bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A14: Engineering pancreatic cancer through molecular and cellular reconstruction
Authors: Akanuma Naoki , Liu Jun , Wang Pei
Published: December 2016

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human malignancies characterized by the accumulation of a series of genetic mutations during disease progression. Despite significant amount of studies using genetically engineered mouse PDAC models, human PDAC still has a dismal prognosis, and there are few models for human PDAC tumorigenesis. To establish a genetic modification system for human pancreatic tissue, we made lentiviral CRISPR to target CDKN2A/p16, p53 and SMAD4. We have confirmed the efficiency of the p16 CRISPR, p53 CRISPR and SMAD4 CRISPR constructs in editing the genome to delete the respective gene loci. We then generated a lentiviral vector to express KRASG12D-mCherry and transduced normal human primary pancreatic exocrine cells with single or multiple viral vector combinations. After one week of culture, two million of the cells were transplanted into the renal sub-capsular space of NOD-SCID mice. The engraftments were harvested 4 months after transplantation. We observed two PanIN lesions in kidneys where KRASG12D mutant cells were transplanted. Human cells were detected using anti-human nuclear antigen antibody (anti-HuNu). Anti-Pan cytokeratin staining proved that the lesions were made up of epithelial cells. The histologic appearance of the lesion from the cells with all four mutations, KRASG12D p16-/- p53-/- SMAD4-/-, differed from that of the two PanIN lesions in that has a single, much larger cyst with mucin rich cytoplasm reminiscent of mucinous cystic neoplasm (MCN). To further define the cellular origin of PDAC initiation, we also developed a flow cytometry-based method to sort viable ductal cells and acinar cells from primary normal human pancreatic cells for genetic modifications. In summary, we have successfully generated PDAC-associated-precancerous lesions from primary normal human pancreatic tissues. The system established in this study could be a valuable platform to address the fundamental mechanisms for the human PDAC tumorigenesis process.

Citation Format: Naoki Akanuma, Jun Liu, Pei Wang.{Authors}. Engineering pancreatic cancer through molecular and cellular reconstruction. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A14.
Abstract A89: Is it justified to have pancreaticoduodenectomy in elderly patients with pancreatic malignancy? A population-based study
Authors: Yang Ching-Yao , Wu Jin-Ming , Kuo Ting-Chun , Lai Hong-Shiee , Tien Yu-Wen
Published: December 2016

Introduction: Although the perioperative outcome of pancreaticoduodenectomy (PD) has improved in these 10 years, and several studies found the short-term, perioperative outcome is similar between the groups in the elderly or younger patients, the issue of PD on eldely patients is still controversial. Most of the studies were performed in single institute or only reported the short-term outcome. The purpose of this study is to use population-based data to analyze the age effect on perioperative and long-term outcome after PD, esp. in the elderly patients more than 75 years old, and with pancreatic malignancy.

Methods: By using the National Health Insurance Research Database (NHIRD) of Taiwan, we performed this nationwide retrospective cohort study.

Results: Between 2001-2010, totally, 4475 adult patients (>= 20 years) who received elective PD with ICD procedure code: 52.7 were included. Overall, the 30-day including in-hospital mortality, and 1-year mortality was 5.2%, and 22.9% in younger patients (<= 75 years), and 14.4% and 40% in the elderly (> 75 years). 3639 cases were malignancy, while only 836 cases were benign disease. We further analyzed the data from patients with pancreatic malignancy, elderly patients have significantly longer hospital stay (41.5 days vs 35.9 days), ICU stay and hospital cost after PD. After multivariate analysis, the elderly has significantly higher 30-day mortality (adjusted OR: 2.425 comparing with the younger), and higher 1-year mortality (adjusted OR: 1.867), the age effect on mortality can also be observed as a significant trend (for patients >80, 70-80, 60-70 comparing with <= 60 years: adjusted OR 3.85, 3.50, 2.12). Other factors to predict higher mortality included patients need PRBC transfusion, CCI>2, patients with preoperative comorbidity: myocardia infarction and renal failure. Patients received PD at high volume center (PD >=20 cases / year) have significant less 30-day, and 1-year mortality (adjusted OR: 0.447, and 0.748). Female patients, and operation during the late era, 2006-2010 are the good predictors for less mortality. Furtherly, decision-tree analysis found the old age and operation at high volume center are the most important effects on mortality.

Conclusion: Elderly patients (> 75 years) with pancreatic malignancy after pancreaticoduodenectomy have significantly higher 30-day and 1-year mortality. We recommended all elderly patients should be treated at high-volume centers.

