bluuebunny/crossref_metadata_2025 huggingface dataset:
The Improved Ant Colony Optimization Algorithm for MLP considering the Advantage from Relationship
Authors: Luo Yabo , Waden Yongo P.
Published: July 2017

An improved ant colony optimization (ACO) is presented to solve the machine layout problem (MLP), and the concept is categorized as follows: firstly, an ideology on “advantage from quantity” and “advantage from relationship” is proposed and an example is demonstrated. In addition, the strategy of attached variables under local polar coordinate systems is employed to maintain search efficiency, that is, “advantage from relationship”; thus, a mathematical model is formulated under a single rectangular coordinate system in which the relative distance and azimuth between machines are taken as attached design variables. Further, the aforementioned strategies are adopted into the ant colony optimization (ACO) algorithm, thereby employing the inverse feedback mechanism for dissemination of pheromone and the positive feedback mechanism for pheromone concentration. Finally, the effectiveness of the proposed improved ACO is tested through comparative experiments, in which the results have shown both the reliability of convergence and the improvement in optimization degree of solutions.
Investigation of Performance and Rotor Tip Flow Field in a Low Speed Research Compressor with Circumferential Groove Casing Treatment at Varying Tip Clearance
Authors: Rolfes Matthias , Lange Martin , Mailach Ronald
Published: July 2017

Experimental investigations in a single-stage low speed axial research compressor are presented. The influence of four different rotor tip clearances on the overall compressor performance and on the rotor tip flow field is investigated in configurations with and without circumferential groove casing treatments. Piezo-resistive pressure transducers are used to capture the unsteady flow field in the rotor tip region. The investigated casing groove is effectively working at the three largest investigated tip clearance sizes. The largest achieved operating range increase by the groove is 6.9%. The groove can delay the upstream movement of the flow interface between leakage flow and main flow and thus increase the stable operating range. Rotating instabilities are shown to exist at large tip clearance sizes in throttled operating conditions. Their amplitudes can be damped by the casing groove. No modal activities could be detected in the current single-stage compressor build.
Application of Mathematical Symmetrical Group Theory in the Creation Process of Digital Holograms
Authors: Pérez-Ramírez Agustín , Guerrero Juk Julian , Sanchez-Lara Rafael , Trejo-Sánchez Joel Antonio , de la Cruz-May Lelio
Published: July 2017

This work presents an algorithm to reduce the multiplicative computational complexity in the creation of digital holograms, where an object is considered as a set of point sources using mathematical symmetry properties of both the core in the Fresnel integral and the image. The image is modeled using group theory. This algorithm has multiplicative complexity equal to zero and an additive complexity (k − 1)N2 for the case of sparse matrices or binary images, where k is the number of pixels other than zero and N2 is the total of points in the image.
Changes in Intraocular Straylight and Visual Acuity with Age in Cataracts of Different Morphologies
Authors: Gholami Sonia , Reus Nicolaas J. , van den Berg Thomas J. T. P.
Published: July 2017

Purpose. To investigate the significance of difference in straylight of cataract eyes with different morphologies, as a function of age and visual acuity.Methods. A literature review to collect relevant papers on straylight, age, and visual acuity of three common cataract morphologies leads to including five eligible papers for the analysis. The effect of morphology was incorporated to categorize straylight dependency on the two variables. We also determined the amount of progression in a cataract group using a control group.Results. The mean straylight was 1.22 log units ± 0.20 (SD) in nuclear (592 eyes), 1.26 log units ± 0.23 in cortical (776 eyes), and 1.48 log units ± 0.34 in posterior subcapsular (75 eyes) groups. The slope of straylight-age relationship was 0.009 (R2=0.20) in nuclear, 0.012 (R2=0.22) in cortical, and 0.014 (R2=0.11) in posterior subcapsular groups. The slope of straylight-visual acuity relationship was 0.62 (R2=0.25) in nuclear, 0.33 (R2=0.13) in cortical, and 1.03 (R2=0.34) in posterior subcapsular groups.Conclusion. Considering morphology of cataract provides a better insight in assessing visual functions of cataract eyes, in posterior subcapsular cataract, particularly, in spite of notable elevated straylight, visual acuity might not manifest severe loss.
Complexity and Application of Tobacco Manufacturer Pricing Game considering Market Segments
Authors: Guo Shubing , Ma Junhai , Zhan Xueli
Published: July 2017

