Genome-wide Analysis using ChIP to Identify Isoform-specific Gene Targets

Recruitment of transcriptional and epigenetic factors to their targets is a key step in their regulation. Prominently featured in recruitment are the protein domains that bind to specific histone modifications. One such domain is the plant homeodomain (PHD), found in several chromatin-binding proteins. The epigenetic factor RBP2 has multiple PHD domains, however, they have different functions (Figure 4). In particular, the C-terminal PHD domain, found in a RBP2 oncogenic fusion in human leukemia, binds to trimethylated lysine 4 in histone H3 (H3K4me3)1. The transcript corresponding to the RBP2 isoform containing the C-terminal PHD accumulates during differentiation of promonocytic, lymphoma-derived, U937 cells into monocytes2. Consistent with both sets of data, genome-wide analysis showed that in differentiated U937 cells, the RBP2 protein gets localized to genomic regions highly enriched for H3K4me33. Localization of RBP2 to its targets correlates with a decrease in H3K4me3 due to RBP2 histone demethylase activity and a decrease in transcriptional activity. In contrast, two other PHDs of RBP2 are unable to bind H3K4me3. Notably, the C-terminal domain PHD of RBP2 is absent in the smaller RBP2 isoform4. It is conceivable that the small isoform of RBP2, which lacks interaction with H3K4me3, differs from the larger isoform in genomic location. The difference in genomic location of RBP2 isoforms may account for the observed diversity in RBP2 function. Specifically, RBP2 is a critical player in cellular differentiation mediated by the retinoblastoma protein (pRB). Consistent with these data, previous genome-wide analysis, without distinction between isoforms, identified two distinct groups of RBP2 target genes: 1) genes bound by RBP2 in a manner that is independent of differentiation; 2) genes bound by RBP2 in a differentiation-dependent manner

Breast cancer in Woman Sitting Half-Dressed beside a stove (1658) by Rembrandt van Rijn

The baroque Dutch painter Rembrandt Harmenszoon van Rijn (1606–1669 CE) was acquainted with pathological modifications of the breast as shown in the canvas Bathsheba at her toilet (1654 CE); his model, Henrijke Stoffels, was depicted with discoloration of the left breast, peau d'orange and distortion of symmetry with axillary fullness. A diagnosis of breast cancer was initally proposed [1] but was later dismissed in favour of cancer mimickers (tuberculous mastitis [2], lactation mastitis following unsuccessful pregnancy [3], Mondor's thrombophlebitis [4]); this was essentially due to Henrjike's long survival (9 years after the depiction) fairly ruling out advanced breast cancer

Interleukin 10 (IL-10): an immunosuppressive factor and independent predictor in patients with metastatic renal cell carcinoma

Interleukin 10 (IL-10) is an immunosuppressive factor and has been detected in tumour cell cultures of renal cell carcinoma and of malignant melanoma. IL-10 has been described as a cytokine of the Th2 response; it is able to suppress antigen-presenting cells (APCs) and may lead to down-regulation of HLA class I and II molecules on dendritic cells and to anergy of T-lymphocytes. We evaluated pretreatment serum levels of soluble IL-10 and various clinical parameters to determine their prognostic value in 80 advanced renal cell carcinoma patients seen at our institution between May 1990 and April 1996. For statistical evaluation we used both univariate and multivariate Cox proportional hazards models. An elevated pretreatment serum level of IL-10 was a statistically independent predictor of unfavourable outcome (P < 0.0028), in addition to the well-known clinical and biochemical risk factors. These data support risk stratification for future therapeutic trials and identify a predictor which needs to be validated in prospective studies and may potentially influence decision making in palliative management of patients with metastatic renal cell carcinoma. These data also suggest a potential role of IL-10 in the development of advanced renal cell carcinoma and in the future design of therapeutic strategies. © 1999 Cancer Research Campaig

Hamburg's Spaces of Danger: Race, Violence and Memory in a Contemporary Global City

Germany today is experiencing the strongest upsurge of right-wing populism since the second world war, most notably with the rise of Pegida and Alternative für Deutschland. Yet wealthy global cities like Hamburg continue to present themselves as the gatekeepers of liberal progress and cosmopolitan openness. This article argues that Hamburg’s urban boosterism relies on, while simultaneously obscuring, the same structures of racial violence that embolden reactionary movements. Drawing on the work of Walter Benjamin and Allan Pred, we present an archaeology of Hamburg’s landscape, uncovering some of its ‘spaces of danger’––sites layered with histories of violence, many of which lie buried and forgotten. We find that these spaces, when they become visible, threaten to undermine Hamburg’s cosmopolitan narrative. They must, as a result, be continually erased or downplayed in order to secure the city as an attractive site for capital investment. To illustrate this argument, we give three historical examples: Hamburg’s role in the Hanseatic League during the medieval and early modern period; the city under the Nazi regime; and the recent treatment of Black African refugees. The article’s main contribution is to better situate issues of historical landscape, collective memory and racialized violence within the political economy of today’s global city

Advancing a holistic systems approach for sustainable cattle development programmes in South Africa: insights from sustainability assessments