Citation Format: Ching-Yao Yang, Jin-Ming Wu, Ting-Chun Kuo, Hong-Shiee Lai, Yu-Wen Tien.{Authors}. Is it justified to have pancreaticoduodenectomy in elderly patients with pancreatic malignancy? A population-based study. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A89.
Abstract A90: Mesothelin confers tumor cell vulnerabilities for gefitinib treatment
Authors: Poteet Ethan , Liang Zhengdong , Wang Youwen , Chen Changyi , Yao Qizhi
Published: December 2016

Combination therapy for pancreatic adenocarcinoma (PDAC) has recently had two successful stage III trials with FOLFIRINOX (combination folinic acid, fluorouracil, irinotecan, and oxalplatin) and combination gemcitabine and paclitaxel. Because of the heterogeneity of PDAC, the benefits of combination therapy are immediately apparent since it targets multiple facets of cancer simultaneously. However, FOLFIRINOX and gemcitabine + paclitaxel are highly toxic and affect all dividing cells, making apparent the need for better understanding of the cell profiles in PDAC. The epidermal growth factor receptor (EGFR) is involved in the pathogenesis and progression of many cancers, with EGFR or its ligands often overexpressed or mutated. Recently we have found that EGFR expression is correlated to mesothelin (MSLN) expression in PDAC. MSLN, a cell surface glycoprotein, has been shown by us and other labs to be overexpressed in 80 to 90% of all PDAC cases. To examine the relationship between MSLN and EGFR, we modulated MSLN expression by generating a MSLN overexpressing cell line from MIA-PaCa2 cells, and a MSLN knockdown cell line from CAPAN-2 cells. The change in EGFR signaling mimicked that of MSLN, with MSLN overexpression significantly increasing EGFR expression and MSLN knockdown significantly decreasing EGFR expression. Furthermore, high MSLN (and therefore high EGFR expression) showed increased sensitivity to gefitinib, an EGFR ATP binding site inhibitor, at concentrations as low as 100 nM, while MSLN low expressing cells did not exhibit any effect from gefitinib at concentrations below 10 µM. Cell Cycle analysis demonstrated that gefitinib increased the number of cells in G1 phase after 24 hours in MSLN high expressing cells, but had no effect on MSLN low expressing cells. In addition, western blot analysis of EGFR downstream pathways showed an increase in phosphorylated phospholipase C-Υ (PLC-Υ) in MSLN high expressing cells, which could be mitigated by treatment with gefitinib. Finally, combination therapy with gemcitabine and 100 nM gefitinib showed an additive effect in MSLN high expressing cells, while in MSLN low expressing cells combination gemcitabine and gefitinib had no additional effect over gemcitabine alone. This study demonstrates the correlation between MSLN expression and EGFR expression and indicates that gefitinib could be a potential addition to combination therapy for PDAC in patients with high MSLN expression.

Citation Format: Ethan Poteet, Zhengdong Liang, Youwen Wang, Changyi Chen, Qizhi Yao.{Authors}. Mesothelin confers tumor cell vulnerabilities for gefitinib treatment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A90.
Abstract B03: Pancreatic cancer stem cells: can it be restrained?
Authors: Chopra Neha , Choudhury Sangeeta , Wajid Saima , Jain Kriti , Mirza Rizwana
Published: December 2016

Over the past decades world-wide, research towards not only understanding the biology, but also attempting to decrease the mortality rate in pancreatic carcinoma has become the forefront in cancers of solid tumor. Recent evidences suggest that pancreatic carcinomas harbour a distinct subpopulation of putative cancer stem cells defined by their self-renewal capacity, differentiation ability, tumorigenicity and ability to drive towards metastasis. Therefore, there is not only a need to identify this population, and also design newer approaches to target these chemo-resistant cell populations, especially in pancreatic cancer which till date shows 5-year survival rate to be below 5%.

Our study identified the potential of CD44hiCD24lo MiaPaCa2/PanC1 cells to possess lower capability to generate spheroids whereas CD44hiCD24hi MiaPaCa2/PanC1 showed higher spheroid forming capacity. Spheroids obtained from both cell-lines showed similar metastatic cancer gene expression pattern. However, a distinctive CXCR4 expression levels were observed between CD44hiCD24lo PanC1-spheroids and CD44hiCD24hi PanC1-spheroids. It was also observed that EMT, CXCR4 and Muc1 were highly expressed in MiaPaCa2-spheroids. Hence, suggesting only a sub-population of tumor cells behave as “cancer initiating cells/stem-like cells” which are associated with cell-cell adhesion and cell matrix interaction.

In order to determine the role of cancer stem-like cells (spheroids/CSCs) to migrate and invade to metastasize particularly in pancreatic carcinoma, experiments were designed to evaluate their self-renewal capability and epithelial to mesenchymal transition (EMT) and their association with developmental genes. An exponential spheroid formation was observed along with stem cell transcriptional genes (Oct4 and Nanog). Interestingly, MiaPaCa2-spheroids exhibited higher expression levels of Sox-2, MMP-9 and Vimentin in comparison to PanC1-spheroids suggesting that MiaPaCa2-spheroids may be more aggressive or has higher invasive potential. It appears that pancreatic CSCs undergoing EMT probably express higher levels of Sox-9, Ngn-3, Pdx-1 and c-Myc genes which attributes to its embryonic stemness.

The results from the study clearly project the role of CSCs in pancreatic carcinoma and thus further studies to delineate the mechanism which might lead to suppression of pancreatic CSCs is crucial. In this direction, a pilot study has been initiated to explore the potential of Mesenchymal Stem Cells to target the pancreatic CSCs.

