A conditional mouse expressing an activating mutation in NRF2 displays hyperplasia of the upper gastrointestinal tract and decreased white adipose tissue

Activation of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or NRF2) transcription factor is a critical and evolutionarily conserved cellular response to oxidative stress, metabolic stress, and xenobiotic insult. Deficiency of NRF2 results in hypersensitivity to a variety of stressors, whereas its aberrant activation contributes to several cancer types, most commonly squamous cell carcinomas of the esophagus, oral cavity, bladder, and lung. Between 10% and 35% of patients with squamous cell carcinomas display hyperactive NRF2 signaling, harboring activating mutations and copy number amplifications of the NFE2L2 oncogene or inactivating mutations or deletions of KEAP1 or CUL3, the proteins of which co-complex to ubiquitylate and degrade NRF2 protein. To better understand the role of NRF2 in tumorigenesis and more broadly in development, we engineered the endogenous Nfe2l2 genomic locus to create a conditional mutant LSL-Nrf2E79Q mouse model. The E79Q mutation, one of the most commonly observed NRF2-activating mutations in human squamous cancers, codes for a mutant protein that does not undergo KEAP1/CUL3-dependent degradation, resulting in its constitutive activity. Expression of NRF2 E79Q protein in keratin 14 (KRT14)-positive murine tissues resulted in hyperplasia of squamous cell tissues of the tongue, forestomach, and esophagus, a stunted body axis, decreased weight, and decreased visceral adipose depots. RNA-seq profiling and follow-up validation studies of cultured NRF2E79Q murine esophageal epithelial cells revealed known and novel NRF2-regulated transcriptional programs, including genes associated with squamous cell carcinoma (e.g. Myc), lipid and cellular metabolism (Hk2, Ppard), and growth factors (Areg, Bmp6, Vegfa). These data suggest that in addition to decreasing adipogenesis, KRT14-restricted NRF2 activation drives hyperplasia of the esophagus, forestomach, and tongue, but not formation of squamous cell carcinoma

Functional Promoter -31G>C Variant in Survivin Gene Is Associated with Risk and Progression of Renal Cell Cancer in a Chinese Population

BACKGROUND: Survivin is an inhibitor of apoptosis protein and is involved in the occurrence and progression of human malignancies. Recently, a functional polymorphism (-31G>C, rs9904341) in the promoter of survivin has been shown to influence its expression and confer susceptibility to different types of cancer. The present study was aimed to investigate whether the polymorphism also influences susceptibility and progression of renal cell cancer (RCC) in a Chinese population. METHODS: We genotyped this polymorphism using the TaqMan assay in a case-control study comprised of 710 RCC patients and 760 controls. The logistic regression was used to assess the genetic association with occurrence and progression of RCC. RESULTS: Compared with the genotypes containing G allele (GG and GC), we found a statistically significant increased occurrence of RCC associated with the CC genotype [P = 0.006, adjusted odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.08-1.76]. The polymorphism was associated with risk of developing advanced stage (OR = 2.02, 95%CI = 1.34-3.07) and moderately differentiated (OR = 1.75; 95%CI = 1.20-2.54) RCC. Furthermore, the patients carrying the CC genotype had a significantly greater prevalence of high clinical stage disease (P(trend) = 0.003). Similar results were also observed when we restricted the analysis to clear cell RCC, a major histological type of RCC. CONCLUSIONS: Our results suggest that the functional -31G>C polymorphism in the promoter of survivin may influence the susceptibility and progression of RCC in the Chinese population. Large population-based prospective studies are required to validate our findings

Is Asthma Related to Choroidal Neovascularization?

