bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral artery disease and outcomes in patients with acute myocardial infarction
Authors: Attar Rubina , Wester Axel , Koul Sasha , Eggert Svend , Andell Pontus
Published: May 2019

Aim

To describe the population of patients with previously diagnosed peripheral artery disease (PAD) experiencing a myocardial infarction (MI) and to investigate 1-year major adverse cardiac events (MACE: all-cause mortality, reinfarction, stroke and heart failure hospitalisation) following MI.

Background

MI patients with PAD constitute a high-risk population with adverse cardiac outcomes. Contemporary real-life data regarding the clinical characteristics of this patient population and clinical event rates following MI remain scarce.

Methods

This observational study included all MI patients presenting with ST-elevation MI or non-ST-elevation MI between 01 January 2005 and 31 December 2014 with (n=4213) and without (n=106 763) a concurrent PAD diagnosis, identified in the nationwide Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry and the National Patient Registry (PAD prevalence: 3.8%). Cox proportional hazard models were applied to compare the outcome between the two populations.

Results

MI patients with PAD were older and more often burdened with comorbidities, such as diabetes, hypertension and previous MI. After adjustments, PAD was significantly associated with higher rates of MACE (HR 1.35, 95% CI 1.27 to 1.44), mortality (HR 1.59, 95% CI 1.43 to 1.76), reinfarction (HR 1.48, 95% CI 1.32 to 1.66), stroke (HR 1.27, 95% CI 1.05 to 1.53), heart failure (HR 1.29, 95% CI 1.20 to 1.40) and bleeding (HR 1.26, 95% CI 1.09 to 1.47) at 1 year.

Conclusion

A concurrent PAD diagnosis was independently significantly associated with higher rates of adverse outcomes following MI in a nationwide real-life MI population. The low prevalence of PAD compared with previous studies suggests significant underdiagnosing. Future studies should investigate if PAD screening with ankle–brachial index may increase diagnosing and subsequently lead to improved treatment of polyvascular disease
Role of the glymphatic system in ageing and diabetes mellitus impaired cognitive function
Authors: Zhang Li , Chopp Michael , Jiang Quan , Zhang Zhenggang
Published: May 2019

Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, and is associated with cognitive impairment and an increased risk of developing dementia. The glymphatic system is a recently characterised brain-wide cerebrospinal fluid and interstitial fluid drainage pathway that enables the clearance of interstitial metabolic waste from the brain parenchyma. Emerging data suggest that DM and ageing impair the glymphatic system, leading to accumulation of metabolic wastes including amyloid-β within the brain parenchyma, and consequently provoking cognitive dysfunction. In this review, we concisely discuss recent findings regarding the role of the glymphatic system in DM and ageing associated cognitive impairment.
Marquage du 2-aminothiazole avec une unité cyclohexadiène fer tricabonyle. Étude structurale et activité antibactérienne du complexe marqué (1-4-η-5-N-2-aminothiazoliocyclohexa-1,3-diène) fer tricarbonyle
Authors: Merniz Salah , Himed Louiza , Mokhtari Mahieddine , Mousser Abdelhamid
Published: May 2019

La réaction du 2-aminothiazole (C3H4N2S) avec le complexe tétrafluoroborate de (1-4-η-5-N-pyridiniocyclohexa-1,3-diène) fer tricarbonyle [C11H12NFe(CO)3]+[BF4]− (1), précurseur du cation marqueur [(1-5-η-C6H7)Fe(CO)3]+ donne un nouveau complexe de formule C9H10N2SFe(CO)3, le (1-4-η-5-N-2-aminothiazolocyclohexa-1,3-diène) fer tricarbonyle (2). La structure de ce complexe a été caractérisée par les méthodes spectroscopiques IR et RMN 1H suivies d’une étude structurale par diffraction des rayons X, qui a montré que le complexe marqué 2 adopte stéréosélectivement une configuration exo. Dans l’édifice cristallin, les composants de la structure sont liés par des liaisons hydrogènes intermoléculaires de type N–H⋯N formant des chaînes dimériques le long de l’axe b. L’évaluation de l’activité antimicrobienne du ligand libre 2-aminothiazole a montré une activité antibactérienne importante. Après sa complexation par le marqueur organo fer tricarbonyle, cette activité a augmenté.
Wideband Input Matching CMOS Low-Noise Amplifier with Noise and Distortion Cancellation
Authors: Tarighat Asieh Parhizkar , Yargholi Mostafa
Published: May 2019

In this paper, a wideband low-noise amplifier (LNA) is designed based on the resistive feedback topology with a TSMC 0.18[Formula: see text][Formula: see text]m standard RF CMOS process. Bandwidth expansion is provided by the second-order Chebyshev filter. The noise figure (NF) increases at high frequency because of the source parasitic capacitors of the cascode transistor; so, noise cancelling technique is applied to the cascode transistor of the proposed LNA. Bias conditions and sizes of the transistors are optimized to cancel the nonlinear transconductance ([Formula: see text]). With this modified technique, low noise figure, high linearity and improved input and output matching can be attained for 3.1–10.6[Formula: see text]GHz frequency band. Post-layout simulation result of the proposed LNA shows the maximum power gain of 17[Formula: see text]dB at 5.5[Formula: see text]GHz frequency, NF of lower than 4.5[Formula: see text]dB over the whole band of 3.1–10.6[Formula: see text]GHz, maximum IIP2 of [Formula: see text]28[Formula: see text]dBm and IIP3 of [Formula: see text]7.5[Formula: see text]dBm, while dissipating 9[Formula: see text]mW (with buffer) from a 1.8 V supply voltage. It occupies [Formula: see text]m silicon die area.
Some antipodes of ideals in Leibniz algebras
Authors: Kurdachenko Leonid A. , Subbotin Igor Ya. , Yashchuk Viktoriia S.
Published: May 2019