This paper considers price as a strategy using two methods of market segmentation through game theory based on the collected data of several typical cities in Shandong province. Three oligarchs are discussed to analyze the complexity of the market in tobacco system. The effect of different factors on the equilibrium price of Nash equilibrium is discussed. What is more, the variation of parameters drives the system to change to uncertain status, even to bifurcation or chaos. We also discuss the model under normal circumstances, when the three parties jointly take chaos control measures, and its impact on the system. Finally, we clarify chaos control of economic significance. The results indicate that only reasonable pricing strategy is a critical point to achieve maximized profit and maintain orderly operation at the same time, which is a constructive suggestion for tobacco companies’ operational strategy.
Histopathological Changes in the Kidney following Congestive Heart Failure by Volume Overload in Rats
Authors: Aboryag Noureddin B. , Mohamed Doaa M. , Dehe Lukas , Shaqura Mohammed , Treskatsch Sacha , Shakibaei Mehdi , Schäfer Michael , Mousa Shaaban A.
Published: July 2017

Background. This study investigated histopathological changes and apoptotic factors that may be involved in the renal damage caused by congestive heart failure in a rat model of infrarenal aortocaval fistula (ACF). Methods. Heart failure was induced using a modified approach of ACF in male Wistar rats. Sham‐operated controls and ACF rats were characterized by their morphometric and hemodynamic parameters and investigated for their histopathological, ultrastructural, and apoptotic factor changes in the kidney. Results. ACF‐induced heart failure is associated with histopathological signs of congestion and glomerular and tubular atrophy, as well as nuclear and cellular degeneration in the kidney. In parallel, overexpression of proapoptotic Bax protein, release of cytochrome C from the outer mitochondrial membrane into cell cytoplasm, and nuclear transfer of activated caspase 3 indicate apoptotic events. This was confirmed by electron microscopic findings of apoptotic signs in the kidney such as swollen mitochondria and degenerated nuclei in renal tubular cells. Conclusions. This study provides morphological evidence of renal injury during heart failure which may be due to caspase‐mediated apoptosis via overexpression of proapoptotic Bax protein, subsequent mitochondrial cytochrome C release, and final nuclear transfer of activated caspase 3, supporting the notion of a cardiorenal syndrome.
Gamma-Glutamyl Transpeptidase-to-Platelet Ratio Predicts Significant Liver Fibrosis of Chronic Hepatitis B Patients in China
Authors: Ren Tianyi , Wang Huan , Wu Ruihong , Niu Junqi
Published: July 2017

Background and Aims. We want to investigate whether a novel noninvasive marker is suitable for Chinese CHB patients. Methods. A total of 160 treatment-naïve CHB patients who underwent liver biopsy were enrolled in our study, and we assessed the diagnostic accuracies of GPR, aspartate transaminase-to-platelet ratio index (APRI), and the fibrosis index based on 4 factors (FIB-4) in them. Results. Of these 160 CHB patients, the numbers of F0, F1, F2, F3, and F4 are 34 (21.3%), 62 (38.8%), 18 (11.3%), 24 (15%), and 22 (13.8%), respectively. The area under the receiver operating characteristic curves (AUROC) of GPR for fibrosis (0.77 versus 0.70, P=0.03), significant fibrosis (0.70 versus 0.63, P=0.02), and extensive fibrosis (0.71 versus 0.64, P=0.02) were significantly higher than those of APRI. The AUROCs of GPR and Fib-4 for fibrosis (0.77 versus 0.75, P=0.14), significant fibrosis (0.70 versus 0.70, P=0.22), extensive fibrosis (0.71 versus 0.68, P=0.13), and cirrhosis (0.64 versus 0.67, P=0.24) were comparable. Conclusions. The GPR can be a routine laboratory marker to stage liver fibrosis in patients with CHB in China.
Location-Aware POI Recommendation for Indoor Space by Exploiting WiFi Logs
Authors: Zheng Zengwei , Chen Yuanyi , Chen Sinong , Sun Lin , Chen Dan
Published: July 2017

