bluuebunny/crossref_metadata_2025 huggingface dataset:
Left and right ventricular hemodynamic forces in healthy volunteers and elite athletes assessed with 4D flow magnetic resonance imaging
Authors: Arvidsson Per M. , Töger Johannes , Carlsson Marcus , Steding-Ehrenborg Katarina , Pedrizzetti Gianni , Heiberg Einar , Arheden Håkan
Published: October 2016

Intracardiac blood flow is driven by hemodynamic forces that are exchanged between the blood and myocardium. Previous studies have been limited to 2D measurements or investigated only left ventricular (LV) forces. Right ventricular (RV) forces and their mechanistic contribution to asymmetric redirection of flow in the RV have not been measured. We therefore aimed to quantify 3D hemodynamic forces in both ventricles in a cohort of healthy subjects, using magnetic resonance imaging 4D flow measurements. Twenty five controls, 14 elite endurance athletes, and 2 patients with LV dyssynchrony were included. 4D flow data were used as input for the Navier-Stokes equations to compute hemodynamic forces over the entire cardiac cycle. Hemodynamic forces were found in a qualitatively consistent pattern in all healthy subjects, with variations in amplitude. LV forces were mainly aligned along the apical-basal longitudinal axis, with an additional component aimed toward the aortic valve during systole. Conversely, RV forces were found in both longitudinal and short-axis planes, with a systolic force component driving a slingshot-like acceleration that explains the mechanism behind the redirection of blood flow toward the pulmonary valve. No differences were found between controls and athletes when indexing forces to ventricular volumes, indicating that cardiac force expenditures are tuned to accelerate blood similarly in small and large hearts. Patients’ forces differed from controls in both timing and amplitude. Normal cardiac pumping is associated with specific force patterns for both ventricles, and deviation from these forces may be a sensitive marker of ventricular dysfunction. Reference values are provided for future studies.

NEW & NOTEWORTHY Biventricular hemodynamic forces were quantified for the first time in healthy controls and elite athletes (n = 39). Hemodynamic forces constitute a slingshot-like mechanism in the right ventricle, redirecting blood flow toward the pulmonary circulation. Force patterns were similar between healthy subjects and athletes, indicating potential utility as a cardiac function biomarker.
The Effect of Wenxin Keli on the mRNA Expression Profile of Rabbits with Myocardial Infarction
Authors: Zheng Min , Liu Zhouying , Liu Nana , Hou Cuihong , Pu Jielin , Zhang Shu
Published: October 2016

Aims. The molecular mechanisms of Chinese traditional medicine Wenxin Keli (WXKL) were unknown. This study was aimed at exploring the effects of WXKL on the gene expression profile and pathological alteration of rabbits with myocardial infarction. Methods. Twenty male adult rabbits were randomly divided into 4 groups: sham, model, WXKL, and captopril groups. Model, WXKL, and captopril groups underwent the ligation of the left anterior descending coronary artery while sham group went through an identical procedure without ligation. WXKL (817 mg/kg/d), captopril (8 mg/kg/d), and distilled water (to model and sham groups) were administered orally to each group. After 4 weeks, the rabbits were examined with echocardiography and the hearts were taken for expression chip and pathological staining (H&E, Masson, and Tunel) studies. Results. The data revealed that WXKL downregulated genes associated with inflammation (CX3CR1, MRC1, and FPR1), apoptosis (CTSC and TTC5), and neurohumoral system (ACE and EDN1) and upregulated angiogenesis promoting genes such as RSPO3. Moreover, the results also showed that WXKL improved cardiac function and prevented histopathological injury and apoptosis. Conclusion. The present study demonstrated that WXKL might play an important role in inhibiting inflammation, renin‐angiotensin system, and apoptosis. It might be a promising Chinese medicine in the treatment of patients with myocardial infarction.
Initiation of Failure for Masonry Subject to In-Plane Loads through Micromechanics
Authors: Berardi V. P.
Published: October 2016

A micromechanical procedure is used in order to evaluate the initiation of damage and failure of masonry with in-plane loads. Masonry material is viewed as a composite with periodic microstructure and, therefore, a unit cell with suitable boundary conditions is assumed as a representative volume element of the masonry. The finite element method is used to determine the average stress on the unit cell corresponding to a given average strain prescribed on the unit cell. Finally, critical curves representing the initiation of damage and failure in both clay brick masonry and adobe masonry are provided.
Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage
Authors: He Xin , Ye YongBin , Xu XiaoJun , Wang Jing , Huang YuXian , Weng GuangYang , Zhang MingWan , Guo KunYuan
Published: October 2016