A subalgebra [Formula: see text] of a Leibniz algebra [Formula: see text] is called a contraideal, if an ideal, generated by [Formula: see text] coincides with [Formula: see text]. We study the Leibniz algebras, whose subalgebras are either ideal or contraideal.
Well-Being at the End of Life
Authors: Carr Deborah , Luth Elizabeth A.
Published: May 2019

This review proposes that the end of life is a uniquely contemporary life course stage. Epidemiologic, technological, and cultural shifts over the past two centuries have created a context in which dying has shifted from a sudden and unexpected event to a protracted, anticipated transition following an incurable chronic illness. The emergence of an end-of-life stage lasting for months or even years has heightened public interest in enhancing patient well-being, autonomy, and the receipt of medical care that accords with patient and family members’ wishes. We describe key components of end-of-life well-being and highlight socioeconomic and race disparities therein, drawing on fundamental cause theory. We describe two practices that are critical to end-of-life well-being (advance care planning and hospice) and identify limitations that may undermine their effectiveness. We conclude with recommendations for future sociological research that could inform practices to enhance patient and family well-being at the end of life.
Security Awareness Level of Smartphone Users: An Exploratory Case Study
Authors: Koyuncu Murat , Pusatli Tolga
Published: May 2019

As smartphone technology becomes more and more mature, its usage extends beyond and covers also applications that require security. However, since smartphones can contain valuable information, they normally become the target of attackers. A physically lost or a hacked smartphone may cause catastrophic results for its owner. To prevent such undesired events, smartphone users should be aware of existing threats and countermeasures to be taken against them. Therefore, user awareness is a critical factor for smartphone security. This study investigates the awareness level of smartphone users for different security-related parameters and compares the awareness levels of different user groups categorized according to their demographic data. It is based on a survey study conducted on a population with a different range of age, education level, and IT security expertise. According to the obtained results, in general, the awareness level of participants is fairly low, which needs considerable improvement. In terms of age, the oldest group has the lowest level followed by the youngest group. Education level, in general, has a positive effect on the awareness level. Having knowledge about IT is another factor increasing the security awareness level of smartphone users.
Sjogren’s Syndrome and TAM Receptors: A Possible Contribution to Disease Onset
Authors: Witas Richard , Peck Ammon B. , Ambrus Julian L. , Nguyen Cuong Q.
Published: May 2019

Sjogren’s syndrome (SS) is a chronic, progressive autoimmune disease featuring both organ-specific and systemic manifestations, the most frequent being dry mouth and dry eyes resulting from lymphocytic infiltration into the salivary and lacrimal glands. Like the related autoimmune disease systemic lupus erythematosus (SLE), SS patients and mouse models display accumulation of apoptotic cells and a Type I interferon (IFN) signature. Receptor tyrosine kinases (RTKs) of the Tyro3, Axl, and Mer (TAM) family are present on the surface of macrophages and dendritic cells and participate in phagocytosis of apoptotic cells (efferocytosis) and inhibition of Type I IFN signaling. This review examines the relationship between TAM receptor dysfunction and SS and explores the potential contributions of TAM defects on macrophages to SS development.
Analysis of Regulatory T Cell Subsets and Their Expression of Helios and PD-1 in Patients with Hashimoto Thyroiditis
Authors: Hu Yifang , Zhang Lijuan , Chen Huanhuan , Liu Xiaoyun , Zheng Xuqin , Shi He , Jiang Lin , Cui Dai
Published: May 2019

Hashimoto thyroiditis (HT) is an autoimmune disease that presumably arises consequent to loss of immune tolerance to autoantigen in thyroid. Regulatory T cells (Tregs) are considered to play a vital role in maintaining the immune balance, as they own intensive suppressive function. This study was undertaken to analyze numbers of Tregs and their expressions of Helios and PD-1 in HT patients. It also aimed to explore the relationship of these with thyroid function and specific autoantibodies. Peripheral blood mononuclear cells (PBMCs) were extracted from blood of 20 healthy controls (HC) and 42 HT patients with varying thyroid functions (10 overt hypothyroidism, 12 subclinical hypothyroidism, and 20 euthyroidism). We performed flow cytometry analysis in PBMCs to detect CD4+CD25+Foxp3+Tregs and their subsets, including CD45RO+Foxp3high activated Treg cells (aTregs), CD45RO-Foxp3low resting Tregs cells (rTregs), and CD45RO+Foxp3low secreting Treg cells (sTregs), as well as the expression of Helios and PD-1 on these cells. The results showed that the percentage of Tregs, aTregs was significantly lower in HT patients and it showed inverse correlation to thyroid function states, in comparison with these in healthy controls. In addition, patients with HT showed decreased expression of Helios in aTregs, while having increased expression of PD-1 in Tregs and sTregs. The levels of Tregs, aTregs, and Helios expressing aTregs were all negatively correlated with antithyroid antibodies. In conclusion, the deficiency of Tregs frequency and aberrant expressions of Helios and PD-1 may possibly contribute to thyroid immune damage in HT.
Prognostic Value of Residual Disease after Neoadjuvant Therapy in HER2-Positive Breast Cancer Evaluated by Residual Cancer Burden, Neoadjuvant Response Index, and Neo-Bioscore
Authors: Steenbruggen Tessa G. , van Seijen Maartje , Janssen Liselore M. , van Ramshorst Mette S. , van Werkhoven Erik , Vrancken Peeters Marie-Jeanne T.D.F. , Wesseling Jelle , Lips Esther H. , Sonke Gabe S.
Published: May 2019

