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1.  Signatures of mutational processes in human cancer 
Alexandrov, Ludmil B. | Nik-Zainal, Serena | Wedge, David C. | Aparicio, Samuel A.J.R. | Behjati, Sam | Biankin, Andrew V. | Bignell, Graham R. | Bolli, Niccolo | Borg, Ake | Børresen-Dale, Anne-Lise | Boyault, Sandrine | Burkhardt, Birgit | Butler, Adam P. | Caldas, Carlos | Davies, Helen R. | Desmedt, Christine | Eils, Roland | Eyfjörd, Jórunn Erla | Foekens, John A. | Greaves, Mel | Hosoda, Fumie | Hutter, Barbara | Ilicic, Tomislav | Imbeaud, Sandrine | Imielinsk, Marcin | Jäger, Natalie | Jones, David T.W. | Jones, David | Knappskog, Stian | Kool, Marcel | Lakhani, Sunil R. | López-Otín, Carlos | Martin, Sancha | Munshi, Nikhil C. | Nakamura, Hiromi | Northcott, Paul A. | Pajic, Marina | Papaemmanuil, Elli | Paradiso, Angelo | Pearson, John V. | Puente, Xose S. | Raine, Keiran | Ramakrishna, Manasa | Richardson, Andrea L. | Richter, Julia | Rosenstiel, Philip | Schlesner, Matthias | Schumacher, Ton N. | Span, Paul N. | Teague, Jon W. | Totoki, Yasushi | Tutt, Andrew N.J. | Valdés-Mas, Rafael | van Buuren, Marit M. | van ’t Veer, Laura | Vincent-Salomon, Anne | Waddell, Nicola | Yates, Lucy R. | Zucman-Rossi, Jessica | Futreal, P. Andrew | McDermott, Ultan | Lichter, Peter | Meyerson, Matthew | Grimmond, Sean M. | Siebert, Reiner | Campo, Elías | Shibata, Tatsuhiro | Pfister, Stefan M. | Campbell, Peter J. | Stratton, Michael R.
Nature  2013;500(7463):415-421.
All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy.
doi:10.1038/nature12477
PMCID: PMC3776390  PMID: 23945592
2.  The Alien Limb Phenomenon 
Journal of neurology  2013;260(7):1880-1888.
Background
Alien limb phenomenon refers to involuntary motor activity of a limb in conjunction with the feeling of estrangement from that limb. Alien limb serves as a diagnostic feature of corticobasal syndrome.
Objective
Our objective was to determine the differential diagnoses of alien limb and to determine the features in a large group of patients with the alien limb with different underlying etiologies.
Methods
We searched the Mayo Clinic Medical Records Linkage system to identify patients with the diagnosis of alien limb seen between January 1, 1996, and July 11, 2011.
Results
One hundred fifty patients with alien limb were identified. Twenty two were followed in the Alzheimer’s Disease Research Center. Etiologies of alien limb included corticobasal syndrome (n=108), stroke (n=14), Creutzfeldt Jacob disease (n=9), Hereditary diffuse leukoencephalopathy with spheroids (n=5), tumor (n=4), progressive multifocal leukoencephalopathy(n=2), demyelinating disease (n=2), progressive dementia not otherwise specified (n=2), posterior reversible encephalopathy syndrome (n=1), corpus callosotomy (n=1), intracerebral hemorrhage (n=1) and thalamic dementia (n=1). Ten of fourteen cerebrovascular cases were right hemisphere in origin. All cases involved the parietal lobe. Of the 44 patients with corticobasal syndrome from the Alzheimer’s Disease Research Center cohort, 22 had alien limb, and 73% had the alien limb affecting the left extremities. Left sided corticobasal syndrome was significantly associated with the presence of alien limb (p=0.004).
Conclusions
These findings support the notion that the alien limb phenomenon is partially related to damage underlying the parietal cortex, especially the right parietal, disconnecting it from other cortical areas.
doi:10.1007/s00415-013-6898-y
PMCID: PMC3914666  PMID: 23572346
Alien limb; corticobasal syndrome
3.  Juxtaposition of chemical and mutation- induced developmental defects in zebrafish reveal a novel copper-chelating activity for kalihinol F 
Chemistry & biology  2013;20(6):753-763.