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a major cause of nonrelapse mortality after allo-HSCT. A conditioning regimen plays a pivotal role in the development of aGVHD. To provide a platform for studying aGVHD and evaluating the impact of different conditioning regimens, we established a murine aGVHD model that simulates the clinical situation and can be conditioned with Busulfan-Cyclophosphamide (Bu-Cy) and Fludarabine-Busulfan (Flu-Bu). In our study, BALB/c mice were conditioned with Bu-Cy or Flu-Bu and transplanted with 2×107 bone marrow cells and 2×107 splenocytes from either allogeneic (C57BL/6) or syngeneic (BALB/c) donors. The allogeneic recipients conditioned with Bu-Cy had shorter survivals (P<0.05), more severe clinical manifestations, and higher hepatic and intestinal pathology scores, associated with increased INF-γ expression and diminished IL-4 expression in serum, compared to allogeneic recipients conditioned with Flu-Bu. Moreover, higher donor-derived T-cell infiltration and severely impaired B-cell development were seen in the bone marrow of mice, exhibiting aGVHD and conditioned with Flu-Bu. Our study showed that the conditioning regimen with Bu-Cy resulted in more severe aGVHD while the Flu-Bu regimen was associated with more extensive and long standing bone marrow damage.
Efficient Regularized Regression withL0Penalty for Variable Selection and Network Construction
Authors: Liu Zhenqiu , Li Gang
Published: October 2016

Variable selections for regression with high-dimensional big data have found many applications in bioinformatics and computational biology. One appealing approach is theL0regularized regression which penalizes the number of nonzero features in the model directly. However, it is well known thatL0optimization is NP-hard and computationally challenging. In this paper, we propose efficient EM (L0EM) and dualL0EM (DL0EM) algorithms that directly approximate theL0optimization problem. WhileL0EM is efficient with large sample size, DL0EM is efficient with high-dimensional (n≪m) data. They also provide a natural solution to allLp  p∈[0,2]problems, including lasso withp=1and elastic net withp∈[1,2]. The regularized parameterλcan be determined through cross validation or AIC and BIC. We demonstrate our methods through simulation and high-dimensional genomic data. The results indicate thatL0has better performance than lasso, SCAD, and MC+, andL0with AIC or BIC has similar performance as computationally intensive cross validation. The proposed algorithms are efficient in identifying the nonzero variables with less bias and constructing biologically important networks with high-dimensional big data.
Privacy Models in Wireless Sensor Networks: A Survey
Authors: de Fuentes J. M. , González-Manzano L. , Mirzaei O.
Published: October 2016

Wireless Sensor Networks (WSNs) are attracting attention from the research community. One of the key issues is to provide them with privacy protection. In recent years, a huge amount of contributions has been focused on this area. Surveys and literature reviews have also been produced to give a systematic view of the different approaches taken. However, no previous work has focused on privacy models, that is, the set of assumptions made to build the approach. In particular, this paper focuses on this matter by studying 41 papers of the last 5 years. We highlight the great differences appearing among related papers that could make them incompatible to be applied simultaneously. We propose a set of guidelines to build comprehensive privacy models so as to foster their comparability and suitability analysis for different scenarios.
Safety and Antihypertensive Effect of Selara® (Eplerenone): Results from a Postmarketing Surveillance in Japan
Authors: Takahashi Shoko , Hiramatsu Megumi , Hotta Shinichi , Watanabe Yukie , Suga Osamu , Endo Yutaka , Miyamori Isamu
Published: October 2016

Prospective postmarketing surveillance of Selara (eplerenone), a selective mineralocorticoid receptor antagonist, was performed to confirm its safety and efficacy for hypertension treatment in Japan. The change in blood pressure after initiation of eplerenone treatment was also examined. Patients with essential hypertension who were eplerenone-naïve were recruited regardless of the use of other antihypertensive drugs. For examination of changes in blood pressure, patients were excluded if eplerenone was contraindicated or used off-label. Patients received 50–100 mg of eplerenone once daily and were observed for 12 weeks. No treatments including antihypertensive drugs were restricted during the surveillance period. Across Japan, 3,166 patients were included for safety analysis. The incidence of adverse drug reactions was 2.4%. The major adverse drug reactions observed were hyperkalemia (0.6%), dizziness, renal impairment, and increased serum potassium (0.2% each). The mean systolic blood pressure decreased from 152.1±19.0 mmHg to 134.8±15.2 mmHg at week 12, and the mean diastolic blood pressure decreased from 85.8±13.7 mmHg to 77.7±11.4 mmHg. There were no significant new findings regarding the type or incidence of adverse reactions, and eplerenone had a clinically significant antihypertensive effect, leading to favorable blood pressure control.
Kirschner Wire Breakage during Removal Requiring Retrieval
Authors: Wong Kai Yuen , Mole Rosalind , Gillespie Patrick
Published: October 2016

Kirschner wires (K-wires) are widely used for fixation of fractures and dislocations in the hand as they are readily available, reliable, and cost-effective. Complication rates of up to 18% have been reported. However, K-wire breakage during removal is rare. We present one such case illustrating a simple technique for retrieval. A 35-year-old male presented with a distal phalanx fracture of his right middle finger. This open fracture was treated with K-wire fixation. Postoperatively, he developed a pin site infection with associated finger swelling. The K-wire broke during removal with the proximal piece completely retained in his middle phalanx. To minimise risk of osteomyelitis, the K-wire was removed with a novel surgical technique. He had full return of hand function. Intraoperative K-wire breakage has a reported rate of 0.1%. In our case, there was no obvious cause of breakage and the patient denied postoperative trauma. On the other hand, pin site infections are much more common with reported rates of up to 7% in the hand or wrist. K-wire fixation is a simple method for bony stabilisation but can be a demanding procedure with complications often overlooked. It is important to be aware of the potential sequelae.
Moyamoya Disease with Coexistent Hypertriglyceridemia in Pediatric Patient
Authors: Chan Jacqueline , D’Ambrosio Rodriguez Fabiola , Sahni Deepank , Boucher-Berry Claudia
Published: October 2016

