bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA19: Mechanisms of alternative telomere recombination
Authors: Greenberg Roger A. 
Published: November 2016

Abstract
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, approximately 10-15% employ a recombination-dependent telomere maintenance pathway known as Alternative Lengthening of Telomeres (ALT), an incompletely understood process that is characterized by multi-telomere clusters. We have recently shown that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis (Cho et. al. Cell 2014). Damaged telomeres initiate increased random surveillance of nuclear volumes before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, implicating a specialized homology searching mechanism that exhibits similarities to meiotic recombination in ALT dependent telomere maintenance. This presentation will describe unpublished data that defines signaling events that are responsible for homology directed telomere synthesis during ALT. Using a novel methodology to purify nascent telomeres, we have identified the basic requirements for break induced telomere synthesis, including the specific DNA polymerases and helicases involved. Data derived from this approach reveals mechanisms of homology directed DNA synthesis that substantially differ from either normal replicative DNA synthesis or from existing models of break induced replication that have been defined in yeast. These data reveal an ordered series of events necessary for ALT telomere synthesis and have implications for homology directed DNA repair at other genomic locations.
This work was supported by NIH grants GM101149, CA138835, and CA17494, and funds from the Abramson Family Cancer Research Institute and Basser Research Center for BRCA
Citation Format: Roger A. Greenberg. Mechanisms of alternative telomere recombination. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA19.
Abstract IA27: Perturbation of host cellular regulatory networks by human papillomaviruses
Authors: Münger Karl 
Published: November 2016

Abstract
Human papillomaviruses (HPVs) are small viruses with ~8,000 bp double-stranded, circular genomes. There are over 200 HPV types and they all infect epithelial cells. While most HPV infections are subclinical others cause overt lesions. Most HPV-associated lesions are benign but some “high-risk” HPVs cause lesions that have a propensity for malignant progression and approximately 10% of all human cancers worldwide are caused by high-risk HPV infections. HPV-associated cancers generally represent non-productive infections, i.e. viral proteins are synthesized but no infectious virus is produced. HPV-associated cancers retain expression of two viral genes, E6 and E7, and continued expression of these two viral genes is necessary for cancer cell proliferation and survival. High-risk HPV E6 and E7 encode small, non-enzymatic proteins of ~150 and ~100 amino acids, respectively. These viral proteins exert their oncogenic activities by associating with and functionally reprogramming critical cellular regulatory nodes; indeed, they have been reported to affect the majority of the “Hallmarks of Cancer” as defined by Hanahan and Weinberg (Cell 144:646). In addition to targeting a number of well-known tumor suppressor pathways including TP53 and RB1, E6 and E7 also, directly and indirectly, affect many other cellular signaling pathways. As a result, HPV E6/E7 expressing cells develop unexpected vulnerabilities to perturbation of signaling pathways that are readily tolerated in normal cells.
Citation Format: Karl Münger. Perturbation of host cellular regulatory networks by human papillomaviruses. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA27.
Abstract PR01: Therapeutic targeting of cdk4 in bladder cancer
Authors: Rubio Carolina , López-Calderón Fernando , Segovia Cristina , Dueñas Marta , Martínez-Fernández Mónica , Otero Irene , Rosa Federico de la , Villacampa Felipe , Castellano Daniel , Paramio Jesús M. 
Published: November 2016

