Identification and pharmacological inactivation of the MYCN gene network as a therapeutic strategy for neuroblastic tumor cells

This research was originally published in Journal of Biological Chemistry. Olesya Chayka, Cosimo Walter D’Acunto, Odette Middleton, Maryam Arab, and Arturo Sala. Identification and Pharmacological Inactivation of the MYCN Gene Network as a Therapeutic Strategy for Neuroblastic Tumor Cells. Journal of Biological Chemistry. 2015; Vol 290 (4) :pp. 2198 - 2212. © the American Society for Biochemistry and Molecular Biology.This article has been made available through the Brunel Open Access Publishing Fund.The MYC family of transcription factors consists of three well characterized members, c-MYC, L-MYC, and MYCN, deregulated in the majority of human cancers. In neuronal tumors such as neuroblastoma, MYCN is frequently activated by gene amplification, and reducing its expression by RNA interference has been shown to promote growth arrest and apoptosis of tumor cells. From a clinical perspective, RNA interference is not yet a viable option, and small molecule inhibitors of transcription factors are difficult to develop. We therefore planned to identify, at the global level, the genes interacting functionally with MYCN required to promote fitness of tumor cells facing oncogenic stress. To find genes whose inactivation is synthetically lethal to MYCN, we implemented a genome-wide approach in which we carried out a drop-out shRNA screen using a whole genome library that was delivered into isogenic neuroblastoma cell lines expressing or not expressing MYCN. After the screen, we selected for in-depth analysis four shRNAs targeting AHCY, BLM, PKMYT1, and CKS1B. These genes were chosen because they are directly regulated by MYC proteins, associated with poor prognosis of neuroblastoma patients, and inhibited by small molecule compounds. Mechanistically, we found that BLM and PKMYT1 are required to limit oncogenic stress and promote stabilization of the MYCN protein. Cocktails of small molecule inhibitors of CKS1B, AHCY, BLM, and PKMYT1 profoundly affected the growth of all neuroblastoma cell lines but selectively caused death of MYCN-amplified cells. Our findings suggest that drugging the MYCN network is a promising avenue for the treatment of high risk, neuroblastic cancers.SPARKS and the Neuroblastoma Society

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic alteration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours with concordant deletion in the 4 most involved loci (3p21, 5q11–13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours without deletions at the corresponding loci (P< 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11–13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations. © 2001 Cancer Research Campaign http://www.bjcancer.co

Performance evaluation of selected infiltration equations for irrigated (FADAMA) soils in Southern Kaduna Plain, Nigeria

ABSTRACT The need for continuous and in-depth study on the applicability and accuracy of infiltration equations cannot be exhausted since equation parameters and performance vary for different soils. The study reported herein, has evaluated four infiltration equations (Kostiakov&apos;s; Philip&apos;s; Horton; Talsma and Parlange). The field water infiltration data used in these equations were based on double ring infiltrometer tests conducted for 4 hours at two fadama irrigation area (Kuda and Kukumdaji). Measurements were made at two sites in each of the two Fadama irrigation area based on land management practice (Cultivated/fallow) giving a total of four experimental sites. The results of the measured infiltration rates reveals that site 2 (Kuda/fallow) gave the highest average final infiltration rate of 69mm/hr followed by site 1(Kuda/cultivated) of value 52mm/hr and then site 3(Kukumdaji/cultivated) of value 35mm/hr while site 4 (Kukumdaji/fallow) recorded the least of 18mm/hr. Results of the Comparism between measured and predicted infiltration rates reveal that Kostiakov&apos;s and Philip&apos;s equation gives the best fit when compared with the rest of the equations tested. Results from the study conclude that Kostiakov&apos;s and Philip&apos;s equation can be used to predict infiltration rates for the soil studied but that Kostiakov&apos;s equation approximated the measured infiltration rates with higher accuracy and best fit than did Philip&apos;s and Horton&apos;s equation. Talsma and Parlange&apos;s equation fail to approximate measured data particularly in the early stage of measurement

Physical structure of the photodissociation regions in NGC 7023: Observations of gas and dust emission with <i>Herschel</i>