Purpose:

In breast cancer, pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) is associated with favorable long-term outcome. Trastuzumab emtansine as additional adjuvant therapy improves recurrence-free survival of patients with HER2-positive breast cancer without pCR, but it is uncertain whether all patients without pCR need additional therapy. We evaluated the prognostic value of residual disease after trastuzumab-based NST in patients with HER2-positive breast cancer using Residual Cancer Burden (RCB), Neoadjuvant Response Index (NRI), and Neo-Bioscore.

Experimental Design:

We included patients with stage II or III HER2-positive breast cancer treated with trastuzumab-based NST and surgery at The Netherlands Cancer Institute between 2004 and 2016. RCB, NRI, and Neo-Bioscore were determined. Primary endpoint was 5-year recurrence-free interval (RFI). A 3% difference compared with the pCR group was considered acceptable as noninferiority margin on the 5-year RFI estimate, based on a proportional hazards model, and its lower 95% confidence boundary.

Results:

A total of 283 women were included. Median follow-up was 67 months (interquartile range 44–100). A total of 157 patients (56%) with pCR (breast and axilla) had a 5-year RFI of 92% (95% CI, 88–97); patients without pCR had a 5-year RFI of 80% (95% CI, 72–88). Patients with an RCB = 1 (N = 40, 15%), an NRI score between 0.75 and 0.99 (N = 30, 11%), or a Neo-Bioscore of 0 to 1 (without pCR; N = 28, 11%) have a 5-year RFI that falls within a predefined noninferiority margin of 3% compared with patients with pCR.

Conclusions:

The RCB, NRI, and Neo-Bioscore can identify patients with HER2-positive breast cancer with minimal residual disease (i.e., RCB = 1, NRI ≥ 0.75, or Neo-Bioscore = 0–1) after NST who have similar 5-year RFI compared with patients with pCR.
Overcoming the Blood–Brain Barrier with an Implantable Ultrasound Device
Authors: Sonabend Adam M. , Stupp Roger
Published: May 2019

Ultrasound-based blood–brain barrier disruption enhances drug delivery. To bypass the human skull, an implantable ultrasound emitter was developed, and proven safe and feasible in a first-in-human trial. Next development steps aim for larger field of disruption, quantification of drug levels, use of various drugs, and ultimately a pivotal trial demonstrating improved outcome.

See related article by Idbaih et al., p. 3793
Abstract SY02-01: Imaging the metastatic process
Authors: Sahai Erik
Published: May 2019

The acquisition of invasive behaviour enables the tumour cells to move into either the surrounding tissue or the vasculature and thereby spread to other parts of the body. The focus of our research is investigating why cancer cells become invasive and how they move. Until recently research into cancer cell movement has used highly artificial environments that do not accurately mimic the tumour environment leading to many contradictory results that could not be confirmed in vivo. The tumour environment is highly complex with numerous non-tumour cell types, variable blood flow and a diverse range of extracellular matrix components. To study cell motility in this environment we perform intravital multi-photon confocal imaging of tumours in anaesthetised mice. To complement intravital imaging, we have established a range of three-dimensional ‘organotypic’ cultures that allow us to model many aspects of the tumour environment in vitro. By using these systems it has become clear that there are a variety of different ways in which tumour cells can move. In particular, we are interested in the rapid movement of ‘amorphous’ single cells, termed amoeboid, and the slower collective movement of cohesive groups of cancer cells. The presentation will be split into two parts: the first part will focus on imaging the activity of signalling pathways that promote amoeboid motility while the second part will focus on the mechanism of collective cancer cell invasion.

Citation Format: Erik Sahai. Imaging the metastatic process [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY02-01
Abstract SY02-04: Regulation of invadopodia formation and cancer cell invasion
Authors: Blouw Barbara , Buschman Matt , Cejudo-Martin Pilar , Diaz Begoña , Gould Christine , Murphy Danielle , Quintavalle Manuela , Heynen Susanne , Azimi Behrad , Price Jeff , Courtneidge Sara A.
Published: May 2019

Cell invasion plays a central role in a wide variety of biological phenomena, and is the cause of tumor growth and metastasis. Understanding the biochemical mechanisms that control cell invasion is one of the major goals of our laboratory. Podosomes and invadopodia are specialized cellular structures present in cells with physiological or pathological invasive behaviors. These transient structures are localized at the ventral cell surface, contain an array of different proteins, and facilitate cell-substrate adhesion as well as the local proteolytic activity necessary for extracellular matrix remodeling and subsequent cellular invasion. We have previously shown that the adaptor protein and Src substrate Tks5 is required for both podosome and invadopodia formation, and for tumor growth in vivo. More recently we also defined a role for the Tks5-mediated generation of reactive oxygen species (ROS). We have developed a high content, cell-based high throughput screening assay that allows us to identify inhibitors and activators of invadopodia formation. As a proof of principle, we tested the LOPAC1280 collection of small molecules and found 7 inhibitory compounds and 2 activators. Of the 7 inhibitors, 4 are cyclin-dependent kinase (Cdk) inhibitors. Loss-of-function experiments demonstrated that Cdk5 is the responsible kinase. On the other hand, paclitaxel was one of the two compounds that increased invadopodia formation. We have also used our high content assay to screen a large compound collection as well as an siRNA library targeting the entire kinome. The mechanisms by which Cdk5 and tubulin regulate invadopodia formation, and the nature of the other regulators, are the subjects of our current investigations.