Abstract
Bladder cancer (BC) is a current clinical and social problem. At diagnosis, 70% of the patients display non-muscle invasive tumor (NMIBC), a relatively indolent disease treated by transurethral resection followed by local instillation in some cases. Unfortunately, NMIBC displays an extremely high recurrence rate, and these recurrent tumors may display tumor progression showing muscle invasive (MIBC) characteristics. MIBC is treated, in most cases, by cystectomy and platinum-based chemotherapy. Nonetheless, the metastatic spreading occurs very often with fatal consequences. Various targeted therapies are being clinically and preclinically tested for BC management. Palbociclib (PD-0332991) is a cdk4/6 inhibitor currently tested for the treatment of other malignancies characterized by the presence of a functional RB1 gene. Since RB1 mutation occurs in only 20-30% of BC, we hypothesized the potential use of Palbociclib for BC management. A series of BC cell lines of known genomic characteristics and differing in their RB1 status, were tested for their sensitivity to Palbociclib. Unexpectedly, we observed a similar response to Palbociclib in pRb wt and pRb mutant cell lines in vitro and in xenografts in vivo, although with different biochemical and cell cycle effects. Genomic characterization of these treated cells shows strong gene expression divergence as a consequence of Palbociclib treatment in pRb wt and mutant cells. Nonetheless, bioinformatic analyses revealed FoxM1 as a possible common regulator of some downregulated genes in both cases. Importantly, FoxM1 has been demonstrated a bona fide cdk4 substrate and may confer cis-platinum resistance. We observed reduced FoxM1 phosphorylation upon Palbociclib treatment in all cell lines tested, and also increased sensitivity to cis-platinum. Remarkably, we found that phosphorylated FoxM1 is a potential poor prognosis factor in human NMIBC clinical samples. Future studies, using various NMBIC and metastatic MIBC transgenic mouse models based on the genetic inactivation of Rb1 with other tumor suppressor genes, will precede the possible development of appropriate clinical trials testing the use of Palbociclib in the management of BC patients.
This abstract is also being presented as Poster A04.
Citation Format: Carolina Rubio, Fernando López-Calderón, Cristina Segovia, Marta Dueñas, Mónica Martínez-Fernández, Irene Otero, Federico de la Rosa, Felipe Villacampa, Daniel Castellano, Jesús M. Paramio. Therapeutic targeting of cdk4 in bladder cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR01.
Abstract PR03: Extended inhibition of CDK4/6 inhibits mTORC1 signaling and induces therapeutic senescence in vemurafenib resistant melanoma
Authors: Yoshida Akihiro , Diehl J. Alan 
Published: November 2016

Abstract
Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle within 24h and continued exposure for 8-days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAFV600E inhibitor, has significant clinical efficacy in BRAFV600E positive melanomas but its impact is hampered by a rapid acquisition of resistance. Strikingly, we found that vemurafenib-resistant tumors remain sensitive to palbociclib suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an avenue to overcome recurrence of vemurafenib resistant, metastatic disease. Taken together these results support palbociclib as a promising therapeutic for treatment of melanoma.
This abstract is also being presented as Poster A14.
Citation Format: Akihiro Yoshida, J. Alan Diehl. Extended inhibition of CDK4/6 inhibits mTORC1 signaling and induces therapeutic senescence in vemurafenib resistant melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR03.
Abstract PR05: RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of SWI/SNF complex
Authors: Velez-Cruz Renier , Manickavinayaham Swarnalatha , Biswas Anup K. , Clary Regina Weaks , Johnson David G. 
Published: November 2016

Abstract
The retinoblastoma (RB) tumor suppressor is widely recognized as a master regulator of the transcriptional program that controls entry into the S phase of the cell cycle. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin-remodelers and modifiers to the promoters of E2F target genes. Here we show that RB localizes to DNA double strand breaks (DSBs) dependent on E2F1 and ATM kinase activity. Moreover, RB promotes DNA end resection and homologous recombination, and its loss results in genome instability. RB mediates this important role in repair by recruiting the SWI/SNF chromatin remodeler BRG1 to DSBs. In agreement with these results, loss of BRG1 also results in impaired DNA end resection and HR. RB is recruited to DSBs through a DNA damage-inducible phospho-specific interaction between E2F1 and TopBP1. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1 and BRG1 to DSBs. This E2F1 mutation also impairs DNA repair, increases genomic instability and renders knock-in mice hypersensitive to IR. We uncover a novel, non-transcriptional function for RB in HR, which could contribute to genome instability associated with RB loss in human cancers and explain their sensitivity to DSB-inducing agents.
This abstract is also being presented as Poster B09.
Citation Format: Renier Velez-Cruz, Swarnalatha Manickavinayaham, Anup K. Biswas, Regina Weaks Clary, David G. Johnson. RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of SWI/SNF complex. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr PR05.
Endothelial SCUBE2 Interacts With VEGFR2 and Regulates VEGF-Induced Angiogenesis
Authors: Lin Yuh-Charn , Chao Tsu-Yi , Yeh Chi-Tai , Roffler Steve R. , Kannagi Reiji , Yang Ruey-Bing 
Published: November 2016

