bluuebunny/crossref_metadata_2025 huggingface dataset:
Element flux to the environment of the passively degassing crater lake-hosting Kawah Ijen volcano, Indonesia, and implications for estimates of the global volcanic flux
Authors: van Hinsberg Vincent , Vigouroux Nathalie , Palmer Stephanie , Berlo Kim , Mauri Guillaume , Williams-Jones Anthony , Mckenzie Jeffrey , Williams-Jones Glyn , Fischer Tobias
Published: December 2015

Volcanoes play an important role in the global cycling of elements by providing a pathway from the deep Earth to its surface. Here, we have constrained the flux to the environment for most elements of the periodic table for the passively degassing, crater lake-hosting Kawah Ijen volcano in the Indonesian arc. Our results indicate that emissions of Kawah Ijen are dominated by acid water outflow, especially for the ligands (Cl, F, Br), with active fumaroles contributing significant (semi)metals (e.g. Se, As, Sb, Hg), as well as C and S. The compositional signature of emissions from Kawah Ijen is similar to that of major volcanic emitters such as Etna, but element fluxes are smaller. This result provides the prerequisite foundation for extrapolating a small set of measured volcanic gas emissions to a global volcanic flux estimate. However, the aqueous flux (i.e. seepage of volcanic hydrothermal fluids and volcano-influenced groundwater) is at least as important in terms of element release, and the consideration of the gaseous flux alone thus represents a significant underestimate of the impact of volcanoes on their environment and the contribution of volcanic hydrothermal systems to global element cycling.

Supplementary material:
The full datasets of water and fumarole gas chemical analyses are available at
https://doi.org/10.6084/m9.figshare.c.2134359
Decreasing capability of the degassing systems at lakes Nyos and Monoun (Cameroon): a new gas removal system applied to Lake Monoun to prevent a future limnic eruption
Authors: Yoshida Yutaka , Kusakabe Minoru , Issa  , Ohba Takeshi , Tanyileke Gregory , Hell Joseph Victor
Published: December 2015

The degassing systems installed in the early 2000s at lakes Nyos and Monoun, Cameroon, have been working well, resulting in significant removal of dissolved gas. However, the systems of both lakes started losing their capability due to a reduced CO
2
partial pressure in the bottom waters, especially after installation of additional pipes in 2011. After initiation of a degassing operation, changes in CO
2
profiles in the bottom layer of Lake Nyos over time showed that gas-poor shallow water has descended to the bottom, leaving little CO
2
in the bottom water. The degassing system at Lake Monoun has completely lost its gas self-lift capability as the reduced CO
2
partial pressure in the bottom water is too low to sustain the gas-lift system, and all the degassing pipes stopped working in 2010. This situation led to the accumulation of CO
2
due to continued natural recharge of magmatic CO
2
. To compensate this recharge of gas, we installed a new deep water removal system that is driven by solar power at Lake Monoun in December 2013. This system does not need power lines, fuel or complicated maintenance, thus it is convenient for remote lakes such as lakes Monoun and Nyos.
Separation Logic for High-Level Synthesis
Authors: Winterstein Felix J. , Bayliss Samuel R. , Constantinides George A.
Published: December 2015

High-Level Synthesis (HLS) promises a significant shortening of the FPGA design cycle by raising the abstraction level of the design entry to high-level languages such as C/C++. However, applications using dynamic, pointer-based data structures and dynamic memory allocation remain difficult to implement well, yet such constructs are widely used in software. Automated optimizations that leverage the memory bandwidth of FPGAs by distributing the application data over separate banks of on-chip memory are often ineffective in the presence of dynamic data structures due to the lack of an automated analysis of pointer-based memory accesses. In this work, we take a step toward closing this gap. We present a static analysis for pointer-manipulating programs that automatically splits heap-allocated data structures into disjoint, independent regions. The analysis leverages recent advances in
separation logic
, a theoretical framework for reasoning about heap-allocated data that has been successfully applied in recent software verification tools. Our algorithm focuses on dynamic data structures accessed in loops and is accompanied by automated source-to-source transformations that enable automatic loop parallelization and memory partitioning by off-the-shelf HLS tools. We demonstrate the successful loop parallelization and memory partitioning by our tool flow using three real-life applications that build, traverse, update, and dispose of dynamically allocated data structures. Our case studies, comparing the automatically parallelized to the direct HLS implementations, show an average latency reduction by a factor of 2 × across our benchmarks.
Central apelin mediates stress-induced gastrointestinal motor dysfunction in rats
Authors: Bülbül Mehmet , İzgüt-Uysal V. Nimet , Sinen Osman , Birsen İlknur , Tanrıöver Gamze
Published: December 2015