Citation Format: Neha Chopra, Sangeeta Choudhury, Saima Wajid, Kriti Jain, Rizwana Mirza.{Authors}. Pancreatic cancer stem cells: can it be restrained? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B03.
Abstract B53: The integrin αvβ6 is a promising therapeutic target for treating PDAC
Authors: Vallath Sabari , Reader Claire , Morton Jennifer , Sansom Owen , Evans Jeff , Biankin Andrew , Barry Simon T. , Kocher Hemant , Marshall John F.
Published: December 2016

Integrins are expressed on the surface of all nucleated cells and permit bi-directional communication for cells with their extracellular environment. The integrin αvβ6 is not usually expressed on adult cells unless they are undergoing tissue remodeling, as αvβ6 activates TGFβ, the cytokine that orchestrates wound healing. We find that αvβ6 is not expressed by normal pancreas but is upregulated on over 90% of PDAC. In vitro experiments show αvβ6 promotes cell survival, adhesion, migration and invasion through Matrigel. Treatment with αvβ6-blocking antibody 264RAD of xenografts of human PDAC cell line CfPac1 co-injected with stellate cells stopped tumor growth. In combination with Gemcitabine 264RAD shrank established (100mm3) tumors significantly (p<0.001). In separate studies we treated novel transgenic mice (Pdx1-Cre; LSL-KRasG12D/+; LSL-Dusp6-/-; developed by Prof. S. Keays) with Gemcitabine or 264RAD+Gemcitabine once they had developed PDAC. The Gemcitabine alone group all died within 17 days but the combination therapy group lived significantly longer, the last animal dying at 59 days. Immunohistological analysis shows that the 264RAD-treated tumors had significantly reduced pErk and Ki67 suggesting reduced growth signaling and proliferation. Additionally strongly reduced endomucin and SMA suggest reduction in angiogenesis and myofibroblast activity in the microenvironment. This may be due to reduced TGFβ signaling since pSMAD3 and nuclear SMAD4 levels were also strongly suppressed. Thus 264RAD suppressed PDAC development by targeting both the pancreatic cancer cells and the microenvironment. These studies have resulted in the funding of a Phase I trial for 264RAD therapy of PDAC patients, sponsored by Cancer Research UK in collaboration with AstraZeneca-Medimmune.

Citation Format: Sabari Vallath, Claire Reader, Jennifer Morton, Owen Sansom, Jeff Evans, Andrew Biankin, Simon T. Barry, Hemant Kocher, John F. Marshall.{Authors}. The integrin αvβ6 is a promising therapeutic target for treating PDAC. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B53.
Abstract B68: Role of CD44 in pancreatic cancer cell plasticity
Authors: Freeman James W. , Zhao Shujie , Chen Chen , Karnad Anand
Published: December 2016

Two subpopulations of pancreatic adenocarcinoma (PDAC) cells were separated from different cell lines on the basis of CD44 expression level. CD44 high and CD44 low expressing cells were compared for their invasive potential, epithelial/mesenchymal phenotype, in vitro response and in vivo development of resistance to gemcitabine. CD44 high cells showed a mesenchymal phenotype, formed tumor spheres, were more invasive and were less responsive to gemcitabine. In contrast, CD44 low cells had an epithelial phenotype, were weakly invasive, did not grow as tumor spheres and showed greater response to gemcitabine. CD44 high cells showed a predominant expression of CD44 standard isoform with lower levels of various CD44 variant isoforms. Interestingly, gemcitabine treatment of CD44 low cells induced a phenotypic switch, loss of ESRP1 expression with concurrent up regulation in expression of CD44 standard. In an orthotopic mouse model, tumors from CD44 high cells had a selective growth advantage and formed metastases more rapidly. Gemcitabine treatment continuously suppressed tumor growth in animals implanted with CD44 low cells during the 22 weeks of the experiment; whereas, tumors from CD44 high cells initially showed some response to gemcitabine but developed resistance by weeks 10-12. Knockdown of CD44 in CD44 high cells from two different PDAC cell lines, inhibited invasion and increased their response to gemcitabine similar to that seen for CD44 low cells. Collectively this study suggests that a subpopulation of CD44 high expressing PDAC cells with a mesenchymal-like phenotype tends to be highly invasive, more resistant to gemcitabine in vitro and to develop gemcitabine resistance in vivo. Thus, initial targeting CD44 or reversing the CD44 high phenotype may improve therapeutic response of PDAC.

Citation Format: James W. Freeman, Shujie Zhao, Chen Chen, Anand Karnad.{Authors}. Role of CD44 in pancreatic cancer cell plasticity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B68.
Abstract IA08: Drugging undruggable kras: will myc do the trick?
Authors: Der Channing J.
Published: December 2016