Objective—
Vascular endothelial growth factor (VEGF), a major mediator of angiogenesis, exerts its proangiogenic action by binding to VEGFR2 (VEGF receptor 2), the activity of which is further modulated by VEGFR2 coreceptors such as neuropilins. However, whether VEGFR2 is regulated by additional coreceptors is not clear. To investigate whether SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2), a peripheral membrane protein expressed in vascular endothelial cells (ECs) known to bind other signaling receptors, functions as a VEGFR2 coreceptor and to verify the role of SCUBE2 in the VEGF-induced angiogenesis.

Approach and Results—

SCUBE2 lentiviral overexpression in human ECs increased and short hairpin RNA knockdown inhibited VEGF-induced EC growth and capillary-like network formation on Matrigel. Like VEGF, endothelial SCUBE2 was upregulated by hypoxia-inducible factor-1α at both mRNA and protein levels. EC-specific
Scube2
knockout mice were not defective in vascular development but showed impaired VEGF-induced neovascularization in implanted Matrigel plugs and recovery of blood flow after hind-limb ischemia. Coimmunoprecipitation and ligand-binding assays showed that SCUBE2 forms a complex with VEGF and VEGFR2, thus acting as a coreceptor to facilitate VEGF binding and augment VEGFR2 signal activity. SCUBE2 knockdown or genetic knockout suppressed and its overexpression promoted the VEGF-induced activation of downstream proangiogenic and proliferating signals, including VEGFR2 phosphorylation and mitogen-activated protein kinase or AKT activation.

Conclusions—
Endothelial SCUBE2 may be a novel coreceptor for VEGFR2 and potentiate VEGF-induced signaling in adult angiogenesis.
Altered Expression of Long Noncoding RNAs in Blood After Ischemic Stroke and Proximity to Putative Stroke Risk Loci
Authors: Dykstra-Aiello Cheryl , Jickling Glen C. , Ander Bradley P. , Shroff Natasha , Zhan Xinhua , Liu DaZhi , Hull Heather , Orantia Miles , Stamova Boryana S. , Sharp Frank R. 
Published: November 2016

Background and Purpose—
Although peripheral blood mRNA and micro-RNA change after ischemic stroke, any role for long noncoding RNA (lncRNA), which comprise most of the genome and have been implicated in various diseases, is unknown. Thus, we hypothesized that lncRNA expression also changes after stroke.

Methods—

lncRNA expression was assessed in 266 whole-blood RNA samples drawn once per individual from patients with ischemic stroke and matched with vascular risk factor controls. Differential lncRNA expression was assessed by ANCOVA (
P
<0.005; fold change>|1.2|), principal components analysis, and hierarchical clustering on a derivation set (n=176) and confirmed on a validation set (n=90). Poststroke temporal lncRNA expression changes were assessed using ANCOVA with confounding factor correction (
P
<0.005; partial correlation with time since event >|0.4|). Because sexual dimorphism exists in stroke, analyses were performed for each sex separately.

Results—
A total of 299 lncRNAs were differentially expressed between stroke and control males, whereas 97 lncRNAs were differentially expressed between stroke and control females. Significant changes of lncRNA expression with time after stroke were detected for 49 lncRNAs in men and 31 lncRNAs in women. Some differentially expressed lncRNAs mapped close to genomic locations of previously identified putative stroke-risk genes, including lipoprotein, lipoprotein(a)-like 2, ABO (transferase A, α1-3-N-acetylgalactosaminyltransferase; transferase B, α1-3-galactosyltransferase) blood group, prostaglandin 12 synthase, and α-adducins.

