bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B46: Immunotherapy of solid tumors with IgE antibodies: Paradigm of a novel concept towards clinical application.
Authors: Karagiannis Sophia N. , Josephs Debra H. , Karagiannis Panagiotis , Saul Louise , Gilbert Amy E. , Dodev Tihomir , Koers Alexander , Blower Philip J. , Beavil Andrew J. , Nestle Frank O. , Spicer James F. , Gould Hannah J.
Published: August 2014

Developing therapeutic antibodies with enhanced effector functions may be key to improving clinical outcomes in cancer. Our strategy to address this entails engineering antibodies directly targeting tumor antigens and bearing Fc regions of the IgE antibody class. Numerous attributes of this class, such as natural immune activatory functions in tissues and high affinity for cognate receptors on frequently tumor-resident effector cells can translate into effector cell activation and superior protection against solid tumors, compared to the conventionally-used antibodies with IgG Fc regions. We have developed a paradigm for this concept, the antibody MOv18 IgE, against the tumor antigen Folate Receptor α. This agent is presently prepared for first-in-man clinical studies, having demonstrated superior efficacy compared to the corresponding IgG1 antibody in three in vivo models of cancer, including one in an immunocompetent host. The antibody also yielded very promising safety profiles in in vivo evaluations, and also in ex vivo readouts normally applied in the field of allergy to examine sensitivity to allergens. The latter studies, conducted using cancer patient blood, suggest that this antibody is unlikely to trigger Type I hypersensitivity in patients. We have now extended the pathway to the design of similarly potent antibodies for the treatment of other solid tumors such as malignant melanoma and breast carcinoma. Two antibodies with Fc regions of the IgG1 and IgE classes and the same specificity for CSPG4, a tumor antigen expressed by 80% of melanomas, were tested in a xenograft model of human melanoma in a humanized host, with evident superior efficacy for the IgE counterpart. On-going evaluations and planned clinical studies in patients with cancer will constitute important metrics of the concept of IgE antibodies in cancer therapy, will inform the emerging field of AllergoOncology and will provide new scope for the design of novel cancer therapies.

Citation Format: Sophia N. Karagiannis, Debra H. Josephs, Panagiotis Karagiannis, Louise Saul, Amy E. Gilbert, Tihomir Dodev, Alexander Koers, Philip J. Blower, Andrew J. Beavil, Frank O. Nestle, James F. Spicer, Hannah J. Gould. Immunotherapy of solid tumors with IgE antibodies: Paradigm of a novel concept towards clinical application. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B46.
Abstract B72: CD8αα+ langerin+ dendritic cells maintain the effector CD8 T cell population after adoptive transfer.
Authors: Gibbins John David , Hermans Ian , Petersen Troels
Published: August 2014

Adoptive cell transfer (ACT) is a promising new area of anti-cancer therapy. The process involves the isolation of T cells from a patient's blood, in vitro stimulation of the T cells against cancer antigens, then re-infusion of the activated cells back into the patient. This process provides a population of effector CD8 T cells capable of recognizing and killing cancer cells. ACT is currently limited by the ability of the transferred cells to survive in high numbers for an extended period of time and therefore overcoming this problem is a focus to improve the efficacy of the treatment.

The activation of cancer-specific CD8 T cells is dependent on the ability of dendritic cells (DCs) to acquire and present exogenous antigens on major histocompatibility complex class I (a process known as cross-presentation) for the stimulation of CD8 T cells. We have previously found a subset of splenic DCs expressing the CD8αα homodimer and the c-type lectin receptor langerin (CD207), that have a strong ability to activate CD8 T cells by cross-presentation. This DC subset is found in the marginal zone of the spleen, is highly efficient at phagocytosing apoptotic cells from the blood, and is believed to play an important role in scanning the blood for antigens. We therefore hypothesized that CD8αα+ langerin+ DCs influence the survival and expansion of adoptively transferred effector CD8 T cells in the blood.

Within this project we have used langerin-diphtheria toxin receptor mice, in which all langerin-expressing cells are ablated in vivo upon injection of diphtheria toxin, to address the role of the CD8αα+ langerin+ DC subset in maintaining the CD8 T cell population after ACT. For this purpose, we challenged mice intravenously with the T cell thymoma EG7.OVA and adoptively transferred in vitro activated OVA-specific CD8 T cells (OT-I T cells) 12 days later with or without prior langerin-DC depletion. We found a larger population of OT-I T cells when these were transferred into an EG7.OVA bearing host when compared to mice without tumors. Interestingly, mice that were depleted of their CD8αα+ langerin+ DCs did not develop this increase in OT-I T cell number and their absence resulted in reduced survival. Our data therefore suggest that antigen presentation by CD8αα+ langerin+ DCs play a role in sustaining high numbers of transferred CD8 T cells after ACT, resulting in increased protection against EG7.OVA. Manipulations that increase the stimulatory capacity of this DC subset could be a way to increase the efficacy of ACT therapy.