KRAS oncogene mutations are found in ~95% of pancreatic ductal adenocarcinoma (PDAC) and are well validated drivers of PDAC initiation and maintenance. Consequently, a major goal for the field is the development of effective anti-KRAS therapies. However, despite more than three decades of intensive effort, no effective pharmacologic inhibitors of the KRAS have reached the clinic, prompting the widely held perception that KRAS is “undruggable”. However, with more advanced knowledge of KRAS function and new technological approaches, there is renewed hope that the time is ripe to revisit targeting KRAS. I will present our studies focused on the RAF-MEK-ERK mitogen-activated protein kinase cascade. This effector signaling network is a well-validated driver of KRAS-dependent cancer growth. Despite this key role, pharmacologic inhibitors of RAF and MEK have been ineffective in inhibiting growth of KRAS-mutated cancers, in large part due to dynamic signal reprogramming leading to ERK reactivation and bypass of inhibitor action. We therefore addressed whether direct ERK inhibition may be a more effective therapeutic approach. We identified a growth suppression mechanism due to pharmacologic inhibition of ERK that involves degradation of the MYC oncoprotein, activation of the p16INK4A-RB1 tumor suppressor pathway and induction of a senescence-like phenotype. We also applied unbiased genetic and chemical functional screens, as well as reverse phase protein array analyses, and identified the PI3K-AKT-mTOR signalling network as a key driver of pancreatic cancer resistance to ERK inhibition. Novel combination inhibitor approaches that synergistically enhanced ERK inhibitor anti-tumor activity were also identified. Finally, we determined that continued expression of KRAS was required for maintenance of MYC protein expression. We determined that previously identified mechanisms of RAS effector signaling alone did not account for MYC protein regulation in PDAC, prompting our search for novel protein kinases that regulate MYC protein degradation. Our efforts are centered defining pharmacologic strategies to accelerate MYC protein degradation as a novel approach for blocking mutant KRAS in PDAC.

Citation Format: Channing J. Der.{Authors}. Drugging undruggable kras: will myc do the trick? [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA08.
Abstract IA13: Stromal regulation and therapeutic targeting of the pancreatic cancer epigenome
Authors: Sherman Mara H. , Evans Ronald M.
Published: December 2016

Though the significance of reciprocal interactions between genetically altered tumor cells and adjacent stroma is increasingly appreciated, this complex crosstalk remains poorly understood. Pancreatic ductal adenocarcinoma (PDAC) has a particularly prominent stromal compartment, shown to exert both tumor-supportive and tumor-suppressive or homeostatic functions in the context of the wound-like tumor microenvironment. To investigate the paracrine effects of PDAC stromal elements on pancreatic cancer cells, we developed a “stromal” culture system, which incorporates structural and diffusible stroma-derived elements into homotypic PDAC cell cultures amenable to functional genomics and metabolomics. These analyses revealed that microenvironmental cues co-regulate cancer metabolism and gene expression. Stromal inputs broadly influenced histone acetylation in the PDAC epigenome, which coincided with induction of genes implicated in anabolic metabolism and inflammation. The gene expression and metabolic changes induced by stromal factors overlap with those previously identified following oncogenic Kras, suggesting functional complementarity between cell-autonomous and microenvironmental pathways characteristic of PDAC. As epigenome modification results in changes in gene expression through the functions of readers, such as the bromodomain-containing BET proteins, we tested JQ1, a small molecule inhibitor of BET family bromodomain-containing proteins, for the capacity to inhibit gene expression changes downstream of stromal factors. Paracrine induction of pro-growth and inflammatory genes was inhibited by JQ1, suggesting that the BET family serves as a key transducer of stromal inputs to drive alterations in gene expression. Inhibition of acetyl-lysine sensing by the BET family reduced pancreatic tumor growth and associated inflammation in vivo, with significant reduction in expression of genes implicated in macromolecule biosynthesis and tumor-permissive immune regulation. This work suggests paracrine epigenome regulation as a conduit through which stromal signals drive metabolic and immune adaptation to a challenging tumor microenvironment.

Citation Format: Mara H. Sherman, Ronald M. Evans.{Authors}. Stromal regulation and therapeutic targeting of the pancreatic cancer epigenome. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA13.
Abstract IA18: Probing tumor heterogeneity with mouse models
Authors: Stanger Ben Z.
Published: December 2016

Although the majority of pancreatic cancers harbor mutations in a small set of cancer genes, individual tumors vary widely with respect to histology, gene expression patterns, and response to therapy. This inter-tumoral heterogeneity is likely due to mutations or epigenetic events affecting less commonly-mutated cancer genes, resulting in tumors that can be broadly grouped into three or four categories based upon transcriptional profiling. To determine the extent to which the KPC model captures the inter-tumoral heterogeneity of pancreatic cancer, we performed RNA-sequencing on isolated tumor cells from 11 murine pancreatic tumors. Using unsupervised clustering, tumors fell into two broad categories: cluster 1 tumors, which were poorly-differentiated and well-vascularized, and cluster 2 tumors, which were moderately- to well-differentiated and poorly-vascularized. Differences in gene expression could account for some of these differences; for example, cluster 1 tumor cells exhibited low levels of Shh expression, consistent with the paucity of stroma. Moreover, mechanisms of EMT differed between the two classes of tumors. Gene set variation analysis with whole transcriptome data from human PDA revealed a correlation between cluster 1 tumors and the squamous or quasi-mesenchymal subtype. Likewise, cluster 2 tumors were correlated with the classical, ADEX, and pancreatic progenitor subtypes of human PDA. These data suggest that the KPC mouse model, despite its foundation on Kras and p53 mutations alone, captures the heterogeneity of human PDA and may therefore be useful for understanding heterogeneous responses to therapy.