Moyamoya disease is a rare chronic and progressive cerebrovascular disease of the arteries of the circle of Willis that can affect children and adults. It has been associated with multiple diseases, including immunologic, like Graves’ disease, diabetes mellitus, and SLE. Hyperlipidemia has been recognized in patients with Moyamoya disease with an incidence of 27–37%. However, no case in pediatric patients has been reported of the coexistence of Moyamoya disease and hyperlipidemia. Here we present a case of a 9-year-old female diagnosed with Moyamoya disease after a stroke with incidental finding of familial hypercholesterolemia. This finding will make our patient a very unique case, since there has not been any reporting of Moyamoya disease and hypercholesterolemia association.
Rituximab Not Effective for Hearing Loss in Cogan’s Syndrome
Authors: Bunker Daniel R. , Kerr Leslie Dubin
Published: October 2016

Importance. Rituximab was not effective in ameliorating the hearing loss in a patient with atypical Cogan’s syndrome.Observations. We report the case of a patient who developed acute bilateral uveitis and sensorineural hearing loss. A diagnosis of atypical Cogan’s syndrome was made. The patient’s hearing loss did not improve despite high dose steroids and azathioprine. Rituximab was administered given a recent report of its efficacy in a patient with refractory disease; however, our patient’s hearing loss did not improve.Conclusion. Hearing loss in Cogan’s syndrome is difficult to treat. Though rituximab was ineffective in our case, earlier administration in the disease course could be effective for future patients.
Minimally Invasive Treatment of Mirizzi Syndrome, a Rare Cause of Cholestasis in Childhood
Authors: Tuncer Ahmet Ali , Yilmaz Sezgin , Yavuz Mustafa , Çetinkurşun Salih
Published: October 2016

Mirizzi syndrome is the compressive blockage of the cystic or choledochal duct caused by a biliary stone occupying the cystic canal or Hartmann’s pouch. This occurrence is rare and, in English literature, three cases defined in children have been observed. In order to draw attention to this rare occurrence, we preferred a 14-year-old male patient with Mirizzi syndrome. In this case, ERCP was performed preoperatively and the diagnosis was carried out with the help of clear visualisation and identification of the tissue structures as well as the stent placed in bile duct; so we protected the patient from the possible iatrogenic injury occurring during surgery.
Performance Investigation of O-Ring Vacuum Membrane Distillation Module for Water Desalination
Authors: Alhathal Alanezi Adnan , Abdallah H. , El-Zanati E. , Ahmad Adnan , Sharif Adel O.
Published: October 2016

A new O-ring flat sheet membrane module design was used to investigate the performance of Vacuum Membrane Distillation (VMD) for water desalination using two commercial polytetrafluoroethylene (PTFE) and polyvinylidene fluoride (PVDF) flat sheet hydrophobic membranes. The design of the membrane module proved its applicability for achieving a high heat transfer coefficient of the order of 103 (W/m2 K) and a high Reynolds number (Re). VMD experiments were conducted to measure the heat and mass transfer coefficients within the membrane module. The effects of the process parameters, such as the feed temperature, feed flow rate, vacuum degree, and feed concentration, on the permeate flux have been investigated. The feed temperature, feed flow rate, and vacuum degree play an important role in enhancing the performance of the VMD process; therefore, optimizing all of these parameters is the best way to achieve a high permeate flux. The PTFE membrane showed better performance than the PVDF membrane in VMD desalination. The obtained water flux is relatively high compared to that reported in the literature, reaching 43.8 and 52.6 (kg/m2 h) for PVDF and PTFE, respectively. The salt rejection of NaCl was higher than 99% for both membranes.
Evaluation of Buccal Cell Samples for Studies of Oral Microbiota
Authors: Yu Guoqin , Phillips Steve , Gail Mitchell H. , Goedert James J. , Humphrys Michael , Ravel Jacques , Ren Yanfang , Caporaso Neil E.
Published: October 2016

Background: The human microbiota is postulated to affect cancer risk, but collecting microbiota specimens with prospective follow-up for diseases will take time. Buccal cell samples have been obtained from mouthwash for the study of human genomic DNA in many cohort studies. Here, we evaluate the feasibility of using buccal cell samples to examine associations of human microbiota and disease risk.

Methods: We obtained buccal cells from mouthwash in 41 healthy participants using a protocol that is widely employed to obtain buccal cells for the study of human DNA. We compared oral microbiota from buccal cells with that from eight other oral sample types collected by following the protocols of the Human Microbiome Project. Microbiota profiles were determined by sequencing 16S rRNA gene V3–V4 region.

Results: Compared with each of the eight other oral samples, the buccal cell samples had significantly more observed species (P < 0.002) and higher alpha diversity (Shannon index, P < 0.02). The microbial communities were more similar (smaller beta diversity) among buccal cells samples than in the other samples (P < 0.001 for 12 of 16 weighted and unweighted UniFrac distance comparisons). Buccal cell microbial profiles closely resembled saliva but were distinct from dental plaque and tongue dorsum.

Conclusions: Stored buccal cell samples in prospective cohort studies are a promising resource to study associations of oral microbiota with disease.