Citation Format: John David Gibbins, Ian Hermans, Troels Petersen. CD8αα+ langerin+ dendritic cells maintain the effector CD8 T cell population after adoptive transfer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B72.
Abstract B83: Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression.
Authors: Mitchem Jonathan B. , Brennan Donal J. , Sanford Dominic E. , Knolhoff Brett L. , Zhu Yu , Brian Belt , Wang-Gillam Andrea , Goedegebuure Peter , Linehan David C. , DeNardo David G.
Published: August 2014

Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination, and the induction of immune suppression. Far from being a static cell population, the presence of cancer stem cells appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact that immune responses have on the differentiation or expansion of tumor stem cells is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by either inhibition of colony stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. We also found that tumor-educated macrophages could directly enhance the tumor-initiating capacity of pancreatic tumor cells through the activation of signal transducer and activator of transcription 3 (STAT3). In turn, these STAT3-activated tumor-initiating cells facilitate macrophage-mediated suppression of CD8+ T lymphocytes. These data suggest that targeting tumor-infiltrating macrophages is an effective strategy for overcoming therapeutic resistance due to the presence of tumor-initiating cells.

Citation Format: Jonathan B. Mitchem, Donal J. Brennan, Dominic E. Sanford, Brett L. Knolhoff, Yu Zhu, Belt Brian, Andrea Wang-Gillam, Peter Goedegebuure, David C. Linehan, David G. DeNardo. Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B83.
Abstract B88: Clinical significance of FOXP3+ T cell heterogeneity in ovarian cancer.
Authors: deLeeuw Ronald J. , Kost Sara E. , Nelson Brad H.
Published: August 2014

Background: CD8+ tumor-infiltrating lymphocytes (TIL) are associated with survival in ovarian cancer. A second subpopulation of TIL – defined by FoxP3 expression – has been reported to inhibit tumor immunity, resulting in decreased patient survival. However, recent studies by our lab and others have challenged this paradigm by showing that FoxP3+ T cells, in some patient cohorts, are associated with favorable prognosis.

Hypothesis: FoxP3 expression encompasses heterogeneous populations of effector and regulatory T cells that vary in proportion between patients and provide differential prognostication.

Methodology: We used multi-parameter flow cytometry to assess CD25, CD28, CD39, CD45RO, CD103, CD127, CTLA-4, CCR4, CCR7, GITR, Helios, ICOS, IFN-gamma, and PD-1 in CD3+CD4+CD8-FoxP3+ TIL in 12 patients with high-grade serous ovarian cancer (HGSC). CD4 and CD8 expression within FoxP3+ TIL was assessed by four channel multi-parameter immuno-histochemistry (mIHC). CD8-FoxP3+ TIL were assessed for CD25 and CD39 expression by mIHC. Survival analysis will be assessed via Kaplan-Meier plots, log-rank tests and Cox regression analyses.

Results: Consistent with prior reports, flow cytometry revealed that FoxP3 was expressed predominantly by CD4+ TIL. All CD4+FoxP3+ cells also expressed CD28, CD45RO, ICOS and CTLA-4, while they lacked expression of CD103 and IFN-gamma. However, we observed highly varied expression of regulatory T cell markers, including CD25, CD39, and GITR. Furthermore, on average, 4% (range 0-25%) of FoxP3+ TIL were CD8+. TCR spectratyping revealed similar TCR Vβ usage patterns between FoxP3- and FoxP3+ TIL. Although mIHC confirmed the variable expression of CD39 in CD8-FoxP3+ TIL, the expression of CD39 by a portion of HGSC tumors eliminated our ability to assess the clinical significance of this subset. The clinical significance of CD25 expression in CD8-FoxP3+ TIL is currently being analyzed in 245 cases of HGSC by mIHC.

Conclusions: FoxP3+ TIL demonstrate profound phenotypic heterogeneity within and between HGSC patients. FoxP3- and FoxP3+ TIL appear to be clonally related, suggesting their distinct phenotypes reflect microenvironmental influences rather than developmental origin or antigen specificity. The variable expression of CD25 and CD39 may be of importance in defining clinically important FoxP3+ TIL subsets. Further study of FoxP3+ TIL subpopulations in HGSC is required to better understand their contributions to tumor immunity and patient survival.

Citation Format: Ronald J. deLeeuw, Sara E. Kost, Brad H. Nelson. Clinical significance of FOXP3+ T cell heterogeneity in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B88.
Abstract IA14: Investigating the ICOS/ICOSL pathway as a target for combination therapy with anti-CTLA-4.
Authors: Sharma Padmanee
Published: August 2014

Biomarker studies used with immunotherapeutic strategies in the clinic have typically involved monitoring immunologic changes within the systemic circulation; however, recent data indicate that immunological changes within tumor tissues will be more likely to predict clinical responses. To obtain such data we conducted the first pre-surgical clinical trial with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. We are also conducting the first combination therapy pre-surgical trial with ipilimumab plus leuprolide acetate in patients with localized prostate cancer. Immunological data from these trials are obtained from both tumor tissues and blood samples.