Citation Format: Barbara Blouw, Matt Buschman, Pilar Cejudo-Martin, Begoña Diaz, Christine Gould, Danielle Murphy, Manuela Quintavalle, Susanne Heynen, Behrad Azimi, Jeff Price, Sara A. Courtneidge. Regulation of invadopodia formation and cancer cell invasion [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY02-04
Abstract SY03-03: Modulating innate and adaptive immunity through the manipulation of dendritic cells
Authors: Bhardwaj Nina
Published: May 2019

Dendritic cells (DC) are potent antigen presenting cells used in clinical trials to treat cancer and infectious diseases such as HIV. We have performed two types of clinical trials to evaluate their immunogenicity in vivo. First, we compared DC to conventional vaccine adjuvants. HLA-A2+ resected melanoma patients were enrolled into a randomized clinical trial to compare vaccines comprised of six HLA-A2-restricted peptide antigens and a foreign protein, KLH, either pulsed onto cytokine-matured, monocyte-derived DCs or emulsified in the mineral oil adjuvant Montanide ISA 51. The frequency, magnitude and quality of antigen-specific cellular immune responses in peripheral blood were found to be greater in patients receiving the Montanide vaccine. Furthermore, the primed cells were functionally superior, indicating a need to improve current DC-based vaccine approaches. Preclinical studies in mice were undertaken to evaluate the mechanism by which DC prime T cells. Contrary to previous assumptions, we found that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches will focus on creating DC vaccines that are more effective at directly priming T cells, by altering maturation factors, or abrogating the tumor induced suppression of endogenous DCs

In a second approach, we used TLR agonists targeting TLR 7, 8 and/or 9 to prime immunity to melanoma associated antigens in a series of clinical trials. They include imiquimod, resiquimod and CpG, agonists for TLR7 and/or TLR 8 and TLR9 respectively. These adjuvants when combined with the cancer testis antigen NY-ESO-1, induced integrated immune responses which were characterized by the induction of both CD4+ and CD8+ T cell immunity as well as antigen-specific antibodies in patients with resected melanoma. Strategies to optimize these various approaches to induce immunity in cancer and other chronic diseases will be discussed.

Citation Format: Nina Bhardwaj. Modulating innate and adaptive immunity through the manipulation of dendritic cells [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY03-03
Abstract SY15-01: Using comparative oncogenomics to guide personalized cancer medicine
Authors: DePinho Ronald A.
Published: May 2019

We exploited mouse models of cancer to identify prognosis determinants for guiding the management of early stage cancer such as prostate cancer. In the case of prostate cancer, effective management has beenchallenged by an elemental understanding of the genetic elements governingdisease progression. We hypothesized that pathways constraining invasive andmetastatic progression would be activated in indolent Pten null mouse prostatecancers and that deactivation of such progression checkpoints would occur upon disease progression in human prostate cancer. Using comparative transcriptomicand pathway analysis, we identifed and biochemically/genetically validated a TGFβ progression block which upon neutralization generates a lethal metastaticphentoype. This use of this metastatic mouse prostate cancer model, then enabled identification of a signature which, upon intersection with human data, can dichotomize men into high and low risk groups for progression.

Citation Format: Ronald A. DePinho. Using comparative oncogenomics to guide personalized cancer medicine [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY15-01
Abstract SY19-01: Cell to cell variability in the responses of tumor cells to death ligands
Authors: Sorger Peter K. , Spencer Sabrina , Flusberg Deborah , Gaudet Suzanne
Published: May 2019

Cell to cell variability in phenotype and fate is important for tissue homeostasis, the emergence of drug resistance and the evolution of tumors. I will discuss cell to cell variability in the responses of clonal populations of human cells to TRAIL, a prototypical inducer of receptor-mediated (extrinsic) apoptosis and an investigational therapeutic. Some TRAIL-treated human cells die within ~40 min, others only after 12 hr and some live indefinitely. During this variable delay initiator caspases (ICs) are active in processing substrates such as Bid and downstream effector caspases (ECs) but mitochondrial membrane permeablization (MOMP) does not occur and ECs are catalytically inactive. We have explored three explanations for cell to cell differences among members of a clonal and notionally uniform population: (i) genetic or epigenetic variation; (ii) the involvement of one or more biochemical processes subject to stochastic fluctuation; (iii) difference in cell state such as position in the cell cycle or protein concentrations.

To distinguish among these three possibilities we compared the fates of sister cells exposed to TRAIL using live-cell microscopy. Genetic and epigenetic factors are transmitted with near-perfect fidelity; reaction rates dominated by stochastic fluctuations are no more similar in sisters than in any two cells chosen at random and variability arising from differences in mRNA or protein levels should be transiently heritable (because division is a binomial process in which sister cells inherit roughly equal numbers of abundant cytosolic and nuclear factors but drift towards the population average over time). The later explanation is correct; natural fluctuations in protein levels dominate phenotypic heterogeneity in extrinsic apoptosis and cause transient phenotypic heritablility. Variability can be manipulated by protein over-expression and drugs and I will describe analytic methods for modeling these perturbations. Finally, I will show that natural variation is sufficient to cause some cells to follow one biochemical pathway to death (a MOMP-dependent Type II pathway) and another set of genetically identical cells to follow a fundamentally different pathway (a MOMP-independent Type I pathway).

