bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C07: Cancer-associated fibroblasts: Co-migrating from primary to metastatic tumor sites
Authors: Ershaid Nour , Yael Raz , Erez Neta 
Published: October 2016

Abstract
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

Abstract
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 &lt; 0.05) in high-fat diet-fed mice; it reduced metastatic cross-sectional area by 46% (p &lt; 0.05) and volume by 69% (p &lt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
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.
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.