Impact: The feasibility of using existing buccal cell collections in large prospective cohorts allows investigations of the role of oral microbiota in chronic disease etiology in large population studies possible today. Cancer Epidemiol Biomarkers Prev; 26(2); 249–53. ©2016 AACR.
Abstract A36: Resistance to IGF-1R targeted therapy by insulin-like growth factor 2-mediated tumor microenvironment network
Authors: Lee Ji-Sun , Lee Ho-Young
Published: October 2016

Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumor microenvironment (TME) to innate resistance to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R mAb that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumor infiltration of stromal cells and metastatic tumor growth and, ultimately, decreases overall survival of mice. Cixutumumab treatment stimulates recruitment of macrophages and fibroblasts via STAT3-dependent transcriptional up-regulation of IGF2 in cancer cells and paracrine IGF2/IGF-2R activation, resulting in the stroma-derived CXCL8 production and thus angiogenic and metastatic environment. Silencing IGF2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and angiogenic activities of vascular endothelial cells. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signaling network may overcome the adverse consequences of anti-IGF-1R mAb-based therapies.

Citation Format: Ji-Sun Lee, Ho-Young Lee. Resistance to IGF-1R targeted therapy by insulin-like growth factor 2-mediated tumor microenvironment network. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A36.
Abstract B21: Exostosin 1 regulates cancer cell stemness in breast cancer cells
Authors: Manandhar Sarala , Kim Chang-gu , Oh Su Young , Lee Sun-Hee , Seok Jiyoon , Jung Yuk-Dong , Lee Hye-Eun , Choi Young-Sun , Lee You Mie*
Published: October 2016

Cancer stem cells (CSCs), a group of cancer cells, are associated with resistance to radiation and chemotherapy and are implicated in recurrent of cancer. Exostosin 1 (EXT1) gene is widely reported as tumor suppressor and its indispensable role in elongation of heparan sulfate (HS) can speculate probable role as tumor promotor. In recent years, a number of tumors are reported to over express EXT1. Here, we investigated the role of EXT1 in the maintenance of cancer cell stemness. MCF7/ADR cells developed by exposing MCF7, breast cancer cells, to doxorubicin for several months in culture, showed high resistance to doxorubicin compared to MCF7, parental cell line. Doxorubicin resistant MCF7/ADR cells have enhanced P-glycoprotein (P-gp) expression. In FACs analysis, MCF7/ADR cells were accounted for high number of CSC population; they possessed large number of ALDH+ and CD44+/CD24- population compared to MCF7. CSC marker, CD44, was found overexpressed in MCF7/ADR compared to MCF7. Besides that, in mammosphere culture, MCF7/ADR cells formed large number of mammospheres in contrast to MCF7. In microarray data analysis, several genes were found upregulated in MCF7/ADR cells and EXT1 was selected as a candidate gene. Overexpressed EXT1 in MCF7/ADR cells was confirmed by real time PCR. The critical role of EXT1 in maintaining cancer cell stemness was confirmed by siRNA mediated knockdown of EXT1. Knockdown of EXT1 repressed CSC markers, reduced population of ALDH+ and CD44+/CD24-, and suppressed expression of CD44. As a molecular mechanism, we detected suppressed expression of heparan sulfate, syndecan1(SDC1) with siEXT1. With these results, we can suggest that EXT1 level might be a determining factor for doxorubicin sensitive breast cancer cells and enhanced expression of EXT1 can take part in development of CSC phenotype on exposure to anthracycline based therapy through upregulation of SDC1.

Citation Format: Sarala Manandhar, Chang-gu Kim, Su Young Oh, Sun-Hee Lee, Jiyoon Seok, Yuk-Dong Jung, Hye-Eun Lee, Young-Sun Choi, You Mie Lee*. Exostosin 1 regulates cancer cell stemness in breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B21.
Abstract C07: Cancer-associated fibroblasts: Co-migrating from primary to metastatic tumor sites
Authors: Ershaid Nour , Yael Raz , Erez Neta
Published: October 2016

Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Cancer-associated fibroblasts (CAFs) are the most abundant cell type in tumor stroma. CAFs are an essential component of the tumor microenvironment involved in many processes that promote tumor progression, including growth promoting, pro-angiogenic and pro-inflammatory signaling. In addition, CAFs were shown to support cancer cell invasion and metastasis via their extracellular matrix remodeling capacities. However, a direct active participation of CAFs in supporting the dissemination of cancer cells to secondary organs and supporting metastatic colonization is still largely obscure.

We show that fibroblasts from mammary tumors are capable of co-migrating with disseminated tumor cells to the lungs and are incorporated into ensuing pulmonary metastases. We utilized novel multi-transgenic mouse models of spontaneous breast carcinoma and lung metastasis (MMTV-PyMT) combined with transgenic mice in which fibroblasts are genetically labeled with fluorescent reporter genes, thus allowing their unbiased tracking and isolation during tumor progression and metastasis. By orthotopic transplantations of fluorescently labeled tumors we were able to detect CAFs derived from primary tumors in lung metastases. We plan to characterize the functional role of co-migrating CAFs by analyzing the transcriptional changes that migrating CAFs undergo in the process. We will seek to uncover specific molecular pathways which contribute to the reciprocal interactions between migrating CAFs and cancer cells which serve to promote and enhance the metastatic process.