SUMMARY
A major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically-induced phenotypes with potential genetic parallels. Specifically, kalihinol F caused an undulated notochord, defects in pigment formation, hematopoiesis and neural development. These phenotypes were strikingly similar to the zebrafish mutant, calamity, an established model of copper deficiency. Further studies into the mechanism of action of kalihinol F revealed a novel copper chelating activity. Our data support a novel mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying new therapeutics and target pathways.
doi:10.1016/j.chembiol.2013.05.008
PMCID: PMC3715381  PMID: 23790486
zebrafish; chemical screen; kalihinol F; copper; notochord
4.  Expression of integrin α3β1 and cyclooxygenase-2 (COX2) are positively correlated in human breast cancer 
BMC Cancer  2014;14:459.
Background
Expression of integrin α3β1 is associated with tumor progression, metastasis, and poor prognosis in several cancers, including breast cancer. Moreover, preclinical studies have revealed important pro-tumorigenic and pro-metastatic functions for this integrin, including tumor growth, survival, invasion, and paracrine induction of angiogenesis. Our previously published work in a preclinical breast cancer model showed that integrin α3β1 promotes expression of cyclooxygenase-2 (COX2/PTGS2), a known driver of breast cancer progression. However, the clinical significance of this regulation was unknown. The objective of the current study was to assess the clinical relevance of the relationship between integrin α3β1 and COX2 by testing for their correlated expression among various forms of human breast cancer.
Methods
Immunohistochemistry was performed to assess co-expression of α3 and COX2 in specimens of human invasive ductal carcinoma (IDC), either on a commercial tissue microarray (n = 59 samples) or obtained from Albany Medical Center archives (n = 68 samples). Immunostaining intensity for the integrin α3 subunit or COX2 was scored, and Spearman’s rank correlation coefficient analysis was performed to assess their co-expression across and within different tumor subtypes or clinicopathologic criteria.
Results
Although expression of integrin α3 or COX2 varied among clinical IDC samples, a statistically significant, positive correlation was detected between α3 and COX2 in both tissue microarrays (rs = 0.49, p < 0.001, n = 59) and archived samples (rs = 0.59, p < 0.0001, n = 68). In both sample sets, this correlation was independent of hormone receptor status, histological grade, or disease stage.
Conclusions
COX2 and α3 are correlated in IDC independently of hormone receptor status or other clinicopathologic features, supporting the hypothesis that integrin α3β1 is a determinant of COX2 expression in human breast cancer. These results support the clinical relevance of α3β1-dependent COX2 gene expression that we reported previously in breast cancer cells. The findings also suggest that COX2-positive breast carcinomas of various subtypes might be vulnerable to therapeutic strategies that target α3β1, and that α3 expression might serve as an independent prognostic biomarker.
doi:10.1186/1471-2407-14-459
PMCID: PMC4069347  PMID: 24950714
Integrin α3β1; COX2; PTGS2; Breast cancer; Invasive ductal carcinoma
5.  Development of a Pfs25-EPA malaria transmission blocking vaccine as a chemically conjugated nanoparticle 
Vaccine  2013;31(28):2954-2962.
Successful efforts to control infectious diseases have often required the use of effective vaccines. The current global strategy for control of malaria, including elimination and eradication will also benefit from the development of an effective vaccine that interrupts malaria transmission. To this end, a vaccine that disrupts malaria transmission within the mosquito host has been investigated for several decades targeting a 25 kDa ookinete specific surface protein, identified as Pfs25. Phase 1 human trial results using a recombinant Pfs25H/Montanide ISA51 formulation demonstrated that human Pfs25 specific antibodies block parasite infectivity to mosquitoes; however, the extent of blocking was likely insufficient for an effective transmission blocking vaccine. To overcome the poor immunogenicity, processes to produce and characterize recombinant Pfs25H conjugated to a detoxified form of Pseudomonas aeruginosa exoprotein A (EPA) have been developed and used to manufacture a cGMP pilot lot for use in human clinical trials. The Pfs25-EPA conjugate appears as a nanoparticle with an average molar mass in solution of approximately 600 kDa by static light scattering with an average diameter 20 nm (range 10 to 40 nm) by dynamic light scattering. The molar ratio of Pfs25H to EPA is about 3 to 1 by amino acid analysis, respectively. Outbred mice immunized with the Pfs25-EPA conjugated nanoparticle formulated on Alhydrogel® had a 75 to 110 fold increase in Pfs25H specific antibodies when compared to an unconjugated Pfs25H/Alhydrogel® formulation. A phase 1 human trial using the Pfs25-EPA/Alhydrogel® formulation is ongoing in the United States.