Apelin, an endogenous ligand for APJ receptor, has been reported to be upregulated in paraventricular nucleus (PVN) following stress. Central apelin is known to stimulate release of corticotropin-releasing factor (CRF) via APJ receptor. We tested the hypothesis that stress-induced gastrointestinal (GI) dysfunction is mediated by central apelin. We also assessed the effect of exogenous apelin on GI motility under nonstressed (NS) conditions in conscious rats. Prior to solid gastric emptying (GE) and colon transit (CT) measurements, APJ receptor antagonist F13A was centrally administered under NS conditions and following acute stress (AS), chronic homotypic stress (CHS), and chronic heterotypic stress (CHeS). Plasma corticosterone was assayed. Strain gage transducers were implanted on serosal surfaces of antrum and distal colon to record postprandial motility. Stress exposure induced coexpression of c-Fos and apelin in hypothalamic PVN. Enhanced hypothalamic apelin and CRF levels in microdialysates were detected following AS and CHeS, which were negatively and positively correlated with GE and CT, respectively. Central F13A administration abolished delayed GE and accelerated CT induced by AS and CHeS. Central apelin-13 administration increased the plasma corticosterone and inhibited GE and CT by attenuating antral and colonic contractions. The inhibitory effect elicited by apelin-13 was abolished by central pretreatment of CRF antagonist CRF9–41 in antrum, but not in distal colon. Central endogenous apelin mediates stress-induced changes in gastric and colonic motor functions through APJ receptor. The inhibitory effects of central exogenous apelin-13 on GI motility appear to be partly CRF dependent. Apelin-13 inhibits colon motor functions through a CRF-independent pathway.
Endurance training prevents negative effects of the hypoxia mimetic dimethyloxalylglycine on cardiac and skeletal muscle function
Authors: Favier Francois B. , Britto Florian A. , Ponçon Benjamin , Begue Gwenaelle , Chabi Beatrice , Reboul Cyril , Meyer Gregory , Py Guillaume
Published: December 2015

Hypoxic preconditioning is a promising strategy to prevent hypoxia-induced damages to several tissues. This effect is related to prior stabilization of the hypoxia-inducible factor-1α via inhibition of the prolyl-hydroxylases (PHDs), which are responsible for its degradation under normoxia. Although PHD inhibition has been shown to increase endurance performance in rodents, potential side effects of such a therapy have not been explored. Here, we investigated the effects of 1 wk of dimethyloxalylglycine (DMOG) treatment (150 mg/kg) on exercise capacity, as well as on cardiac and skeletal muscle function in sedentary and endurance-trained rats. DMOG improved maximal aerobic velocity and endurance in both sedentary and trained rats. This effect was associated with an increase in red blood cells without significant alteration of skeletal muscle contractile properties. In sedentary rats, DMOG treatment resulted in enhanced left ventricle (LV) weight together with impairment in diastolic function, LV relaxation, and pulse pressure. Moreover, DMOG decreased maximal oxygen uptake (state 3) of isolated mitochondria from skeletal muscle. Importantly, endurance training reversed the negative effects of DMOG treatment on cardiac function and restored maximal mitochondrial oxygen uptake to the level of sedentary placebo-treated rats. In conclusion, we provide here evidence that the PHD inhibitor DMOG has detrimental influence on myocardial and mitochondrial function in healthy rats. However, one may suppose that the deleterious influence of PHD inhibition would be potentiated in patients with already poor physical condition. Therefore, the present results prompt us to take into consideration the potential side effects of PHD inhibitors when administrated to patients.
Regional specific modulation of the glycocalyx and smooth muscle cell contractile apparatus in conduit arteries of tail-suspended rats
Authors: Kang Hongyan , Fan Yubo , Zhao Ping , Ren Changhui , Wang Zhenze , Deng Xiaoyan
Published: December 2015

The glycocalyx is a key mechanosensor on the surfaces of vascular cells (endothelial cells and smooth muscle cells), and recently, we reported that the redistribution of the hemodynamic factors in tail-suspended (TS) hindlimb-unloaded rats induces the dimensional adaptation of the endothelial glycocalyx in a regional-dependent manner. In the present study, we investigated the coverage and gene expression of the glycocalyx and its possible relationship with smooth muscle contractility in the conduit arteries from the TS rats. The coverage of the glycocalyx, determined by the area analysis of the fluorescein isothiocyanate-labeled wheat germ agglutinin (WGA-FITC) staining to the cryosections of rat vessels, showed a 27.2% increase in the common carotid artery, a 13.3 and 8.0% decrease in the corresponding abdominal aorta and the femoral artery after 3 wk of tail suspension. The relative mRNA levels of syndecan-2, 3, 4, glypican-1, smooth muscle protein 22 (SM22), smoothelin (SMTN), and calponin were enhanced to 1.40, 1.53, 1.70, 1.90, 2.93, 2.30, and 5.23-fold, respectively, in the common carotid artery of the TS rat. However, both glycocalyx-related genes and smooth muscle contractile apparatus were totally or partially downregulated in the abdominal aorta and femoral artery of the TS rat. A linear positive correlation between the normalized coverage of glycocalyx and normalized mRNA levels of SM22, SMTN, and calponin exists. These results suggest the regional-dependent adaptation of the glycocalyx in simulated microgravity condition, which may affect its mechanotransduction of shear stress to regulate the contractility of the smooth muscle, finally contributing to postspaceflight orthostatic intolerance.
The regulation of autophagy during exercise in skeletal muscle
Authors: Vainshtein Anna , Hood David A.
Published: December 2015