In summary, we were able to uncover a novel role for mammary CAFs in which they co-migrate with cancer cells from the primary tumor to metastatic sites in the lungs.

Citation Format: Nour Ershaid, Raz Yael, Neta Erez. Cancer-associated fibroblasts: Co-migrating from primary to metastatic tumor sites. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C07.
Abstract C33: Effects of monocyte chemotactic protein-1 deficiency on spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet
Authors: Yan Lin , Sundaram Sneha
Published: October 2016

Obesity is a risk factor for cancer. Adipose tissue is considered an endocrine organ that produces pro-inflammatory adipokines, e.g. monocyte chemotactic protein-1 (MCP-1), that may contribute to obesity-related malignant progression. This study investigated effects of MCP-1 deficiency on pulmonary metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice using a spontaneous metastasis model. The high-fat diet (45% of energy from fat) significantly increased the number and size (cross-sectional area and volume) of lung metastases compared to the AIN93G control diet (16% of energy from fat). Deficiency of MCP-1 reduced the number of lung metastases by 37% (p < 0.05) in high-fat diet-fed mice; it reduced metastatic cross-sectional area by 46% (p < 0.05) and volume by 69% (p < 0.05) compared to wild-type mice. Adipose and plasma concentrations of MCP-1 were significantly higher in high-fat diet-fed wild-type mice than in their AIN93G-fed counterparts, but they were not detectable in MCP-1 deficient mice regardless of diets. Plasma concentrations of plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly higher in MCP-1 deficient mice than in wild-type mice. We conclude that adipose-produced MCP-1, at least partly, contributes to high-fat diet-enhanced metastasis and suggest that the overproduction of inflammatory cytokines (PAI-1, TNF-α) and angiogenic factors (VEGF, TIMP-1) in the absence of MCP-1 may support the metastatic development and growth of LLC in MCP-1 deficient mice.

Citation Format: Lin Yan, Sneha Sundaram. Effects of monocyte chemotactic protein-1 deficiency on spontaneous metastasis of Lewis lung carcinoma in mice fed a high-fat diet. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C33.
Abstract C35: Epigenetic repression of hexokinase 2 is responsible for the heterogeneity of 18F-FDG uptake in hepatocellular carcinoma
Authors: Hyemi Kim , Gyu Lee Hyun , Myun Lee Jae , Han Park Jeon
Published: October 2016

The clinical usefulness of 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET), based on aerobic glycolysis, has been recently challenged in hepatocellular carcinoma (HCC) due to the heterogeneity of 18F-FDG uptake. Although inconsistent 18F-FDG uptake in HCCs is explained by the heterogeneous expression of hexokinase 2 (HK2), the underlying molecular mechanism remains elusive. Here, we examined the methylation status of the HK2 promoter and its influence on hypoxia-inducible factor-1α (HIF-1α) binding. We first confirmed inconsistent 18F-FDG uptake and correlative HK2 expression. Utilizing the HumanMethylation450 array, we discovered hypermethylation of the HK2 promoter CpG island (CGI) region in HK2negative HCCs. Studies using HK2 promoter luciferase constructs showed that a newly defined hypoxia responsive element (HRE) regulates HK2 expression. We also found that differential glucose uptake is caused by the differential HK2 expression due to differential methylation of the HK2 promoter CGI region in HCC cell lines. Finally, treatment with 5-Aza-2-deoxycytidine and hypoxic stimuli significantly increased HK2 expression due to increased HIF-1α binding to the HRE, resulting in increased glucose uptake in HK2negative SNU449 cells. Conclusion: These data indicate that methylation changes in the HK2 promoter CGI region in HCCs influence HK2 expression by regulating HIF-1α binding to the HRE in the CGI region. Hypermethylation of the HK2 promoter CGI region in HK2negative tissues inhibits the binding of HIF-1α to the HK2 promoter, resulting in the suppression of HK2 expression, which contributes to the heterogeneity of 18F-FDG uptake.

Citation Format: Kim Hyemi, Lee Hyun Gyu, Lee Jae Myun, Park Jeon Han. Epigenetic repression of hexokinase 2 is responsible for the heterogeneity of 18F-FDG uptake in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C35.
Abstract C43: Role of microRNAs in determining the cancer associated fibroblast phenotype
Authors: Abidin Siti Amalina Zainal , Hunt Stuart , Lambert Dan
Published: October 2016

Cancer-associated fibroblasts (CAF) are among the predominant cell types present within the tumour microenvironment. The presence of CAF expressing markers of myofibroblast transdifferentiation is associated with high-grade malignancies and poor prognoses in human diseases. The molecular mechanisms underlying myofibroblast transdifferentiation in CAF however, remain poorly understood. MicroRNAs regulate many biological processes, but their role in determining the fate of fibroblasts in the tumour microenvironment remains unclear.

Objective: To elucidate the role of miRNA in the conversion of resident fibroblast to myofibroblastic CAF.

Methods: Human primary oral fibroblasts were treated with different concentrations of TGF-β (0.05-5 ng/ml) for 24 and 48 hrs. Markers of CAF transdifferentiation such as alpha-smooth muscle actin (α-SMA) and fibronectin-EDA (FN-EDA) were analysed using qRT-PCR. Protein expression of α-SMA was analysed by western blot and formation of stress fiber was visualised using immunocytochemistry. Collagen gels were used to analyse fibroblast contractility and Taqman Low Density Array (TLDA) and qRT-PCR to determine miRNA expression profiles of experimentally-derived CAF.

Results: qRT-PCR and western blotting demonstrated an increase in α-SMA expression in TGF-β-induced, experimentally-derived CAF. TGF-β induced stress fiber formation and enhanced contraction of fibroblasts. TGF-β induced differential expression of a number of miRNAs in experimentally-derived CAF, including; miR-424, miR-200c and miR-145.

Conclusion: The role of miRNAs in the phenotypic changes observed in CAF has not been studied extensively. Here we show widespread alterations in miRNA expression profiles of experimentally-derived myofibroblastic CAF. Future studies will examine the role of these miRNA in reprogramming of normal fibroblasts to CAF-like phenotype and examine whether miRNA alterations contribute to the heterogeneity of the CAF phenotype observed in vivo.

Citation Format: Siti Amalina Zainal Abidin, Stuart Hunt, Dan Lambert. Role of microRNAs in determining the cancer associated fibroblast phenotype. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C43.
Abstract IA09: Non-cell autonomous regulation of senescence in cancer and cancer therapy
Authors: Alimonti Andrea
Published: October 2016

Loss of the tumor suppressor gene PTEN opposes malignant transformation by triggering a cellular senescence response. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumor cells to senescence. I will discuss recent findings demonstrating that at the onset of senescence, PTEN null prostate tumors are infiltrated by a population of CD11b+Gr-1+ myeloid cells that protect a fraction of proliferating tumor cells from senescence, thus sustaining tumor growth. Mechanistically, I found that Gr-1+ cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype (SASP) of the tumor through the secretion of interleukin-1 receptor antagonist. Therapeutically, I will present evidence that therapy-induced senescence and efficacy can be enhanced in PTEN null tumors by treatment that affect the recruitment of tumor-infiltrating CD11b+Gr-1+ myeloid cells or that reprogram the SASP. Taken together these data identify a novel non-cell-autonomous network, established by the innate immunity, that controls senescence evasion and chemoresistance in cancer. Targeting this network provides novel opportunities for cancer therapy.

Citation Format: Andrea Alimonti. Non-cell autonomous regulation of senescence in cancer and cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA09.
Abstract IA22: Modeling and targeting the tumor microenvironment of pancreatic cancer
Authors: Saur Dieter
Published: October 2016

Maintenance and drug resistance of pancreatic ductal adenocarcioma (PDAC) depends on cancer cell intrinsic mechanisms and a stroma that supports tumor growth. Mouse models of human PDAC have provided important insights into the evolution of this highly lethal tumor, but there are no models that allow secondary genetic manipulation of autochthonous tumors, the tumor microenvironment or the metastatic host niche once the tumor has formed.

We generated an inducible dual-recombinase system by combining Flp/frt and Cre/loxP. This novel PDAC model permits spatial and temporal control of gene expression enabling unbiased genetic approaches to study the role of tumor cell-autonomous and non-autonomous functions in endogenous cancers. This tool provides unparalleled access to the native biology of cancer cells and their hosting stroma, and rigorous genetic validation of candidate therapeutic targets. We performed tumor cell-autonomous and non-autonomous targeting, uncovered hallmarks of human multistep carcinogenesis, validated genetic tumor therapy, and showed that mast cells in the tumor microenvironment, which had been thought to be key oncogenic players, are in fact dispensable for tumor formation.

Citation Format: Dieter Saur. Modeling and targeting the tumor microenvironment of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr IA22.
Abstract PR10: A glycoprotein-mediated mechanical switch promotes glioma aggression
Authors: Barnes J Matthew , Miroshnikova Yekaterina A. , Tung Jason C. , Bainer Russel O. , Weaver Valerie M.
Published: October 2016

Glioblastoma multiforme (GBM) is a malignant brain tumor whose progression is associated with rampant extracellular matrix (ECM) remodeling. We recently found that ECM stiffness correlates with poor survival in human GBM specimens. Glycoproteins are the major constituent of normal brain ECM and many are overexpressed in brain tumors, yet the interplay between glycoproteins and mechanical signaling in GBM pathogenesis remains poorly understood. Here, we show that bulky glycoproteins and sugar-binding proteins are broadly upregulated in GBM relative to lower grade gliomas. Further, these genes are overexpressed in the mesenchymal (Mes) relative to the proneural (Pro) GBM subclass, the former of which is associated with treatment resistance and relapse. We took a specific interest in the hyaluronic acid (HA)-producing enzyme, HAS2, and the galactoside-binding lectin galectin-1 (Gal1) due to their ability to modulate tissue structure and rheology. Using mouse models of human GBM we showed that Mes tumors are enriched in HA and fibronectin, coincident with elevated ECM stiffness and mechanical signaling. These data suggest the possibility that aberrant glycoprotein expression drives GBM aggression through enhanced mechanical signaling resulting from tissue stiffening. Consistent with this hypothesis, by elevating mechanical signaling in Pro GBMs we induce a robust Mes-like transition and we see the opposite when reducing Gal1 expression or HA content in Mes tumors. Our data provides evidence of a feed-forward mechanism whereby mechanical signaling drives Gal1 and HA production which reinforce ECM stiffness, thus sustaining pro-tumorigenic mechanical signaling.