doi:10.1016/j.vaccine.2013.04.034
PMCID: PMC3683851  PMID: 23623858
Pfs25; malaria; transmission blocking vaccine; nanoparticle; chemical-conjugate; recombinant protein
6.  Fever of unknown origin: a rare retroperitoneal cause 
BMJ Case Reports  2012;2012:bcr0320126122.
The authors present a patient with fever of unknown origin and vague loin pain. Baseline investigations revealed elevated inflammatory markers and imaging eventually identified a renal mass. Radical nephrectomy was performed at a collaborative surgical list involving both the urology and vascular surgical teams. Histological examination confirmed a retroperitoneal paraganglioma and the patient made a rapid recovery and remains well at follow-up. This case draws attention to the rare diagnosis of retroperitoneal paraganglioma and the potential for diagnostic delay. Furthermore, the vital multi-disciplinary approach to the optimum management of patients with such tumours is highlighted.
doi:10.1136/bcr.03.2012.6122
PMCID: PMC3387458  PMID: 22707686
7.  Distinguishing between Exploratory and Confirmatory Preclinical Research Will Improve Translation 
PLoS Biology  2014;12(5):e1001863.
Kimmelman and colleagues argue that the key to improving preclinical research lies in distinguishing between two different modes of research: exploratory vs. confirmatory.
Preclinical researchers confront two overarching agendas related to drug development: selecting interventions amid a vast field of candidates, and producing rigorous evidence of clinical promise for a small number of interventions. We suggest that each challenge is best met by two different, complementary modes of investigation. In the first (exploratory investigation), researchers should aim at generating robust pathophysiological theories of disease. In the second (confirmatory investigation), researchers should aim at demonstrating strong and reproducible treatment effects in relevant animal models. Each mode entails different study designs, confronts different validity threats, and supports different kinds of inferences. Research policies should seek to disentangle the two modes and leverage their complementarity. In particular, policies should discourage the common use of exploratory studies to support confirmatory inferences, promote a greater volume of confirmatory investigation, and customize design and reporting guidelines for each mode.
doi:10.1371/journal.pbio.1001863
PMCID: PMC4028181  PMID: 24844265
8.  Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort 
Acta Neuropathologica  2014;128:137-149.
This study aimed to prospectively evaluate clinical, histopathological and molecular variables for outcome prediction in medulloblastoma patients. Patients from the HIT2000 cooperative clinical trial were prospectively enrolled based on the availability of sufficient tumor material and complete clinical information. This revealed a cohort of 184 patients (median age 7.6 years), which was randomly split at a 2:1 ratio into a training (n = 127), and a test (n = 57) dataset in order to build and test a risk score for this population. Independent validation was performed in a non-overlapping cohort (n = 83). All samples were subjected to thorough histopathological investigation, CTNNB1 mutation analysis, quantitative PCR, MLPA and FISH analyses for cytogenetic variables, and methylome analysis. By univariable analysis, clinical factors (M-stage), histopathological variables (large cell component, endothelial proliferation, synaptophysin pattern), and molecular features (chromosome 6q status, MYC amplification, subgrouping) were found to be prognostic. Molecular consensus subgrouping (WNT, SHH, Group 3, Group 4) was validated as an independent feature to stratify patients into different risk groups. When comparing methods for the identification of WNT-driven medulloblastoma, this study identified CTNNB1 sequencing and methylation profiling to most reliably identify these patients. After removing patients with particularly favorable (CTNNB1 mutation, extensive nodularity) or unfavorable (MYC amplification) markers, a risk score for the remaining “intermediate molecular risk” population dependent on age, M-stage, pattern of synaptophysin expression, and MYCN copy-number status was identified, with speckled synaptophysin expression indicating worse outcome. Test and independent validation of the score confirmed significant discrimination of patients by risk profile. Methylation subgrouping and CTNNB1 mutation status represent robust tools for the risk stratification of medulloblastoma. A simple clinico-pathological risk score was identified, which was confirmed in a test set and by independent clinical validation.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1276-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-014-1276-0
PMCID: PMC4059991  PMID: 24791927
Medulloblastoma; Biomarker; Risk stratification; Prospective; Clinical trial cohort; Methylation profiling
9.  Is This Cell a Human Being? 
The Linacre Quarterly  2013;80(2):186-189.
