The role of noncoding mutations in blood cancers

The search for oncogenic mutations in haematological malignancies has largely focused on coding sequence variants. These variants have been critical in understanding these complex cancers in greater detail, ultimately leading to better disease monitoring, subtyping and prognostication. In contrast, the search for oncogenic variants in the noncoding genome has proven to be challenging given the vastness of the search space, the intrinsic difficulty in assessing the impact of variants that do not code for functional proteins, and our still primitive understanding of the function harboured by large parts of the noncoding genome. Recent studies have broken ground on this quest, identifying somatically acquired and recurrent mutations in the noncoding genome that activate the expression of proto-oncogenes. In this Review, we explore some of the best-characterised examples of noncoding mutations in haematological malignancies, and highlight how a significant majority of these variants impinge on gene regulation through the formation of aberrant enhancers and promoters. We delve into the challenges faced by those that embark on a search for noncoding driver mutations, and provide a framework distilled from studies that have successfully identified such variants to overcome some of the most salient hurdles. Finally, we discuss the current therapeutic strategies being explored to target the oncogenic mechanism supported by recurrent noncoding variants. We postulate that the continued discovery and functional characterisation of somatic variants in the noncoding genome will not only advance our understanding of haematological malignancies, but offer novel therapeutic avenues and provide important insights into transcriptional regulation on a broader scale

Therapeutic targeting of "undruggable" MYC

c-MYC controls global gene expression and regulates cell proliferation, cell differentiation, cell cycle, metabolism and apoptosis. According to some estimates, MYC is dysregulated in ≈70% of human cancers and strong evidence implicates aberrantly expressed MYC in both tumor initiation and maintenance. In vivo studies show that MYC inhibition elicits a prominent anti-proliferative effect and sustained tumor regression while any alteration on healthy tissue remains reversible. This opens an exploitable window for treatment that makes MYC one of the most appealing therapeutic targets for cancer drug development. This review describes the main functional and structural features of the protein structure of MYC and provides a general overview of the most relevant or recently identified interactors that modulate MYC oncogenic activity. This review also summarizes the different approaches aiming to abrogate MYC oncogenic function, with a particular focus on the prototype inhibitors designed for the direct and indirect targeting of MYC

Role of the Notch signalling pathway in acute leukaemia

The Notch signalling pathway is important in development and differentiation of a diverse range of both embryonic and adult tissues. There is now strong evidence implicating aberrant Notch signalling in the pathogenesis of T-cell acute lymphoblastic leukaemia (T-ALL), with over 50% of paediatric patients having activating mutations in NOTCH-1. This thesis aims to explore several aspects of the Notch pathway in both T-ALL and acute myeloid leukaemia (AML). Chapter one summarises the published data on the Notch signalling pathway itself, addressing the basic understanding of Notch activation through cell-to-cell interaction, as well as the mechanisms through which it is regulated. The role that Notch signaling plays in normal haematopoiesis is also discussed. Chapter three addresses the incidence and characteristics of NOTCH-1 mutations in a cohort of adult patients with T-ALL in comparison to the published study of paediatric T-ALL, as well as in a cohort of patients with infantile leukaemia and AML. Secondly, the prognostic significance of NOTCH-1 and FBXW7 mutation status of adult T-ALL patients treated on the UKALLXII was investigated. Thirdly, a novel mutation affecting the LNR domain of NOTCH-1 is reported. Chapter four includes data quantifying NOTCH-1 mutation level in T-ALL patients, as well as the stability of NOTCH-1 mutations at presentation and relapse. These data indicate NOTCH-1 mutations commonly occur as secondary events in leukaemia pathogenesis, and suggest widespread clonal heterogeneity in T-ALL. Chapter five explores the functional and prognostic consequences of a novel alternatively spliced isoform of the CSL transcription factor in AML, which was termed CSL-TREX (for TRuncates Exon X). The functional consequences of expressing CSL-TREX in CD34+ cells, in luciferase reporter assays and co-immunoprecipitation experiments with NOTCH-1 is reported. Chapter six summarises the overall implications of these findings to T-ALL and AML, and the future directions of research in this area

The role of intraoperative ultrasound in the assessment of hepatic deposits in intra-abdominal malignancies

Introduction/backgroundThe liver is the most common site of metastatic disease with up to 40-50% of all cancers having the potentiality for sending liver metastasis during the disease. Consequently, there has been increasing value for surgical resection of hepatic deposits of different types of cancers. The need for accurate evaluation of the extent of hepatic metastasis was established for choosing the most suitable patients for surgery and in planning the extent of hepatic resection.AimThe aim of this study was to evaluate the role of intraoperative ultrasound (IOUS) in the detection of hepatic deposits in intra-abdominal malignancies with special emphasis on its accuracy, sensitivity, and specificity.Patients and methodsThis study was carried out on 30 patients who were admitted to the Gastrointestinal Surgery Unit, Main Alexandria University Hospital, with intra-abdominal malignancies for whom elective open surgical intervention was recommended in the period from 1 September 2017 till the 31 March 2018.ResultsThis study consisted of 17 (56.7%) men and 13 (43.3%) women. Their mean age at admission was 52.77 +/- 9.12 years. Six (20%) of the included patients were found to have hepatic lesions by using IOUS including the four (13.3%) cases already detected by preoperative imaging. Two (6.67%) cases were newly discovered in the operative room by using IOUS.ConclusionThis study has proved that IOUS demonstrates superior lesion detection over the various noninvasive preoperative imaging modalities causing significant impact on change of the planned surgical strategy

The Falling Dollar and Its Impact on the Saudi Economy

As foreign exchange studies show, after a fairly strong performance in 2014, the US Dollar (USD) plunged in 2015 in relation to the Euro, British Pound, Japanese Yen, and other global currencies (US Forex 2015). While the trend on US currency fall similarly happened in the past, the weak global confidence now on the US economy has cast serious apprehension on the prospect for any renewed global economic stability. Whenever the USD, as central world currency, declines or appreciates significantly in value, the change impacts the economies of most nations around the world (Amadeo 2015).  One of the countries that stand most vulnerable to any serious and unwanted dysfunction of the USD is Saudi Arabia, which, as a matter of key economic policy, has fixed its currency exchange to Saudi Arabia Riyals (SAR) 3.75 to USD 1.00 since 1986 (Al-Hamidy 2013).  This paper aims at Highlighting the risks of devaluation of the dollar on the Saudi economy There are seven sections in the paper after the introduction. In sections two The changing price of gold and oil in term of USD…; section three The Impacts of fixed exchange rate on the Saudi Economy …;The rationale and implication for the fixed rate,  Policy measures to overcome the risk caused by the depreciation of USD…Possible Policy Options in the Short…, and in the last section Concluding Remarks…

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Journal ArticleThe technology of modifying endogenous genes has recently been extended from mice to Drosophila and sheep. Concurrently, genomic sequencing is uncovering thousands of previously uncharacterized genes. Armed with today's technologies, what are our best options for delineating the functions of these new genes

Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1’s role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical “developmental tumor”, NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation