bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of molecular markers and morphology for Neidium taxa (Bacillariophyta) from eastern North America
Authors: Lefebvre Keely E. , Hamilton Paul B. , Pick Frances R. 
Published: April 2017

Historically, a morphological species concept has applied shape subjectively in the delimitation of diatom species. This has led to confusion between taxa within the benthic diatom genus Neidium. Samples from Ontario, Quebec, Nova Scotia, Newfoundland (Canada) and New York (USA) were examined for Neidium taxa under LM and SEM. Fourier shape analysis showed that shape as a taxonomic character was not able to discern all species. Isolated individuals from the samples were amplified and sequenced for three chloroplast molecular markers (rbcL, psbC, and psbA) and one nuclear ribosomal molecular marker (18S). Phylogenetic reconstructions were completed with the concatenated chloroplast and 18S dataset using Maximum Likelihood and Bayesian analyses. The concatenated chloroplast dataset exhibited a species‐level resolution phylogeny of Neidium taxa. The 18S dataset had a lower level of sequence divergence and was unable to differentiate between Neidium taxa. We present emended species descriptions and sequence data for four previously described species: Neidium sacoense, N. longiceps, N. fossum, and N. affine. We describe three novel species (Neidium lowei, N. promontorium, and N. potapovae) and identify two forms with unique molecular signatures. The distinguishing features of N. lowei are its size, valve shape, and longitudinal canal structure. Distinguishing features of N. promontorium are its valve shape, longitudinal canal and apex formation, and surface depression along the axial area. Neidium potapovae is distinguished by its size, formation of valve and apices and single longitudinal canal. This paper demonstrates how future phylogenetic treatments using single cell multigene sequencing can help resolve taxonomic confusion within diatoms.
Short‐term (48 hours) intravenous serelaxin infusion has no effect on myogenic tone or vascular remodeling in rat mesenteric arteries
Authors: Jelinic Maria , Leo Chen Huei , Marshall Sarah A. , Senadheera Sevvandi N. , Parry Laura J. , Tare Marianne 
Published: April 2017

AbstractBackgroundShort‐term IV sRLX (recombinant human relaxin‐2) infusion enhances endothelium‐dependent relaxation in mesenteric arteries. This is initially underpinned by increased NO followed by a transition to prostacyclin. The effects of short‐term IV sRLX treatment on pressure‐induced myogenic tone and vascular remodeling in these arteries are unknown. Therefore, we investigated the effects of sRLX infusion on pressure‐induced myogenic tone and passive mechanical wall properties in mesenteric arteries.MethodsMesenteric artery myogenic tone and passive mechanics were examined after 48‐hours and 10‐days infusion of sRLX. Potential mechanisms of action were assessed by pressure myography, qPCR, and Western blot analysis.ResultsNeither 48‐hours nor 10‐days sRLX treatment had significant effects on myogenic tone, passive arterial wall stiffness, volume compliance, or axial lengthening. However, in 48‐hours sRLX ‐treated rats, incubation with the NO synthase blocker L‐NAME significantly increased myogenic tone (P<.05 vs placebo), demonstrating an increased contribution of NO to the regulation of myogenic tone. eNOS dimerization, but not phosphorylation, was significantly upregulated in the arteries of sRLX ‐treated rats.ConclusionIn mesenteric arteries, 48‐hours sRLX treatment upregulates the role of NO in the regulation of myogenic tone by enhancing eNOS dimerization, without altering overall myogenic tone or vascular remodeling.
Genome‐wide association mapping for phenotypic plasticity in rice
Authors: Kikuchi Shinji , Bheemanahalli Raju , Jagadish Krishna S.V. , Kumagai Etsushi , Masuya Yusuke , Kuroda Eiki , Raghavan Chitra , Dingkuhn Michael , Abe Akira , Shimono Hiroyuki 
Published: April 2017