Citation Format: Ben Z. Stanger.{Authors}. Probing tumor heterogeneity with mouse models. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA18.
Abstract PR10: CXCR2 Inhibition Suppresses Metastasis and Improves the Response to Immunotherapy in Pancreatic Cancer
Authors: Steele Colin , Karim Saadia , Leach Josh , Bailey Peter , Biankin Andrew , Nibbs Rob , Barry Simon , Sansom Owen , Morton Jen
Published: December 2016

PDAC is predicted to become the second commonest cause of cancer death in the western world by 2030. Aggressive invasion and early metastases are characteristic of the disease, and even the few patients eligible for potentially curative resection inevitably develop recurrent or metastatic disease.

We now show that CXCR2 signalling is upregulated in human pancreatic cancer, predominantly in neutrophils at the tumour invasive edge. In mouse models, genetic ablation or inhibition of CXCR2 abrogated metastasis while inhibition also slowed tumorigenesis, particularly when combined with chemotherapy. Depletion of neutrophils also suppressed metastasis, suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche.

Indications from trials thus far suggest that immunotherapy will not work as a single agent strategy in pancreatic cancer patients. Importantly, we find that loss or inhibition of CXCR2 improved T-cell entry and combined inhibition of CXCR2 and PD1 in mice with established disease caused a significant extension of survival.

Thus, our data highlight two novel therapeutic opportunities for PDAC: first the use of CXCR2 inhibitors in surgically-resected patients to prevent recurrence at distant sites, and second, the use of CXCR2 inhibition in combination with immunotherapy in surgically unresectable advanced disease.

This abstract is also being presented as Poster B55

Citation Format: Colin Steele, Saadia Karim, Josh Leach, Peter Bailey, Andrew Biankin, Rob Nibbs, Simon Barry, Owen Sansom, Jen Morton.{Authors}. CXCR2 Inhibition Suppresses Metastasis and Improves the Response to Immunotherapy in Pancreatic Cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr PR10.
Optimizing Cerebral Autoregulation May Decrease Neonatal Regional Hypoxic-Ischemic Brain Injury
Authors: Lee Jennifer K. , Poretti Andrea , Perin Jamie , Huisman Thierry A.G.M. , Parkinson Charlamaine , Chavez-Valdez Raul , O'Connor Matthew , Reyes Michael , Armstrong Jillian , Jennings Jacky M. , Gilmore Maureen M. , Koehler Raymond C. , Northington Frances J. , Tekes Aylin
Published: December 2016

Background: Therapeutic hypothermia provides incomplete neuroprotection for neonatal hypoxic-ischemic encephalopathy (HIE). We examined whether hemodynamic goals that support autoregulation are associated with decreased brain injury and whether these relationships are affected by birth asphyxia or vary by anatomic region. Methods: Neonates cooled for HIE received near-infrared spectroscopy autoregulation monitoring to identify the mean arterial blood pressure with optimized autoregulatory function (MAPOPT). Blood pressure deviation from MAPOPT was correlated with brain injury on MRI after adjusting for the effects of arterial carbon dioxide, vasopressors, seizures, and birth asphyxia severity. Results: Blood pressure deviation from MAPOPT related to neurologic injury in several regions independent of birth asphyxia severity. Greater duration and deviation of blood pressure below MAPOPT were associated with greater injury in the paracentral gyri and white matter. Blood pressure within MAPOPT related to lesser injury in the white matter, putamen and globus pallidus, and brain stem. Finally, blood pressures that exceeded MAPOPT were associated with reduced injury in the paracentral gyri. Conclusions: Blood pressure deviation from optimal autoregulatory vasoreactivity was associated with MRI markers of brain injury that, in many regions, were independent of the initial birth asphyxia. Targeting hemodynamic ranges to optimize autoregulation has potential as an adjunctive therapy to hypothermia for HIE.
Abnormal Time Experiences in Major Depression: An Empirical Qualitative Study
Authors: Stanghellini Giovanni , Ballerini Massimo , Presenza Simona , Mancini Milena , Northoff Georg , Cutting John
Published: December 2016

Background: Phenomenological psychopathology, through theoretical and idiographic studies, conceptualizes major depressive disorder (MDD) as a disorder of time experience. Investigations on abnormal time experience (ATE) in MDD adopting methodologies requested by the standards of empirical sciences are still lacking. Our study aimed to provide a qualitative analysis, on an empirical ground and on a large scale, of narratives of temporal experiences of persons affected by MDD. Methods: We interviewed 550 consecutive patients affected by affective and schizophrenic disorders. Clinical files were analysed by means of consensual qualitative research. Results: Out of 100 MDD patients, 96 reported at least 1 ATE. The principal categories of ATE are vital retardation - the experience of a stagnation of endogenous vital processes (37 patients), the experience of present and future dominated by the past (29 patients), and the experience of the slackening of the flow oftime (25 patients). A comparison with ATE in schizophrenia patients showed that in MDD, unlike in schizophrenia, there is no disarticulation of time experience (disorder of temporal synthesis) but rather a disorder of conation or inhibition of becoming. Limitations: The interview style was not meant to make a quantitative assessment (“false negatives” cannot be excluded). Conclusions: Our findings confirm the relevance of distinctive features of ATE in MDD, support the hypothesis of an intrinsic disordered temporal structure in depressive symptoms, and may have direct implications in clinical practice, especially in relation to differential diagnosis, setting the boundaries between “true” and milder forms of depression, and neurobiological research.
Hippocampal Characteristics and Invariant Sequence Elements Distribution of GLRA2 and GLRA3 C-to-U Editing
Authors: Schaefermeier Philipp , Heinze Sarah
Published: December 2016