Indoor shopping trajectories provide us with a new approach to understanding user’s behaviour pattern in urban shopping mall, which can be derived from user-generated WiFi logs using indoor localization technology. In this paper, we propose a location-aware Point-of-Interest (POI) recommendation service in urban shopping mall that offers a user a set of indoor POIs by considering both personal interest and location preference. The POI recommendation service cannot only improve user’s shopping experience but also help the store owner better understand user’s shopping preference and intent. Specifically, the proposed method consists of two phases: offline modelling and online recommendation. The offline modelling phase is designed to learn user preference by mining his/her historical shopping trajectories. The online recommendation phase automatically produces top-k recommended POIs based on the learnt preference. To demonstrate the utility of our proposed approach, we have performed a comprehensive experiment evaluation on a real-world dataset collected by 468 users over 33 days. The experimental results show that the proposed recommendation service achieves much better recommendation performance than several existing benchmark methods.
Abstract 1: Galectins in glioblastoma: opportunities for combined therapy
Authors: Cachia David , Chatterjee Arindam Rano , Vandergrift William Alexander , Patel Sunil J. , Rabinovich Gabriel A. , Das Arabinda
Published: July 2017

Background: Despite aggressive treatment, including surgical resection, radiation and chemotherapy, over 90% of glioblastoma (GB) patients experience tumor recurrence. This may be due to high migratory potential, angiogenesis, molecular heterogeneity and a strong immunosuppressive environment. GB expresses high levels of carbohydrate-binding galectin proteins and histone deacetylase (HDAC) activity. The aim of this study was: 1) identify the differential expressions of galectin 1-15 protein levels in human GB patient samples as compared to normal tissue (obtained from Institutional Tissue Bank) and (2) modulate the galectin functions with and without a HDAC inhibitor (DATS: Dially Triisulfide and SAHA: Suberoylanilide Hydroxamic Acid ) or bevacizumab in in vitro GB models.

Methods: The effects of TMZ, ionizing radiation, or combined chemoradiation on galectin protein secretion and expression were assessed in human GB cells and human umbilical vein endothelial cells (HUVECs).

Results: We found increased galectin-1 protein expression in human GB tissue. We also observed that HUVEC co-culture with GB cells increased galectin-1 protein expression by 14 - 20% following bevacizumab, and conferred a bevacizumab protective benefit to GB cells. Our in vitro models promisingly demonstrated that 72 hr treatments with 25 µM of galectin 1 inhibitor + HDAC inhibitor induce antitumor activity in GB cells. Western blot and activities assay results also demonstrated that combination blockade of HDAC activity and galectin-1 augmented apoptosis in GB cells, which mechanistically involves activation of caspase-3 and inhibition of anti-apoptotic protein (survivin, p-Akt, and Mcl-1 expression).

Conclusion: Our in vitro culture results suggest possible benefit in combining a galectin inhibitor with an HDAC inhibitor in GB. Further studies in different animal models are warranted.

Citation Format: David Cachia, Arindam Rano Chatterjee, William Alexander Vandergrift, Sunil J. Patel, Gabriel A. Rabinovich, Arabinda Das. Galectins in glioblastoma: opportunities for combined therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1. doi:10.1158/1538-7445.AM2017-1
Abstract 108: In vitro and in vivo characterization of novel scorpion venom-based peptides for the treatment of colon cancer
Authors: Li Bin , KWOK Hang Fai
Published: July 2017

In the last decade, many of the venom-based bioactive peptides demonstrated with a broad and diverse spectrum of pharmacological activities, which help to enlarging the current drug-screening library for searching of new specific biomarkers and novel prototype drugs for diagnosis of diseases such as cancer. Moreover, it paved a new insight to overcome the current drug discovery problems, which including drug resistance problem, side effect and so on.