AbstractPhenotypic plasticity of plants in response to environmental changes is important for adapting to changing climate. Less attention has been paid to exploring the advantages of phenotypic plasticity in resource‐rich environments to enhance the productivity of agricultural crops. Here, we examined genetic variation for phenotypic plasticity in indica rice (Oryza sativa L.) across two diverse panels: (1) a Phenomics of Rice Adaptation and Yield (PRAY) population comprising 301 accessions; and (2) a Multi‐parent Advanced Generation Inter‐Cross (MAGIC) indica population comprising 151 accessions. Altered planting density was used as a proxy for elevated atmospheric CO2 response. Low planting density significantly increased panicle weight per plant compared with normal density, and the magnitude of the increase ranged from 1.10 to 2.78 times among accessions for the PRAY population and from 1.05 to 2.45 times for the MAGIC population. Genome‐wide‐association studies validate three Environmental Responsiveness (ER) candidate alleles (qER1–3) that were associated with relative response of panicle weight to low density. Two of these alleles were tested in 13 genotypes to clarify their biomass responses during vegetative growth under elevated CO2 in Japan. Our study provides evidence for polymorphisms that control rice phenotypic plasticity in environments that are rich in resources such as light and CO2.
The role of ILC2 in hookworm infection
Authors: Filbey K. , Bouchery T. , Le Gros G. 
Published: April 2017

SummaryHookworm is a major public health concern, yet still relatively little is known about the immunological responses involved in human infection. Animal studies are mainly confined to using the natural rodent helminth Nippostrongylus brasiliensis as this has been proposed as the most accurate model of hookworm infection in the mouse, with both its life cycle and the immune responses it invokes having been extremely well characterized. In this review, we examine the roles that type 2 innate lymphoid cells (ILC2s) play in immunity and host tolerance to hookworm infection, particularly N. brasiliensis. This includes their role in the initiation and regulation of immune responses, as well as in the resolution and limitation of tissue damage required after an infection with a large organism, such as a helminth.
Model-based falsification of an artificial pancreas control system
Authors: Sankaranarayanan Sriram , Kumar Suhas Akshar , Cameron Faye , Bequette B. Wayne , Fainekos Georgios , Maahs David M. 
Published: April 2017

We present a model-based falsification scheme for artificial pancreas controllers. Our approach performs a closed-loop simulation of the control software using models of the human insulin-glucose regulatory system. Our work focuses on testing properties of an overnight control system for hypoglycemia/hyperglycemia minimization in patients with type-1 diabetes. This control system is currently the subject of extensive phase II clinical trials.
We describe how the overall closed loop simulator is constructed, and formulate properties to be tested. Significantly, the closed loop simulation incorporates the control software, as is, without any abstractions. Next, we demonstrate the use of a simulation-based falsification approach to find potential property violations in the resulting control system. We formulate a series of properties about the controller behavior and examine the violations obtained. Using these violations, we propose modifications to the controller software to improve its performance under these adverse (corner-case) scenarios. We also illustrate the effectiveness of robustness as a metric for identifying interesting property violations. Finally, we identify important open problems for future work.
Pancreatic Cancer Genomes: Implications for Clinical Management and Therapeutic Development
Authors: Dreyer Stephan B. , Chang David K. , Bailey Peter , Biankin Andrew V. 
Published: April 2017

Abstract
Pancreatic cancer has become the third leading cause of cancer-related death, with little improvement in outcomes despite decades of research. Surgery remains the only chance of cure, yet only 20% of patients will be alive at 5 years after pancreatic resection. Few chemotherapeutics provide any improvement in outcome, and even then, for approved therapies, the survival benefits are marginal. Genomic sequencing studies of pancreatic cancer have revealed a small set of consistent mutations found in most pancreatic cancers and beyond that, a low prevalence for targetable mutations. This may explain the failure of conventional clinical trial designs to show any meaningful survival benefit, except in small and undefined patient subgroups. With the development of next-generation sequencing technology, genomic sequencing and analysis can be performed in a clinically meaningful turnaround time. This can identify therapeutic targets in individual patients and personalize treatment selection. Incorporating preclinical discovery and molecularly guided therapy into clinical trial design has the potential to significantly improve outcomes in this lethal malignancy. In this review, we discuss the findings of recent large-scale genomic sequencing projects in pancreatic cancer and the potential relevance of these data to therapeutic development. Clin Cancer Res; 23(7); 1638–46. ©2017 AACR.
See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked
Authors: Evan Gerard I. , Hah Nasun , Littlewood Trevor D. , Sodir Nicole M. , Campos Tania , Downes Michael , Evans Ronald M. 
Published: April 2017