BACKGROUND: Age-related degeneration (AMD) and asthma are both diseases that are related to the activation of the complement system. The association between AMD and asthma has been debated in previous studies. The authors investigated the relationship between AMD and asthma systemically. PRINCIPAL FINDINGS: The epidemiological study showed that asthma was related to choroidal neovascularization (CNV) subtype (OR = 1.721, P = 0.023). However, the meta-analysis showed there was no association between AMD and asthma. In an animal model, we found more fluoresce in leakage of CNV lesions by FA analysis and more angiogenesis by histological analysis in rats with asthma. Western blot demonstrated an elevated level of C3α-chain, C3α'-chain and VEGF. After compstatin was intravitreally injected, CNV leakage decreased according to FA analysis, with the level of C3 and VEGF protein decreasing at the same time. SIGNIFICANCE: This study first investigated the relationship between AMD and asthma systematically, and it was found that asthma could be a risk factor for the development of AMD. The study may provide a better understanding of the disease, which may advance the potential for screening asthma patients in clinical practice

Advancing the application of systems thinking in health: managing rural China health system development in complex and dynamic contexts

Background: This paper explores the evolution of schemes for rural finance in China as a case study of the long and complex process of health system development. It argues that the evolution of these schemes has been the outcome of the response of a large number of agents to a rapidly changing context and of efforts by the government to influence this adaptation process and achieve public health goals. Methods:The study draws on several sources of data including a review of official policy documents and academic papers and in-depth interviews with key policy actors at national level and at a sample of localities. Results: The study identifies three major transition points associated with changes in broad development strategy and demonstrates how the adaptation of large numbers of actors to these contextual changes had a major impact on the performance of the health system. Further, it documents how the Ministry of Health viewed its role as both an advocate for the interests of health facilities and health workers and as the agency responsible for ensuring that government health system objectives were met. It is argued that a major reason for the resilience of the health system and its ability to adapt to rapid economic and institutional change was the ability of the Ministry to provide overall strategy leadership. Additionally, it postulates that a number of interest groups have emerged, which now also seek to influence the pathway of health system development. Conclusions: This history illustrates the complex and political nature of the management of health system development and reform. The paper concludes that governments will need to increase their capacity to analyze the health sector as a complex system and to manage change processes.UKaid: DFI

Unfolded protein response in cancer: the Physician's perspective

The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). Cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress and other metabolic dysregulation that cause ER stress and activation of the UPR. Depending on the duration and degree of ER stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic pathways, or death signals by inducing cell death programs. Sustained induction or repression of UPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In this review, we discuss the basic mechanisms of UPR and highlight the importance of UPR in cancer biology. We also update the UPR-targeted cancer therapeutics currently in clinical trials

Varying phenotypes in swine versus murine transgenic models constitutively expressing the same human Sonic hedgehog transcriptional activator, K5-HGLI2 Delta N

This study was undertaken to characterize the effects of constitutive expression of the hedgehog transcriptional activator, Gli2, in porcine skin. The keratinocyte-specific human transgene, K5-hGli2 Delta N, was used to produce transgenic porcine lines via somatic cell nuclear transfer techniques. In mice, K5-hGli2 Delta N induces epithelial downgrowths resembling basal cell carcinomas. Our porcine model also developed these basal cell carcinoma-like lesions, however gross tumor development was not appreciated. In contrast to the murine model, diffuse epidermal changes as well as susceptibility to cutaneous infections were seen in the swine model. Histologic analysis of transgenic piglets revealed generalized epidermal changes including: epidermal hyperplasia (acanthosis), elongated rete ridges, parakeratotic hyperkeratosis, epidermal neutrophilic infiltration, capillary loop dilation and hypogranulosis. By 2 weeks of age, the transgenic piglets developed erythematic and edematous lesions at high contact epidermal areas and extensor surfaces of distal limb joints. Despite antibiotic treatment, these lesions progressed to a deep bacterial pyoderma and pigs died or were euthanized within weeks of birth. Non-transgenic littermates were phenotypically normal by gross and histological analysis. In summary, constitutive expression of the human hGli2 Delta N in keratinocytes, results in cutaneous changes that have not been reported in the K5-hGli2 Delta N murine model. These findings indicate a need for a multiple species animal model approach in order to better understand the role of Gli2 in mammalian skin