Here we report the discovery of a panel of novel venom-based peptides, which can significantly inhibit the growth of human colon cancer cells. Through our in-house developed high throughput screening techniques and bioinformatics analysis, we successfully isolated eight novel peptides from scorpion venoms with anticancer activities. We performed a series of anti-proliferative assays to demonstrate that these peptides could inhibit the growth of a broad spectrum of tumor cells, especially in human colon cancer cell line; while almost have no effect on normal human epithelial cells. Haemolysis assay was also performed to show our peptides do not cause any harm on normal human red blood cells, which point to the direction of bringing those peptides into the preclinic trial studies. Before the in vivo studies, we are currently investigating the anticancer mechanisms and involved signal pathways of these peptides. LDH assay and real-time live cell analysis were performed, and from those data it indicates that the peptides might actually work by inhibiting the cancer cell growth instead of disrupt their cell membrane directly. Flow cytometry and western bolt results also showed that the peptides have a significant G1 phase cell cycle arrest effect through inhibiting cyclin dependent kinases CDK4 and up-regulating the expression of cell cycle protein regulator Cyclin D3, p27, p21. Moreover, from our current data, it demonstrated that our peptides wouldn’t induce any apoptosis during the cell cycle process. With the solid anticancer mechanism/pathway data, the potential anticancer peptides to target in vivo malignant tumor will be evaluated in cancer xenograft animal model to demonstrate the growth inhibitor activity of our lead peptides.

In summary, our study demonstrate that our peptides can inhibit tumor cell growth via cell-cycle arrest, and almost have no cytotoxicity on human epithelial cells, which could lead our lead peptides to further clinical investigation for the new strategy of peptide mono-/combination therapy.

Citation Format: Bin Li, Hang Fai KWOK. In vitro and in vivo characterization of novel scorpion venom-based peptides for the treatment of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 108. doi:10.1158/1538-7445.AM2017-108
Abstract 124: Imipridone ONC201 promotes intra-tumoral accumulation of CD3+/NK+ cells that contribute to its anti-tumor efficacy
Authors: Wagner Jessica , Kline C. Leah , Zhou Lanlan , Zloza Andrew , Chesson Charles , Newman Jenna , Kaufman Howard , Bertino Joseph , Stein Mark , El-Deiry Wafik
Published: July 2017

ONC201, a first-in-class oral anti-tumor agent, upregulates the pro-apoptotic immune cytokine TRAIL and activates the integrated stress response leading to upregulation of death receptor 5 in bulk tumor and cancer stem cells. We previously demonstrated that ONC201 exerts a dose- and schedule-dependent effect on tumor progression in vivo while suppressing Akt/ERK signaling in tumors in a dose/frequency-dependent manner (Wagner et al., AACR, 2016). We also provided evidence that ONC201 exhibits a potent anti-metastatic effect (Wagner et al., AACR, 2016). We observe accumulation and activation of TRAIL-secreting NK+ cells within ONC201-treated tumors in C57/BL6, Balb/c, and athymic nude tumor-bearing mice. Importantly, ONC201 exerts in vivo anti-tumor efficacy on tumor cell lines that are ONC201-resistant in vitro, including acquired stable resistance. Using the NK-depleting antibody GM1, we demonstrate that the activation and TRAIL secretion of NK cells by ONC201 significantly contributes to in vivo anti-tumor efficacy, including TRAIL/ONC201-resistant tumors. We are currently investigating how ONC201 recruits NK cells to the tumor by examining NK-recruiting chemokine factors within the tumor site. We have also demonstrated upregulation of CD3+ T cells by ONC201 in syngeneic mice. Finally, we observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients upon ONC201 administration in the clinic. Our results demonstrate novel and potentially significant increases in cytotoxic NK cell recruitment to tumors. The results offer a unique pathway of immune stimulation for cancer therapy that may be combined with immune checkpoint or targeted cancer therapy strategies. We are currently investigating the role of NK cells and CD3+ cells in ONC201’s ability to inhibit metastasis by using a metastatic model that involves surgically removing the primary tumor and allowing metastases to grow in vivo before treatment. These findings indicate that ONC201 possess immunomodulatory activity and provide a rationale for combining ONC201 with PD-1/PDL-1 inhibitors, a combination we are currently testing in syngeneic immunocompetent mouse models.