The merits of exercise on muscle health and well-being are numerous and well documented. However, the mechanisms underlying the robust adaptations induced by exercise, particularly on mitochondria, are less clear and much sought after. Recently, an evolutionary conserved cellular recycling mechanism known as autophagy has been implicated in the adaptations to acute and chronic exercise. A basal level of autophagy is constantly ongoing in cells and tissues, ensuring cellular clearance and energy homeostasis. This pathway can be further induced, as a survival mechanism, by cellular perturbations, such as energetic imbalance and oxidative stress. During exercise, a biphasic autophagy response is mobilized, leading to both an acute induction and a long-term potentiation of the process. Posttranslational modifications arising from upstream signaling cascades induce an acute autophagic response during a single bout of exercise by mobilizing core autophagy machinery. A transcriptional program involving the regulators Forkhead box O, transcription factor EB, p53, and peroxisome proliferator coactivator-1α is also induced to fuel sustained increases in autophagic capacity. Autophagy has also been documented to mediate chronic exercise-induced metabolic benefits, and animal models in which autophagy is perturbed do not adapt to exercise to the same extent. In this review, we discuss recent developments in the field of autophagy and exercise. We specifically highlight the molecular mechanisms activated during acute exercise that lead to a prolonged adaptive response.
Abstract A22: Identification of novel tumor derived factors that inhibit angiogenesis
Authors: Walshe Tony E. , Bourdelais Justin , Lee Arleide , Ouro-Djobo Rakibou , Vishnudas Vivek , Sarangarajan Rangaprasad , Narain Niven
Published: December 2015

Background: Cell-cell communication in the tumor micro-environment drive tumor growth and facilitate neovessel recruitment from the adjacent vasculature. The present study was designed to identify novel cancer derived factors that modulate the vascular endothelial response in a paracrine manner.

Methods: An array of cancer cell lines from multiple tissue types (Panc1; HepG2; LnCap; Skmel; Hep3B; PL45; SCC25; CaCo2; PaCa2; SKBR3) were grown under normoxic or hypoxic (1% oxygen) conditions for a total of 20 different conditions. After 48 hours, conditioned media was collected and filtered prior to testing on endothelial cells. The effects of the conditioned media on endothelial apoptosis, proliferation and tube formation were investigated. In tandem with these endothelial cell fate assays, the proteomic profile of these 20 conditions was profiled and assessed using the Berg Interrogative Biology™ platform.

Results & Discussion: Our results reveal that conditioned media from all cancer cells tested can alter endothelial cell apoptosis, proliferation rate and tube formation in 3D matrigel assays i.e. critical cell fate decisions that enable formation of nascent vessel formation. As predicted, the predominant effect of tumor-derived conditioned media on endothelial apoptosis was a protective anti-apoptotic effect, with the discernable exception of normoxic Panc1 derived media. An unexpected finding was the general anti-proliferative effects of tumor-derived conditioned media on endothelial cell growth, with the exception of Hep2G, LnCap and PaCa2 cell derived media. Using a media fractionation strategy and Interrogative Biology™, we identified several endothelial anti-apoptotic candidates from Panc1 cells within a unique molecular weight range. Upon application of ASO gene knockdown in Panc1 cells, these targets were verified for apoptotic and proliferation effects on vascular endothelial cells.

Conclusion: Specific factors that determine paracrine cell-cell interaction in the tumor microenvironment have been identified and validated employing Berg Interrogative Biology™. The technology presented herein represents a viable platform for identifying clinically relevant biomarkers and factors that alter cancer angiogenesis.

Citation Format: Tony E. Walshe, Justin Bourdelais, Arleide Lee, Rakibou Ouro-Djobo, Vivek Vishnudas, Rangaprasad Sarangarajan, Niven Narain. Identification of novel tumor derived factors that inhibit angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A22.
Abstract B01: Profiling of serum and plasma angiogenic biomarkers in breast cancer and colon cancer using Luminex xMAP technology-based human angiogenesis multiplex immunoassay panels
Authors: Lie Wen-Rong , Droll Deborah , Mistry Jehangir
Published: December 2015