We found an increased frequency of CD4 and CD8 T cells expressing high levels of inducible costimulator (ICOS) and decreased frequency of FOXP3-expressing CD4 T cells within tumor tissues of treated patients. The CD4+ICOShi population contained effector T cells that produced IFN-γ and recognized the cancer-testis antigen NY-ESO-1 expressed on tumor cells. We therefore identified ICOS as marker of a subset of effector T cells that is increased in frequency after anti-CTLA-4 therapy. ICOS+ T cells are being explored as both a pharmacodynamic marker for treatment with anti-CTLA-4 as well as a novel target to improve the efficacy of anti-CTLA-4 therapy.

These observations led us to test the possibility that engagement of ICOS could enhance the efficacy of anti-CTLA-4 therapy. To this end we transduced mouse B16F10 melanoma cells with a cDNA encoding ICOSL or a control construct. B16-ICOSL+ cells (IVAX) and control B16 cells were irradiated and used alone or in combination with anti-CTLA-4 to treat mice bearing established B16F10 tumors. We found that combination of the IVAX with anti-CTLA-4 was markedly more effective than the control vaccine plus anti-CTLA-4 or that of any single treatment alone. The increase in therapeutic efficacy was accompanied by a marked in increase in the density and functionality of CD4 and CD8 T cells within the tumor.

These results suggest a novel strategy for manipulating the immune system to enhance anti-tumor responses: checkpoint blockade coupled with provision of agonist signals to enhance costimulation mediated by ICOS.

Citation Format: Padmanee Sharma. Investigating the ICOS/ICOSL pathway as a target for combination therapy with anti-CTLA-4. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA14.
Abstract IA15: Role of PD-1 and LAG-3 in cancer immunotherapy.
Authors: Drake Charles G.
Published: August 2014

PD-1 and LAG-3 are negative regulatory molecules expressed on the cell surface of “exhausted” or non-functional CD8 T cells in both cancer and in infectious disease. In several cancer models, blocking both molecules shows a synergistic anti-tumor effect, without overt signs of autoimmunity. In more recent studies, we have examined the role of LAG-3 and/or PD-1 blockade on memory induction in vivo. Interestingly, we found that a short course (1 week) of combined antibody blockade results in a significant increase in the frequency of memory T cells over 30 weeks later. Augmented CD8 T cell responses were not apparent in the secondary lymphoid organs, but rather manifested as an increase in tissue resident responses. Responding cells in the combined blockade group also showed an increase in polyfunctional cytokine production, confirming the potential for increased effector function. Taken together, these data support our previous studies implying that simultaneous blockade of multiple immune checkpoints may be required for optimal anti-tumor immunity.

Citation Format: Charles G. Drake. Role of PD-1 and LAG-3 in cancer immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA15.
Abstract IA2: The molecular basis of tumor immunogenicity.
Authors: Schreiber Robert D.
Published: August 2014

Cancer Immunoediting is the process by which the immune system controls and shapes cancer. We originally envisaged that cancer immunoediting would occur in three phases: Elimination (also known as cancer immunosurveillance, the host protective phase of the process), Equilibrium (the phase in which tumor cells that survive immune elimination remain under immunologic growth control resulting in a state of functional tumor dormancy) and Escape (the phase where clinically apparent tumors emerge because immune sculpting of the tumor cells has produced variants that display either reduced immunogenicity or enhanced immunosuppressive activity). Strong experimental data has now been obtained using mouse models of cancer to demonstrate the existence of each phase of the cancer immunoediting process and compelling clinical data suggests that a similar process may also occur during the evolution of certain types of human cancer. Our efforts now focus on elucidating the molecular and cellular mechanisms that underlie each phase of cancer immunoediting and identifying the critical checkpoints that regulate progression from one phase of the process to the next. This approach has helped identify the nature of antigens seen by immunity in nascent developing cancers and has further shown that immunoselection is a major mechanism of immunoediting. Moreover, we have found that edited tumors can still be controlled by the immune system if natural mechanisms that prevent autoimmunity are suspended. As reported by others, we have confirmed that inhibition of CTLA-4 induces ejection of edited MCA sarcomas. However, we have also found that inhibition of PD-L1 does the same, although by perhaps different mechanisms. These differences will be discussed.

Citation Format: Robert D. Schreiber. The molecular basis of tumor immunogenicity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA2.
Drugs for Plant Chromosome and Chromatin Research
Authors: Pecinka Ales , Liu Chun-Hsin
Published: August 2014

Eukaryotic genomes are organized into chromosomes. Genetic information regularly becomes damaged and requires repair in order to ensure genome stability. Furthermore, expression of individual genetic elements on the chromosome(s) is controlled by several factors, including chromatin. Understanding the functions of chromatin may provide efficient tools for regulating gene expression. There has been great progress in understanding genome control using genetic mutations, but the use of mutants is sometimes not possible or may require additional interference with DNA or chromatin structure using specific treatments in order to obtain phenotypes. Therefore, chemical genetics has become an integral part of plant genome research. Here, we summarize information on the most commonly used drugs for chromatin and DNA damage repair studies, with the aim of simplifying the choice of drug and the estimation of possible side effects for current and future research.
Kinetics of Primary Bile Acids in Patients after Proctocolectomy and Ileal Pouch-Anal Anastomosis
Authors: Gotthardt Daniel Nils , Sauer Peter , Schaible Anja , Stern Josef , Stiehl Adolf , Beuers Ulrich
Published: August 2014

