bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B52: Brusatol inhibits oral squamous cell carcinoma cells by targeting glycolytic metabolism
Authors: Zhang Guilian , Su Ying , Chen Suhong , Zhang Xinyan 
Published: May 2018

Abstract
Brusatol is a natural terpenoid that is isolated from the Brucea javanica plant, a medicine plant distributed widely throughout Asia, and its bitter fruits have been used traditionally in medicine for treating various ailments and controlling some pests. Brusatol has recently been shown to be capable of inducing a variety of biologic effects, including a potential antitumor effect. The goal of this study was to investigate the role of brusatol in oral squamous cell carcinoma (OSCC) cells and its mechanism. Brusatol treatment had broad effects against oral cancer cells in vitro including inhibition of proliferation, colony formation, cell migration and invasion, and induction of apoptosis. Mechanism studies showed that brusatol inhibited glucose uptake and lactate secretion and glycolytic pathway key enzymes HK and PK activity in vitro. Brusatol inhibited glycolysis, glycolytic capacity, and reserve capacity by Seahorse XF glycolysis stress test assay. In vivo study showed that brusatol suppresses tumor growth in a nude mouse xenograft model by inhibiting cell proliferation and angiogenesis and by inducing apoptosis. Glycolysis-related genes were also deceased in the nude mice xenografts. Taken together, these data clearly indicated that brusatol is a promising chemotherapeutic agent for OSCC treatment.
Citation Format: Guilian Zhang, Ying Su, Suhong Chen, Xinyan Zhang. Brusatol inhibits oral squamous cell carcinoma cells by targeting glycolytic metabolism [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B52.
Abstract IA15: Normal and cancer stem cells in multistage carcinogenesis
Authors: Balmain Allan 
Published: May 2018

Abstract
Mouse models of cancer have been instrumental in the development of our understanding of the processes that drive multistage carcinogenesis from the initiation stage to metastasis. In particular, tumors induced in mice by exposure to chemicals that act as mutagens or tumor promoters replicate many of the biologic and genetic features of multistage cancer in human populations. Such models often have a high burden of point mutations and gene copy number changes similar to human tumors of the lung, colon, or skin that are associated with exposure to exogenous environmental agents. These are important features that contribute to tumor heterogeneity—a major cause of drug resistance and poor response to therapy in human cancer patients. The availability of mouse models of tumors with a high mutation burden also offers possibilities for development of immunotherapy approaches that are dependent on expression of novel tumor antigens resulting from carcinogen-induced mutations in tumor DNA.
Initiation of chemical carcinogenesis in the mouse is frequently caused by point mutations in genes of the Ras family. The nature of the initiating Ras mutation depends on the carcinogen used, but a similar “mutation signature” is seen throughout the genome of the initiated cell. Tumor cells, however, continually acquire additional new genetic alterations, leading to the emergence of multiple, genetically distinct tumor subclones. By combining the 4-color lineage tracing Confetti mouse with a chemical carcinogenesis model of skin cancer, we have investigated clonal and evolutionary dynamics at every stage of chemical carcinogenesis, from the initiated cell to benign tumors, malignant carcinomas, and ultimately to distant metastases. These studies reveal distinct patterns of clonal evolution at different stages of progression. The growth of subclones within tumors is driven by a stem cell population marked by expression of the Lgr6 gene—a known marker of normal skin stem cells and mediator of Wnt signaling in the epidermis. The use of mouse models for identification of patterns of clonal heterogeneity, and the drivers of clonal growth from cancer stem cells, may offer new possibilities for prevention or treatment of squamous carcinomas.
Citation Format: Allan Balmain. Normal and cancer stem cells in multistage carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA15.
Abstract IA16: The global proteome and phospho-proteome of K-Ras mutant tissues
Authors: Haigis Kevin 
Published: May 2018