Tumors require neovascularization for growth. Consequently, the angiogenesis process is key to understanding tumor development and progression, as well as diagnosis and treatment. Measuring the levels of pro- and anti-angiogenic factors in plasma or serum in cancer patients may provide prognostic information concerning disease processes and mechanisms and the elucidation of potential biomarkers for epidemiological studies or clinical trials. The Luminex xMAP technology, a bead-based multiplex immunoassay for the simultaneous measurement of multiple analytes in a small sample size, has been widely used in cancer biomarker discoveries. We report here the use of two newly developed multiplex human angiogenesis panels to profile the circulating biomarkers commonly used in the angiogenesis pathway analysis. The two panels are 1) MILLIPLEX MAP Human Angiogenesis Panel 1, a 17-plex multiplex immunoassay for the simultaneous quantification of the following 17 angiogenesis biomarkers: Angiopoietin-2, BMP-9, EGF, Endoglin, Endothelin-1, FGF-1, FGF-2, Follistatin, G-CSF, HB-EGF, HGF, IL-8, Leptin, PLGF, VEGF-A, VEGF-C, and VEGF-D, and 2) MILLIPLX MAP Human Angiogenesis Panel 2, a 20-plex multiplex immunoassay for simultaneous quantitation of the following 20 human angiogenesis biomarkers: Angiostatin, soluble E-Selectin, Osteopontin, PDGF-AB/BB, PECAM-1/sCD31, Tenascin C, Thrombospondin-2 (TSP-2), soluble AXL, soluble c-Kit, soluble EGFR, soluble Her2/ErbB2, soluble Her3/ErbB3, soluble HGFR/c-Met, soluble IL-6Rα, soluble Neuropilin-1, soluble Tie-2, soluble urokinase receptor (suPAR), soluble VEGFR1, soluble VEGFR2, and soluble VEGFR3. In this study, we report the use of these 37 angiogenic, growth factor and soluble receptor biomarkers to profile serum samples and plasma samples from a panel of breast cancer and colon cancer patients, with a similar number of normal serum and plasma samples, as a corresponding set, to generate a tumor profile of angiogenic factors using the Luminex xMAP platform. The results of this study demonstrated the utility of these human angiogenesis panels in studying cancer development and cancer biomarker discovery, as well as its potential application in translational research.

Citation Format: Wen-Rong Lie, Deborah Droll, Jehangir Mistry. Profiling of serum and plasma angiogenic biomarkers in breast cancer and colon cancer using Luminex xMAP technology-based human angiogenesis multiplex immunoassay panels. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B01.
Abstract B12: Endothelial stabilizer SAC-1004 normalizes tumor vasculature and potentiates docetaxel chemotherapy in prostate cancer
Authors: Kang Yoo Hyun , Heo Jun Hyeok , Jin Hyun A , Park Ki Chung , Hong Sung Joon , Han Kyung Seok
Published: December 2015

Background: Since tumor requires excessive oxygen and nutrients due to their rapid growth, tumor is generally vascular. However, tumor vasculature is not physiologic but leaky, dilated, and tortuous. The inefficiency of tumor vessels in terms of perfusion induces hypoxic stress that makes the tumor more aggressive. Here, we investigated the role of a novel endothelial stabilizer SAC-1004 on tumor vascular normalization and its effects on tumor growth in prostate cancer.

Methods: Human vascular endothelial cell (HUVEC) was used to evaluate the effects of SAC-1004 on endothelial cells. Immunocytochemical staining and immunofluorescent confocal imaging was performed for E-cadherin expression in HUVECs. MTS assay was performed to assess cell proliferation of HUVECs and PC-3 cells after SAC-1004 treatment. Immunohistochemical staining with anti-CD31 and anti-SMA antibodies was performed to assess vasculature in vivo. PC-3 subcutaneous xenografts were developed to evaluate the effects of SAC-1004 on tumor vasculature and tumor growth in prostate cancer. Magnetic resonance images were taken to assess vascular perfusion in xenografts. SAC-1004 was administrated via tail vein once a day for 7 days. Docetaxel was administrated intravenously once a week.

Results: SAC-1004 restored junction protein E-cadherin in vitro in endothelial cells and significantly reduced VEGF-induced retinal vascular leakage. SAC-1004 promoted proliferation of HUVECs in vitro in a dose-dependent manner. However, proliferation of cancer cells was not significantly affected by SAC-1004 treatment. Reduced vascular leakiness was found in PC-3 xenografts treated with SAC-1004 treatment and magnetic resonance imaging after SAC-1004 treatment for 7 days confirmed improved perfusion in the PC-3 xenografts treated with SAC-1004 compared with control. Interestingly, SAC-1004 treatment suppressed tumor growth in PC-3 xenografts but SAC-1004 followed by intravenous docetaxel treatment showed the most potent tumor suppression compared with control in PC-3 xenografts.

Conclusions: SAC-1004 restored abnormal leak vasculature of tumor by restoring endothelial cell junction in prostate cancer. Vascular normalization by SAC-1004 induced tumor regression and combination with docetaxel following vascular normalization potentiated anti-tumor effects of docetaxel in prostate cancer.