Background: The high incidence of cholesterol gallstones in patients after proctocolectomy with ileal pouch-anal anastomosis (IPAA) may be due to an increased loss of bile acids. We aimed to evaluate the kinetics of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) in these patients. Methods: Pool sizes, synthesis rates, and fractional turnover rates of CA and CDCA were determined by combined capillary gas chromatography/isotope ratio mass spectrometry in serum samples after administration of [13C]CA and [13C]CDCA in 6 patients and 9 healthy volunteers. Results: In patients with IPAA, pool sizes of CA and CDCA were 11.5 (8.2-23.8) and 12.1 (6.7-20.1) µmol/kg, respectively, and were significantly lower than in healthy controls [36.0 (24-47) and 29.0 (21-42) µmol/kg, respectively; p < 0.05, each]. Fractional turnover rates of CA [1.19 (1.06-1.82) vs. 0.31 (0.13-0.54) per day] and CDCA [1.01 (0.50-1.63) vs. 0.23 (0.09-0.36) per day] were increased fourfold in patients with IPAA (p < 0.05, each). Synthesis rates of CDCA [10.2 (5.2-32.9) vs. 6.6 (2.7-10.5) µmol/kg per day, p = 0.05] and CA [15.1 (9.3-39.4) vs. 11.5 (3.1-20.5) µmol/kg per day, n.s.] tended to be higher in patients with IPAA than in controls. Conclusion: The reduced pool size of primary bile acids may contribute to the high incidence of cholesterol gallstones in patients after proctocolectomy and IPAA.
A Unique Case of an Indolent Myometrial T-Cell Lymphoproliferative Disorder with Phenotypic Features Resembling Uterine CD8+ Resident Memory T Cells
Authors: Tabanelli Valentina , Valli Riccardo , Righi Simona , Nucera Giuseppe , Zecchini Barrese Tomás , Pileri Stefano , Sabattini Elena
Published: August 2014

Objective: Indolent extranodal T-cell lymphoproliferative disorders have recently been described as new entities in the gastrointestinal tract and acral sites displaying clonal T-cell receptor (TCR) rearrangement and nonactivated cytotoxic CD8+ T-cell phenotypes. Methods/Results: We report a unique case of an atypical myometrial T-cell lymphoproliferation in a 39-year-old multiparous woman, which shares many of the features mentioned above: CD8+/TIA1+/granzyme B- phenotype, clonal TCR rearrangement and indolent course. Conclusion(s): We hypothesize that it might derive from a subset of uterine nonrecirculating CD8+ resident memory T cells expanded after repeated exposure to allo-extravillous trophoblastic antigen.
Changes in DNA Methylation Levels and Nuclear Distribution Patterns after Microspore Reprogramming to Embryogenesis in Barley
Authors: El-Tantawy Ahmed-Abdalla , Solís María-Teresa , Risueño María C. , Testillano Pilar S.
Published: August 2014

Under specific stress treatments, the microspore can be induced in vitro to deviate from its gametophytic development and to reprogram towards embryogenesis, becoming a totipotent cell and forming haploid embryos. These can further regenerate homozygous plants for production of new isogenic lines, an important biotechnological tool for crop breeding. DNA methylation constitutes a prominent epigenetic modification of the chromatin fiber which regulates gene expression. Changes in DNA methylation accompany the reorganization of the nuclear architecture during plant cell differentiation and proliferation; however, the relationship between global DNA methylation and genome-wide expression patterns is still poorly understood. In this work, the dynamics of global DNA methylation levels and distribution patterns were analyzed during microspore reprogramming to embryogenesis and during pollen development in Hordeum vulgare. Quantification of global DNA methylation levels and 5-methyl-deoxycytidine (5mdC) immunofluorescence were conducted at specific stages of pollen development and after reprogramming to embryogenesis to analyze the epigenetic changes that accompany the change of developmental program and cell fate. The results showed low DNA methylation levels in microspores and a high increase along pollen development and maturation; an intense 5mdC signal was concentrated in the generative and sperm nuclei whereas the vegetative nucleus exhibited a weaker DNA methylation signal. After inductive stress treatment, low methylation levels and faint 5mdC signals were observed in nuclei of reprogrammed microspores and 2-4-cell proembryos. This data revealed a global DNA hypomethylation during the change of the developmental program and first embryogenic divisions. This is in contrast with the hypermethylation of generative and sperm cells of the male germline during pollen maturation, suggesting an epigenetic regulation after induction of microspore embryogenesis. At later embryogenesis stages, global DNA methylation progressively increased, accompanying embryo development and differentiation events like in zygotic embryos, corroborating that DNA methylation is critical for the regulation of gene expression in microspore embryogenesis.
How to Create Evidence for the Integration of Local and Locoregional Treatments in Future Oncological Treatment Concepts?
Authors: Lordick Florian , Ricke Jens , Mohnike Konrad , Hacker Ulrich
Published: August 2014