doi:10.1179/0024363913Z.00000000018
PMCID: PMC4018015
10.  Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge 
Nature reviews. Cancer  2014;14(2):92-107.
Preface
We have extended our understanding of the molecular biology underlying adult glioblastoma over many years. In contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and revealed deeper insights into gliomagenesis across all age groups, highlighting key distinctions, but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.
doi:10.1038/nrc3655
PMCID: PMC4003223  PMID: 24457416
11.  A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis 
BMJ Open  2014;4(4):e004552.
Objective
The current pathological diagnostic criteria for sporadic inclusion body myositis (IBM) lack sensitivity. Using immunohistochemical techniques abnormal protein aggregates have been identified in IBM, including some associated with neurodegenerative disorders. Our objective was to investigate the diagnostic utility of a number of markers of protein aggregates together with mitochondrial and inflammatory changes in IBM.
Design
Retrospective cohort study. The sensitivity of pathological features was evaluated in cases of Griggs definite IBM. The diagnostic potential of the most reliable features was then assessed in clinically typical IBM with rimmed vacuoles (n=15), clinically typical IBM without rimmed vacuoles (n=9) and IBM mimics—protein accumulation myopathies containing rimmed vacuoles (n=7) and steroid-responsive inflammatory myopathies (n=11).
Setting
Specialist muscle services at the John Radcliffe Hospital, Oxford and the National Hospital for Neurology and Neurosurgery, London.
Results
Individual pathological features, in isolation, lacked sensitivity and specificity. However, the morphology and distribution of p62 aggregates in IBM were characteristic and in a myopathy with rimmed vacuoles, the combination of characteristic p62 aggregates and increased sarcolemmal and internal major histocompatibility complex class I expression or endomysial T cells were diagnostic for IBM with a sensitivity of 93% and specificity of 100%. In an inflammatory myopathy lacking rimmed vacuoles, the presence of mitochondrial changes was 100% sensitive and 73% specific for IBM; characteristic p62 aggregates were specific (91%), but lacked sensitivity (44%).
Conclusions
We propose an easily applied diagnostic algorithm for the pathological diagnosis of IBM. Additionally our findings support the hypothesis that many of the pathological features considered typical of IBM develop later in the disease, explaining their poor sensitivity at disease presentation and emphasising the need for revised pathological criteria to supplement the clinical criteria in the diagnosis of IBM.
doi:10.1136/bmjopen-2013-004552
PMCID: PMC4010816  PMID: 24776709
Neurology
12.  Inhibition of Breast Cancer Metastasis Suppressor 1 Promotes a Mesenchymal Phenotype in Lung Epithelial Cells That Express Oncogenic K-RasV12 and Loss of p53 
PLoS ONE  2014;9(4):e95869.
Expression of the breast cancer metastasis suppressor 1 (BRMS1) protein is dramatically reduced in non-small cell lung cancer (NSCLC) cells and in primary human tumors. Although BRMS1 is a known suppressor of metastasis, the mechanisms through which BRMS1 functions to regulate cell migration and invasion in response to specific NSCLC driver mutations are poorly understood. To experimentally address this, we utilized immortalized human bronchial epithelial cells in which p53 was knocked down in the presence of oncogenic K-RasV12 (HBEC3-p53KD-K-RasV12). These genetic alterations are commonly found in NSCLC and are associated with a poor prognosis. To determine the importance of BRMS1 for cytoskeletal function, cell migration and invasion in our model system we stably knocked down BRMS1. Here, we report that loss of BRMS1 in HBEC3-p53KD-K-RasV12 cells results in a dramatic increase in cell migration and invasion compared to controls that expressed BRMS1. Moreover, the loss of BRMS1 resulted in additional morphological changes including F-actin re-distribution, paxillin accumulation at the leading edge of the lamellapodium, and cellular shape changes resembling mesenchymal phenotypes. Importantly, re-expression of BRMS1 restores, in part, cell migration and invasion; however it does not fully reestablish the epithelial phenotype. These finding suggests that loss of BRMS1 results in a permanent, largely irreversible, mesenchymal phenotype associated with increased cell migration and invasion. Collectively, in NSCLC cells without p53 and expression of oncogenic K-Ras our study identifies BRMS1 as a key regulator required to maintain a cellular morphology and cytoskeletal architecture consistent with an epithelial phenotype.