Citation Format: Peter K. Sorger, Sabrina Spencer, Deborah Flusberg, Suzanne Gaudet. Cell to cell variability in the responses of tumor cells to death ligands [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY19-01
Abstract SY27-01: Differential efficacy of the angiogenesis inhibitor thrombospondin-1 in different organs
Authors: Baek Kwan-Hyuck , Lee Yoon Jin , Karl Daniel , Zaslavsky Alexander , Yoon Sam , Ryeom Sandra W.
Published: May 2019

Tumor angiogenesis is negatively regulated by a number of angiogenesis inhibitors, of which thrombospondin-1 (TSP-1) is one of the most potent. We examined the efficacy of TSP-1 in suppressing tumor growth using both transplantable and inducible tumor and metastasis models in the lung and liver. Although the lung exhibits high levels of endogenous TSP-1, experimental metastases in the lungs of Tsp-1-/- mice showed no differences in growth or microvessel density compared to wild-type mice. However, experimental metastases in the liver were significantly increased in Tsp-1-/- mice versus wild-type mice. Similarly, the growth of tumor cells over-expressing TSP-1 was dramatically inhibited when inoculated into the liver but not in the lung. To further investigate the function of TSP-1 in the lung, we utilized an inducible lung tumor model driven by sporadic activation of oncogenic K-ras. The progression of benign lesions is restrained, in part, by oncogenic activation of cellular senescence. Oncogenic Ras is a prototypical example of this, triggering senescence in many cell types, including lung epithelium. The loss of TSP-1 in this inducible genetically engineered mouse model of lung cancer led to a significant increase in tumor progression. Unexpectedly, we found that TSP-1 plays a critical but previously unidentified role in suppressing K-ras-induced lung tumorigenesis by mediating senescence. Oncogenic ras-induced senescence is abrogated by Tsp-1 deficiency, leading to a marked decrease in overall survival of mice. Similarly, Tsp-1-/- fibroblasts are refractory to oncogenic Ras-induced senescence, which is restored upon TSP-1 re-expression. Moreover, K-ras induces TSP-1 upregulation in a p53-dependent manner. Together, these data indicate that TSP-1 is a critical and cell-autonomous mediator of oncogenic Ras-induced senescence in the lung and suggests a novel role for TSP-1 in the lung, independent of its anti-angiogenic function.

Citation Format: Kwan-Hyuck Baek, Yoon Jin Lee, Daniel Karl, Alexander Zaslavsky, Sam Yoon, Sandra W. Ryeom. Differential efficacy of the angiogenesis inhibitor thrombospondin-1 in different organs [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY27-01
Abstract SY31-03: Global signaling mechanisms that regulate autophagy
Authors: Yi Caroline , Yuan Junying
Published: May 2019

Apoptosis is an evolutionally conserved cellular suicide mechanism that can be activated in response to a variety of stressful stimuli. Increasing evidence suggests that apoptotic regulation relies on specialized cell death signaling pathways and also integrates diverse signals from additional regulatory circuits, including those of cellular metabolism. Cell metabolism is exquisitely linked to multiple aspects of cell physiology relevant for cancer development, including cell proliferation, growth, and death. However, the mechanism by which cellular metabolism controls apoptotic sensitivity is unknown. We conducted a genome-wide RNA interference screen to systematically identify regulators of apoptosis induced by DNA damage in Drosophila melanogaster cells. This screen identified 47 double- stranded RNAs that target a functionally diverse set of genes, including several with a known function in promoting cell death. Further characterization uncovers 10 genes that influence caspase activation upon the removal of Drosophila inhibitor of apoptosis 1 (DIAP1). This set includes the Drosophila initiator caspase Dronc and, surprisingly, several metabolic regulators, and an N-acetyltransferase, ARD1. Importantly, several of these genes show functional conservation in regulating apoptosis in mammalian cells. Our data suggest a previously unappreciated fundamental connection between various cellular processes and caspase-dependent cell death. We have further explored the functional role and the mechanism by which ARD1 regulates apoptotic sensitivity in mammalian cells. We found that a reduction of N-alpha-acetylation mediated by ARD1 leads to inhibit apoptosis by blocking the interaction of a caspase with its activating complex. We further demonstrate the levels of protein N-alpha-acetylation is controlled by the availability of acetyl-CoA, a key intermediate metabolite. Our study provides a mechanistic link between cellular metabolism and apoptotic sensitivity and suggests that targeting the mechanism of protein N-alpha-acetylation may provide a new therapeutic approach for anti-cancer drug development.