Background: While local treatment using more innovative technologies is increasingly applied in contemporary treatment of advanced cancer, its impact on outcomes is not well understood. Methods: We reviewed the literature using PubMed and major oncology congress websites, and report here about the understanding of oligometastatic disease, about the role of primary tumor resection in metastatic disease, and about the value of cytoreduction and tumor ablation. Results: The Achilles' heel of local treatment is the current lack of evidence of its efficacy. When considering how this lack of knowledge can be overcome, we arrive at three suggestions: First, adequately powered clinical trials must be performed to allow for the proper assessment of differences in survival outcomes. Second, the effect of local treatment on the biological evolution of the disease needs to be studied; analysis of circulating tumor DNA may help to assess these effects. Third and foremost, patient-reported outcomes like quality of life, symptom control, and satisfaction with treatment should define when to use and when to omit local treatment. Conclusions: Innovative trial designs in future oncology research will be required for assessing the true value of local and locoregional therapy.
Die Funktionsanalyse in der Verhaltenstherapie
Authors: Külz Anne Katrin
Published: August 2014

Die funktionale Betrachtung von psychischen Störungen ist allen Ansätzen gemein, die verhaltenstherapeutische Prinzipien nutzen. Allerdings variieren die Ansätze beträchtlich bezüglich der Aspekte, die sie in den Fokus der Funktionsanalyse stellen. Insbesondere die teleologische Betrachtung psychischer Symptome im Sinne der Zweckdienlichkeit problematischer Verhaltensweisen erweist sich häufig als außerordentlich wertvoll für Verständnis und Modifikation einer bestimmten Symptomatik. Der vorliegende Beitrag gibt einen Überblick über die Funktionsanalyse in der Tradition der Verhaltenstherapie sowie in neueren Ansätzen der sogenannten Dritten Welle und stellt Möglichkeiten zur Erschließung von Funktionalitäten im Rahmen des psychotherapeutischen Prozesses vor.
Searching for the Molecular Benchmark of Physiological Intestinal Anastomotic Healing in Rats: An Experimental Study
Authors: Seifert Gabriel J. , Seifert Michael , Kulemann Birte , Holzner Philipp A. , Glatz Torben , Timme Sylvia , Sick Olivia , Höppner Jens , Hopt Ulrich T. , Marjanovic Goran
Published: August 2014

Purpose: This investigation focuses on the physiological characteristics of gene transcription of intestinal tissue following anastomosis formation. Methods: In eight rats, end-to-end ileo-ileal anastomoses were performed (n = 2/group). The healthy intestinal tissue resected for this operation was used as a control. On days 0, 2, 4 and 8, 10-mm perianastomotic segments were resected. Control and perianastomotic segments were examined with an Affymetrix microarray chip to assess changes in gene regulation. Microarray findings were validated using real-time PCR for selected genes. In addition to screening global gene expression, we identified genes intensely regulated during healing and also subjected our data sets to an overrepresentation analysis using the Gene Ontology (GO) and Kyoto Encyclopedia for Genes and Genomes (KEGG). Results: Compared to the control group, we observed that the number of differentially regulated genes peaked on day 2 with a total of 2,238 genes, decreasing by day 4 to 1,687 genes and to 1,407 genes by day 8. PCR validation for matrix metalloproteinases-3 and -13 showed not only identical transcription patterns but also analogous regulation intensity. When setting the cutoff of upregulation at 10-fold to identify genes likely to be relevant, the total gene count was significantly lower with 55, 45 and 37 genes on days 2, 4 and 8, respectively. A total of 947 GO subcategories were significantly overrepresented during anastomotic healing. Furthermore, 23 overrepresented KEGG pathways were identified. Conclusion: This study is the first of its kind that focuses explicitly on gene transcription during intestinal anastomotic healing under standardized conditions. Our work sets a foundation for further studies toward a more profound understanding of the physiology of anastomotic healing.
Recovery of Visual Function after Administration of Dabigatran Etexilate
Authors: Schönfeld Carl-Ludwig , Fischer Marie , Distelmaier Peter , Philipp Sebastian , Paquet Patrick , Haller Katharina , Meyer Linda
Published: August 2014

A 46-year-old Caucasian female underwent pars plana vitrectomy (ppv) for retinal detachment. After the procedure, the patient could only distinguish hand movements; the condition was tentatively diagnosed as nonarteritic anterior ischemic optic neuropathy. Conventional treatment with systemic corticosteroids and acetylsalicylic acid was ineffective and yielded substantial steroid-related side effects. Additional administration of 2 × 110 mg dabigatran etexilate (Pradaxa®), a novel direct thrombin inhibitor, resulted in a prompt and marked improvement of visual acuity, which indicated improved blood flow in the central vessels of the optic nerve. Dabigatran etexilate may provide a promising alternative for the treatment of postprocedural vision loss after ppv.
Optimal duration of anticoagulation
Authors: Barbar Sofia , Milan Marta , Campello Elena , Spiezia Luca , Piovella Chiara , Pesavento Raffaele , Prandoni Paolo
Published: August 2014

