Focus on 16p13.3 Locus in colon cancer

Background : With one million new cases of colorectal cancer (CRC) diagnosed annually in the world, CRC is the third most commonly diagnosed cancer in the Western world. Patients with stage I-III CRC can be cured with surgery but are at risk for recurrence. Colorectal cancer is characterized by the presence of chromosomal deletions and gains. Large genomic profiling studies have however not been conducted in this disease. The number of a specific genetic aberration in a tumour sample could correlate with recurrence-free survival or overall survival, possibly leading to its use as biomarker for therapeutic decisions. At this point there are not sufficient markers for prediction of disease recurrence in colorectal cancer, which can be used in the clinic to discriminate between stage II patients who will benefit from adjuvant chemotherapy. For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence. The benefits of adjuvant chemotherapy in stage II disease are less certain, the risk for relapse is much smaller in the overall group and the specific patients at risk are hard to identify. Materials and Methods : In this study, array-comparative genomic hybridization analysis (array-CGH) was applied to study high-resolution DNA copy number alterations in 93 colon carcinoma samples. These genomic data were combined with parameters like KRAS mutation status, microsatellite status and clinicopathological characteristics. Results : Both large and small chromosomal losses and gains were identified in our sample cohort. Recurrent gains were found for chromosome 1q, 7, 8q, 13 and 20 and losses were mostly found for 1p, 4, 8p, 14, 15, 17p, 18, 21 and 22. Data analysis demonstrated that loss of chromosome 4 is linked to a worse prognosis in our patients series. Besides these alterations, two interesting small regions of overlap were identified, which could be associated with disease recurrence. Gain of the 16p13.3 locus (including the RNA binding protein, fox-1 homolog gene, RBFOX1) was linked with a worse recurrence-free survival in our patient cohort. On the other hand, loss of RBFOX1 was only found in patients without disease recurrence. Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers. Conclusions : In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer

Focal DNA copy number changes in neuroblastoma target MYCN regulated genes

Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system cells. Recurrent genomic alterations include MYCN and ALK amplification as well as recurrent patterns of gains and losses of whole or large partial chromosome segments. A recent whole genome sequencing effort yielded no frequently recurring mutations in genes other than those affecting ALK. However, the study further stresses the importance of DNA copy number alterations in this disease, in particular for genes implicated in neuritogenesis. Here we provide additional evidence for the importance of focal DNA copy number gains and losses, which are predominantly observed in MYCN amplified tumors. A focal 5 kb gain encompassing the MYCN regulated miR-17,92 cluster as sole gene was detected in a neuroblastoma cell line and further analyses of the array CGH data set demonstrated enrichment for other MYCN target genes in focal gains and amplifications. Next we applied an integrated genomics analysis to prioritize MYCN down regulated genes mediated by MYCN driven miRNAs within regions of focal heterozygous or homozygous deletion. We identified RGS5, a negative regulator of G-protein signaling implicated in vascular normalization, invasion and metastasis, targeted by a focal homozygous deletion, as a new MYCN target gene, down regulated through MYCN activated miRNAs. In addition, we expand the miR-17,92 regulatory network controlling TGFß signaling in neuroblastoma with the ring finger protein 11 encoding gene RNF11, which was previously shown to be targeted by the miR-17,92 member miR-19b. Taken together, our data indicate that focal DNA copy number imbalances in neuroblastoma (1) target genes that are implicated in MYCN signaling, possibly selected to reinforce MYCN oncogene addiction and (2) serve as a resource for identifying new molecular targets for treatment

Informal settlement upgrading in Cape Town's Hangberg : local government, urban governance and the 'Right to the City'

