Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas

Germline mutations in the fumarate hydratase gene at 1q43 predispose to dominantly inherited skin and uterine leiomyomata and leiomyosarcomas. The enzyme, which is a component of the tricarboxylic acid cycle, acts as a tumour suppressor. To evaluate fumarate hydratase in respective sporadic tumours, we analysed a series of 26 leiomyosarcomas and 129 uterine leiomyomas (from 21 patients) for somatic mutations in fumarate hydratase and allelic imbalance around 1q43. None of the 26 leiomyosarcomas harboured somatic mutations in fumarate hydratase. Fifty per cent of leiomysarcomas tested showed evidence of allelic imbalance at 1q, but this was not confined to the vicinity of fumarate hydratase. Only 5% (seven out of 129) of the leiomyomas showed allele imbalance at 1q42-q43 and no somatic mutations in fumarate hydratase were observed. Our findings indicate that mutations in fumarate hydratase do not play a major role in the development of sporadic leiomyosarcomas or uterine leiomyomas

Conducting Science in Disasters: Recommendations from the NIEHS Working Group for Special IRB Considerations in the Review of Disaster Related Research.

Research involving human subjects after public health emergencies and disasters may pose ethical challenges. These challenges may include concerns about the vulnerability of prospective disaster research participants, increased research burden among disaster survivors approached by multiple research teams, and potentially reduced standards in the ethical review of research by institutional review boards (IRBs) due to the rush to enter the disaster field. The NIEHS Best Practices Working Group for Special IRB Considerations in the Review of Disaster Related Research was formed to identify and address ethical and regulatory challenges associated with the review of disaster research. The working group consists of a diverse collection of disaster research stakeholders across a broad spectrum of disciplines. The working group convened in July 2016 to identify recommendations that are instrumental in preparing IRBs to review protocols related to public health emergencies and disasters. The meeting included formative didactic presentations and facilitated breakout discussions using disaster-related case studies. Major thematic elements from these discussions were collected and documented into 15 working group recommendations, summarized in this article, that address topics such as IRB disaster preparedness activities, informed consent, vulnerable populations, confidentiality, participant burden, disaster research response integration and training, IRB roles/responsibilities, community engagement, and dissemination of disaster research results. https://doi.org/10.1289/EHP237

G1 checkpoint protein and p53 abnormalities occur in most invasive transitional cell carcinomas of the urinary bladder

The G1 cell cycle checkpoint regulates entry into S phase for normal cells. Components of the G1 checkpoint, including retinoblastoma (Rb) protein, cyclin D1 and p16INK4a, are commonly altered in human malignancies, abrogating cell cycle control. Using immunohistochemistry, we examined 79 invasive transitional cell carcinomas of the urinary bladder treated by cystectomy, for loss of Rb or p16INK4a protein and for cyclin D1 overexpression. As p53 is also involved in cell cycle control, its expression was studied as well. Rb protein loss occurred in 23/79 cases (29%); it was inversely correlated with loss of p16INK4a, which occurred in 15/79 cases (19%). One biphenotypic case, with Rb+p16– and Rb-p16+ areas, was identified as well. Cyclin D1 was overexpressed in 21/79 carcinomas (27%), all of which retained Rb protein. Fifty of 79 tumours (63%) showed aberrant accumulation of p53 protein; p53 staining did not correlate with Rb, p16INK4a, or cyclin D1 status. Overall, 70% of bladder carcinomas showed abnormalities in one or more of the intrinsic proteins of the G1 checkpoint (Rb, p16INK4a and cyclin D1). Only 15% of all bladder carcinomas (12/79) showed a normal phenotype for all four proteins. In a multivariate survival analysis, cyclin D1 overexpression was linked to less aggressive disease and relatively favourable outcome. In our series, Rb, p16INK4a and p53 status did not reach statistical significance as prognostic factors. In conclusion, G1 restriction point defects can be identified in the majority of bladder carcinomas. Our findings support the hypothesis that cyclin D1 and p16INK4a can cooperate to dysregulate the cell cycle, but that loss of Rb protein abolishes the G1 checkpoint completely, removing any selective advantage for cells that alter additional cell cycle proteins. © 1999 Cancer Research Campaig

Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

Why Parliament Now Decides on War: Tracing the Growth of the Parliamentary Prerogative through Syria, Libya and Iraq

Research Highlights and Abstract: Precedents set in debates over Iraq, Libya and Syria established a new parliamentary prerogative, that MPs must vote before military action can legitimately be launched. Tony Blair conceded the Iraq vote to shore up Labour back-bench support, because he was convinced he would win, and because he was unwilling to change course regardless. David Cameron allowed a vote on Libya because he believed parliament should have a say, because UN support meant he was certain to win, and to gain plaudits for not being Blair. Cameron then had to allow a vote on Syria despite its greater political sensitivity. He mishandled the vote, and lost, and felt constrained to pull out of mooted military action. Collectively these three precedents comprise a new constitutional convention, which will constrain the executive in future whether the law is formally changed or not. Parliament now decides when Britain goes to war. The vote against military intervention in Syria on 29 August 2013 upheld a new parliamentary prerogative that gradually developed through debates over earlier actions in Iraq and Libya. While the academic community and much of the British political elite continue to focus on the free rein granted to prime ministers by the historic royal prerogative, this article argues it is critically constrained by its parliamentary counterpart. It traces the way political conditions, individual policymaker preferences, and the conventional nature of the unwritten British constitution allowed parliament to insert itself into the policymaking process without the consent of successive governments. It concludes that MPs will in future expect the right to vote on proposals to deploy the armed forces overseas, and that the legitimacy of military action will depend on the government winning such a vote

Theotonio dos Santos (1936-2018), the revolutionary intellectual who pioneered dependency theory

This article analyzes the origins and development of the dependency theory through the life and work of Theotonio Dos Santos. His formative years at the academy and his early political activism in Brazil are examined, particularly, his time at the University of Brasilia with Vania Bambirra, Ruy Mauro Marini and André Gunder Frank ("the quartet"). This is followed by a discussion about their years of exile in Chile where the quartet regrouped at the Center for Socio-Economic Studies (ceso) of the University of Chile, and where they wrote their founding texts on dependency theory. Chile provided fertile ground for the development of this theory due to its intellectual climate, institutionality, and the country's political transformations in the late 1960s and early 1970s. The military overthrow of the Allende government on that fateful September 11th, 1973 forced the quartet once again into exile. The article continues with an analysis of Dos Santos' writings during his exile in Mexico and then back in Brazil. During this period he became involved with world system theory which culminated in the publication of his extensive trilogy on the contemporary crisis of capitalism and social theory

Mr. Greenthumb\u27s Garden

Investigations is a regular feature of the journal and highlights activities that develop conceptual understanding of mathematics topics