Abstract
The “hallmarks” of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity, and maintenance. Hence, interfering with such super enhancer–driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extraterminal motif proteins, have shown the feasibility of disrupting super enhancer–dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanisms suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease. Clin Cancer Res; 23(7); 1647–55. ©2017 AACR.
See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”
Abstract A06: Regulation of homologous recombination by the SUMO ligase NSMCE2
Authors: Pond Kelvin W. , DeRenty Christelle , Yagle Mary , Ellis Nathan 
Published: April 2017

Abstract
Introduction: The purpose of this study is to determine the role of the E3 SUMO ligase NSMCE2 in BLM regulation and homologous recombination (HR).
Background: DNA damage generated during replication is a major source of mutations and failure to repair this damage can cause genomic instability. HR is a high-fidelity DNA repair pathway activated primarily by replication-associated DNA damage. Numerous HR proteins are regulated by sumoylation, but the mechanisms that control sumoylation and their roles in HR are poorly understood. Cells deficient in the SUMO E3 ligase NSMCE2 are sensitive to DNA damaging agents and have defects in HR. Our preliminary data indicated that BLM sumoylation is dependent on NSMCE2. Because BLM sumolyation is required to recruit RAD51 to stalled forks, we hypothesized that NSMCE2-deficient cells are deficient in HR due to a defect in BLM-dependent RAD51 recruitment.
Results: To test this hypothesis, we transfected HeLa cells with siRNAs specific to NSMCE2 and tested whether cells could recruit RAD51 to replication forks stalled with hydroxyurea (HU). Contrary to our hypothesis, we found that the amount of RAD51 protein that accumulated at stalled forks was greater in HU-treated NSMCE2-deficient cells compared to HU-treated control cells. To our surprise, the amount of single-stranded DNA binding protein RPA was diminished by half in HU-treated NSMCE2-deficient cells and DNA damage signaling was similarly diminished as evidenced by the lower levels of γ-H2AX. Consistent with the low levels of γ-H2AX, the double-strand breaks (DSB) that normally form after extended treatment with HU were also greatly diminished in NSMCE2-deficient cells. Consistent with previous reports, we found that the levels of HU-induced sister chromatid exchange were also low. These data indicated that despite the over-accumulation of RAD51 to sites of stalled replication forks, cells are unable to perform HR repair efficiently, indicating that RAD51 is unable to complete its function there.
Conclusions: The hyper-accumulation of RAD51 at stalled forks we observed in NSMCE2-deficient cells suggests the sumoylation of one or more substrates by NSMCE2 is required for the remodeling of stalled forks that normally leads to unloading of RAD51 at the fork, strand breakage, and repair by HR. We suggest that the RAD51 accumulation that is observed in a substantial fraction of cancers may not be sufficient to demonstrate that the cells are HR proficient. Based on our data, RPA staining combined with RAD51 may be able to distinguish HR-proficient and deficient cells.
Citation Format: Kelvin W. Pond, Christelle DeRenty, Mary Yagle, Nathan Ellis. Regulation of homologous recombination by the SUMO ligase NSMCE2 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A06.
Abstract A11: RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1
Authors: Vélez-Cruz Renier , Manickavinayaham Swarnalatha , Biswas Anup K. , Clary Regina W. , Johnson David G. 
Published: April 2017

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. Its loss, which is a hallmark of cancer, leads to uncontrolled cell proliferation. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers and remodelers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double strand breaks (DSBs) dependent on E2F1 and ATM kinase activity. RB promotes DNA end resection and DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. 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 knock-in mutation also impairs DNA repair, increases genomic instability and renders mice hypersensitive to IR. Importantly, depletion of either RB or BRG1 in osteosarcoma and breast cancer cell lines results in sensitivity to DNA damaging agents, thus underscoring the importance of these factors in DNA repair. We uncover a novel, non-transcriptional function for RB in HR, which could contribute to genome instability associated with RB loss.
Citation Format: Renier Vélez-Cruz, Swarnalatha Manickavinayaham, Anup K. Biswas, Regina W. Clary, David G. Johnson. RB localizes to DNA double strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A11.
Abstract A39: Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetorchore-microtubule attachments
Authors: Yu Lan , Shang Zeng-Fu , Chen Benjamin P. C. , Saha Debabrata 
Published: April 2017