doi:10.1371/journal.pone.0095869
PMCID: PMC3999110  PMID: 24763730
13.  Using Debate to Teach Pharmacy Students About Ethical Issues 
Objective. To create, implement, and evaluate debate as a method of teaching pharmacy undergraduate students about ethical issues.
Design. Debate workshops with 5 hours of contact with student peers and facilitators and 5 hours of self-study were developed for second-year pharmacy students. Student development of various skills and understanding of the topic were assessed by staff members and student peers.
Assessment. One hundred fifty students completed the workshops. The mean score for debating was 25.9 out of 30, with scores ranging from 23.2 to 28.7. Seventy percent of students agreed that the debates were a useful teaching method in the degree program.
Conclusion. A series of workshops using debates effectively delivered course content on ethical issues and resulted in pharmacy students developing skills such as teamwork, peer assessment, communication, and critical evaluation. These findings suggest that pharmacy students respond favorably to a program using debates as a teaching tool.
doi:10.5688/ajpe78357
PMCID: PMC3996389  PMID: 24761018
communication skills; critical evaluation; debate; ethics; team-based learning
14.  In Vivo DPP-4 Inhibition to Enhance Engraftment of Single-Unit Cord Blood Transplants in Adults with Hematological Malignancies 
Stem Cells and Development  2012;22(7):1007-1015.
Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21–58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days −1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5–5.2)×107/kg, engrafted at median of 21 (range, 13–50) days with cumulative incidence of 94% (95% confidence interval, 84%–100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6,000 activity·h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had 10-fold lower colony forming units after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome.
doi:10.1089/scd.2012.0636
PMCID: PMC3607909  PMID: 23270493
15.  Epigenetic regulation of colon cancer and intestinal stem cells 
Current opinion in cell biology  2013;25(2):177-183.
Summary
The importance and role of the cellular epigenome in cell fating and development has been studied for decades. The epigenome encompasses a range of attributes including DNA methylation, histone modifications, and chromatin remodelers; together these components define the cellular transcriptome, identity, and function. The cellular epigenome is dynamic in response to environmental signals, modifiable during normal cell differentiation and is heritable in daughter cells. This plasticity, however, poses a risk for misregulation and may underlie a number of hereditary disorders, development defects, and cancer. Although the first epigenetic change described in cancer was gene hypomethylation [1,2], we know that cancers display global hypomethylation, as well as, site-specific gene hypermethylation in addition to changes in chromatin modifications. Mechanisms explaining the sometimes paradoxical epigenetic changes observed in cancer, their contributions to tumor initiation and progression and how epigenetics relate to genetic events are poorly understood. In this review we will briefly discuss recent findings on the epigenomic states observed in colon cancer, in particular, how perturbations to the genome and epigenome together may contribute to initiation and progression of colon cancer.
doi:10.1016/j.ceb.2013.01.007
PMCID: PMC3615052  PMID: 23402869
16.  Small-Molecule Inhibition of the uPAR·uPA Interaction: Synthesis, Biochemical, Cellular, in vivo Pharmacokinetics and Efficacy Studies in Breast Cancer Metastasis 
Bioorganic & medicinal chemistry  2013;21(7):2145-2155.
The uPAR·uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR·uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to uPAR with sub-micromolar affinity of 0.2 μM. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration-dependent manner. 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5 hours and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10 hours. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy.
doi:10.1016/j.bmc.2012.12.047
PMCID: PMC3625246  PMID: 23411397
17.  RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia 
Nature genetics  2014;46(2):116-125.