Thesis (MPhil)--Stellenbosch University, 2011.ENGLISH ABSTRACT: Integrating the poor into the fibre of the city is an important theme in housing and urban policies in post-apartheid South Africa. In other words, the need for making place for the ‘black’ majority in urban spaces previously reserved for ‘whites’ is premised on notions of equity and social change in a democratic political dispensation. However, these potentially transformative thrusts have been eclipsed by more conservative, neoliberal developmental trajectories. Failure to transform apartheid spatialities has worsened income distribution, intensified suburban sprawl, and increased the daily livelihood costs of the poor. After a decade of unintended consequences, new policy directives on informal settlements were initiated through Breaking New Ground (DoH 2004b). Local governments have nevertheless been slow to implement this new instrument despite more participatory, flexible, integrated and situational responsive policies contained therein. The City of Cape Town was one of the first applicants for Upgrading of Informal Settlements Programme (DoH 2004a, DHS 2009) funding in upgrading Hangberg’s informal settlement after effective lobbying by local civic Hout Bay Civic Association (HBCA) assisted by the Cape Town-based NGO, Development Action Group (DAG). However, in September 2010 the upgrading project came to a standstill when Metropolitan Police clashed violently with community members who allegedly broke a key agreement when building informal structures on the Sentinel Mountain firebreak. Using the case study research methodology, the study seeks to unravel the governance complexities elicited by this potentially progressive planning intervention. Four theoretical prisms are used to probe and investigate the primary case study (Hangberg) due to the different ways of ‘seeing and grappling’ and ‘narrating’ a complex tale. This is characterised by the dialectics of power and powerlessness; regime stabilisation and destabilisation; formalisation and informalisation; continuity and discontinuity. These prisms are: urban informality, urban governance, deepening democracy, and socio-spatial justice. By utilising these four theoretical prisms, the study found the Hangberg case to be atypical of development trajectories, on the one hand, and conforming to the enduring neoliberal governance logics, on the other. In the concluding chapter, the study critically engages prospects of realising post-apartheid spatialities by considering recent policy shifts and programmes with the potential of realising the poor’s ‘right to the city’.AFRIKAANSE OPSOMMING: ‘n Belangrike tema in post-apartheid behuising- en stedelike beleide is die integrasie van arm mense in die weefsel van die stad. Anders gestel, die nodigheid om plek te maak vir die ‘swart’ meerderheid in stedelike spasies wat voorheen vir ‘wittes’ uitgesonder is, is gebaseer op die uitgangspunt van regverdigheid en sosiale verandering in ‘n demokratiese bedeling. Hierdie potensiële hervormings-nosies is egter verduister deur meer konserwatiewe, neo-liberale ontwikkelings-trajekte. Die mislukte pogings om apartheids-ruimtes te omvorm, beteken dat inkomsteverdeling vererger is, wydstrekkende verstedeliking in meer intensiewe vorms voorkom, en die daaglikse lewenskoste van die armes verhoog het. Na ‘n dekade van onopsetlike gevolge is nuwe beleids-riglyne vir informele nedersettings voorgestel deur Breaking New Ground (DoH 2004a). Plaaslike owerhede was egter tot dusver traag om hierdie nuwe instrument te implementeer, ten spyte daarvan dat meer deelnemende, buigsame, geïntegreerde en situasioneel-aanpasbare beleide daarin vervat is. Die Stad Kaapstad was een van die eerste applikante vir Upgrading of Informal Settlements Programme (DoH 2004b, DHS 2009) befondsing om Hangberg se informele nedersetting te opgradeer, nadat effektiewe druk uitgeoefen is deur die Hout Bay Civic Association (HBCA), met ondersteuning van die NRO, Development Action Group (DAG), wat in Kaapstad gebaseer is. Maar in September 2010 het die opgradering-projek tot stilstand gekom nadat die Metropolitaanse Polisie gewelddadig met gemeenskapslede gebots het, omdat die gemeenskap na bewering ‘n belangrike ooreenkoms gebreek het deur informele strukture op die brandstrook te bou. Deur van die gevalstudie navorsing-metodologie gebruik te maak, beoog hierdie studie om die bestuurskompleksiteite te ontrafel wat deur hierdie potensiële omvormde beplannings-intervensie uitgelok is. Vier teoretiese prismas word gebruik om die primêre geval (Hangberg) te ondersoek in die lig van die verskillende maniere waarop hierdie komplekse narratief gesien kan word. Dit word gekenmerk deur die dialekte van mag en magteloosheid; stabilisasie en destabilisasie van die staatsbestel; formalisering en deformalisering; samehangendheid en onsamehangendheid. Die prismas is: stedelike informaliteit, stedelike bestuur, verdieping van demokrasie en sosio-ruimtelike regverdigheid. Deur van hierdie vier prismas gebruik te maak, wys die studie tot watter mate die Hangberg geval aan die een kant atipies tot ontwikkelings-trajekte is, en aan die ander kant konformeer tot die voortdurende neo-liberale bestuurslogika. In die slothoofstuk, is die studie krities bemoei met die vooruitsig om die post-apartheid-stad te realiseer deur huidige beleidsveranderinge en programme te ondersoek met die vergrootglas op hul potensiaal vir transformasie en om die armes se ‘reg tot die stad’ te bevorder

