The Raf/MEK/ERK cascade is a therapeutic target in human cancers with deregulated Ras signaling, which includes tumours that have inactivated the Nf1 tumour suppressor1. Nf1 encodes neurofibromin, a GTPase activating protein that terminates Ras signalling by stimulating hydrolysis of Ras•GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed due to outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4, and Mapk14, which encodes p38α. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance.

Summary A prospective study was conducted to evaluate the impact of home enteral tube feeding on quality of life in 39 consecutive patients treated for head and neck or oesophageal cancer at the Centre François Baclesse in Caen, France. Patients were taken as their own controls. Quality of life was evaluated using the EORTC QLQ-C30 core questionnaire, and the EORTC H&N35 and OES24 specific questionnaires. The feeding technique tolerance was evaluated using a questionnaire specifically developed for this study. Two evaluations were made, the first a week after hospital discharge (n = 39) and the second 3 weeks later (n = 30). Overall, the global health status/quality of life scale score slightly improved; among symptoms, scale scores that significantly improved (P < 0.05) concerned constipation, coughing, social functioning and body image/sexuality. The physical feeding technique tolerance was acceptable while the technique was psychologically less tolerated with two-thirds of the patients longing to have the tube removed. One third of the patients was also uncomfortable about their body image. Home enteral tube feeding was responsible for not visiting family or close relations in 15% of patients, and not going out in public in 23%. We conclude that home enteral tube feeding is a physically well accepted technique although a substantial proportion of patients may experience psychosocial distress.

Although this study did not produce the outcomes desired, the literature supports a potential to use canines for human cancer detection. Better management of urine samples and a more stringent training protocol during our study may have provided new evidence as to the feasibility of using canines for cancer detection. A comparison of the 3 dog cancer scenting studies is also presented.

IntroductionCytogenetic abnormalities that arise frequently in cancer cells are starting points for identifying genes that initiate or cooperate in tumorigenesis. In the study of leukemia in particular, major advances have come from the cloning of genes located at translocation breakpoints. Most notably, these genes have included BCR, ABL, MLL, PML, RARA, AML1/ RUNX1, and CBF␤, 1 many of which have proven to be essential for normal hematopoiesis in addition to their involvement in cancer.Segmental deletions, such as those involving chromosome bands 5q31, 7q22, and 20q12, are also recurring leukemiaassociated genomic abnormalities. In contrast to translocations, however, much less is known about how the deletions influence tumorigenesis. It is hypothesized that the deleted intervals contain tumor suppressor genes (TSGs) and that the deletion of these genes deregulates cell division, survival, or differentiation. It is unclear, however, whether such deregulation occurs solely as a consequence of haploinsufficiency of the putative TSGs 2,3 or whether "second-hit" mutations that result in biallelic inactivation are required.Loss of chromosome 7 (monosomy 7) and deletion of a segment of the long arm [del(7q)] are recurring cytogenetic abnormalities in myeloid malignancies, including myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), therapy-associated leukemia, and leukemias that arises in the context of inherited predispositions such as Fanconi anemia or neurofibromatosis type 1. 4 Many of these myeloid malignancies are associated with resistance to current treatments and a poor prognosis. Cytogenetic analysis of patients with myeloid disorders characterized by a del(7q) has revealed frequent involvement of band q22, and fluorescence in situ hybridization (FISH) studies of cases with proximal or distal breakpoints within 7q22 defined a commonly deleted segment (CDS) spanning 2.5 Mb that is bounded by D7S1503 and D7S1841 5 .Molecular analysis of the 14 known genes within this interval has not uncovered either pathogenic mutations or epigenetic silencing. 6,7 Here, we focus on the function of the mouse homolog of MLL5, a candidate TSG that is located within the 7q22 CDS. 8 MLL5 is a member of the mammalian Trithorax Group (trxG) of genes, several of which have been implicated in cancer. Most notably, MLL is a frequent target of translocations in leukemia, with more than 40 different fusion partner genes described to date. 9 Inactivation of the mouse homologue of MLL blocks definitive hematopoiesis in mouse embryos 10,11 and compromises hematopoietic stem cell (HSC) function. 12,13 Little is known about the normal function of MLL5. The gene is active in multiple tissues, with prominent expression in the hematopoietic system. 8,14 Overexpression or small interfering RNA-mediated knockdown of MLL5 causes cell-cycle arrest in multiple cell lines, 15,16 and an MLL5-GFP fusion protein localizes to foci in the nuclei of transfected cells. 15 Consistent with a possible role in cell-cycle regulation, Mll5 was r...

In the course of developing an atlas and reference system for the normal human brain throughout the human age span from structural and functional brain imaging data, the International Consortium for Brain Mapping (ICBM) developed a set of "normal" criteria for subject inclusion and the associated exclusion criteria. The approach was to minimize inclusion of subjects with any medical disorders that could affect brain structure or function. In the past two years, a group of 1,685 potential subjects responded to solicitation advertisements at one of the consortium sites (UCLA). Subjects were screened by a detailed telephone interview and then had an in-person history and physical examination. Of those who responded to the advertisement and considered themselves to be normal, only 31.6% (532 subjects) passed the telephone screening process. Of the 348 individuals who submitted to in-person history and physical examinations, only 51.7% passed these screening procedures. Thus, only 10.7% of those individuals who responded to the original advertisement qualified for imaging. The most frequent cause for exclusion in the second phase of subject screening was high blood pressure followed by abnormal signs on neurological examination. It is concluded that the majority of individuals who consider themselves normal by self-report are found not to be so by detailed historical interviews about underlying medical conditions and by thorough medical and neurological examinations. Recommendations are made with regard to the inclusion of subjects in brain imaging studies and the criteria used to select them.Over the course of the last 100 years, there have been a number of attempts to develop atlases that describe human brain anatomy, both as an end in itself and also as a tool for organizing and referencing new neuroscience information [Talairach and Tournoux, 1988;Bailey and von Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroimage. Author manuscript; available in PMC 2010 February 1. Bonin, 1951;von Economo and Koskinas, 1925;Friston et al., 1994Friston et al., , 1995. These efforts have provided new and useful information for neuroscience research as well as for clinical applications. Nevertheless, the large and previously undefined variance of brain structure and function, across individuals in the population, limits the range of applications for past atlases. This is because the early atlases [Talairach and Tournoux, 1988;Bailey and von Bonin, 1951;von Economo and Koskinas, 1925;Brodmann, 1909] were based on the analysis of a single bra...