RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression.

DZIP3/hRUL138 is a poorly characterized RNA-binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3' untranslated region of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle, where it is needed for cell-cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1-E2F axes. Taken together, this study demonstrates for the first time that DZIP3 uses a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell-cycle and cancer progression. SIGNIFICANCE: These findings show that DZIP3 is a novel driver of cell-cycle and cancer progression via its control of Cyclin D1 mRNA and protein stability in a cell-cycle phase-dependent manner. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/2/315/F1.large.jpg.

Determinants of disposal of child faeces in latrines in urban slums of Odisha, India: a cross-sectional study.

BACKGROUND: Even among households that have access to improved sanitation, children's faeces often do not end up in a latrine, the international criterion for safe disposal of child faeces. METHODS: We collected data on possible determinants of safe child faeces disposal in a cross-sectional study of 851 children <5 y of age from 694 households in 42 slums in two cities in Odisha, India. Caregivers were asked about defecation and faeces disposal practices for all the children <5 y of age in the household. RESULTS: Only a quarter (25.5%) of the 851 children's faeces were reported to be disposed of in a latrine. Even fewer (22.3%) of the 694 households reported that the faeces of all children <5 y of age in the home ended up in the latrine the last time the child defecated. In multivariate analysis, factors associated with being a safe disposal household were education and religion of the primary caregiver, number of children <5 y of age in the household, wealth, type and location of the latrine used by the household, household members >5 y of age using the latrine for defecation and mobility of children <5 y of age in the household. CONCLUSIONS: Few households reported disposing of all of their children's faeces in a latrine. Improving latrine access and specific behaviour change interventions may improve this practice.

Understanding and defining sanitation insecurity: women's gendered experiences of urination, defecation and menstruation in rural Odisha, India.

BACKGROUND: Research suggests that the lived experience of inadequate sanitation may contribute to poor health outcomes above and beyond pathogen exposure, particularly among women. The goal of this research was to understand women's lived experiences of sanitation by documenting their urination-related, defecation-related and menstruation-related concerns, to use findings to develop a definition of sanitation insecurity among women in low-income settings and to develop a conceptual model to explain the factors that contribute to their experiences, including potential behavioural and health consequences. METHODS: We conducted 69 Free-List Interviews and eight focus group discussions in a rural population in Odisha, India to identify women's sanitation concerns and to build an understanding of sanitation insecurity. FINDINGS: We found that women at different life stages in rural Odisha, India have a multitude of unaddressed urination, defecation and menstruation concerns. Concerns fell into four domains: the sociocultural context, the physical environment, the social environment and personal constraints. These varied by season, time of day, life stage and toilet ownership, and were linked with an array of adaptations (ie, suppression, withholding food and water) and consequences (ie, scolding, shame, fear). Our derived definition and conceptual model of sanitation insecurity reflect these four domains. DISCUSSION: To sincerely address women's sanitation needs, our findings indicate that more is needed than facilities that change the physical environment alone. Efforts to enable urinating, defecating and managing menstruation independently, comfortably, safely, hygienically, privately, healthily, with dignity and as needed require transformative approaches that also address the gendered, sociocultural and social environments that impact women despite facility access. This research lays the groundwork for future sanitation studies to validate or refine the proposed definition and to assess women's sanitation insecurity, even among those who have latrines, to determine what may be needed to improve women's sanitation circumstances.

Identifying Potential Sources of Exposure Along the Child Feces Management Pathway: A Cross-Sectional Study Among Urban Slums in Odisha, India.

Child feces represent a particular health risk to children due to increased prevalence of enteric agents and a higher risk of exposure owing to exploratory behaviors of young children. The safe management of such feces presents a significant challenge, not only for the 2.4 billion who lack access to improved sanitation, but also due to unhygienic feces collection and disposal and poor subsequent handwashing practices. We assessed potential sources of fecal exposure by documenting child feces management practices in a cross-sectional study of 851 children < 5 years of age from 694 households in 42 slums in two cities in Odisha, India. No preambulatory children and only 27.4% of ambulatory children defecated directly in the latrine. Children that did not defecate in a latrine mainly defecated on the ground, whether they were preambulatory or ambulatory. Use of diapers (1.2%) or potties (2.8%) was low. If the feces were removed from the ground, the defecation area was usually cleaned, if at all, only with water. Most children's feces were disposed of in surrounding environment, with only 6.5% deposited into any kind of latrine, including unimproved. Handwashing with soap of the caregiver after child feces disposal and child anal cleaning with soap after defecation was also uncommon. While proper disposal of child feces in an improved latrine still represents a major challenge, control of the risks presented requires attention to the full range of exposures associated to the management of child feces, and not simply the place of disposal.