Adeus Lenin Dublado Download Torrent 17: A Satirical and Poignant Story of a Family Caught in the Mi

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On the boat returning from Samoa, Mead met her second husband, Reo Fortune, a New Zealander headed to Cambridge, England, to study psychology. They were married in 1928, after Mead's divorce from Luther Cressman. They traveled together to Pere, a small village on the island of Manus, in what was then the Admiralty Islands and is now part of Papua New Guinea. Mead wanted to study the thought processes of children in preliterate cultures and asked the children of Pere to prepare drawings for her. On the trip she collected approximately 35,000 pieces of children's artwork. Contrary to prevailing thought, she discovered that what is considered childlike in thought varies according to the emphases of the culture. In a culture such as Manus, where the supernatural permeates everyday life, Mead found that children showed no particular interest in the supernatural in their drawings. They focused instead on realistic depictions of the world around them. She published her findings in Growing Up in New Guinea (1930), a book written for a general audience. But, as with her Samoan research, she also published a technical monograph on Manus for her peers entitled titled Kinship in the Admiralty Islands (1934).

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It is well-established that cancer treatment substantially increases the risk of long-term adverse health outcomes among childhood cancer survivors. However, there is limited research on the underlying mechanisms. To elucidate the pathophysiology and a possible causal pathway from treatment exposures to cardiometabolic conditions, we conducted epigenome-wide association studies (EWAS) to identify the DNA methylation (DNAm) sites associated with cancer treatment exposures and examined whether treatment-associated DNAm sites mediate associations between specific treatments and cardiometabolic conditions.

In childhood cancer survivors, cancer treatment exposures are associated with DNAm patterns present decades following the exposure. Treatment-associated DNAm sites may mediate the causal pathway from specific treatment exposures to certain cardiometabolic conditions, suggesting the utility of DNAm sites as risk predictors and potential mechanistic targets for future intervention studies.

Progress in cancer treatment has dramatically improved the 5-year survival following a childhood cancer diagnosis to more than 85% between 2010 and 2016 [1]. Thus, the population of childhood cancer survivors has grown rapidly and is estimated to exceed 500,000 persons in the USA [2]. Unfortunately, the treatment of childhood malignancies is associated with long-term morbidity and mortality [3,4,5,6,7]. Mounting evidence suggests that reduced physical activity, muscular weakness, metabolic derangements, and cognitive declines are common problems among adults treated for childhood malignancies [7,8,9,10,11]. Furthermore, premature cellular senescence, sterile inflammation, and mitochondrial dysfunction resulting from a primary cancer diagnosis or treatment-related toxicity may contribute to adverse health outcomes [12]. Accordingly, survivors of childhood cancer often develop treatment-related late effects with 60% to more than 90% of survivors experiencing one or more long-term chronic health conditions (CHCs) [13], an approximately 2-fold greater burden of CHCs than community controls [4]. Treatment-related adverse health outcomes encompass a broad range of CHCs [4, 14, 15], hospitalizations [16], premature frailty [17], and early mortality [14]. Some of the most commonly observed CHCs among survivors include obesity [18, 19], diabetes mellitus [20], cardiovascular diseases [21, 22], hypertension [9, 22, 23], and subsequent neoplasms [24, 25].