Glycine receptor α2 and α3 subunit (GLRA2/GLRA3) high- affinity variants, of which the subjacent amino acid substitutions issue from C-to-U RNA editing, are thought to influence tonic inhibition and pathophysiology. In light of the detection of GLRA3 NM_006529:r.1157C>U and GLRA2 NM_002063:r.1416C>U exchanges in hippocampus explants of temporal lobe epilepsy patients, we now examine the healthy situation and relate it to the epileptic situation by ascertaining controls in a legitimate reanalysis. The GLRA2 and GLRA3 editing events that would ultimately result in a glycine receptor with increased affinity occur in the postmortem nonepileptic hippocampus. Most notably, their relative amounts do not significantly differ from those in increased damaged hippocampus explants, whereas curbed relative amounts in epileptic explants without cell loss come out statistically significant. Local sequence alignment reveals invariant sequence stretches consistent in GLRA2/ GLRA3 and other edited transcripts that coincide with known APOB sequence elements. Concerning the essential mooring element, GLRA2/GLRA3 comply strictly only with the motif's 5′ part. While this lack of canonical mooring elements and uncertain action of the famous deaminase APOBEC1 suggest a specific regulation of GLRA2/GLRA3 editing, its reduction in the less-damaged epileptic hippocampus could be attributed to anomalous epileptic neurogenesis.
Juggling the Balance between Preventive Security and Human Rights in Europe
Authors: Den Boer Monica
Published: December 2016

Within the European Union (eu), security issues are increasingly framed as risks and threats that can be controlled bypreventive measures. Theeuhas established several agencies, legal instruments and databases to facilitate the prevention of crime, terrorism and irregular migration. This article takes stock of the way in which theeuseeks to balance the preventive security logic with its own human rights framework. While human rights can jointly be considered an evolving normative framework in theeu, there is a need to identify which human rights are at risk and how (non-) compliance ought to be monitored.

The article states some concerns about equal access to human rights as well as the lack of a strong general oversight mechanism. Continued structural attention should be given toex antehuman-rights impact assessments and there needs to be more emphasis on regular external evaluations of human rights complianceex post facto. In relation to the external action of theeu, theeumust practice what it preaches and needs to reflect critically on the necessity and proportionality of precautionary security measures.
Preventism, Disaster Risk Reduction and the Consequences for Human Rights
Authors: da Costa Karen
Published: December 2016

This article explores the notion of preventism and how it relates to disaster risk reduction (drr). It then ponders how the combination of preventism with disaster risk reduction may influence human rights. Different scenarios are considered in which the interaction of these concepts is relevant. The main argument is that preventism may lead to more drr initiatives and that this may well be considered a positive development to a certain extent, but that care should be taken not to jeopardize human rights in this process.
On the identity of Sium frigidum (Apiaceae)
Authors: WANG LISONG , ZHANG HONGRUI , WATSON MARK F. , KNAPP SANDRA
Published: December 2016

Taxonomic identity of Sium frigidum remains confusing; the taxon has been treated as belonging to four different genera including Apium, Sium, Chamaesium and Sinocarum. After field investigation, detailed examination of herbarium specimens, and analyses of molecular data, the results show that S. frigidum represent plants only known from southwest China, and conspecific with Apium ventricosum. Therefore, a new combination name, Sium ventricosum, is proposed with full taxonomic treatments. Taxonomic confusing related with this species is also discussed.
A new species of the genus Meganola Dyar, 1898 (Lepidoptera, Nolidae, Nolinae) from China
Authors: HAN HUILIN , HU YANQING
Published: December 2016

Meganola is a large and morphologically rather diverse genus, which is widely distributed on all continents, although it proved to be the most species rich in the mountains of Southeast Asia. In this article, the new species Meganola tibetensis was collected at Tibet and reminds externally Himalayan-Indochinese species Meganola mediofusca László, Ronkay & Witt, 2007. These two species have similar configuration of female genitalia concerning the spinulose signum, but their male genitalia are totally different. In male genitalia, harpe approximate trapezoid and aedeagus without cornuti in new species, while in M. mediofusca harpe claw-like and aedeagus armed with many spines. Adults and genitalia of both species are illustrated.
Doppler Radar Analysis of a Tornadic Miniature Supercell during the Landfall of Typhoon Mujigae (2015) in South China
Authors: Zhao Kun , Wang Mingjun , Xue Ming , Fu Peiling , Yang Zhonglin , Chen Xiaomin , Zhang Yi , Lee Wen-Chau , Zhang Fuqing , Lin Qing , Li Zhaohui
Published: December 2016

On 4 October 2015, a miniature supercell embedded in an outer rainband of Typhoon Mujigae produced a major tornado in Guangdong province of China, leading to 4 deaths and up to 80 injuries. This study documents the structure and evolution of the tornadic miniature supercell using coastal Doppler radars, a sounding, videos, and a damage survey. This tornado is rated at least EF3 on the enhanced Fujita scale. It is by far the strongest typhoon rainband tornado yet documented in China, and possessed double funnels near its peak intensity.