Clientelism as civil society? Unpacking the relationship between clientelism and democracy at the local level in South Africa

This article, building on analyses from the global south, attempts to reframe democratic expectations by considering where previously maligned practices such as clientelism may hold moments of democracy. It does so by comparing the theory of civil society with that of clientelism, and its African counterpart neo-patrimonialism. It argues that clientelism as civil society may fulfil democratic tasks such as holding the (local) state accountable, strengthening civil and political liberties and providing channels of access for previously marginalised groups. Clientelism is not necessarily a reflection of imposed power relations but, at times, can demonstrate a conscious political strategy, to generate development, on the part of its protagonists.IS

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition.

Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.This work was supported by the Medical Research Council (UK). S.F. was supported by a Herchel Smith Research Studentship and K.F. by an MRC Career Development Award. E.R.M is supported by the ERC Advanced Researcher award 323004–ONCOTREAT. P.H.M. is supported by Senior Investigator Awards from the Wellcome Trust and NIHR. The Cambridge Human Research Tissue Bank and A.W. are supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Nature Publishing at http://dx.doi.org/10.1038/nature19353

The microRNA body map : dissecting microRNA function through integrative genomics

While a growing body of evidence implicates regulatory miRNA modules in various aspects of human disease and development, insights into specific miRNA function remain limited. Here, we present an innovative approach to elucidate tissue-specific miRNA functions that goes beyond miRNA target prediction and expression correlation. This approach is based on a multi-level integration of corresponding miRNA and mRNA gene expression levels, miRNA target prediction, transcription factor target prediction and mechanistic models of gene network regulation. Predicted miRNA functions were either validated experimentally or compared to published data. The predicted miRNA functions are accessible in the miRNA bodymap, an interactive online compendium and mining tool of high-dimensional newly generated and published miRNA expression profiles. The miRNA bodymap enables prioritization of candidate miRNAs based on their expression pattern or functional annotation across tissue or disease subgroup. The miRNA bodymap project provides users with a single one-stop data-mining solution and has great potential to become a community resource

Slachtofferschap van geweldsdelicten onder universiteitsstudenten : de opstart van een cohorteonderzoek aan de Universiteit Gent

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Rationale, design and objectives of two phase III, randomised, placebo-controlled studies of GLPG1690, a novel autotaxin inhibitor, in idiopathic pulmonary fibrosis (ISABELA 1 and 2)

Introduction While current standard of care (SOC) for idiopathic pulmonary fibrosis (IPF) slows disease progression, prognosis remains poor. Therefore, an unmet need exists for novel, well-tolerated agents that reduce lung function decline and improve quality of life. Here we report the design of two phase III studies of the novel IPF therapy, GLPG1690. Methods and analysis Two identically designed, phase III, international, randomised, double-blind, placebocontrolled, parallel-group, multicentre studies (ISABELA 1 and 2) were initiated in November 2018. It is planned that, in each study, 750 subjects with IPF will be randomised 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or placebo, once daily, on top of local SOC, for at least 52 weeks. The primary endpoint is rate of decline of forced vital capacity (FVC) over 52 weeks. Key secondary endpoints are week 52 composite endpoint of disease progression or all-cause mortality (defined as composite endpoint of first occurrence of ≥10% absolute decline in per cent predicted FVC or all-cause mortality at week 52); time to first respiratory-related hospitalisation until end of study; and week 52 change from baseline in the St George’s Respiratory Questionnaire total score (a qualityof-life measure). Ethics and dissemination Studies will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peerreviewed publication. Trial registration numbers NCT03711162; NCT03733444