Once anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years after a first episode is consistently around 30%. This risk is higher in patients with unprovoked than in those with (transient) provoked VTE, and among the latter in patients with medical than in those with surgical risk factors. Baseline parameters that have been found to be related to the risk of recurrent VTE are the proximal location of deep-vein thrombosis, obesity, old age, male sex and non-0 blood group, whereas the role of inherited thrombophilia is controversial. The persistence of residual vein thrombosis at ultrasound assessment has consistently been shown to increase the risk, as do persistently high values of D-dimer and the early development of the post-thrombotic syndrome. Although the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D-dimer have the potential to identify subjects in whom anticoagulation can be safely discontinued. Moreover, new opportunities are offered by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving the same effectiveness; and by low-dose aspirin, which has the potential to prevent the occurrence of both venous and arterial thrombotic events.
Keepsakes, Promises, Exchange: Female Friendship in Harriet Beecher Stowe's The Pearl of Orr's Island
Authors: Bannett Nina
Published: August 2014

Given its sentimental trappings, readers have failed to appreciate the gynocentric plot of Harriet Beecher Stowe's The Pearl of Orr's Island. Here, empowered as agents, two women exchange a man between them-a loving, sentimental gifting that upends the “traffic in women” that underwrites traditional, patriarchal constructions of marriage.
The Society of Jesus in Wales, c.1600–1679
Authors: Thomas Hannah
Published: August 2014

This article will analyze and evaluate the surviving volumes from the Cwm Jesuit Library, seized and brought to Hereford Cathedral by Bishop Herbert Croft in 1679 at the height of the national hysteria attending the alleged Popish Plot.1 Located originally at the Cwm, on the Herefordshire-Monmouthshire border, the headquarters of the Jesuit College of St. Francis Xavier (a territorial missionary district rather than an educational establishment), the library lay at the heart of the seventeenth-century Welsh Jesuit mission.2 Unanalyzed since 1679, the Cwm collection is the largest known surviving post-Reformation Jesuit missionary library in Britain and, as such, reveals a great deal about post-Reformation life in Wales and the English borderlands. This paper will reveal fresh information about the importance of the Welsh mission to the successes of the Jesuits in England and Wales.
Characteristics of 50–200-m Winds and Temperatures Derived from an Iowa Tall-Tower Network
Authors: Walton Renee A. , Takle Eugene S. , Gallus William A.
Published: August 2014

Limitations in skill of wind speed forecasts lead to conservative bids of wind-plant production in the day-ahead energy market and usually to an underutilization of wind resources. Improvements are needed in understanding wind characteristics in the turbine-rotor layer (40–120 m) for developing refined forecast models. The seasonal and diurnal behavior of wind speed, wind direction, and temperature were analyzed from data taken on five tall meteorological towers across Iowa. Several significant high-shear events, which would have the potential to cause problems by inducing substantial stress on the infrastructure of the wind turbine, were observed, with vertical shear up to 15 m s−1 accompanied by 30° of directional shear between 50 and 200 m. These events exhibited supergeostrophic wind speeds by 50% through the night followed by a collapse of shear through midday, indicating the influence of an inertial oscillation.
Terrain-Induced Turbulence Intensity during Tropical Cyclone Passage as Determined from Airborne, Ground-Based, and Remote Sensing Sources
Authors: Hon Kai-Kwong , Chan Pak-Wai
Published: August 2014

Low-level turbulence [rapid headwind fluctuations below 1600 ft (500 m)] poses potential safety hazards to landing/departing aircraft and is capable of disrupting air traffic. Timely, accurate alerts of low-level turbulence require reliable determination of its intensity, quantified by an internationally adopted aircraft-independent metric [cube root of the eddy dissipation rate (EDR1/3)], which cannot be directly measured but only inferred from observational data. In this paper, a large-scale survey of terrain-induced low-level turbulence intensity around the Hong Kong International Airport (HKIA) during tropical cyclone (TC) passage is presented, utilizing EDR1/3 values determined from multiple remote sensing and in situ sources, including the scanning Doppler lidar, the terminal Doppler weather radar (TDWR), a high-resolution anemometer, and the operational Windshear and Turbulence Warning System (WTWS) at HKIA. Over a 18 720-min study period spanning five TC cases between 2010 and 2012, ground-based EDR1/3 was computed using a variety of first-principle and empirical methods and was shown to demonstrate a strong linear correlation with airborne values determined from quick access recorder (QAR) data of over 350 landing flights. Spatiotemporal features as experienced on board aircraft were also reproduced by the lidar- and TDWR-derived profiles. Positive skill could be extracted from threshold-based alerting of low-level turbulence events by considering each ground-based source individually, while a combination of lidar and TDWR alerts demonstrated enhanced performance and hence the potential value of complementary surveillance under clear-air and in rain conditions. This study serves to establish the ability of ground-based instruments in correlating with airborne EDR1/3 and the performance of threshold-based alerting algorithms for turbulence events, contributing toward improvements in turbulence-alerting techniques for the aviation community.
Longitudinal Voice Outcomes Following Laryngeal Reinnervation Via Vagus-to-Recurrent Laryngeal Nerve Anastomosis After Vagal Nerve Sacrifice
Authors: Ward Greg M. , Sauder Cara , Olson Garth T. , Nuara Michael J.
Published: August 2014