This abstract is also presented as Poster A21.

Citation Format: J Matthew Barnes, Yekaterina A. Miroshnikova, Jason C. Tung, Russel O. Bainer, Valerie M. Weaver. A glycoprotein-mediated mechanical switch promotes glioma aggression. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr PR10.
Phytochemical studies of new herbal collection with antidiabetic action (notice I – substance of primary synthesis)
Authors: Marchyshyn S. M. , Savych A. O.
Published: October 2016

There was studied the chemical composition of the anti-diabetic herbal collection. It was established the presence and determined the quantitative content of the substances of primary synthesis: polysaccharides, including inulin, organic acids and ascorbic acid, amino acids and fat acids. 17 organic acids and 18 fatty acids were identified by gas chromatography and 23 amino acids by high performance liquid chromatography (HPLC).
Research of cardioprotective properties of tincture of mullein herbs usual
Authors: Hanusevych M. I. , Fira L. S. , Lykhatskyi P. H.
Published: October 2016

In experiments on rats, which simulated adrenaline cardiomyopathy there were established antioxidant, membrane- and cardioprotective properties tincture of mullein herb. It is proved that this pharmacological drug at a dose of 0.2 ml/kg body weight causes a decrease in the activity of processes of lipid peroxidation in serum and myocardium of animals, restoring antioxidant system performance and reducing hepatocyte membrane permeability, as indicated by decreased activity of aminotransferases in serum and increase their in the myocardium. The resultsindicate the feasibility of further study the pharmacological properties of tincture of mullein herb.
FORMATION OF THE ADAPTIVE RESPONSE OF THE CENTRAL NERVOU S SYSTEM IN EXPE RIMENTA L HYPOTHY ROI DISM : ONTO GENETIC ASPECTS
Authors: Rodynskyi O. H. , Kondratyeva O. Yu. , Demchenko O. M.
Published: October 2016

In experiment on rats of three age groups – juvenile (5–6 weeks), the young (5–6 months) and old (20–24 months), there was studied the degree of formation of adaptive reactions cortex and hippocampus in a hyperthyroid condition. Increased levels of thyroid hormones (TH ) was accompanied by changes in the concentration of free fatty acids (C18:2.3) in these brain structures. In juvenile animals showed a significant increase the concentration of linoleic and linolenic acids in the cortex and hippocampus in 3.2 and 5.4 times. In young rats was also observed increase in this fraction of free fatty acids (FFA) in the neocortex to 104.8 %, in the hippocampus – 51.8 %. In older animals, as opposed to the two younger age groups, hypothyroidism caused a decrease in PUFA in the cerebral cortex of 66.4 %. These restructuring the fatty acid spectrum can modify the viscous properties of the membranes and modulatereceptor activity of serotonin mediator systems of the brain.
PHYSIOLOGICAL PROPERTIE S OF CO2 AS SUBSTANTIATION OF ORIINALITY OF CARBOXYTHERAPY
Authors: Drogovoz S. M. , Shtrygol S. Yu. , Kononenko A. V. , Zupanets M. V. , Levinskaya E. V. V.
Published: October 2016

CO2 due to the optimal mechanism of maintaining of its reserve is a universal condition for the existence of thebody. A physiological concentration of CO2 in the cells is an absolutely necessary condition for normal course ofbiochemical processes. CO2 is a natural regulator of respiration, blood circulation, metabolism, electrolyte balance,acid-base balance, the excitability of nerve cells, smooth muscle tone. Physiological properties provide CO2 diverselocal and resorptive effects, due to this carboxytherapy has become an effective and safe method of treatment inmany areas of medicine.
Influence of fish oil on usage of [1-14С] palmitic acid in the synthesis of lipids in the tissues of guinea pigs under hypercholesterolemia in vitro
Authors: Pokotylo О. S. , Pokotylo O. O. , Yaroshenko T. Ya. , Koval M. I.
Published: October 2016

It’s studied in vitro the intensity of lipid synthesis of various classes (fatty acids, cholesterol, phospholipids and acylglycerols) in homogenates of liver, brain, small intestinal mucosa and adipose tissue after daily single injection of guinea pigs with cholesterol (300 mg/kg body weight) for 30 days. For this purpose, it’s determined the radioactivity of the lipid fractions of the referred above tissue homogenates of guinea pigs that was incubated with [1-14C] palmitic acid. It’s established the inhibitory effect of exogenous cholesterol, under increase its level in the diet of guinea pigs, on the diacylglycerol synthesis and on the free cholesterol in the small intestine mucosa and on the triacylglycerol synthesis in adipose tissue under usage as a precursor – [1-14C] palmitic acid. It’s determined a significant reduction in the intensity of total lipids and individual lipid classes by using as a precursor [1-14C] palmitic acid in in vitro conditions in the brain, liver, small intestinal mucosa and adipose tissue of guinea pigs with hypercholesterolemia when it’s given them fish oil as feed.
Electronic characteristics and reactivity of 5-(((5-adamantane- 1-yl)-4-phenyl-4H-1,2,4-triazole-3-yl)thio)methyl-4-phenyl-4H-1,2,4- triazole-3-thiol molecule
Authors: Odyntsova V. M.
Published: October 2016