Conclusions—
This study provides evidence of altered and sexually dimorphic lncRNA expression in peripheral blood of patients with stroke compared with that of controls and suggests that lncRNAs have potential for stroke biomarker development. Some regulated lncRNA could regulate some previously identified putative stroke-risk genes.
Impact of Clinical Trial Results on the Temporal Trends of Carotid Endarterectomy and Stenting From 2002 to 2014
Authors: Hussain Mohamad A. , Mamdani Muhammad , Tu Jack V. , Saposnik Gustavo , Khoushhal Zeyad , Aljabri Badr , Verma Subdoh , Al-Omran Mohammed 
Published: November 2016

Background and Purpose—
Randomized trials provide conflicting data for the efficacy of carotid-artery stenting compared with endarterectomy. The purpose of this study was to examine the impact of conflicting clinical trial publications on the utilization rates of carotid revascularization procedures.

Methods—
We conducted a population-level time-series analysis of all individuals who underwent carotid endarterectomy and stenting in Ontario, Canada (2002–2014). The primary analysis examined temporal changes in the rates of carotid revascularization procedures after publications of major randomized trials. Secondary analyses examined changes in overall and age, sex, carotid-artery symptom, and operator specialty–specific procedure rates.

Results—

A total of 16 772 patients were studied (14 394 endarterectomy [86%]; 2378 stenting [14%]). The overall rate of carotid revascularization decreased from 6.0 procedures per 100 000 individuals ≥40 years old in April 2002 to 4.3 procedures in the first quarter of 2014 (29% decrease;
P
<0.001). The rate of endarterectomy decreased by 36% (
P
<0.001), whereas the rate of carotid-artery stenting increased by 72% (
P
=0.006). We observed a marked increase (
P
=0.01) in stenting after publication of the SAPPHIRE trial (Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy) in 2004, whereas stenting remained relatively unchanged after subsequent randomized trials published in 2006 (
P
=0.11) and 2010 (
P
=0.34). In contrast, endarterectomy decreased after trials published in 2006 (
P
=0.04) and 2010 (
P
=0.005).

Conclusions—
Although the overall rates of carotid revascularization and endarterectomy have fallen since 2002, the rate of carotid-artery stenting has risen since the publication of stenting-favorable SAPPHIRE trial. Subsequent conflicting randomized trials were associated with a decreasing rate of carotid endarterectomy.
Improving the Simulation of Large Lakes in Regional Climate Modeling: Two-Way Lake–Atmosphere Coupling with a 3D Hydrodynamic Model of the Great Lakes
Authors: Xue Pengfei , Pal Jeremy S. , Ye Xinyu , Lenters John D. , Huang Chenfu , Chu Philip Y. 
Published: November 2016

Abstract
Accurate representations of lake–ice–atmosphere interactions in regional climate modeling remain one of the most critical and unresolved issues for understanding large-lake ecosystems and their watersheds. To date, the representation of the Great Lakes two-way interactions in regional climate models is achieved with one-dimensional (1D) lake models applied at the atmospheric model lake grid points distributed spatially across a 2D domain. While some progress has been made in refining 1D lake model processes, such models are fundamentally incapable of realistically resolving a number of physical processes in the Great Lakes. In this study, a two-way coupled 3D lake-ice–climate modeling system [Great Lakes–Atmosphere Regional Model (GLARM)] is developed to improve the simulation of large lakes in regional climate models and accurately resolve the hydroclimatic interactions. Model results are compared to a wide variety of observational data and demonstrate the unique skill of the coupled 3D modeling system in reproducing trends and variability in the Great Lakes regional climate, as well as in capturing the physical characteristics of the Great Lakes by fully resolving the lake hydrodynamics. Simulations of the climatology and spatiotemporal variability of lake thermal structure and ice are significantly improved over previous coupled, 1D simulations. At seasonal and annual time scales, differences in model results are primarily observed for variables that are directly affected by lake surface temperature (e.g., evaporation, precipitation, sensible heat flux) while no significant differences are found in other atmospheric variables (e.g., solar radiation, cloud cover). Underlying physical mechanisms for the simulation improvements using GLARM are also discussed.
L‘Orologio: Il romanzo della politica
Authors: Leogrande Alessandro 
Published: November 2016