Objective:

This study aimed to describe longitudinal voice outcomes of vagus-to-recurrent laryngeal nerve anastomosis following operative vagal nerve sacrifice.

Methods:

Two patients who underwent anastomosis were assessed by a multidisciplinary voice team at 1, 4, 9, 12, and 18 months after vagal sacrifice.

Results:

Long-term changes in voice function based on auditory perceptual measures of voice quality and visual perceptual changes in glottal closure were observed and maintained for 18 months after vagus-to-recurrent laryngeal nerve anastomosis in 2 patients with proximal vagal nerve sacrifice. Patients achieved acceptable voice outcomes and elected not to undergo further treatment, which was supported by Voice Handicap Index scores.

Conclusion:

Gradual restoration of voice following operative vagal sacrifice can be achieved over an 18-month period using vagus-to-recurrent laryngeal nerve anastomosis and warrants further investigation in appropriately selected patients.
Twelve-month prevalence and predictors of self-reported suicidal ideation and suicide attempt among Korean adolescents in a web-based nationwide survey
Authors: Kang Eun-Ho , Hyun Min Kyung , Choi Seong Mi , Kim Ji-Min , Kim Gyung-Mee , Woo Jong-Min
Published: August 2014

Objective:

The suicide rate in South Korea was the highest among the Organisation for Economic Co-operation and Development (OECD) countries in 2011. Although the suicide rate in adolescents is lower than that of adults and is reported to be decreasing in young males in some countries, it has consistently increased in recent years in South Korea. We aimed to determine the prevalence, pattern, and predictors of suicidal ideation and attempt in the past 12 months.

Methods:

A total sample of 72,623 adolescents aged 12–18 years who responded to a web-based anonymous self-reported survey between September and October 2010 was used for the analysis.

Results:

The suicidal ideation and suicide attempt rates were 19.1% and 4.9%, respectively. Being female, having a poor perceived socioeconomic status and a poor perceived academic performance, subjective feelings of depression, cigarette smoking, alcohol use, perceived general medical health, and experiences of any involvement with sexual intercourse were the contributing factors that predicted elevated risks for suicidal ideation and suicide attempt. In contrast to previous reports in other countries, the suicide attempt rate in Korean female adolescents peaked at age 13 years, and there were no differences in suicidal ideation in females by age. There were no differences in both suicidal ideation and attempt rates in males by age.

Conclusion:

A multidisciplinary approach that takes into consideration the characteristics of Korean adolescents with suicidal ideation or suicide attempt is warranted for developing prevention and treatment programs.
Three-dimensional static and free vibration analysis of laminated cylindrical panel with viscoelastic interfaces
Authors: Alibeigloo A
Published: August 2014

In this paper, three-dimensional theory of elasticity is employed to investigate bending and free vibration behavior of simply supported cylindrical panel with special emphasis on incorporating viscoelastic interfacial imperfection. Analysis is carried out by using Fourier series along the axial and circumferential directions and state space technique along the radial direction. Time-dependent behavior is investigated by solving first-order differential equation of sliding displacement at the viscoelastic interfaces. Numerical results depict good agreement between the present numerical results and the available published results. In addition, the effects of solid, elastic and viscous interfaces, time, aspect ratio and mid radius to thickness ratio on the bending and vibration behavior of laminated cylindrical panel are discussed.
Improving Children’s Oral Health
Authors: Casamassimo P.S. , Lee J.Y. , Marazita M.L. , Milgrom P. , Chi D.L. , Divaris K.
Published: August 2014

Despite the concerted efforts of research and professional and advocacy stakeholders, recent evidence suggests that improvements in the oral health of young children in the United States has not followed the prevailing trend of oral health improvement in other age groups. In fact, oral health disparities in the youngest children may be widening, yet efforts to translate advances in science and technology into meaningful improvements in populations’ health have had limited success. Nevertheless, the great strides in genomics, biological, behavioral, social, and health services research in the past decade have strengthened the evidence base available to support initiatives and translational efforts. Concerted actions to accelerate this translation and implementation process are warranted; at the same time, policies that can help tackle the upstream determinants of oral health disparities are imperative. This article summarizes the proceedings from the symposium on the interdisciplinary continuum of pediatric oral health that was held during the 43rd annual meeting of the American Association for Dental Research, Charlotte, North Carolina, USA. This report showcases the latest contributions across the interdisciplinary continuum of pediatric oral health research and provides insights into future research priorities and necessary intersectoral synergies. Issues are discussed as related to the overwhelming dominance of social determinants on oral disease and the difficulty of translating science into action.
Municipal ID Cards for Undocumented Immigrants
Authors: de Graauw Els
Published: August 2014