Citation Format: Yoo Hyun Kang, Jun Hyeok Heo, Hyun A Jin, Ki Chung Park, Sung Joon Hong, Kyung Seok Han. Endothelial stabilizer SAC-1004 normalizes tumor vasculature and potentiates docetaxel chemotherapy in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B12.
Abstract B19: Anti-VEGF treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery
Authors: Datta Meenal , Via Laura E. , Kamoun Walid S. , Liu Chong , Chen Wei , Seano Giorgio , Weiner Danielle M. , Schimel Daniel , England Kathleen , Martin John D. , Gao Xing , Xu Lei , Barry Clifton E. , Jain Rakesh K.
Published: December 2015

Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. TB patients require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low molecular weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced vascular endothelial growth factor (VEGF) expression in both species. In tumors, anti-angiogenic, specifically anti-VEGF, treatments can “normalize” their vasculature, reducing hypoxia and creating a window-of-opportunity for conjunctive chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential new avenue to improve delivery and efficacy of current treatment regimens.

Citation Format: Meenal Datta, Laura E. Via, Walid S. Kamoun, Chong Liu, Wei Chen, Giorgio Seano, Danielle M. Weiner, Daniel Schimel, Kathleen England, John D. Martin, Xing Gao, Lei Xu, Clifton E. Barry, III, Rakesh K. Jain. Anti-VEGF treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B19.
Abstract IA19: Immune checkpoint blockade in cancer therapy: New insights and opportunities
Authors: Allison James P.
Published: December 2015

The existence of multiple non-redundant inhibitory pathways that limit T cell responses offers novel strategies for unleasing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen presenting cells. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (>10 years) survival benefit in about 20% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease.

The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms.

PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25% . A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients.

These studies and their implications for cancer therapy will be discussed.

Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights and opportunities. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA19.
Abstract IA21: Vascular phenotyping: Using genomics to inform antiangiogenesis
Authors: Benjamin Laura E.
Published: December 2015

Anti-angiogenesis therapy has proven to be an important tool for oncologists particularly in metastatic disease. To date much of the success has been built on targeting the VEGF/VEGFR pathways and FDA approvals have been granted in many disease settings including CRC, RCC, NSCLC, and others. In 2014 Cervical Cancer and Gastric cancer were new cancers added to this list. Still, it's fair to say that we have a limited understanding of how to identify the patients who will receive optimal benefit from the available therapeutic agents, and how inhibitors of non-VEGF pathways will compare or combine with currently approved therapies. This presentation will discuss new findings that use molecular analysis to understand heterogeneity in cancer vascular beds and how they relate to preclinical efficacy for VEGF pathway inhibitors. Linking these findings to clinical outcomes in the future may provide a bridge between the wealth of data being generated in cancer genomics and patients most likely to derive benefit from anti-angiogenesis.

Citation Format: Laura E. Benjamin. Vascular phenotyping: Using genomics to inform antiangiogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA21.
Abstract PR06: Formation of lymph node metastases is not angiogenesis dependent
Authors: Jones Dennis , Jeong Han-sin , Liao Shan , Padera Timothy P.
Published: December 2015

Background: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting. The presence of lymph node metastases dictate treatment decisions, however their reliance on angiogenesis for growth has not been described. Furthermore, recent data show that radiation and chemotherapy can treat limited lymph node disease in breast cancer patients with equal efficacy to complete lymph node dissection. This has led to a reduction in the use of complete lymph node dissection as the primary treatment option in these patients. Thus, greater numbers of patients will have cancer in lymph nodes after surgery that requires adjuvant therapy.

Methods: Here, we developed a novel chronic lymph node window (CLNW) model to longitudinally image the growth and spread of lymph node metastases using intravital optical microscopy techniques. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes. We further test our results in murine and patient samples using molecular and biochemical methods. Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW.

Results: We reveal the surprising lack of sprouting angiogenesis during metastatic growth in lymph nodes using both intravital microscopy and ex vivo methods. Vascular endothelial growth factor was not produced by the metastatic lesion despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases in our models. We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab.

Conclusion: We provide pre-clinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, which reveals a mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases. Based on longitudinal intravital imaging, it appears that metastatic cancer cells in the lymph node invade the lymph node parenchyma where the native blood vessels reside in order to secure a supply of oxygen and nutrients for the survival and growth of the metastatic lesion.