Citation Format: Caroline Yi, Junying Yuan. Global signaling mechanisms that regulate autophagy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY31-03
Abstract 2099: Apo-10’-lycopenoic acid functions as a peroxisome proliferator-activated receptor gamma activator and inhibits cell growth both in vitro and in vivo ob/ob mice treated with diethylnitrosamine
Authors: Hu Kang-Quan , Wang Yan , Smith Donald E. , Russell Robert M. , Wang Xiang-Dong
Published: May 2019

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is involved in controlling metabolism, cell growth, inflammatory responses and tumorigenesis. Specific PPAR-gamma agonists, such as rosiglitazone, inhibit growth and induce differentiation in several different cancer cell lines including liver cancer cells. Lycopene has been shown to decrease the initiation of hepatic preneoplastic foci induced by diethylnitrosamine (DEN) in rats. Recently, we showed that apo-10’-lycopenoic acid, an enzymatic metabolite of lycopene, suppresses carcinogenesis in a mouse model. However, the underlying mechanism(s) is not well defined. In the present study, we examined the effects of apo-10’-lycopenoic acid treatment on cell growth and apoptosis, as well as PPAR-gamma activation in both human liver cells and in livers of ob/ob mice treated with DEN. We reported that apo-10’-lycopenoic acid dose-dependently increased the mRNA expression and protein levels of PPAR-gamma in human THLE-2 liver cells. Apo-10’-lycopenoic acid (from 5 µM to 20 µM) produced concentration-dependent increases in luciferase activity, as compared with PPAR-gamma agonist rosiglitazone in cells co-transfected with constructs containing PPAR-gamma and PPRE-luciferase reporter construct. Additionally, apo-10’-lycopenoic acid dose-dependently inhibited cell growth and induced apoptosis in THLE-2 liver cells by stimulating the cyclin-dependent kinase inhibitor p21 and by reducing activation of c-Jun NH2-terminal kinase (JNK) and cyclin D1 gene expression. However, human HepG2 liver cancer cells were less sensitive to apo-10’-lycopenoic acid treatment, as compared with THLE-2 cells. We further examined the effect of apo-10’-lycopenoic acid treatment (120 mg/Kg diet) in ob/ob mice administered intraperitoneally with a single-dose of DEN (30 mg/Kg body weight). After eight weeks, we found lower expression of PPAR-gamma but higher levels of tumor necrosis factor-alpha and phosphorylated JNK in the liver of ob/ob mice injected with DEN, as compared with controls. Furthermore, apo-10’-lycopenoic acid supplementation prevented DEN-down-regulated expression of PPAR-gamma in the liver of ob/ob mice and significantly inhibited DEN-induced expression of proliferating cell nuclear antigen and cyclinD1. In addition, apo-10’-lycopenoic acid supplementation inhibited DEN-induced tumor necrosis factor-alpha expression and JNK activation in the liver of ob/ob mice. Together, our findings indicate that apo-10’-lycopenoic acid produced from lycopene metabolism may function as a natural ligand of PPAR-gamma and as a potential chemopreventive agent against hepatic tumorigenesis.
Abstract 2545: Response to a preventive HER2/neu peptide (E75) vaccine based on HER2/neu status
Authors: Benavides Linda C , Gates Jeremy D , Carmichael Mark G , Holmes Jarrod P , Hueman Matthew T , Mittendorf Elizabeth A , Patil Ritesh , Stojadinovic Alexander , Craig Dianna , Ponniah Sathibalan , Peoples George E
Published: May 2019

Background: HER2/neu is a source of immunogenic peptides and is over-expressed in 30% of early stage breast cancer (BCa) patients. We have conducted clinical trials with the HER2/neu E75-peptide vaccine in node-positive and node-negative BCa patients demonstrating all levels of HER2/neu expression.

Methods: A subset analysis review was performed of 165 BCa patients enrolled in our E75 vaccine trial based on the level of HER2/neu expression. Patients were HLA typed; HLA-A2+/A3+ patients were vaccinated (V); HLA-A2-/A3- patients served as controls (C). HER2/neu over-expressers (OE) were defined as FISH >2.0 and IHC 3+ HER2/neu tumors. Low-expressers (LE) included patients with IHC ranging from 0 to 2+. These 2 groups were assessed by clinicopathologic factors, immunologic response (in vivo DTH reactions and in vitro HLA-A2:IgG dimer assay) to the vaccine, and post-vaccine clinical responses (recurrence and survival).

Results: Of 165 patients assessed; 94 were vaccinated (30 OE = 32%, 64 LE = 68%) and 71 were controls (22 OE = 31%, 49 LE = 69%). HER2/neu over-expressers were similar regarding prognostic and treatment factors, except a statistically larger number of V-OE patients were hormone receptor negative (ER/PR-; p=0.02) and node-negative (p=0.007). Clinicopathologic factors were not significantly different between control and V-LE patients. Immunologic responses were similar as measured by DTH reactions (post DTH V-OE=12.7+1.9 vs. V-LE=15.1+1.8; p=0.6), but V-OE demonstrated a decreased number of E75-specific CD8+ T cells when compared to V-LE post-vaccination (V-OE vs. V-LE Dimer: 0.6+0.06% vs. 0.8+0.07%; p=0.08; V-OE vs. V-LE Max Dimer: 1.5+0.1% 1.9+0.1%; p=0.04). At 30 months median follow-up, disease recurrence rates (RR) were similar between V-OE and C-OE patients (V-OE vs. C-OE RR: 4.3% vs. 5.6%; p=0.7); however there was a 50% reduction in mortality rate (MR) among patients that recurred (V-OE vs. C-OE MR: 25% vs. 50%; p=NS). RR was reduced for vaccinated patients with low HER2/neu expression (V-LE vs. C-LE RR: 6.4% vs. 11.3%; p=0.3). Importantly, MR among those that recurred was 0% vs. 38% (p=0.2) for V-LE and C-LE BCa patients, respectively.

