'Aquaporin-omics': mechanisms of aquaporin-2 loss in polyuric disorders.

Animal models of a variety of acquired nephrogenic diabetes insipidus (NDI) disorders have identified a common feature: all such models are associated with the loss of aquaporin-2 (AQP2) from collecting duct principal cells, explaining the associated polyuria. To discover mechanisms of AQP2 loss, previous investigators have carried out either transcriptomics (lithium-induced NDI, unilateral ureteral obstruction, endotoxin-induced NDI) or proteomics (hypokalaemia-associated NDI, hypercalcaemia-associated NDI, bilateral ureteral obstruction), yielding contrasting views. Here, to address whether there may be common mechanisms underlying loss of AQP2 in acquired NDI disorders, we have used bioinformatic data integration techniques to combine information from all transcriptomic and proteomic data sets. The analysis reveals roles for autophagy/apoptosis, oxidative stress and inflammatory signalling as key elements of the mechanism that results in loss of AQP2. These processes can cause AQP2 loss through the combined effects of repression of Aqp2 gene transcription, generalized translational repression, and increased autophagic degradation of proteins including AQP2. Two possible types of stress-sensor proteins, namely death receptors and stress-sensitive protein kinases of the EIF2AK family, are discussed as potential triggers for signalling processes that result in loss of AQP2. KEY POINTS: Prior studies have shown in a variety of animal models of acquired nephrogenic diabetes insipidus (NDI) that loss of the aquaporin-2 (AQP2) protein is a common feature. Investigations of acquired NDI using transcriptomics (RNA-seq) and proteomics (protein mass spectrometry) have led to differing conclusions regarding mechanisms of AQP2 loss. Bioinformatic integration of transcriptomic and proteomic data from these prior studies now reveals that acquired NDI models map to three core processes: oxidative stress, apoptosis/autophagy and inflammatory signalling. These processes cause loss of AQP2 through translational repression, accelerated degradation of proteins, and transcriptional repression.

Circadian gene expression in mouse renal proximal tubule.

Circadian variability in kidney function is well recognized but is often ignored as a potential confounding variable in physiological experiments. Here, we have created a data resource consisting of expression levels for mRNA transcripts in microdissected proximal tubule segments from mice as a function of the time of day. Small-sample RNA sequencing was applied to microdissected S1 proximal convoluted tubules and S2 proximal straight tubules. After stringent filtering, the data were analyzed using JTK-Cycle to detect periodicity. The data set is provided as a user-friendly webpage at https://esbl.nhlbi.nih.gov/Databases/Circadian-Prox2/. In proximal convoluted tubules, 234 transcripts varied in a circadian manner (4.0% of the total). In proximal straight tubules, 334 transcripts varied in a circadian manner (5.3%). Transcripts previously known to be associated with corticosteroid action and with increased flow were found to be overrepresented among circadian transcripts peaking during the "dark" portion of the day [zeitgeber time (ZT)14-22], corresponding to peak levels of corticosterone and glomerular filtration rate in mice. To ask whether there is a time-of-day dependence of protein abundances in the kidney, we carried out LC-MS/MS-based proteomics in whole mouse kidneys at ZT12 and ZT0. The full data set (n = 6,546 proteins) is available at https://esbl.nhlbi.nih.gov/Databases/Circadian-Proteome/. Overall, 293 proteins were differentially expressed between ZT12 and ZT0 (197 proteins greater at ZT12 and 96 proteins greater at ZT0). Among the regulated proteins, only nine proteins were found to be periodic in the RNA-sequencing analysis, suggesting a high level of posttranscriptional regulation of protein abundances.NEW & NOTEWORTHY Circadian variation in gene expression can be an important determinant in the regulation of kidney function. The authors used RNA-sequencing transcriptomics and LC-MS/MS-based proteomics to identify gene products expressed in a periodic manner. The data were used to construct user-friendly web resources.

Factors related to employers' intent to hire, retain and accommodate cancer survivors: the Singapore perspective.