The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction; ~30-fold enrichment at promoters and enhancers of genes actively transcribed in B-cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single cell tracking shows that this mechanism is active throughout leukemic evolution with evidence of localized clustering and re-iterated deletions. Integration of point mutation and rearrangement data identifies ATF7IP and MGA as two new tumor suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B-cell differentiation.
doi:10.1038/ng.2874
PMCID: PMC3960636  PMID: 24413735
18.  Increased cardiovascular risk factors in breast cancer survivors identified by routine measurements of body composition, resting heart rate and arterial blood pressure 
SpringerPlus  2014;3:150.
Purpose
The main objective of this prospective study was to obtain a better understanding of the body composition and vital sign measures of cancers survivors (CS) when compared to regular (R) patients.
Methods
A total of 9,315 female patients were evaluated: 476 CS and 8,839 R patients. Kinesiologists worked side by side with the medical/oncology team to collect a number of base-line measurements on body composition, resting heart rate, and blood pressure as part of the standard intake evaluation during the female patients’ annual checkup.
Results
CS were more likely to have a higher BMI (P = 0.001) and a larger waist circumference (P = 0.001) than R patients. CS were also shown to have higher blood pressure values: diastolic pressure of 76.9 mmHg ± 10.5 VS 75.5 mmHg ± 9.9, (P = 0.01) and systolic pressure of 129.8 mmHg ± 17.2 VS 126.7 mmHg ±17.4 (P = 0.001) compared to R patients, respectively. Regression analysis looking at the relationship between mean arterial pressure and waist circumference did not show any difference between the two groups (CS vs R).
Conclusion
CS who had a higher BMI, a larger waist circumference and higher blood pressure levels, are probably at greater risk for developing cardiovascular disease, diabetes, various musculoskeletal problems as well as an increased risk for various forms of cancers including reoccurrence of previously treated cancer when compared to R patients. Changes in body composition should be considered by the medical team when looking at preventative healthcare strategies for their CS patients.
doi:10.1186/2193-1801-3-150
PMCID: PMC4002997  PMID: 24790808
Breast cancer; Waist circumference; Blood pressure
19.  De Novo Structure Prediction of Globular Proteins Aided by Sequence Variation-Derived Contacts 
PLoS ONE  2014;9(3):e92197.
The advent of high accuracy residue-residue intra-protein contact prediction methods enabled a significant boost in the quality of de novo structure predictions. Here, we investigate the potential benefits of combining a well-established fragment-based folding algorithm – FRAGFOLD, with PSICOV, a contact prediction method which uses sparse inverse covariance estimation to identify co-varying sites in multiple sequence alignments. Using a comprehensive set of 150 diverse globular target proteins, up to 266 amino acids in length, we are able to address the effectiveness and some limitations of such approaches to globular proteins in practice. Overall we find that using fragment assembly with both statistical potentials and predicted contacts is significantly better than either statistical potentials or contacts alone. Results show up to nearly 80% of correct predictions (TM-score ≥0.5) within analysed dataset and a mean TM-score of 0.54. Unsuccessful modelling cases emerged either from conformational sampling problems, or insufficient contact prediction accuracy. Nevertheless, a strong dependency of the quality of final models on the fraction of satisfied predicted long-range contacts was observed. This not only highlights the importance of these contacts on determining the protein fold, but also (combined with other ensemble-derived qualities) provides a powerful guide as to the choice of correct models and the global quality of the selected model. A proposed quality assessment scoring function achieves 0.93 precision and 0.77 recall for the discrimination of correct folds on our dataset of decoys. These findings suggest the approach is well-suited for blind predictions on a variety of globular proteins of unknown 3D structure, provided that enough homologous sequences are available to construct a large and accurate multiple sequence alignment for the initial contact prediction step.
doi:10.1371/journal.pone.0092197
PMCID: PMC3956894  PMID: 24637808
20.  Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-Ray and Thermodynamic Characterization 
ACS medicinal chemistry letters  2013;4(3):338-343.
The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a sub-micromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. thermodynamic signatures indicate a binding preference for the (R,R)-over the (S,S)-enantiomer. The crystal structure of the small molecule-gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4:gp120 interface is an effective tactic to enhance the neutralization potency of small molecule HIV-1 entry inhibitors.
doi:10.1021/ml300407y
PMCID: PMC3647702  PMID: 23667716
HIV; gp120; CD4; entry inhibitor; structure-based drug design; thermodynamics; x-ray crystallography; viral inhibition; protein-protein interactions
21.  Evaluation of Dissolved Organic Carbon as a Soil Quality Indicator in National Monitoring Schemes 
PLoS ONE  2014;9(3):e90882.