Citation Format: Dennis Jones, Han-sin Jeong, Shan Liao, Timothy P. Padera. Formation of lymph node metastases is not angiogenesis dependent. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr PR06.
Optical Coherence Tomography Findings in Anterior Chamber Ointment Globule after Phacoemulsification
Authors: Mansour Ahmad M. , Haddad Randa S. , Salti Haytham I. , Habbal Zuhair
Published: December 2015

We present 2 cases of anterior chamber ointment with evidence of progressive endothelial cell loss. In both cases, an anterior segment optical coherence tomography (OCT) was similar to an OCT of a tobramycin-dexamethasone ointment placed on a pen tip. An anterior segment OCT also demonstrated the direct contact of the globule with the corneal endothelium. A gas chromatography/mass spectrometry analysis documented the similarity to tobramycin-dexamethasone ointment in 1 case. Anterior segment OCT can help in confirming the diagnosis. Corneal endothelial injury is a continuous process, and its clinical manifestation is related to the size of the globule, the initial endothelium count, and the duration of ointment contact, which is related to supine positioning. It is advisable to avoid ointments in the immediate postoperative period, especially in corneal wounds larger than 3 mm.
Eyelid Metastatic Thyroid Papillary Carcinoma
Authors: Mudhar Hardeep Singh , Nuruddin Murtuza , Roy Soma Rani
Published: December 2015

Purpose: The aim of this study was to report the clinical and histopathological features of an eyelid metastasis in a 70-year-old male with no prior medical history. Methods: A 70-year-male presented with a painless, hard, red nodular growth in his left lower medial eyelid of 6 months duration, involving the canaliculus and punctum. He did not complain of any other ocular or systemic abnormality. The clinical differential diagnosis included lymphoma or a primary adnexal tumour. The lesion was excised under local anaesthetic cover and sent for routine histopathological analysis. Results: The histology revealed a carcinoma involving the posterior and anterior lamella of the lower lid. It was composed of papillary and follicular areas. The tumour nuclei were optically clear, overlapping, had nuclear grooves and were associated with eosinophilic colloid material. The tumour cells were strongly positive for nuclear thyroid transcription factor-1 and thyroglobulin (which also stained some of the eosinophilic colloid material). The histological and immunohistochemical features were those of metastatic papillary carcinoma of the thyroid. Unfortunately, the patient's thyroid has yet to be examined because of loss to follow-up. Conclusion: To the best of our knowledge, this is the first report of thyroid papillary carcinoma metastasizing to the eyelid as the presenting feature of the disease. A review of the literature of metastatic thyroid carcinoma to the eyelids is presented, to place the findings of this case report in context.
Antimicrobial Peptides as Anti-Infectives against Staphylococcus epidermidis
Authors: Agarwal Sangya , Sharma Garima , Dang Shweta , Gupta Sanjay , Gabrani Reema
Published: December 2015

Staphylococcus epidermidis has emerged as the main causative agent for graft-related and nosocomial infections. Rampant use of antibiotics and biofilm formed by the organism results in poor penetration of the drug and further aggravates the antibiotic resistance, emphasizing an urgent need to explore alternative treatment modalities. Antimicrobial peptides (AMPs), produced as effector molecules of the innate immunity of living organisms, have therapeutic potential that can be used to inhibit the growth of microbes. In addition, the susceptibility of a microbe to become resistant to an AMP is relatively low. The AMPs are amphipathic peptides of 12-100 residues, which have broad-spectrum activity against microbes. There are scattered reports of AMPs listed against S. epidermidis and there is an urgent need to systematically study the AMPs. Various natural AMPs as well as synthetic peptides have been investigated against S. epidermidis. These peptides have been shown to inhibit both planktonic culture and S. epidermidis biofilm effectively. The multiple modes of action in killing the organism minimize the chances for the development of resistance. This review focused on various natural and synthetic peptides that demonstrate activity against S. epidermidis.
Narrativas e fronteiras em duas jornadas latino-americanas
Authors: Guerreiro Alexandre Silva
Published: December 2015

A transposição da fronteira entre México e EUA ocupa um lugar comum nos filmes baseados em jornadas de heróis latinos em busca de uma vida melhor. A partir dos limites da representação dessa jornada, propomos uma discussão, com ênfase na análise fílmica, de duas obras latino-americanas, a saber, Maria Full of Grace e La Jaula de Oro, como exemplares da travessia obrigatória almejada pelos seus protagonistas.  Interessa-nos observar o modo como a narcofronteira é apresentada nesses dois filmes, bem como de que maneira a narrativa se constrói em torno dessa fronteira e a forma como uma certa repetição inscreve a transposição da fronteira como elemento fundamental às narconarrativas de fronteiras latino-americanas.
Que coisas nossas são estas? Música popular, disco e o início do cinema sonoro no Brasil
Authors: Miranda Suzana Reck
Published: December 2015

Este artigo destaca elementos históricos e estilísticos que cercam o filme Coisas Nossas (1931), apontado como o primeiro longa-metragem musical brasileiro ‘inteiramente sincronizado’ com o uso do sistema vitaphone. Interessa-nos, sobretudo, o seu repertório musical. Observaremos possíveis ligações dos estilos e dos intérpretes com a dinâmica da indústria fonográfica do período, na tentativa de compreender o que, naquele momento, foi tomado como sendo as “nossas coisas”
Apresentação
Authors: Cardenuto Filho Reinaldo , Prioste Marcelo
Published: December 2015