UV absorption’s spectra of 5-(((5-adamantane-1-yl)-4-phenyl-4H-1,2,4-triazole-3-yl)thio)methyl)-4-phenyl-4H- 1,2,4-triazole-3-thiol are studied in solvents of different polarity (water, 95 % ethanol, 0.1 M solution of acid chloride, 0.1 M solution of sulphate acid, 0.1 M solution of sodium hydroxide, n-hexane). It is established that the values of half-width and the integral intensity of the absorption bands, the oscillator strength and the matrix element transition of electrons are important constants of organic compounds for their identification and establishing a relationship between the absorption’s spectra and structure of the studied molecule. Absorption’s bands observed electronic spectra are quite intensive. The magnitude of the integrated intensities indicate a high probability of transition of electrons, and the values of the oscillator’s strength indicate that the electron transitions are allowed. Quantitative values of the matrix electronic transition indicate that the main chromaphore groups of the studied compounds are highly reactive. The results of the calculation of atomic charges of the molecules allow to study the possibility of electrophilic substitution reactions. Electronacceptor impact of triazole fragment on an aromatic ring is characterized by the activation of the metapositions in the SE reactions. Installed deficiency of electrons on the carbon atom -S-CH2- allows to make a conclusion about the carring out the reaction of nucleophilic substitution. However, in the presence of two triazole cycles are defined spherical complications for the transition of the nucleophile. High negative charge unsubstituted nitrogen atoms of the triazole ring gives the opportunity to foresee carring out the reactions of АЕ.
A televisão é capaz de informar?
Authors: Charaudeau Patrick
Published: October 2016

This article approaches the television matter as information media. It shows that television is a vehicle of democracy, which serves the “masses” (a more wide-ranging type of audience than traditional press readers), but, at the same time, is not capable of manipulating them with ease. It is considered that television audience is an interested part in the process of its proposed spectacularization of world seen on TV. Television assumes a particular role, even though it is possible to affirm that there is no meaning without verbal language. Television puts its viewer, a “kaleidoscope of opinions”, in a dual position: as a “world spectator” and as a “television spectator”.
Adaptação, disrupção e regulação em dispositivos midiáticos
Authors: Ferreira Jairo
Published: October 2016

In this article, we present propositions about the processes of uncertainty and indeterminacy in mediatization contexts. The objective of this reflection is to develop a field of hypotheses for the analysis of media processes, in their relations with social processes, focusing on media dispositifs. Three hypotheses are presented according to specific epistemological perspectives: that which we categorize as activated by the sign; the second, by the systems of intelligibility; the third, the technological systems, in particular the digital ones. These relations – between logic and processes – are, in the conclusions, disposed in three hexagons, in which the hypotheses, situated as competitors and relational, suggest new prospects about the uncertainty and indeterminacy in mediatization scenarios.
Coronary Artery Bypass Graft Versus Percutaneous Coronary Intervention
Authors: Kurlansky Paul , Herbert Morley , Prince Syma , Mack Michael
Published: October 2016

Background:

Multiple studies have compared coronary artery bypass graft (CABG) with percutaneous coronary interventions (PCI) for coronary revascularization. There is considerable evidence that adherence to medical therapy can affect the outcomes of therapeutic interventions. However, the long-term influence of compliance with recommended medical therapy on the comparative outcomes of CABG versus PCI remains to be defined.

Methods:

All non–ST-segment–elevation myocardial infarction patients undergoing coronary revascularization in an 8-hospital network were followed for up to 8 years to determine medication history and major adverse cardiac events: all-cause mortality, nonfatal myocardial infarction, and reintervention. All mortalities were checked against the Social Security Death Index. Survival curves were derived with Kaplan-Meier methods; hazard ratios were calculated with the Cox proportional hazard model; and propensity score matching was used to account for differences in patient selection.

Results:

Among the 973 CABG and 2255 PCI patients, Kaplan-Meier major adverse cardiac event–free survival curves demonstrated a significant benefit for antiplatelet, lipid-lowering, and β-blocker therapy in both the CABG and PCI groups (
P
=0.001 for all 3 medications). Cox regression identified compliance with optimal medical therapy as a more powerful predictor of major adverse cardiac event–free survival than choice of therapy (hazard ratio for noncompliance=2.79; 95% confidence limits, 2.19–3.54;
P
<0.001; hazard ratio for PCI versus CABG=1.68, 95% confidence limits, 138–2.04;
P
<0.001). In propensity-matched patients, CABG outcomes were superior to PCI outcomes in patients nonadherent to optimal medical therapy (
P
=0.001) but were not different in patients adherent to optimal medical therapy (
P
=0.574).

Conclusions:

Regardless of coronary revascularization strategy, medication adherence has a dramatic effect on long-term outcome. Among comparable patients who adhere to optimal medical therapy, outcomes of PCI and CABG may not differ; however, among nonadherent patients, CABG affords better major adverse cardiac event–free survival. Therefore, patient compliance with medical therapy may inform clinical decision making and should be incorporated into all future comparative studies of comparative coronary revascularization strategies.