Conclusions: Patients with HER2/neu over-expressing breast cancer (FISH amplified (>2.0) and IHC 3+) respond well to the E75 vaccine immunologically and have a 50% absolute reduction in mortality compared to controls. Unexpectedly, patients with low-expressing (0 - 2+ on IHC) HER2/neu tumors show better response not only immunologically, but clinically with decreased breast cancer recurrence and 0% mortality following E75 peptide vaccination.
Abstract 5832: Overexpression of ODC1 is associated with poor outcome in childhood neuroblastoma and represents an important therapeutic target
Authors: Haber Michelle , Cheng Ngan , Smith Janice , Murray Jayne , Hogarty Michael D. , London Wendy B , Marshall Glenn M , Norris Murray D.
Published: May 2019

MYCN gene amplification is a powerful predictor of poor clinical outcome in neuroblastoma, the most common solid tumor of young children. The mechanism by which MYCN amplification influences the prognosis of this disease has not been well defined. MYCN is a known transcription factor and available evidence indicates that ornithine decarboxylase (ODC1) is a critical downstream target for this oncoprotein. ODC1 is the rate-limiting enzyme in the synthesis of polyamines and overexpression of this gene has been observed in a range of tumor cells, including neuroblastoma. In particular, a number of studies have provided evidence for the oncogenic and transforming abilities of ODC1. To investigate the role of ODC1 in neuroblastoma, we used Real-Time PCR to analyze ODC1 expression in a large cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in this cohort. ODC1 expression was significantly higher in MYCN-amplified tumors by comparison with non-amplified tumors (p<0.0001). Kaplan-Meier survival analysis indicated that high levels of ODC1 expression were strongly predictive of both event-free-survival (p<0.001) and overall survival (p<0.001) in this cohort as well as in patients whose tumors lacked MYCN amplification (p=0.01). Furthermore, a functionally important single nucleotide polymorphism within the ODC1 promoter (G316A) that has been shown previously to influence gene transcription rates, was found to be significantly associated with outcome in patients whose tumors lacked MYCN amplification (p<0.05). These data suggest that inhibiting ODC1 activity would have therapeutic advantage in treating neuroblastoma. To test this hypothesis, MYCN transgenic mice that spontaneously develop neuroblastoma closely mimicking the human disease, were treated either with cisplatin alone or in combination with the ODC1 inhibitor, Î±-difluoromethylornithine (DFMO). Importantly, DFMO therapy, either concomitant with or following cisplatin treatment, resulted in prolonged tumor-free survival (p<0.01) in these mice, by comparison with cisplatin administered alone. Similar results were obtained with cyclophosphamide treatment in combination with DFMO. No overt toxicity attributable to DFMO therapy was noted in treated mice. Collectively, these findings provide strong evidence that ODC1 contributes to the malignant phenotype of neuroblastoma and suggest that targeting this oncogene for suppression of polyamine synthesis is potentially a valuable therapeutic approach for inhibiting neuroblastoma growth.
Abstract LB-201: Updated results from a Phase I study of AV-951 (KRN951), a potent and selective VEGFR-1, -2 and -3 tyrosine kinase inhibitor, in patients with advanced solid tumors
Authors: Eskens Ferry A.l.m. , de Jonge Maja J.a. , Esteves Brooke , Cotreau Monette , Bhargava Pankaj , Ryan John , van Doorn Leny , Isoe Toshiyuki , Hayashi Kunihiko , Ekman Lena , Burger Herman , Verweij Jaap
Published: May 2019

Background: AV-951 inhibits phosphorylation of VEGF receptors (VEGFR)-1, -2, and -3 at picomolar concentrations (IC50 of 0.21, 0.16, and 0.24 nM, respectively) and inhibits c-Kit and PDGFR at 10-times higher concentrations (IC50 of 1.63 and 1.72 nM, respectively). In a dose-escalation study of AV-951 given orally on a 4 week on, 2 week off schedule, the maximum tolerated dose (MTD) was determined to be 1.5 mg/day and clinical activity was observed in renal (RCC), colon, and lung cancers [Proc ASCO 2006;24(18S):2034]. Thereafter, the study was amended to enroll an additional 10 patients at 1.0 mg/day in order to compare the safety profile, pharmacokinetics (PK), effects on tumor blood flow, and antitumor activity across all dose levels.

Results: 40 patients (26M/14F), were enrolled at AV-951 doses of 1 (n=16), 1.5 (n=16), and 2.0 mg (n=8). At 2 mg DLTs consisting of grade 3 proteinuria, grade 3 ataxia, and grade 4 intracranial hemorrhage were seen in one patient each. The primary toxicity across all dose levels was hypertension (HTN), as listed in Table 1. HTN was dose-dependent, and could be controlled with standard anti-hypertensive agents. Only two patients, both at 1.5 mg, required dose reduction to 1.0 mg for control of HTN. PK analysis revealed dose dependent drug exposure and peak plasma concentrations. DCE-MRI analysis indicated a decrease in tumor perfusion in selected patients. Among 9 patients with RCC, there were 2 confirmed partial responses at 2.0 mg (n=1) and 1.5 mg (n=1) lasting 128 weeks and 42 weeks, respectively, and 7 patients with stable disease (lasting >12 wks) at 1.0 mg (n=5), 1.5 mg (n=1), and 2.0 mg (n=1). Clinical activity was observed in multiple tumor types.