The determination of the physical conditions in molecular clouds is a key step towards our understanding of their formation and evolution of associated star formation. We investigate the density, temperature, and column density of both dust and gas in the photodissociation regions (PDRs) located at the interface between the atomic and cold molecular gas of the NGC 7023 reflection nebula. We study how young stars affect the gas and dust in their environment. Our approach combining both dust and gas delivers strong constraints on the physical conditions of the PDRs. We find dense and warm molecular gas of high column density in the PDRs

Awareness of cognitive decline trajectories in asymptomatic individuals at risk for AD

Background: Lack of awareness of cognitive decline (ACD) is common in late-stage Alzheimer’s disease (AD). Recent studies showed that ACD can also be reduced in the early stages. Methods: We described different trends of evolution of ACD over 3 years in a cohort of memory-complainers and their association to amyloid burden and brain metabolism. We studied the impact of ACD at baseline on cognitive scores’ evolution and the association between longitudinal changes in ACD and in cognitive score. Results: 76.8% of subjects constantly had an accurate ACD (reference class). 18.95% showed a steadily heightened ACD and were comparable to those with accurate ACD in terms of demographic characteristics and AD biomarkers. 4.25% constantly showed low ACD, had significantly higher amyloid burden than the reference class, and were mostly men. We found no overall effect of baseline ACD on cognitive scores’ evolution and no association between longitudinal changes in ACD and in cognitive scores. Conclusions: ACD begins to decrease during the preclinical phase in a group of individuals, who are of great interest and need to be further characterized. Trial registration: The present study was conducted as part of the INSIGHT-PreAD study. The identification number of INSIGHT-PreAD study (ID-RCB) is 2012-A01731-42

Combined cytogenetic and molecular methods for taxonomic verification and description of Brassica populations deriving from different origins

Agriculture faces great challenges to overcome global warming and improve system sustainability, requiring access to novel genetic diversity. So far, wild populations and local landraces remain poorly explored. This is notably the case for the two diploid species, Brassica oleracea L. (CC, 2n=2x=18) and B. rapa L. (AA, 2n=2x=20). In order to explore the genetic diversity in both species, we have collected populations in their centre of origin, the Mediterranean basin, on a large contrasting climatic and soil gradient from northern Europe to southern sub-Saharan regions. In these areas, we also collected 14 populations belonging to five B. oleracea closely related species. Our objective was to ensure the absence of species misidentification at the seedling stage among the populations collected and to describe thereafter their origins. We combined flow cytometry, sequencing of a species-specific chloroplast genomic region, as well as cytogenetic analyses in case of unexpected results for taxonomic verification. Out of the 112 B. oleracea and 154 B. rapa populations collected, 103 and 146, respectively, presented a good germination rate and eighteen populations were misidentified. The most frequent mistake was the confusion of these diploid species with B. napus. Additionally for B. rapa, two autotetraploid populations were observed. Habitats of the collected and confirmed wild populations and landraces are described in this study. The unique plant material described here will serve to investigate the genomic regions involved in adaptation to climate and microbiota within the framework of the H2020 Prima project ‘BrasExplor’

Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease

Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD)

Intrathoracic solitary fibrous tumor - an international multicenter study on clinical outcome and novel circulating biomarkers

Intrathoracic solitary fibrous tumor (SFT) is a rare disease. Radical resection is the standard of care. However, estimating prognosis and planning follow-up and treatment strategies remains challenging. Data were retrospectively collected by five international centers to explore outcome and biomarkers for predicting event-free-survival (EFS). 125 histological proven SFT patients (74 female; 59.2%; 104 benign; 83.2%) were analyzed. The one-, three-, five- and ten-year EFS after curative-intent surgery was 98%, 90%, 77% and 67%, respectively. Patients age (>/=59 vs. 10 cm vs. 5 vs. < 5 HR 3.91, CI 1.40-10.89, p = 0.009) were prognostic after univariate analyses. After multivariate analyses tumor-dignity and fibrinogen remained as independent prognosticators. Besides validating the role of age, tumor-dignity, tumor-size, stage and resection margins, we identified for the first time inflammatory markers as prognosticators in SFT