Abstract
K-Ras is the most commonly mutated oncogene in cancer, and it plays a predominant role in the pathogenesis of cancers of the pancreas, colon, and lung. Mutationally activated K-Ras influences cellular behaviors through broad and complex effects on downstream signal transduction pathways. In an effort to understand the molecular mechanisms underlying the oncogenic properties of mutant forms of K-Ras, we have used multiplexed mass spectroscopy (MS) to quantify proteome-wide changes in protein phosphorylation in primary mouse tissues that are engineered to express mutant K-Ras, either alone or in combination with mutations in other cancer genes. This multidimensional dataset highlights the context dependence of K-Ras signaling because the significant changes in protein abundance and/or phosphorylation due to activation of K-Ras are highly dependent upon both tissue context and cooperating mutations. The dataset also paints a complex picture of signaling downstream of K-Ras within a given tissue, as phosphorylation of many proteins in known Ras effector pathways (i.e., MAPK and PI3K) are unaffected or downregulated by mutationally activated K-Ras. Overall, this study provides an unprecedented view of K-Ras signaling on a global scale and reveals a variety of novel insights into the signal transduction properties of mutant K-Ras alleles.
Citation Format: Kevin Haigis. The global proteome and phospho-proteome of K-Ras mutant tissues [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA16.
Abstract IA21: Interrogating cancer drivers and dependencies using non-germline mouse models
Authors: Lowe Scott W. 
Published: May 2018

Abstract
Cancer is a heterogeneous disease involving various genetic and epigenetic alterations that initiate and maintain the disease. Our laboratory is interested in understanding how such alterations contribute to tumorigenesis, alter treatment response, and create vulnerabilities that may be targeted therapeutically. To interrogate cancer in vivo, we have developed a range of non-germline mouse models that enable a wide variety of cancer genotypes to be produced in a fraction of the time and cost of traditional germline methods. Approaches vary depending on the particular question, and can involve genetic manipulation and retransplantation of tissue stem cells and/or organoid cultures, the generation of multi-allelic ES cells and subsequent use in chimeric mice, and direct somatic engineering of mutations in particular tissues. Additionally, we have incorporated RNAi and CRISPR/Cas9 technologies to expedite our ability to study gene function in these models. Collectively, the combination of these tools has allowed us to identify and characterize new cancer drives using one-by-one or multiplexed approaches, and to perform rapid in vivo validation of “hits” from functional genomic screens. Examples of each method and approach will be presented.
Citation Format: Scott W. Lowe. Interrogating cancer drivers and dependencies using non-germline mouse models [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA21.
Abstract IA28: Using mouse models to develop therapies for Ras-driven cancers
Authors: Cichowski Karen 
Published: May 2018

Abstract
Selective kinase inhibitors have changed the standard of care in cancers that are driven by oncogenic kinases. Nevertheless, therapeutic effects are often temporary and it is becoming increasingly apparent that the majority of human malignancies will not be eradicated by a single drug. Ras-driven cancers are particularly problematic; agents that target individual Ras effectors are ineffective and successful therapeutic combinations have not yet been identified. Therefore, it is imperative that we rationally conceptualize and test new therapeutic combinations that either function to suppress orthogonal pathways in tumors or converge on a specific cancer-cell vulnerability. Mouse models provide a powerful tool to identify and evaluate such combinations. Not only can they be used to identify critical therapeutic targets and dissect therapeutic mechanisms of action, but they can also directly inform clinical trials. In this presentation therapeutic strategies that (co)target kinases, epigenetic regulators, and immunoregulatory proteins will be discussed. Importantly, the mechanisms by which various combinations function reveal nodal points of convergence between these distinct pathways and reveal new vulnerabilities that can be targeted in cancer.
Citation Format: Karen Cichowski. Using mouse models to develop therapies for Ras-driven cancers [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA28.
Abstract PR01: Modeling colorectal cancer in vivo through CRISPR-based genome editing
Authors: Han Teng , Schatoff Emma M. , Murphy Charles , Zafra Maria Paz , Wilkinson John , Elemento Olivier , Dow Lukas E. 
Published: May 2018