Background
Monitoring the properties of dissolved organic carbon (DOC) in soil water is frequently used to evaluate changes in soil quality and to explain shifts in freshwater ecosystem functioning.
Methods
Using >700 individual soils (0–15 cm) collected from a 209,331 km2 area we evaluated the relationship between soil classification (7 major soil types) or vegetation cover (8 dominant classes, e.g. cropland, grassland, forest) and the absorbance properties (254 and 400 nm), DOC quantity and quality (SUVA, total soluble phenolics) of soil water.
Results
Overall, a good correlation (r2 = 0.58) was apparent between soil water absorbance and DOC concentration across the diverse range of soil types tested. In contrast, both DOC and the absorbance properties of soil water provided a poor predictor of SUVA or soluble phenolics which we used as a measure of humic substance concentration. Significant overlap in the measured ranges for UV absorbance, DOC, phenolic content and especially SUVA of soil water were apparent between the 8 vegetation and 7 soil classes. A number of significant differences, however, were apparent within these populations with total soluble phenolics giving the greatest statistical separation between both soil and vegetation groups.
Conclusions
We conclude that the quality of DOC rather than its quantity provides a more useful measure of soil quality in large scale surveys.
doi:10.1371/journal.pone.0090882
PMCID: PMC3954595  PMID: 24633085
22.  Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-ray and Thermodynamic Characterization 
ACS Medicinal Chemistry Letters  2013;4(3):338-343.
The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a submicromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 μM, respectively), without promoting CD4-independent viral entry. The thermodynamic signatures indicate a binding preference for the (R,R)- over the (S,S)-enantiomer. The crystal structure of the small-molecule/gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4–gp120 interface is an effective tactic to enhance the neutralization potency of small-molecule HIV-1 entry inhibitors.
doi:10.1021/ml300407y
PMCID: PMC3647702  PMID: 23667716
HIV; gp120; CD4; entry inhibitor; structure-based drug design; thermodynamics; X-ray crystallography; viral inhibition; protein−protein interactions
23.  Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma 
Jones, David T.W. | Hutter, Barbara | Jäger, Natalie | Korshunov, Andrey | Kool, Marcel | Warnatz, Hans-Jörg | Zichner, Thomas | Lambert, Sally R. | Ryzhova, Marina | Quang, Dong Anh Khuong | Fontebasso, Adam M. | Stütz, Adrian M. | Hutter, Sonja | Zuckermann, Marc | Sturm, Dominik | Gronych, Jan | Lasitschka, Bärbel | Schmidt, Sabine | Şeker-Cin, Huriye | Witt, Hendrik | Sultan, Marc | Ralser, Meryem | Northcott, Paul A. | Hovestadt, Volker | Bender, Sebastian | Pfaff, Elke | Stark, Sebastian | Faury, Damien | Schwartzentruber, Jeremy | Majewski, Jacek | Weber, Ursula D. | Zapatka, Marc | Raeder, Benjamin | Schlesner, Matthias | Worth, Catherine L. | Bartholomae, Cynthia C. | von Kalle, Christof | Imbusch, Charles D. | Radomski, Sylwester | Lawerenz, Chris | van Sluis, Peter | Koster, Jan | Volckmann, Richard | Versteeg, Rogier | Lehrach, Hans | Monoranu, Camelia | Winkler, Beate | Unterberg, Andreas | Herold-Mende, Christel | Milde, Till | Kulozik, Andreas E. | Ebinger, Martin | Schuhmann, Martin U. | Cho, Yoon-Jae | Pomeroy, Scott L. | von Deimling, Andreas | Witt, Olaf | Taylor, Michael D. | Wolf, Stephan | Karajannis, Matthias A. | Eberhart, Charles G. | Scheurlen, Wolfram | Hasselblatt, Martin | Ligon, Keith L. | Kieran, Mark W. | Korbel, Jan O. | Yaspo, Marie-Laure | Brors, Benedikt | Felsberg, Jörg | Reifenberger, Guido | Collins, V. Peter | Jabado, Nada | Eils, Roland | Lichter, Peter | Pfister, Stefan M.