Abstract
The DAB2IP tumor suppressor protein is a member of the Ras GTPase-activating protein family and is often downregulated by epigenetic silencing in many advanced cancer types. Current literature indicates that DAB2IP plays a crucial role in suppression of the PI3K-Akt pathway and epithelial-mesenchymal transition. Loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is associated with increased androgen receptor signaling and poor patient prognosis. Here we report that loss of DAB2IP is also resulted in chromosomal instability due to defects in kinetochore-microtubule (KT-MT) attachment and the spindle assembly checkpoint (SAC) during mitotic cell cycle transition. Chromosomal instability is one of the key hallmarks of carcinogenesis and has been linked to metastasis, poor prognosis, and therapy resistance in cancer. Our results further indicate that DAB2IP directly interacts with Plk1, and its loss attenuates Plk1 kinase activity and Plk1-dependent BubR1 phosphorylation which is required for BubR1 localization at the kinetochore during mitosis and SAC regulation. Consequently, loss of DAB2IP leads to increased resistance of PCa cells toward microtubule stabilizing drugs (paclitaxel, docetaxel) and Plk1 inhibitor (BI2536). Our findings demonstrate a novel function of DAB2IP in the maintenance of KT-MT structure and proper SAC regulation during mitosis to promote chromosomal stability and genome integrity.
Citation Format: Lan Yu, Zeng-Fu Shang, Benjamin P. C. Chen, Debabrata Saha. Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetorchore-microtubule attachments [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A39.
Abstract B21: The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma
Authors: Burgenske Danielle , Mladek Ann , Sarkaria Jann 
Published: April 2017

Abstract
Glioblastoma (GBM) represents one of the most aggressive cancer types with the vast majority of patients succumbing to disease within the first five years. This dire prognosis reflects the limited efficacy of our frontline therapies which include radiation therapy and temozolomide (TMZ) chemotherapy. The cellular response to these therapies is critically mediated by DNA damage response signaling networks that are regulated by Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR). Preliminary studies from our laboratory suggest the ATR inhibitor VX-970 has single agent efficacy in both established and primary GBM cell lines. Moreover, combined treatment with TMZ demonstrated therapeutic responses that, following regression analysis, were deemed synergistic (p&lt;0.001). Validation studies using siRNA confirmed ATR as a central mediator of TMZ sensitivity as knockdown of ATM elicited no added benefit when tested in combination. VX-970 also enhanced radiation effects in neurosphere formation assays to suggest it may also be used as a radiosensitizer. While the specific mechanism responsible for these observations has yet to be determined, VX-970 treatment was found to exert anti-proliferative effects in a dose-dependent manner. This collection of work suggests that ATR inhibition may represent a worthwhile treatment strategy in GBM.
Citation Format: Danielle Burgenske, Ann Mladek, Jann Sarkaria. The selective ATR inhibitor VX-970 enhances the therapeutic effects of standards of care in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B21.
Abstract B37: PARP inhibitor olaparib induces genomic instability in normal mammalian cells
Authors: Vanoli Fabio , Ito Shuhei , Frock Richard L. , Alt Frederick W. , Moynahan Mary Ellen , Jasin Maria 
Published: April 2017

Abstract
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA damage response pathways to be targeted by specific inhibitors for clinical benefit. Tumors with defects in homologous recombination (HR) are hypersensitive to PARP inhibitors (PARPi), and early phase clinical trials have been promising in patients with advanced BRCA1 and BRCA2-associated breast, ovary and prostate cancer. Unlike HR-defective cells, HR-proficient cells manifest low cytotoxicity when exposed to PARPi. Nonetheless, they mount a DNA damage response and show a genomic instability phenotype as demonstrated by an increased frequency of sister chromatid exchange. To study molecular mechanisms underlying PARPi-generated genomic instability, we took advantage of olaparib an agent in clinical use. Our results in mouse embryonic stem cells show that olaparib increases HR leading to copy number alterations and induces a mutator phenotype. Further, using a genome wide approach we finally demonstrate that PARPi treatment increases DNA double-strand breaks genome-wide which can lead to translocations and other genome aberrations. Our findings have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration in prevention strategies or for non-oncologic indications.
Citation Format: Fabio Vanoli, Shuhei Ito, Richard L. Frock, Frederick W. Alt, Mary Ellen Moynahan, Maria Jasin. PARP inhibitor olaparib induces genomic instability in normal mammalian cells [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B37.