Abstract
In addition to activating and inactivating mutations in protein coding genes, cancer cells commonly show gross structural abnormalities in their genomes. These include deletions, duplications, inversions, and translocations. Unfortunately, conventional gene targeting- and RNAi-based approaches are not easily applied to study chromosome rearrangements. To enable this, we developed flexible CRISPR-based in vivo models systems that drive the generation of targeted genomic breaks, and the induction of gross chromosomal aberrations, without the need for viral delivery of CRISPR components. Using this approach we have produced novel transgenic systems to recapitulate two recurrent genomic rearrangements observed in human colorectal cancer and provide the first evidence that these events are sufficient to initiate tumor development. Further, we show that these tumors, while histologically similar to Apc mutant CRC, are molecularly distinct and are exquisitely sensitive to therapies targeting the Wnt pathway. We are now using this and other genome-editing platforms to systematically investigate the role of other recurrent genetic alterations in GI malignancies.
Citation Format: Teng Han, Emma M. Schatoff, Charles Murphy, Maria Paz Zafra, John Wilkinson, Olivier Elemento, Lukas E. Dow. Modeling colorectal cancer in vivo through CRISPR-based genome editing [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR01.
Abstract PR08: Altered nucleolar trafficking of the Blm helicase in the mouse reduces size, increases DNA damage and tumor susceptibility, and facilitates premature aging
Authors: McIlhatton Michael , Fernandez Max , Acharya Samir , Coppola Vincenzo , Groden Joanna L. 
Published: May 2018

Abstract
Bloom's syndrome (BS) is a recessive human chromosome breakage disorder caused by mutations in the recQ-like helicase BLM, sometimes known as RECQL2. Its clinical phenotype invariably includes male infertility, dwarfism, cancer susceptibility, and growth defects related to now characterized biochemical functions in DNA repair and rDNA transcription. The BLM protein includes two serines within a highly conserved carboxy-terminal nuclear localization sequence (NLS) that are critical for dynamic nucleolar trafficking of BLM where it facilitates rRNA transcription through direct interactions with RNA polymerase I and topoisomerase 1. CRISPR/Cas9-directed gene editing techniques generated homozygous murine models with these two conserved amino acids substituted by aspartic acids or alanines, and Blm proteins that were invariably excluded (DD) or constitutively localized (AA) within the nucleolus. Both protein isoforms retain biochemical functions and nuclear localization; BLM-/- cells transfected with the DD transgene display increases in nucleolar DNA damage compared to those transfected with the wild-type gene. BlmDD/DD mice with excluded Blm, but not BlmAA/AA mice, are smaller than their wild-type littermates at 8, 12, and 16 weeks of age; BlmDD/DD mice develop significantly more adenomas than littermates when crossed to the ApcMin/+ model of intestinal tumor formation. Finally, BlmDD/DD mice, but not their wild-type littermates, display signs of premature aging by one year of age, with weight loss, changes in coat color and quality, and spontaneous tumor formation. Our studies demonstrate functions for dynamic Blm nucleolar localization in maintaining stability of both the nucleolar and non-nucleolar genomes. A role for Blm/BLM in the prevention of aging is also exposed by these mouse models as only RecqL4 (RECQL4 mutations lead to Rothmund-Thomson syndrome in the human), but not Wrn/RecqL3 (WRN mutations lead to Werner's syndrome in the human), localizes to the murine nucleolus. Both Werner's syndrome and Rothmund-Thomson syndrome are associated with DNA repair deficiency, tumor susceptibility, and premature aging in the human. Our murine models also permit the definition of amino acid sequences and mechanisms that target or exclude proteins from the nucleolus.
This abstract is also being presented as Poster A30.
Citation Format: Michael McIlhatton, Max Fernandez, Samir Acharya, Vincenzo Coppola, Joanna L. Groden. Altered nucleolar trafficking of the Blm helicase in the mouse reduces size, increases DNA damage and tumor susceptibility, and facilitates premature aging [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR08.
Beyond Irritable Bowel Syndrome: The Efficacy of the Low Fodmap Diet for Improving Symptoms in Inflammatory Bowel Diseases and Celiac Disease
Authors: Testa Anna , Imperatore Nicola , Rispo Antonio , Rea Matilde , Tortora Raffaella , Nardone Olga Maria , Lucci Lucia , Accarino Grazia , Caporaso Nicola , Castiglione Fabiana 
Published: May 2018

