Acute Hypersensitivity of Pluripotent Testicular Cancer-Derived Embryonal Carcinoma to Low-Dose 5-Aza Deoxycytidine Is Associated with Global DNA Damage-Associated p53 Activation, Anti-Pluripotency and DNA Demethylation

<div><p>Human embryonal carcinoma (EC) cells are the stem cells of nonseminoma testicular germ cells tumors (TGCTs) and share remarkable similarities to human embryonic stem (ES) cells. In prior work we found that EC cells are hypersensitive to low nanomolar doses of 5-aza deoxycytidine (5-aza) and that this hypersensitivity partially depended on unusually high levels of the DNA methyltransferase, DNMT3B. We show here that low-dose 5-aza treatment results in DNA damage and induction of p53 in NT2/D1 cells. In addition, low-dose 5-aza results in global and gene specific promoter DNA hypomethylation. Low-dose 5-aza induces a p53 transcriptional signature distinct from that induced with cisplatin in NT2/D1 cells and also uniquely downregulates genes associated with pluripotency including NANOG, SOX2, GDF3 and Myc target genes. Changes in the p53 and pluripotency signatures with 5-aza were to a large extent dependent on high levels of DNMT3B. In contrast to the majority of p53 target genes upregulated by 5-aza that did not show DNA hypomethylation, several other genes induced with 5-aza had corresponding decreases in promoter methylation. These genes include RIN1, SOX15, GPER, and TLR4 and are novel candidate tumors suppressors in TGCTs. Our studies suggest that the hypersensitivity of NT2/D1 cells to low-dose 5-aza is multifactorial and involves the combined activation of p53 targets, repression of pluripotency genes, and activation of genes repressed by DNA methylation. Low-dose 5-aza therapy may be a general strategy to treat those tumors that are sustained by cells with embryonic stem-like properties.</p> <p>GEO number for the microarray data: GSE42647.</p> </div

Emerging Adulthood as a Critical Stage in the Life Course

Book Summary: This handbook synthesizes and analyzes the growing knowledge base on life course health development (LCHD) from the prenatal period through emerging adulthood, with implications for clinical practice and public health. It presents LCHD as an innovative field with a sound theoretical framework for understanding wellness and disease from a lifespan perspective, replacing previous medical, biopsychosocial, and early genomic models of health. Interdisciplinary chapters discuss major health concerns (diabetes, obesity), important less-studied conditions (hearing, kidney health), and large-scale issues (nutrition, adversity) from a lifespan viewpoint. In addition, chapters address methodological approaches and challenges by analyzing existing measures, studies, and surveys. The book concludes with the editors’ research agenda that proposes priorities for future LCHD research and its application to health care practice and health policy. Topics featured in the Handbook include: The prenatal period and its effect on child obesity and metabolic outcomes. Pregnancy complications and their effect on women’s cardiovascular health. A multi-level approach for obesity prevention in children. Application of the LCHD framework to autism spectrum disorder. Socioeconomic disadvantage and its influence on health development across the lifespan. The importance of nutrition to optimal health development across the lifespan. The Handbook of Life Course Health Development is a must-have resource for researchers, clinicians/professionals, and graduate students in developmental psychology/science; maternal and child health; social work; health economics; educational policy and politics; and medical law as well as many interrelated subdisciplines in psychology, medicine, public health, mental health, education, social welfare, economics, sociology, and law

RAR and RXR modulation in cancer and metabolic disease

Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. The success of RAR modulation in the treatment of acute promyelocytic leukaemia (APL) has stimulated considerable interest in the development of RAR and RXR modulators. This has been aided by recent advances in the understanding of the biological role of RARs and RXRs and in the design of selective receptor modulators that might overcome the limitations of current drugs. Here, we discuss the challenges and opportunities for therapeutic strategies based on RXR and RAR modulators, with a focus on cancer and metabolic diseases such as diabetes and obesity

Hypogonadism in Systemic Diseases

Serum testosterone is often lower than normal in patients with acute or chronic systemic diseases. The underlying mechanisms involved in the reduced testosterone secretion depend on the type of systemic disease; thus, many pathogenetic mechanisms might be involved. These mechanisms involve the hypothalamus and the pituitary (secondary hypogonadism), the testis (primary hypogonadism), or both. The resulting low-serum testosterone could be reversible or not depending on the pathogenetic mechanism. Furthermore, the relationships between hypogonadism and the systemic disease are complex since these two clinical conditions may interact with each other in a bidirectional interplay. How to interpret low-serum testosterone in systemic diseases is not easy and univocal. Biochemical hypogonadism should be differentiated into overt clinical hypogonadism and functional hypogonadism, and testosterone treatment should be offered taking into account the primary systemic disease and the possible beneficial or harmful effect on it, as well as the presence of signs and symptoms of hypogonadism. In this chapter the main systemic illnesses associated with hypogonadism will be discussed together with their underlying pathogenetic mechanisms, clinical significance, relevance, and clinical and practical implications