PURPOSE: Despite the growing importance of cancer and return-to-work issues in occupational rehabilitation literature in the last decade, academic discussion is largely limited to survivors' perspectives and some exploratory studies from the employer side. This paper applies two classic theoretical models-Theory of Planned Behavior and Social Cognitive Theory-and key measures from previous studies to identify explicit relationships that explain employer factors to hire and retain cancer survivors. METHODS: Data were collected from online surveys with senior management executives and senior human resource specialists from various organizations in Singapore, with a total of 145 responses. The 72-item survey instrument included a series of independent variables: (1) Attitudes toward cancer and cancer survivors; (2) Employers' efficacy; (3) Perceived moral obligation; (4) Employers' experience; (5) Outcome expectations; (6) Employment situation; (7) Social norms; and (8) Incentives, and dependent variables: (a) Employers' intention to hire cancer survivors; and (b) Employers' intention to retain cancer survivors. RESULTS: Regression analyses showed that the top three factors related to employers' intention to retain cancer survivors are perceived moral obligations (ß = .39, p < .001), followed by attitudes toward cancer (ß = .25, p < .01), and employment situation (ß = .17, p < .05). Employers' efficacy was associated with intention to hire (ß = .22, p < .05), coupled with attitude toward cancer survivors (ß = .22, p < .01). The findings also indicated the important role of existing relationship between an employer and an employee when it comes to retaining cancer survivors and government incentives for hiring cancer survivors in the workforce. CONCLUSIONS: The present study provided an avenue to implement the proposed model-a potential study framework for the management of cancer survivors at work. Findings revealed that different messages should be tailored to employers toward hiring and retention issues and provided useful guidelines for employer education materials.

Toward an occupational rehabilitation policy community for cancer survivors in Singapore: a stakeholder perspective from the SME employers.

INTRODUCTION: Cancer and return to work has been extensively studied in the Western context and yet it has not received much academic attention in Asia. This paper aims to review the current Singapore government rehabilitation initiatives in collaboration with the policy community, identify the socio-environmental barriers to implementing the existing programs for cancer survivors, highlights the demand-side of research development and illustrates the viewpoints of small and medium enterprise employers in Singapore from a recent study. Implications and future directions in developing evidence-based rehabilitation policies and initiatives for cancer survivors in Singapore and the Southeast Asian region are also discussed. METHODS: A review of occupational rehabilitation literature relevant to Singapore looking at legislation, policies, initiatives and services was performed. Current state-of-art research in occupational rehabilitation from an employer perspective was also synthesized. RESULTS: Challenges and barriers of adopting the current rehabilitation initiatives and programs for cancer survivors exist largely due to the lack of centralized effort, clear definitions and understanding between people with disabilities, chronic illness and cancer as well as an evidence-based policy community. In addition, too much emphasis on new hiring than retaining in current services and there are no specific guidelines to help employers deal with issues when retaining employees with health history, such as workplace accommodation, appraisal, discrimination and grievance handling. CONCLUSIONS: Palpable blind spots in the current occupational rehabilitation system and policy were highlighted in this paper. Coupled with systemic improvements, continuous government resource support and developing an evidence-based policy community between the government, employers, healthcare professionals, industry and community partners and non-profit organizations, a positive change of the rehabilitation initiatives and services is promising.

Unintended consequences: the social context of cancer survivors and work.

PURPOSE: This article describes the ways in which socioeconomic characteristics and workplace contexts shape the unintended consequences that cancer survivors can experience as they return to work. The study was conducted in an employment setting where there is a major focus on productivity and economic growth in the business sector. METHODS: Five focus groups (N = 33 participants) were conducted in 2012 in Singapore. Questions were directed at obtaining information related to the meaning of a job and reactions to return to work as a cancer survivor completes primary cancer treatment. A thematic analysis using a two-staged analytical process was conducted to identify (1) work-related challenges faced by survivors as a result of the interplay between their self-identity as someone with a critical illness and organizational structure, and (2) unintended social consequences (USCs) related to the interaction between the workplace and cancer survivor. RESULTS: Eight emerging themes of work-related challenges and unintended consequences were categorized. Fear of losing out by compromising one's expectation, downplaying illness to avoid being a burden to others, working harder to meet expectations, and passive acceptance to perceived discrimination. Unintended consequences were also observed in relation to policies, procedures, and economic factors in the context of a heightened economically driven social climate. CONCLUSIONS: This study contributes to the understanding of how cancer survivors perceive their work situation. These findings can inform health care providers, employers, and policy makers regarding the challenges faced by cancer survivors as they return to the workplace in a culture of a rapidly growing emphasis on economic concerns. IMPLICATIONS FOR CANCER SURVIVORSHIP: These findings offer a new perspective on the complexities that can occur when cancer survivors interact with their workplace. Awareness of the existence and types of unintended consequences in this context can help provide a more comprehensive understanding of the cancer survivor and work interface.