<b><i>Background and Aim:</i></b> To evaluate the usefulness of a low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) diet on patients with irritable bowel syndrome (IBS), non-active inflammatory bowel diseases (IBD), and celiac disease (CD) on a gluten-free diet (GFD). <b><i>Methods:</i></b> Dietetic interventional prospective study. IBS, IBD, and CD subjects were evaluated to check if they fulfilled the Rome III criteria. Each subject was educated to follow a low FODMAP diet after being evaluated by filling out questionnaires that assessed the quality of life (QoL) and symptoms experienced (IBS-SSS and SF-36), and was reevaluated after 1 and 3 months. <b><i>Results:</i></b> One hundred twenty-seven subjects were enrolled: 56 with IBS, 30 with IBD, and 41 with CD. IBS-SSS showed that abdominal symptoms improved after 1 and 3 months of diet in all subjects, with significant difference among the 3 groups at T0 (average scores IBS: 293 ± 137, IBD: 206 ± 86, CD: 222 ± 65, <i>p</i> &#x3c; 0.001), but no difference at T3 (IBS: 88 ± 54, IBD: 73 ± 45, CD: 77 ± 49, <i>p</i> = ns). By analyzing the SF-36 questionnaire, we did not observe any difference between the 3 groups, in terms of response to diet (<i>p</i> = ns), we observed a clinical improvement from T0 to T3 for most of the questionnaire’s domains. <b><i>Conclusions:</i></b> A low FODMAP diet could be a valid option to counter ­abdominal symptoms in patients with IBS, non-active IBD, or CD on a GFD, and thus, improve their QoL and social ­relations.
Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion
Authors: Sheikh Nabeel , Papadakis Michael , Wilson Mathew , Malhotra Aneil , Adamuz Carmen , Homfray Tessa , Monserrat Lorenzo , Behr Elijah R. , Sharma Sanjay 
Published: May 2018

Background:
T-wave inversion (TWI) is common in patients with cardiomyopathy. However, up to 25% of athletes of African/Afro-Caribbean descent (black athletes) and 5% of white athletes also have TWI of unclear clinical significance despite comprehensive clinical evaluation and long-term follow-up. The aim of this study was to determine the diagnostic yield from genetic testing, beyond clinical evaluation, when investigating athletes with TWI.

Methods:
We investigated 50 consecutive asymptomatic black and 50 white athletes 14 to 35 years of age with TWI and a normal echocardiogram who were referred to a UK tertiary center for cardiomyopathy and sports cardiology. Subjects underwent exercise testing, 24-hour ambulatory ECG, signal-averaged ECG, cardiac magnetic resonance imaging, and a blood-based analysis of a comprehensive 311-gene panel for cardiomyopathies and ion channel disorders associated with TWI, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, long-QT syndrome, and Brugada syndrome.

Results:

In total, 21 athletes (21%) were diagnosed with cardiac disease on the basis of comprehensive clinical investigations. Of these, 8 (38.1%) were gene positive (myosin binding protein C[
MYBPC3
], myosin heavy chain 7 [
MYH7
], galactosidase alpha [
GLA
], and actin alpha, cardiac muscle 1 [
ACTC1
] genes) and 13 (61.9%) were gene negative. Of the remaining 79 athletes (79%), 2 (2.5%) were gene positive (transthyretin [
TTR
] and sodium voltage-gated channel alpha subunit 5 [
SCN5A
] genes) in the absence of a clinical phenotype. The prevalence of newly diagnosed cardiomyopathy was higher in white athletes compared with black athletes (30.0% versus 12%;
P=0
.027). Hypertrophic cardiomyopathy accounted for 90.5% of all clinical diagnoses. All black athletes and 93.3% of white athletes with a clinical diagnosis of cardiomyopathy or a genetic mutation capable of causing cardiomyopathy exhibited lateral TWI as opposed to isolated anterior or inferior TWI; the genetic yield of diagnoses from lateral TWI was 12.3%.