Apresentação da revista Significação, número 44.
Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects
Authors: Ronsein Graziella E. , Hutchins Patrick M. , Isquith Daniel , Vaisar Tomas , Zhao Xue-Qiao , Heinecke Jay W.
Published: December 2015

Objective—

We investigated relationships between statin and niacin/statin combination therapy and the concentration of high-density lipoprotein particles (HDL-P) and cholesterol efflux capacity, 2 HDL metrics that might better assess cardiovascular disease risk than HDL-cholesterol (HDL-C) levels.

Approach—

In the Carotid Plaque Composition Study, 126 subjects with a history of cardiovascular disease were randomized to atorvastatin or combination therapy (atorvastatin/niacin). At baseline and after 1 year of treatment, the concentration of HDL and its 3 subclasses (small, medium, and large) were quantified by calibrated ion mobility analysis (HDL-P
IMA
). We also measured total cholesterol efflux from macrophages and ATP-binding cassette transporter A1 (ABCA1)–specific cholesterol efflux capacity.

Results—

Atorvastatin decreased low-density lipoprotein cholesterol by 39% and raised HDL-C by 11% (
P
=0.0001) but did not increase HDL-P
IMA
or macrophage cholesterol efflux. Combination therapy raised HDL-C by 39% (
P
<0.0001) but increased HDL-P
IMA
by only 14%. Triglyceride levels did not correlate with HDL-P
IMA
(
P
=0.39), in contrast to their strongly negative correlation with HDL-C (
P
<0.0001). Combination therapy increased macrophage cholesterol efflux capacity (16%,
P
<0.0001) but not ABCA1-specific efflux. ABCA1-specific cholesterol efflux capacity decreased significantly (
P
=0.013) in statin-treated subjects, with or without niacin therapy.

Conclusions—

Statin therapy increased HDL-C levels but failed to increase HDL-P
IMA
. It also reduced ABCA1-specific cholesterol efflux capacity. Adding niacin to statin therapy increased HDL-C and macrophage efflux, but had much less effect on HDL-P
IMA
. It also failed to improve ABCA1-specific efflux, a key cholesterol exporter in macrophages. Our observations raise the possibility that niacin might not target the relevant atheroprotective population of HDL.
Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Coronary Heart Disease Due To Combined Estrogen Plus Progestin Therapy
Authors: Johnson Karen C. , Aragaki Aaron K. , Jackson Rebecca , Reiner Alex , Sandset Per Morten , Rosing Jan , Dahm Anders E.A. , Rosendaal Frits , Manson JoAnn E. , Martin Lisa W. , Liu Simin , Kuller Lewis H. , Cushman Mary , Rossouw Jacques E.
Published: December 2015

Objective—

To examine whether tissue factor pathway inhibitor or acquired activated protein C (APC) resistance influences the increased risk of coronary heart disease (CHD) due to estrogen plus progestin therapy.

Approach and Results—

Prospective nested case–control study of 205 cases of CHD and 481 matched controls in the Women’s Health Initiative randomized trial of estrogen plus progestin therapy. After multivariable covariate adjustment, both baseline tissue factor pathway activity (
P
=0.01) and APC resistance (
P
=0.004) were associated positively with CHD risk. Baseline tissue factor pathway activity and APC resistance singly or jointly did not significantly modify the effect of estrogen plus progestin on CHD risk. Compared with placebo, estrogen plus progestin decreased tissue factor pathway inhibitor activity and increased APC resistance but these changes did not seem to modify or mediate the effect of estrogen plus progestin on CHD risk.

Conclusions—

Tissue factor pathway inhibitor activity and APC resistance are related to CHD risk in women, but may not explain the increased CHD risk due to estrogen plus progestin therapy. The data from this study do not support the clinical use of measuring these hemostatic factors to help stratify risk before hormone therapy.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00000611.
Touching and Interacting with Inaccessible Cultural Heritage
Authors: Nicolas Théophane , Gaugne Ronan , Tavernier Cédric , Petit Quentin , Gouranton Valérie , Arnaldi Bruno
Published: December 2015

The sense of touch provides a particular access to our environment, enabling a tangible relation with it. In the particular case of cultural heritage, touching the past, apart from being a universal dream, can provide essential information to analyze, understand, or restore artifacts. However, archaeological objects cannot always offer tangible access, either because they have been destroyed or are too damaged, or because they are part of a larger assembly. In other cases, it is the context of use that has become inaccessible, as it is related to an outdated activity. We propose a workflow based on a combination of computed tomography, 3D images, and 3D printing to provide concrete access to cultural heritage, and we illustrate this workflow in different contexts of inaccessibility. These technologies are already used in cultural heritage, but seldom combined, and are most often employed for exceptional artifacts. We propose to combine these technologies in case studies corresponding to relevant archaeological situations.
Underlying Temporalities of Big History
Authors: Wood Barry
Published: December 2015