Conclusions: AV-951 could be safely administered at 1.0 and 1.5 mg doses. The primary toxicity was dose-dependent HTN, a biomarker of VEGFR inhibition. Clinical activity was observed across all dose levels. In future combination studies, AV-951 may be administered at a dose of either 1.0 mg or 1.5 mg.

Table 1.Primary toxicity of AV-951 across all dose levelsHypertensionAV-951 DoseGrade 1-2Grade 3Grade 4All Grades1.0 mg (n=16)6% (n=1)31% (n=5)0%37% (n=6)1.5 mg (n=16)0% (n=0)56% (n=9)0%56% (n=9)2.0 mg (n=8)25% (n=2)75% (n=6)0%100% (n=8)
Abstract LB-238: Immunotransplant filters out regulatory T cells and cures large lymphoma tumors.
Authors: Brody Joshua D , Goldstein Matthew J , Levy Ronald
Published: May 2019

Background: The potency of transferring ex vivo activated tumor-infiltrating lymphocytes into lymphodepleted recipients has been demonstrated in clinical trials, though the use of in vivo vaccine-primed anti-tumor lymphocytes could make this approach sufficiently feasible for broad clinical application. We previously described a vaccination maneuver against murine B-cell lymphoma combining chemotherapy (CTX) and intra-tumoral injection of an immunostimulant CpG, which induced T-cell immunity and eradicated established tumors. An ongoing clinical trial of this maneuver has demonstrated complete and partial responses in lymphoma patients, though immune-regulatory factors such as regulatory T cells (Tregs) and limiting amounts of “homeostatic” cytokines might block even more powerful antitumor immunity. Transfer of tumor-specific lymphocytes into lymphodepleted recipients may eliminate these immune-regulatory obstacles.

Methods: Splenocytes and bone marrow from CpG/CTX vaccinated mice were transplanted into lethally irradiated recipients, i.e., “immunotransplant.” Recipients received high dose tumor challenge with A20 murine B-cell lymphoma and followed clinically for tumor growth and for tumor-specific CD8 T cell IFNγ responses by multi-color flow cytometry.

Results: We observed selective filtering against Tregs, doubling of the transferred Teffector:Treg ratio, and preferential expansion of transferred tumor-specific CD8 T cells in immunotransplant recipients. Immunotransplant cures large subcutaneous (>100 mm2) and metastatic tumors in 100% of recipients and enhances tumor-specific T cell memory. The addition of a vaccine “boost” to the immunotransplant maneuver results in an additional 3-fold increase in tumor-specific immunity and the use of cured recipients as subsequent donors in serial immunotransplant experiments demonstrated even greater tumor protection.

Conclusions: As hematopoietic stem cell transplantation is a standard therapy for lymphoma patients, pre-transplant vaccination followed by post-transplant transfer of tumor-specific T cells could be tested in clinical trials. Our model suggests that this immunotransplant approach would allow the benefit of cancer vaccines to be revealed and might lead to cure of otherwise resistant malignancies.
Abstract LB-244: A phase 0 trial of riluzole in patients with resectable stage III or IV melanoma.
Authors: Yip Dana , Le Maithao , Lee Jonathan H , Chen Suzie , Goydos James S
Published: May 2019

Recently, our group described a murine model of melanoma that is based on ectopic expression of metabotropic glutamate receptor 1 (Grm1). Grm1 is a normally occurring receptor in the central nervous system of mammals that controls excitatory neural impulses. Ectopic expression of this receptor in melanocytes results in transformation of these cells into a murine form of melanoma indistinguishable from human melanoma. We also found that >60% of human melanoma samples tested ectopically to date express Grm1 while normal skin and melanocytes from the same patients fail to express this protein. Furthermore, stimulation of this receptor in vitro results in downstream upregulation of phosphorylated (activated) ERK, demonstrating that this receptor is involved in the regulation of the MAPK pathway, a pathway in the cell important in melanoma formation and growth. Finally, a murine xenograft model of melanoma treated with riluzole, an oral Grm1 blocking agent, showed decreased tumor growth in the treated mice compared to the untreated controls. The goal of this study was to validate Grm1 as a therapeutic target in humans with melanoma. To accomplish this we enrolled patients with resectable stage III and stage IV melanoma on a Phase 0 NCI Quick Trial of oral riluzole. We performed a pre-treatment biopsy, treated the patients with 200 mg of oral riluzole per day for 14 days, and then resected the patients’ remaining tumors. We compared the level of pERK in the pre- and post-treatment tumor samples to determine if treatment with an oral Grm1 blocking agent results in modulation of the Grm1 signaling pathway in human melanoma. We also assessed overall metabolic activity and proliferation of the tumors pre- and post-treatment, using PET scanning, assessement of pre- and post-treatment mitotic rate of the tumors, and pre- and post-treatment Ki-67 staining intensity. We have accrued 10 of the 15 patients we need for this trial and all 10 appear to express Grm1. Preliminary results demonstrate a significant decrease in pERK in post-treatment tumor samples as compared to pre-treatment samples in 50% of the cases so far (P<0.01). We also found a significant decrease in post-treatment Ki-67 staining in one patient. Three patients had a significant decrease in PET intensity post-treatment while all other patients had similar pre- and post-treatment PET scan findings except for one patient whose post-treatment PET scan revealed progressive disease. Our preliminary data demonstrates that glutamate-blockade with riluzole can inhibit signaling through the MAPK pathway and suppress metabolic activity of melanoma in a significant number of patients. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma and targeting this pathway may be an effective therapy for patients with melanoma.