Conclusions:
Up to 10% of athletes with TWI revealed mutations capable of causing cardiac disease. Despite the substantial cost, the positive diagnostic yield from genetic testing was one half that from clinical evaluation (10% versus 21%) and contributed to additional diagnoses in only 2.5% of athletes with TWI in the absence of a clear clinical phenotype, making it of negligible use in routine clinical practice.
Morning, Paramin
Authors: Fumagalli Maria Cristina 
Published: May 2018

Abstract
In Morning, Paramin (2016), 51 new poems by Derek Walcott are in dialogue with 51 paintings by Peter Doig. Walcott, also an accomplished painter, has often engaged with the visual arts, but this is the first volume in which every poem “cor-responds” to a painting, offering unique opportunities to examine Walcott’s ekphrastic practices and the way in which they might offer alternatives to current paradigms. Rejecting the paradigm of a paragonal struggle for dominance, I will argue that Morning, Paramin is shaped by an ekphrasis of Relation (resonating with Glissant’s poetics of Relation) in which the verbal and the visual interact in complex ways, exercising mutual reclaimings of agency and transformative dialogues that engender new composite works of art governed by a noncompetitive, nonexploitative approach; as otherness is reconfigured, the right to “opacity” is upheld, and each image and word contribute to a whole bigger than the sum of its parts.
Further Jewish Neo-Aramaic Innovations
Authors: Mutzafi Hezy 
Published: May 2018

Abstract
The present article presents new findings related to Jewish Neo-Aramaic (JNA) innovations in the framework of North-Eastern Neo-Aramaic (NENA). The dialectal spectrum of JNA is so wide and variegated, that some geographically distant JNA varieties are markedly different from each other on all levels of language structure. Despite this great heterogeneity, the JNA dialects share supra-regional features that bind these varieties together to the exclusion of all, or the vast majority of, the Christian NENA (C.NENA) dialects. There appear to be no grounds, however, for a genetic classification of NENA into two principal branches, JNA and C.NENA. Distinct Jewish versus Christian NENA isoglosses have, rather, most plausibly emerged by gradual diffusion of innovations throughout NENA-speaking communities of the same confession (Jewish or Christian), while skipping geographically adjacent, but religiously distinct, NENA-speaking communities.
A new species of myrmecophilous lady beetle in the genus Diomus (Coleoptera: Coccinellidae: Diomini) from Chiapas, Mexico that feeds on green coffee scale, Coccus viridis (Green) (Hemiptera: Coccidae)
Authors: VANDENBERG NATALIA J. , IVERSON AARON , LIERE HEIDI 
Published: May 2018

A new species of myrmecophilous lady beetle, Diomus lupusapudoves, sp. nov. (Coleoptera: Coccinellidae: Diomini), is described from a coffee agroecosystem in Chiapas, Mexico. The new species was found preying on the green coffee scale pest, Coccus viridis (Green), tended primarily by Azteca sericeasur Longino and Pheidole synanthropica Longino ants. The larval, pupal, and adult stages of the new species are described and habitus illustrations or photos provided along with anatomical details of the adult male and female genitalia. The species is most similar to Diomus thoracicus Fabricius (=type species of Diomus), another myrmecophile, which inhabits ant nests and feeds on ant brood. The new species has a peculiar onisciform larva that lacks dorsal setae, features that it shares with D. thoracicus. The new species is only the second species in the genus reported as a myrmecophile, although the life histories of most species have been poorly documented.