Efforts to exploit the central roles of cattle to drive agriculture and rural development in low-income countries recorded limited success owing to their narrow focus on modernizing and commercializing low-input cattle farming. Most programs failed to take cognizance of the heterogeneous range of complex relationships between the environmental, economic, social and institutional challenges that limit low-input cattle farming. The current qualitative literature review evaluates the environmental, economic and social sustainability delivery impacts of the leading cattle development programs in the low-input farming sector in South Africa using a holistic systems approach. A mixed method procedure involving stratified sampling was used to allocate local and international-based programs while, purposive sampling was used to select programs with a wider scale of operation. The review then draws on the crosscutting key constraints emerging from the case studies to provide a better grounding for subsequent sustainability sensitive recommendations. Local-based cattle development programs advanced more market-led interventions while, their international-based counterparts had more interventions including, soil and rangeland improvement. The narrow focus by both local and international developmental programs is inadequate to address a wide array of environmental, economic, social, technical and institutional challenges faced by low-input cattle producers in South Africa.The Department of Science and Technology-National Research Foundation (DST-NRF) Centre of Excellence (CoE) in Food Security [140102].https://www.tandfonline.com/loi/wjsa212021-01-23hj2020Gordon Institute of Business Science (GIBS

Generic Escherichia coli Contamination of Spinach at the Preharvest Stage: Effects of Farm Management and Environmental Factors

The objective of this study was to determine the effects of farm management and environmental factors on preharvest spinach contamination with generic Escherichia coli as an indicator of fecal contamination. A repeated cross-sectional study was conducted by visiting spinach farms up to four times per growing season over a period of 2 years (2010 to 2011). Spinach samples (n = 955) were collected from 12 spinach farms in Colorado and Texas as representative states of the Western and Southwestern United States, respectively. During each farm visit, farmers were surveyed about farm-related management and environmental factors using a questionnaire. Associations between the prevalence of generic E. coli in spinach and farm-related factors were assessed by using a multivariable logistic regression model including random effects for farm and farm visit. Overall, 6.6% of spinach samples were positive for generic E. coli. Significant risk factors for spinach contamination with generic E. coli were the proximity (within 10 miles) of a poultry farm, the use of pond water for irrigation, a >66-day period since the planting of spinach, farming on fields previously used for grazing, the production of hay before spinach planting, and the farm location in the Southwestern United States. Contamination with generic E. coli was significantly reduced with an irrigation lapse time of >5 days as well as by several factors related to field workers, including the use of portable toilets, training to use portable toilets, and the use of hand-washing stations. To our knowledge, this is the first report of an association between field workers' personal hygiene and produce contamination with generic E. coli at the preharvest level. Collectively, our findings support that practice of good personal hygiene and other good farm management practices may reduce produce contamination with generic E. coli at the preharvest level

Demographic influences on the behavior of chimpanzees

Recent research has revealed substantial diversity in the behavior of wild chimpanzees. Understanding the sources of this variation has become a central focus of investigation. While genetic, ecological, and cultural factors are often invoked to explain behavioral variation in chimpanzees, the demographic context is sometimes overlooked as a contributing factor. Observations of chimpanzees at Ngogo, Kibale National Park, Uganda, reveal that the size and structure of the unit group or community can both facilitate and constrain the manifestation of behavior. With approximately 150 individuals, the Ngogo community is much larger than others that have been studied in the wild. We have taken advantage of the unusual demographic structure of this community to document new and intriguing patterns of chimpanzee behavior with respect to hunting, territoriality, and male social relationships. Chimpanzees at Ngogo hunt often and with a considerable degree of success. In addition, male chimpanzees there frequently patrol the boundary of their territory and engage in repeated bouts of lethal intergroup aggression. By forming two distinct subgroups, male chimpanzees at Ngogo also develop social bonds above the level of dyadic pairs. While the sheer number of chimpanzees contributes to differences in hunting, patrolling, mating, and subgrouping at Ngogo, the demographic situation may also constrain behavioral interactions. At Ngogo, male chimpanzees who are closely related genetically through the maternal line do not appear to affiliate or cooperate with each other. Demographic constraints may be responsible for this finding. In this paper, I use these examples to illustrate how the demographic context affects the possible range of behavioral options open to individuals and ultimately contributes to the explanation of behavioral diversity in chimpanzees.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41615/1/10329_2005_Article_139.pd

Hexokinase 2 in Liver Cancer

A major focus of cancer biologists is to identify novel therapeutic strategies to improve cancer-patient outcomes. One of the most prevalent cancer-specific phenotypes is glucose addiction, manifest, by the specific upregulation of glycolysis in the presence of oxygen (aerobic glycolysis), and thus, cancer metabolism has been under investigation to learn how to best exploit this vulnerability to selectively eradicate cancer cells. Hexokinase (HK) enzymes catalyze the first, committed step of the glycolysis pathway, phosphorylating glucose to produce the product glucose-6-phosphate (G6P), that is used in a number of ways to support cell viability and proliferation. In liver cancer, an isoform switch is observed, whereby the normal, adult isoform, Glucokinase (GCK), is repressed and the embryonic form, Hexokinase 2 (HK2) is upregulated, and is the only isoform expressed. Therefore, liver cancer could be selectively targeted by HK2 ablation sparing the normal hepatocytes. We found that by targeting HK2 in two independent human HCC cell lines, HepG2 and Huh7, reduced hexokinase activity, proliferation, and tumorigenicity was observed in in-vitro and in-vivo assays. These phenotypes were rescued by exogenous expression of a rat, wt-HK2 orthologue that is resistant to silencing by shRNA used in the cells to target human HK2, but that both catalytic and mitochondrial-binding mutants could not, indicating that both of these functions are required for HK2 to exert tumorigenic potential. GCK could not phenocopy HK2 in rescue experiments either. Cells with HK2 knockdown that exhibited reductions in glycolysis also showed a compensatory upregulation in respiration. By targeting both glycolysis and OXPHOS, with HK2 shRNA and Metformin treatment, respectively, we were able to inhibit tumor growth in mouse tumorigenesis models. Treatment with Metformin in combination with HK2 loss also synergistically downregulates the mTORC1 signaling pathway through the REDD1 protein. Data suggests that targeting HK2 and Metformin co-treatment should be considered for HCC cancer therapy