Traditional history, beginning around 3000bce, depends on dateable written records. The expanded scope of big history (13.8 byr) requires new understandings of time. Following the work of J. T. Fraser, I explore the underlying temporalities of big history. To Fraser’satemporalityandeotemporality, which govern the history of galaxy, star, and planet formation, I addpetrotemporaliitywhich governs three processes—in the freezing of time in mineralized fossils, the chronological structuring of geohistory from stratified rock, and the slow unwinding of time through the decay of radioactive isotopes—andgenotemporalitywhich bypasses the vagaries of species transition and extinction, utilizing instead the incorporation of viraldnawithin the human genome and its continuity of umwelt to construct a big history of life that connects the earliest life forms with humans. I conclude that the possibility of constructing a big history depends on these underlying temporalities.
The View of the European Court of Human Rights on Competent Patients’ Right of Informed Consent. Research in the Light of Articles 3 and 8 of the European Convention on Human Rights
Authors: Buelens Wannes , Herijgers Coralie , Illegems Steffi
Published: December 2015

It is an internationally recognized principle that patients should give their informed consent to a treatment in order to avoid a violation of their right to personal autonomy. This article discusses this principle in the light of Articles 3 and 8 of The European Convention on Human Rights and the view of the European Court of Human Rights on this matter. Indeed, nowadays more complaints related to (the lack of) informed consent not only concern a possible violation of Article 8 of the Convention, but Article 3 has also gained importance, especially when a treatment is intrusive.
When young are more conspicuous than adults: a new ranid species (Anura: Ranidae) revealed by its tadpole
Authors: GROSJEAN STÉPHANE , BORDOLOI SABITRY , CHUAYNKERN YODCHAIY , CHAKRAVARTY PARAMITA , OHLER ANNEMARIE
Published: December 2015

Tadpoles of Clinotarsus alticola collected nearby the type locality in Assam, India are barcoded and described. A detailed morphological and morphometrical description of the specimens, along with a study of the anatomy of the buccal cavity are provided. A comparison of these tadpoles with “Clinotarsus alticola” tadpoles from peninsular Thailand and of the genetic variation of a fragment of their mtDNA 16S gene led us to assign the population of peninsular Thailand to a new species, Clinotarsus penelope sp. n. The holotype of the new species is chosen among the tadpole series as no adult could be found in the type locality. Presumed conspecific adults of nearby localities are morphologically described and compared to barcoded adults of Clinotarsus alticola, waiting for further molecular confirmation. The tadpole of the new species differs from that of C. alticola by a much greater size at comparative stages (e.g., 77.7 mm vs. 53.3 mm in stage 36, respectively), a black coloration (vs. a yellow-olive tinge), several ocelli on the tail muscle (vs. only one), a rounded snout (vs. a more pointed snout) and a different Keratodont Row Formula (KRF; nine keratodonts rows maximum on both labia in C. penelope vs. eight maximum in C. alticola). A discussion about the choice of the holotype, the assignment of adult specimens and the future confirmation of this assignment are provided, as well as a comparison with older descriptions of “Clinotarsus alticola” sensu lato tadpoles and with Clinotarsus curtipes tadpoles from Karnataka, India. The lectotype of Clinotarsus alticola is redescribed.
First record and establishment of Branchiomma coheni (Polychaeta: Sabellidae) in the Atlantic Ocean and review of non–indigenous species of the genus
Authors: KEPPEL ERICA , TOVAR–HERNÁNDEZ MARIA ANA , RUIZ GREGORY
Published: December 2015

Sabellidae are among the most visible polychaetes of the hard substrate fouling communities and are colonizing new geographic areas. The fouling community was surveyed in 25 shallow coastal estuaries on the Atlantic and Pacific coasts of the United States with the specific goal of detecting non–indigenous species. During surveys in 2012 and 2014, specimens of Branchiomma coheni Tovar-Hernández and Knight-Jones, 2006 were found for the first time in Tampa Bay, Florida, occurring at the same marina site (27°53'7.58"N, 82°32'2.29"W) each year and suggesting it is established here. The species was not detected at other sites surveyed in the United States, and has not been reported from the eastern Atlantic or the Mediterranean basin. Type material of B. coheni, specimens from southern Gulf of California, and specimens from the Pacific coast of Mexico, were used to corroborate identification. The transfer of this species by ships via the Panama Canal is a probable mechanism of introduction, based on the current known distribution and shipping traffic patterns. This represents the first record of the species in the Atlantic Ocean. A worldwide update of the records of this species and a list of valid species of the genus Branchiomma with notes on introduced populations are provided, as well as recommendations for accurate identification and sampling.