
Journal: Nat Genet. 2017 Jun 19. doi: 10.1038/ng.3898.
Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-κB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon-γ (IFN-γ). The mTORC1 and IFN-γ production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis.
Authors: Zhu Y, Olsen SF, Mendola P, Halldorsson TI, Rawal S, Hinkle SN, Yeung EH, Chavarro JE, Grunnet LG, Granström C, Bjerregaard AA, Hu FB, Zhang C
Journal: Int J Epidemiol. 2017 Jun 6. doi: 10.1093/ije/dyx095.
BACKGROUND: Artificial sweeteners are widely replacing caloric sweeteners. Data on long-term impact of artificially sweetened beverage (ASB) consumption during pregnancy on offspring obesity risk are lacking. We prospectively investigated intake of ASBs and sugar-sweetened beverages (SSBs) during pregnancy in relation to offspring growth through age 7 years among high-risk children born to women with gestational diabetes.
METHODS: In a prospective study of 918 mother-singleton child dyads from the Danish National Birth Cohort, maternal dietary intake was assessed by a food frequency questionnaire during pregnancy. Offspring body mass index z-scores (BMIZ) and overweight/obesity status were derived using weight and length/height at birth, 5 and 12 months and 7 years. Linear regression and Poisson regression with robust standard errors were used, adjusting for major risk factors.
RESULTS: Approximately half of women reported consuming ASBs during pregnancy and 9% consumed daily. Compared to never consumption, daily ASB intake during pregnancy was positively associated with offspring large-for-gestational age [adjusted relative risk (aRR) 1.57; 95% CI: 1.05, 2.35 at birth], BMIZ (adjusted β 0.59; 95% CI: 0.23, 0.96) and overweight/obesity (aRR 1.93; 95% CI; 1.24, 3.01) at 7 years. Per-serving-per-day substitution of ASBs with water during pregnancy was related to a lower overweight/obesity risk at 7 years (aRR 0.83; 95% CI: 0.76, 0.91), whereas SSB substitution with ASBs was not related to a lower risk (aRR 1.14; 95% CI: 1.00, 1.31).
CONCLUSIONS: Our findings illustrated positive associations between intrauterine exposure to ASBs and birth size and risk of overweight/obesity at 7 years. Data with longer follow-up are warranted.
Authors: Weinberg CR, Shi M, Basso O, DeRoo LA, Harmon Q, Wilcox AJ, Skjærven R
Journal: Environ Health Perspect. 2017 Jun 29;125(6):067022. doi: 10.1289/EHP963.
BACKGROUND: Preeclampsia (PE) is a dangerous and unpredictable pregnancy complication. A seasonal pattern of risk would suggest that there are potentially preventable environmental contributors, but prior analyses have not adjusted for confounding by PE risk factors that are associated with season of conception.
METHODS: Seasonal effects were modeled and tested by representing each day of the year as an angle on a unit circle and using trigonometric functions of those angles in predictive models, using "harmonic analysis." We applied harmonic Cox regression to model confounder-adjusted effects of the estimated day of the year of conception on risk of PE for births from the Medical Birth Registry of Norway for deliveries between 1999 and 2009. We also examined effect measure modification by parity, latitude (region), fetal sex, and smoking.
RESULTS: In adjusted models, PE risk was related to season, with higher risk in spring conceptions and lower risk in autumn conceptions, with a risk amplitude (maximum compared with minimum) of about 20%. The pattern replicated across subpopulations defined by parity, latitude (region), fetal sex, and smoking.
CONCLUSIONS: These results suggest that there is a seasonal driver for PE, with effects that are not modified by parity, latitude, fetal sex, or smoking.
Authors: Gilman SE, Hornig M, Ghassabian A, Hahn J, Cherkerzian S, Albert PS, Buka SL, Goldstein JM
Journal: Proc Natl Acad Sci U S A. 2017 Jun 12. pii: 201617698. doi: 10.1073/pnas.1617698114.
Children raised in economically disadvantaged households face increased risks of poor health in adulthood, suggesting that inequalities in health have early origins. From the child's perspective, exposure to economic hardship may begin as early as conception, potentially via maternal neuroendocrine-immune responses to prenatal stressors, which adversely impact neurodevelopment. Here we investigate whether socioeconomic disadvantage is associated with gestational immune activity and whether such activity is associated with abnormalities among offspring during infancy. We analyzed concentrations of five immune markers (IL-1β, IL-6, IL-8, IL-10, and TNF-α) in maternal serum from 1,494 participants in the New England Family Study in relation to the level of maternal socioeconomicdisadvantage and their involvement in offspring neurologic abnormalities at 4 mo and 1 y of age. Median concentrations of IL-8 were lower in the most disadvantaged pregnancies [-1.53 log(pg/mL); 95% CI: -1.81, -1.25]. Offspring of these pregnancies had significantly higher risk of neurologic abnormalities at 4 mo [odds ratio (OR) = 4.61; CI = 2.84, 7.48] and 1 y (OR = 2.05; CI = 1.08, 3.90). This higher risk was accounted for in part by fetal exposure to lower maternal IL-8, which also predicted higher risks of neurologic abnormalities at 4 mo (OR = 7.67; CI = 4.05, 14.49) and 1 y (OR = 2.92; CI = 1.46, 5.87). Findings support the role of maternal immune activity in fetal neurodevelopment, exacerbated in part by socioeconomic disadvantage. This finding reveals a potential pathophysiologic pathway involved in the intergenerational transmission of socioeconomic inequalities in health.
Authors: Hart KM, Fabre T, Sciurba JC, Gieseck RL 3rd, Borthwick LA, Vannella KM, Acciani TH, de Queiroz Prado R, Thompson RW, White S, Soucy G, Bilodeau M, Ramalingam TR, Arron JR, Shoukry NH, Wynn TA
Journal: Sci Transl Med. 2017 Jun 28;9(396). pii: eaal3694. doi: 10.1126/scitranslmed.aal3694.
Nonalcoholic fatty liver disease (NAFLD) is now the most common progressive liver disease in developed countries and is the second leading indication for liver transplantation due to the extensive fibrosis it causes. NAFLD progression is thought to be tied to chronic low-level type 1 inflammation originating in the adipose tissue during obesity; however, the specific immunological mechanisms regulating the progression of NAFLD-associated fibrosis in the liver are unclear. To investigate the immunopathogenesis of NAFLD more completely, we investigated adipose dysfunction, nonalcoholic steatohepatitis (NASH), and fibrosis in mice that develop polarized type 1 or type 2 immune responses. Unexpectedly, obese interleukin-10 (IL-10)/IL-4-deficient mice (type 1-polarized) were highly resistant to NASH. This protection was associated with an increased hepatic interferon-γ (IFN-γ) signature. Conversely, IFN-γ-deficient mice progressed rapidly to NASH with evidence of fibrosis dependent on transforming growth factor-β (TGF-β) and IL-13 signaling. Unlike increasing type 1 inflammation and the marked loss of eosinophils seen in expanding adipose tissue, progression of NASH was associated with increasing eosinophilic type 2 liver inflammation in mice and human patient biopsies. Finally, simultaneous inhibition of TGF-β and IL-13 signaling attenuated the fibrotic machinery more completely than TGF-β alone in NAFLD-associated fibrosis. Thus, although type 2 immunity maintains healthy metabolic signaling in adipose tissues, it exacerbates the progression of NAFLDcollaboratively with TGF-β in the liver.