While the substantially increased risk and total burden of adverse health outcomes among childhood cancer survivors have been extensively described, there is a need to unravel the complex interplay between therapeutic exposures and genetic susceptibility in order to elucidate the pathogenesis of specific health conditions [6]. Pathogenic germline mutations in DNA repair genes contribute to the subsequent neoplasm risk in childhood cancer survivors, especially among those who received high cumulative doses of specific agents and modalities [26]. Unlike germline genetics (DNA sequence), which is largely static throughout the life course, epigenetic patterns are plastic and can be modified in response to internal and external insults including medical treatments [27]. Population-based studies among breast cancer [28] and gastric cancer [29] patients have provided evidence supporting that chemotherapy, radiotherapy, or a combination of anticancer treatments have a profound impact on epigenetic alterations, primarily in the form of CpG methylation. The processes leading to aberrant DNA methylation (DNAm) are poorly understood. How epigenetic alterations resulting from cancer therapy interact with downstream gene regulation machineries and ultimately lead to the development of CHCs in individual survivors is still largely unknown. Possible biological mechanisms have been suggested; for instance, cellular oxidative stress and DNA damage can induce aberrant DNAm by recruiting DNA methyltransferase complex [30]. Emerging evidence suggests that alterations in DNAm in the blood can at least influence immune regulation [31] or blood lipids and metabolites [32]. Several population-based studies of adult-onset cancers have identified treatment-induced blood DNAm changes and associated these changes with health outcomes, specifically cognitive decline in breast cancer patients [28] and poor survival for colorectal cancer [33], lung cancer [34, 35], and ovarian cancer patients [36, 37]. Thus, epigenetic alterations due to cancer therapeutic agents may mediate or modify gene regulation potentially resulting in systemic changes contributing to the development of CHCs.

It is biologically plausible that treatments used during active childhood cancer could leave an epigenetic mark. Hence, we hypothesized that cancer treatment modalities cause aberrant hypo- or hyper-DNAm, which may affect the long-term risk of CHC among childhood cancer survivors. In this study, epigenome-wide association studies (EWAS) were conducted among adult survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE) to identify differentially methylated DNA CpG sites between survivors exposed or unexposed to a certain treatment and their associations with CHCs. We specifically focused on seven common cardiometabolic conditions including obesity, hypertension, hypercholesterolemia, hypertriglyceridemia, abnormal glucose metabolism, cardiomyopathy, and myocardial infarction, given that blood DNAm plays a role in the regulation of blood lipids and other metabolites [32].

The biological basis underlying treatment-related risks for adverse health outcomes among survivors of childhood cancer is largely unknown. We speculated that one plausible casual pathway is the acquisition and persistent soma-wide alterations in DNAm. In this study, the first large-scale association analyses between cancer treatments and DNA methylation in survivors of childhood cancer, our mediation analyses provide compelling evidence in substantiating this hypothesis. Moreover, we identify unique and overlapping methylation signatures across different cancer treatments that may serve as mechanistic targets for future intervention studies.

Our study has some limitations. First, due to frequent use of multimodality therapy, delineation of independent associations was not always feasible. To identify independent hits for each treatment, EWAS for each treatment was adjusted for other treatment exposures except for specific treatments that were highly correlated. Furthermore, due to the fact that cancer treatment is determined by cancer type together with age at diagnosis and era of diagnosis, our EWAS findings of treatment-specific effects may be driven by an underlying specific cancer diagnosis. Moreover, the lack of detailed stage information for all study participants precluded adjustment for childhood cancer stage in the analysis. Second, we did not consider other factors that affect the methylation landscape such as social economic status, health behaviors, and environmental exposures which could confound the findings. Third, even though we considered temporality among treatment exposures, DNAm (measured at a single time point), and incidence of CHCs, we could not definitively infer causality among three entities. Fourth, our study focused on European ancestry survivors of childhood cancer. Further replication with larger and more diverse survivor populations and validation to confirm generalizability to other ethnicities are needed to confirm the role of DNAm in associations between cancer treatments and adverse health outcomes. Lastly, the other limitation of the study is that we did not consider co-morbidity in the analysis of the association between DNAm and cardiometabolic conditions; therefore, when each specific condition was analyzed, survivors also had a range of other CHCs that could impact methylation.

In summary, we identified thousands of CpG sites associated with specific cancer treatments at genome-wide significant levels, suggesting that DNAm is an important biological embedding mechanism for prior cancer treatment exposures. We observed hundreds of these treatment-associated CpG sites significantly associated with one or more of the seven cardiometabolic CHC risks after adjusting for multiple testing. Moreover, dozens of these sensor CpG sites showed full or partial mediation effects for the association between specific treatment exposure and cardiometabolic CHC, suggesting DNAm, as a biomarker, can be used as a risk predictor and potential mechanistic target for future intervention studies among survivors of childhood cancer. Our study has limitations that require cautious interpretation of the results presented. Future studies are warranted to further validate and replicate these findings. 2ff7e9595c