L’eccesso di politica produce paradossalmente una spoliazione della politica, per come essa era stata immaginata nei lunghi anni dell’esilio in bilico tra la vita e la morte: è questa la riflessione posta al centro del secondo romanzo di Carlo Levi, L’Orologio, uscito nel 1950. L’Orologio è un libro che narra l’origine e la deflagrazione di una crisi politica (quella dei partiti politici che avevano fatto la Resistenza al nazifascismo, già negli ultimi mesi del 1945), i rapporti tra le diverse forze partitiche in quel frangente della storia d’Italia, e soprattutto le vicissitudini del Partito d’Azione, il piccolo partito liberal-socialista, o socialista-libertario, nato dall’esperienza di Giustizia e libertà, a cui Levi (già autore con Leone Ginzburg del fondamentale saggio Il concetto di autonomia nel programma di G.L.) aveva aderito. Il saggio si propone di analizzare la genesi e la struttura del romanzo, il rapporto tra esso e l’attività politico-giornalistica di Levi in quegli anni, lo stile del suo autore, le relazioni che egli intrattiene con un’Italia socialmente vivissima, eppure incamminata verso nuove restaurazioni.
La scrittura di viaggio di Carlo Levi
Authors: Scianatico Giovanna 
Published: November 2016

Partendo dall’analisi di Cristo si è fermato ad Eboli in chiave odeporica, se ne individua lo schema di approccio al diverso, poi messo in atto nei successivi reportages dall’Europa e dall’Oriente (in particolare Russia, Cina, India). Si tratta di viaggi all’interno di una dimensione spaziotemporale, dove si congiungono dialetticamente arcaico e moderno, dove nell’ignoto dell’altrove si rintraccia l’identità dell’io, e all’esotismo pittorico e fantasmagorico delle immagini è correlata la problematica politico-sociale dei Paesi attraversati.
Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice
Authors: Askew David , Pareek Tej K. , Eid Saada , Ganguly Sudipto , Tyler Megan , Huang Alex Y. , Letterio John J. , Cooke Kenneth R. 
Published: November 2016

Key Points
Cdk5 function is required for optimal lymphocyte activation and migration following allo-HCT. Targeting Cdk5 may be a particularly attractive strategy to reduce GVHD and maintain antitumor activity.
SABRE: a method for assessing the stability of gene modules in complex tissues and subject populations
Authors: Shannon Casey P. , Chen Virginia , Takhar Mandeep , Hollander Zsuzsanna , Balshaw Robert , McManus Bruce M. , Tebbutt Scott J. , Sin Don D. , Ng Raymond T. 
Published: November 2016

Abstract
Background
Gene network inference (GNI) algorithms can be used to identify sets of coordinately expressed genes, termed network modules from whole transcriptome gene expression data. The identification of such modules has become a popular approach to systems biology, with important applications in translational research. Although diverse computational and statistical approaches have been devised to identify such modules, their performance behavior is still not fully understood, particularly in complex human tissues. Given human heterogeneity, one important question is how the outputs of these computational methods are sensitive to the input sample set, or stability. A related question is how this sensitivity depends on the size of the sample set. We describe here the SABRE (Similarity Across Bootstrap RE-sampling) procedure for assessing the stability of gene network modules using a re-sampling strategy, introduce a novel criterion for identifying stable modules, and demonstrate the utility of this approach in a clinically-relevant cohort, using two different gene network module discovery algorithms.

Results
The stability of modules increased as sample size increased and stable modules were more likely to be replicated in larger sets of samples. Random modules derived from permutated gene expression data were consistently unstable, as assessed by SABRE, and provide a useful baseline value for our proposed stability criterion. Gene module sets identified by different algorithms varied with respect to their stability, as assessed by SABRE. Finally, stable modules were more readily annotated in various curated gene set databases.

Conclusions
The SABRE procedure and proposed stability criterion may provide guidance when designing systems biology studies in complex human disease and tissues.