This article examines the municipal ID card programs in New Haven and San Francisco. With a municipal ID card, undocumented immigrants can access basic city services and identify themselves with police and other city officials. The article draws on twenty-eight interviews with key stakeholders to show that city officials navigated the conflicting demands of ID card supporters and opponents to create a local membership policy focused on improving city administration, not expanding the rights of undocumented immigrants. In capitalizing on their discretionary administrative powers to develop programs that safeguard the health, safety, and welfare of all city residents, officials in New Haven and San Francisco managed to promote the integration of undocumented immigrants into city affairs without upsetting the federal monopoly over immigration and citizenship powers. This new form of local bureaucratic membership has implications for the urban citizenship literature and illustrates that city officials have some freedom to develop programs that benefit undocumented immigrants.
Invisible Victims
Authors: Délano Alexandra , Nienass Benjamin
Published: August 2014

This article examines the processes of investigation and gathering evidence about victims of the September 11 attacks to better understand the inability of state and nonstate institutions to effectively deal with the invisibility of undocumented migrants in terms of providing assistance and recognition at a moment of tragedy. The failure to make the invisible visible or to address the very question of visibility publicly is explained by three major reasons: 1) A general fear of coming forward on the part of undocumented migrants or their families, partly as a result of their legal status and their lack of trust in government agencies, which was compounded by ineffective communication about available relief services; 2) different procedural requirements and logics of evidence used by government and nongovernmental relief agencies, which, in some cases, made it impossible for undocumented migrants or their families to provide proof of their presence at the site or employment in the businesses affected; 3) the context of 9/11 as a disruptive event that influenced the overall climate in which issues of victimhood and immigration status could be addressed.
Assessment of the heat and moisture transfer in a multilayer protective fabric system under various ambient conditions
Authors: He Jiazhen , Li Jun , Kim Eunae
Published: August 2014

This study was conducted to investigate the effect of multilayer protective clothing on heat and moisture transport under various ambient conditions. By using the Human-Clothing-Environment simulator, a four-layered clothing system was exposed to a high rate of sweat pulse for a duration of 3 hours in seven different ambient conditions: extremely hot and humid (EH, 40℃, 90% relative humidity (RH)), extremely hot and dry (ED, 40℃, 30% RH), hot and humid (HH, 34℃, 75% RH), hot and dry (HD, 34℃, 30% RH), warm and dry (WD, 27℃, 30% RH), slightly cold (SC, –3℃, 20% RH) and cold (CO, –10℃, 20% RH). The temperature and RH in the microclimate were measured and the distribution of within layers was analyzed. Several dynamic stage changes of the microclimate were observed throughout the test. Variations in ambient condition have an effect on the microclimate and the distribution of moisture accumulated within layers. Heat and moisture transport through the clothing system would be influenced by the condensation within layers. In cold conditions, 80% of the moisture accumulated in the clothing system was located in the thermal liner and moisture barrier, whereas in other conditions, most of it was accumulated in the thermal liner.
Research on mechanical properties of the Siro-spinning triangle using the Finite Element Method
Authors: Liu Xinjin , Liu Na , Su Xuzhong
Published: August 2014

Siro-spinning (two-strand yarn spinning) is a new kind of modified ring spinning method, which is achieved by feeding two rovings into the apron zone at a predetermined separation simultaneously. There are three spinning triangles, including two primary spinning triangles and one final spinning triangle, in Siro-spinning. Therefore, in this paper, the quantitative relationships between the mechanical performance of a Siro-spinning triangle and the spinning parameters are investigated by using the Finite Element Method. The finite element model of the Siro-spinning triangle is constructed under the assumption in which the constituent fibers are considered as three-dimensional elastic beam elements with tensile, compressive, torsion, and bending capabilities. Three different cases where the ends of all fibers, the initial strain of all fibers, and the angle between any two adjacent fibers gripped in the front roller nip distribute evenly are discussed. Meanwhile, in each case, three different cases where the initial strains of the shortest boundary fiber, the central fiber, and the virtual fiber on the direction of yarn spinning tension are set as zero are discussed respectively. Then, taking the spinning triangle in Ne40 (14.6 tex) cotton Sirospun yarn as an example, the fiber tension distribution and fiber torsion distribution in the corresponding Siro-spinning triangle with and without fiber buckling are numerical simulated. It is shown that the fiber tension distributions are influenced by the setting of the fiber initial strain, while the magnitudes of fiber tension are not affected. Finally, Ne40 cotton ring yarns were spun on an EJM128K ring spinning machine, and the properties of spun yarns were evaluated and analyzed according to the simulation results.