Radar analysis indicates that this tornadic miniature supercell exhibited characteristics similar to those found in United States landfalling hurricanes, including a hook echo, low-level inf low notches, an echo top below 10 km, a small and shallow mesocyclone, and a long lifespan (3 h). The environmental conditions—which consisted of moderate convective available potential energy (CAPE), a low lifting condensation level, a small surface dewpoint depression, a large veering low-level vertical wind shear, and a large cell-relative helicity—are favorable for producing miniature supercells. The mesocyclone, with its maximum intensity at 2 km above ground level (AGL), formed an hour before tornadogenesis. A tornado vortex signature (TVS) was identified between 1 and 3 km AGL, when the parent mesocyclone reached its peak radar-indicated intensity of 30 m s−1. The TVS was located between the updraft and forward-flank downdraft, near the center of the mesocyclone. Dual-Doppler wind analysis reveals that tilting of the low-level vorticity into the vertical direction and subsequent stretching by a strong updraft were the main contributors to the mesocyclone intensification.
Preliminary Test of a Data Assimilation System with a Regional High-Resolution Atmosphere–Ocean Coupled Model Based on an Ensemble Kalman Filter
Authors: Kunii Masaru , Ito Kosuke , Wada Akiyoshi
Published: December 2016

An ensemble Kalman filter (EnKF) that uses a regional mesoscale atmosphere–ocean coupled model was preliminarily examined to provide realistic sea surface temperature (SST) estimates and to represent the uncertainties of SST in ensemble data assimilation strategies. The system was evaluated through data assimilation cycle experiments over a one-month period from July to August 2014, during which time a tropical cyclone (TC) as well as severe rainfall events occurred. The results showed that the data assimilation cycle with the coupled model reproduced SST distributions realistically even without assimilating SST and sea surface salinity observations, and atmospheric variables provided to ocean models can, therefore, control oceanic variables physically to some extent. The forecast error covariance calculated in the EnKF with the coupled model showed dependency on oceanic vertical mixing for near-surface atmospheric variables due to the difference of variability between the atmosphere and the ocean as well as the influence of SST variations on the atmospheric boundary layer. The EnKF with the coupled model reproduced the intensity change of Typhoon Halong (2014) during the mature phase more realistically than with an uncoupled atmosphere model, although there remained a degradation of the SST estimate, particularly around the Kuroshio region. This suggests that an atmosphere–ocean coupled data assimilation system should be developed that is able to physically control both atmospheric and oceanic variables.
Garden visiting as a meaningful occupation for people in later life
Authors: Leaver Rosemary , Wiseman Tania
Published: December 2016

Introduction

Garden visiting, as described in this study, involves visiting private gardens which householders have temporarily opened to the public, in support of charity. In the United Kingdom, garden visiting is a popular occupation which attracts 750,000 people each year. The connections between active gardening and wellbeing are well established, particularly for people in later life. This research explores visiting other people’s gardens for leisure in order to deepen our understanding of how garden visiting is experienced as an occupation.

Method

Seven people aged between 60 and 81 years old who considered themselves fully retired were interviewed whilst walking through parks and public gardens. Thematic analysis with inductive coding was used to analyse the data.

Findings

Four themes emerged: time and wellbeing, embodied wellbeing, being part of a gardening community and pondering the creator.

Conclusion

Garden visiting is a complex occupation which brings far-reaching benefits to individuals and communities. Garden visiting also has important implications for increasing wellbeing by grounding people in the present and promoting sensory engagement.
Optimal threshold estimation for binary classifiers using game theory
Authors: Sanchez Ignacio Enrique
Published: December 2016

Many bioinformatics algorithms can be understood as binary classifiers. They are usually trained by maximizing the area under the receiver operating characteristic (ROC) curve. On the other hand, choosing the best threshold for practical use is a complex task, due to uncertain and context-dependent skews in the abundance of positives in nature and in the yields/costs for correct/incorrect classification. We argue that considering a classifier as a player in a zero-sum game allows us to use the minimax principle from game theory to determine the optimal operating point. The proposed classifier threshold corresponds to the intersection between the ROC curve and the descending diagonal in ROC space and yields a minimax accuracy of 1-FPR. Our proposal can be readily implemented in practice, and reveals that the empirical condition for threshold estimation of “specificity equals sensitivity” maximizes robustness against uncertainties in the abundance of positives in nature and classification costs.
EVOLUTION OF SUSTAINABLE DEVELOPMENT THEORY: EMERGENCE OF NEW THEORIES
Authors: Ватолкина Н , Vatolkina N , Левкина Альбина , Levkina Albina
Published: December 2016

The article discusses the evolution of the concept of sustainable development at the present stage in the context of the emergence of new approaches providing theoretical justification and instrument set for this concept. An overview of the new approaches is undertaken in the context of the three spheres of sustainable development: ecological sphere – circular economy and bio-economy; social sphere – the concept of corporate social responsibility; the economic sphere – the concept of corporate sustainability. The concept of "green economy" and theory of resilience thinking are considered by the authors as promising theories that may provide a new quality of relationship of interdependence of the components of sustainable development.
MODELING OF SUSTAINABLE DEVELOPMENT INDICATORS: REGIONAL ASPECT
Authors: Гуськова Надежда , Guskova Nadezhda , Вдовин Сергей , Vdovin Sergey , Иванова Ирина , Ivanova Irina
Published: December 2016