Nature genetics  2013;45(8):927-932.
Pilocytic astrocytoma, the most common childhood brain tumor1, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations2. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression3 and often becoming a chronic disease with substantial morbidities4.
Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n=73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and novel NTRK2 fusion genes in non-cerebellar tumors. New BRAF activating changes were also observed. MAPK pathway alterations affected 100% of tumors analyzed, with no other significant mutations, indicating pilocytic astrocytoma as predominantly a single-pathway disease.
Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in NF15. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
doi:10.1038/ng.2682
PMCID: PMC3951336  PMID: 23817572
24.  Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma 
Acta neuropathologica  2012;125(3):373-384.
Recent sequencing efforts have described the mutational landscape of the pediatric brain tumor medulloblastoma. Although MLL2 is among the most frequent somatic single nucleotide variants (SNV), the clinical and biological significance of these mutations remains uncharacterized. Through targeted re-sequencing, we identified mutations of MLL2 in 8 % (14/175) of MBs, the majority of which were loss of function. Notably, we also report mutations affecting the MLL2-binding partner KDM6A, in 4 % (7/175) of tumors. While MLL2 mutations were independent of age, gender, histological subtype, M-stage or molecular subgroup, KDM6A mutations were most commonly identified in Group 4 MBs, and were mutually exclusive with MLL2 mutations. Immunohistochemical staining for H3K4me3 and H3K27me3, the chromatin effectors of MLL2 and KDM6A activity, respectively, demonstrated alterations of the histone code in 24 % (53/220) of MBs across all subgroups. Correlating these MLL2-and KDM6A-driven histone marks with prognosis, we identified populations of MB with improved (K4+/K27−) and dismal (K4−/K27−) outcomes, observed primarily within Group 3 and 4 MBs. Group 3 and 4 MBs demonstrate somatic copy number aberrations, and transcriptional profiles that converge on modifiers of H3K27-methylation (EZH2, KDM6A, KDM6B), leading to silencing of PRC2-target genes. As PRC2-mediated aberrant methylation of H3K27 has recently been targeted for therapy in other diseases, it represents an actionable target for a substantial percentage of medulloblastoma patients with aggressive forms of the disease.
doi:10.1007/s00401-012-1070-9
PMCID: PMC3580007  PMID: 23184418
MLL2; KDM6A; Histone lysine methylation; Medulloblastoma; PRC2
25.  Auxin secretion by Bacillus amyloliquefaciens FZB42 both stimulates root exudation and limits phosphorus uptake in Triticum aestivum 
BMC Plant Biology  2014;14:51.
Background
The use of auxin-producing rhizosphere bacteria as agricultural products promises increased root production and therefore greater phosphate (Pi) uptake. Whilst such bacteria promote root production in vitro, the nature of the bacteria-plant interaction in live soil, particularly concerning any effects on nutrient uptake, are not known. This study uses Bacillus amyloliquefaciens FZB42, an auxin-producing rhizobacterium, as a dressing on Triticum aestivum seeds. It then examines the effects on root production, Pi uptake, Pi-related gene expression and organic carbon (C) exudation.
Results
Seed treatment with B. amyloliquefaciens FZB42 increased root production at low environmental Pi concentrations, but significantly repressed root Pi uptake. This coincided with an auxin-mediated reduction in expression of the Pi transporters TaPHT1.8 and TaPHT1.10. Applied exogenous auxin also triggered an increase in root C exudation. At high external Pi concentrations, root production was promoted by B. amyloliquefaciens FZB42, but Pi uptake was unaffected.
Conclusions
We conclude that, alongside promoting root production, auxin biosynthesis by B. amyloliquefaciens FZB42 both re-models Pi transporter expression and elevates organic C exudation. This shows the potential importance of rhizobacterial-derived auxin following colonisation of root surfaces, and the nature of this bacteria-plant interaction in soil.
doi:10.1186/1471-2229-14-51
PMCID: PMC4015440  PMID: 24558978
Bacillus amyloliquefaciens FZB42; Seed treatment; Wheat; Auxin; Phosphate; Root; Exudation

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