Strategic management is aimed at socio-economic development of region at the effective use of his potential. Questions of development of strategy of increase of stability of regional development and forming of mechanism of its realization are actual. Transformation of the territorial systems, development and acceptance of the administrative decisions aimed at providing of their competitive edges and stability of development must be reasonable mathematical and instrumental methods. In this research the methodical approach to prognostication of basic indicators of steady development of the regional systems and ground of administrative decisions on the increase of stability of development of region are worked out, the integral indexes of stability of socio-economic development of subjects of Russian are built, complex estimation is conducted with the use of econometrics design (systems of simultaneous equalizations). Attained results of research allow using the worked out model for an estimation, comparative analysis and prognostication of the regional systems on the level of stability of their development.
INTERACTION MARKETING AS A BASIS TO DEVELOP LONG-TERM PARTNERSHIPS IN BUSINESS
Authors: Никитина Ирина , Nikitina Irina , Резник Галина , Ryeznik Galina
Published: December 2016

The article reveals the essence of the concept of marketing interaction, presents the evolution of marketing concepts, describes the results of investigation of relationship marketing on the example of a small business, and gives recommendations for ensuring long-term interaction between consumers, manufacturers and key business partners.
EVALUATION OF ECOLOGIC AND ECONOMIC EFFICIENCY OF DEVELOPMENT OF AUTOMOBILE TRANSPORT SYSTEMS IN THE REGIONS OF RUSSIA
Authors: Иосифов Валерий , Iosifov Valeriy , Ратнер Светлана , Ratnyer Svyetlana
Published: December 2016

This article shows a method of evaluating relative efficiency of regional automobile transport systems based on a set of indicators, which reflect the economic and ecological aspects of their activity. This method is based on the data envelopment analysis methodology, and uses negative ecologic effects of automobile transport development as inputs, which includes the yearly volume of polluting emissions and the area of the land mass used for roads. As outputs, we use the GRP volume and the population of the region. With this definition of the problem, the regions with a minimal integral volume of negative ecologic effects and the maximal possible GRP and population are considered effective. We have presented results of calculations for efficiency measures and target projections on negative ecologic effects (inputs). The calculations were performed using the MaxDEA software, with a radial adaptive algorithm, using statistical data from 2014. With the selected ecological and economic parameters, the following automobile transport systems are considered effective: Moscow Region, Ingushetia Republic, Tatarstan Republic, Penza Region, Sakhalin Region, Chuckotsky Autonomous Region. The least effective are the Kalmykia Republic, the Altai Republic and the Kamchatka Region.
METHODOLOGICAL BASES AND PRACTICAL EXPERIENCE OF THE FOREIGN COMPANIES IN THE ORGANIZATION OF NETWORK INTERACTION OF SUBJECTS OF INNOVATIVE BUSINESS
Authors: Неретина Евгения , Neretina Evgeniya , Гришнева Анастасия , Grishneva Anastasiya
Published: December 2016

In the conditions of globalization of social and economic processes, growth of dynamism and uncertainty of factors of environment network interaction of economic agents, especially in the innovative sphere, becomes the important instrument of formation of competitive advantage due to access to various combinations of ideas, advanced knowledge and technologies, unique resources. In this regard in article methodological basics of creation of intercompany networks are covered: the categories opening the maintenance of intersubject networks, dual approach to structural interaction of subjects of innovative activity, theoretical prerequisites of formation of mechanisms of formation of network structures (the theory of information, chaos, synergetrics, nonequilibrium thermodynamics). The practice of network interaction within the portfolios of alliances created by the international companies Sony and Sumsung allowing to reveal features in the organization of intra firm interaction of structural divisions, management of the companies and also in creation of portfolios of alliances is studied. The analysis of various configurations of networks, their advantages and shortcomings is carried out, the factors having impact on success of network interaction of subjects of innovative business, their competitive advantages are established. It is shown that the Russian business still has no understanding of importance of change of organizational forms of both intra firm, and intercompany interaction, wide use of the experience of creation of interindustry and international networks which is saved up by the foreign companies on the basis of strategic partnership and alliances.
A New Species of Ismarus Haliday (Hymenoptera: Ismaridae) from Brazil and a New Occurrence Record for Ismarus gracilis Masner
Authors: Comério Emerson Fraga , Perioto Nelson Wanderley , Lara Rogéria Inês Rosa
Published: December 2016

A new species of Ismarus Haliday (Hymenoptera: Ismaridae) from Brazil is described, illustrated and a key to females of Ismarus of the New World is given. The geographic range of Ismarus gracilis Masner, 1976, is extended about 5,200 km farther to southeast.Uma Nova Espécie de Ismarus Haliday para o Brasil e novo Registro de Ocorrência de Ismarus gracilis MasnerResumo. Uma nova espécie de Ismarus Haliday (Hymenoptera: Ismaridae) do Brasil é descrita, ilustrada e é fornecida chave de identificação para fêmeas de Ismarus do Novo Mundo. A distribuição geográfica de Ismarus gracilis Masner, 1976 é estendida por cerca de 5.200 km em direção ao sudeste.