Citation Format: Jessica Wagner, C. Leah Kline, Lanlan Zhou, Andrew Zloza, Charles Chesson, Jenna Newman, Howard Kaufman, Joseph Bertino, Mark Stein, Wafik El-Deiry. Imipridone ONC201 promotes intra-tumoral accumulation of CD3+/NK+ cells that contribute to its anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 124. doi:10.1158/1538-7445.AM2017-124
Abstract 1275: Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility
Authors: Zhang Liren , Zhang Yanwei , Li Rong , Chang David W. , Ye Yuanqing , Minna John D. , Roth Jack A. , Han Baohui , Wu Xifeng
Published: July 2017

Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatics analyses, The Cancer Genome Atlas (TCGA) project has recently identified panels of genetic mutations that contributed to or associated with the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these highly mutated genes and lung cancer susceptibility. In this multi-phase study, we aimed to comprehensively evaluate the 1655 tagSNPs located in the 127 significantly mutated genes (SMGs) identified by TCGA, and test their association with risk of lung cancer in a total of 7355 patients and 7301 healthy controls. We found that 11 SNPs in 8 genes showed consistent association (P<0.1) and 8 SNPs significantly associated with lung cancer risk (P<0.05) in both discovery and validation phases. The most significant SNP A was associated with a decreased risk of lung cancer (OR=0.91, 95%CI: 0.87-0.96, P=2.3×10-4). Cumulative analysis of the 11 SNPs showed consistently elevated risk with increasing number of unfavorable genotypes (P for trend=1.2×10-10). In stratified analyses, the association of SNP A and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The eQTL-analysis indicated that genotypes of four SNPs significantly correlated with the expression of their genes respectively. From TCGA data, expression of the identified genes were significantly different in lung tumors compared with normal tissues, and the genes’ highest mutation frequency was found in lung cancers. Integrative pathway analysis (IPA) indicated the identified genes were mainly involved in major cell cycle regulatory pathway suggesting the underlying biological processes. In summary, this study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.

Citation Format: Liren Zhang, Yanwei Zhang, Rong Li, David W. Chang, Yuanqing Ye, John D. Minna, Jack A. Roth, Baohui Han, Xifeng Wu. Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1275. doi:10.1158/1538-7445.AM2017-1275
Abstract 13: Chromatin unfolding small molecules as a novel type of anticancer agents
Authors: Gurova Katerina V.
Published: July 2017

Although targeted therapy was the major focus of anti-cancer drug development, recently revealed enormous heterogeneity of tumors planted a seed of doubt in it as a potential cure for cancer. Very few universal cancer targets are known and they lack cancer specificity. DNA is one of this sort, but activity of drugs targeting DNA was traditionally attributed to their ability to block DNA replication and cause DNA damage with a plethora of harmful long lasting effects in normal cells. We have found that reversible binding of DNA by non-DNA damaging small molecules, curaxins, has strong anticancer effect in different preclinical models without deleterious consequences associated with DNA damage (REF). In this study we explained the mechanism of activity of curaxin clinical lead, CBL0137, through alteration of chromatin organization in tumor cells. Intercalation of the curaxin carbazole moiety between base pairs and DNA major and minor groove binding with curaxin side chains cause an increase in inter base pair distance and untwisting of the double helix (~18o). Such alteration of DNA helical shape leads to decreased nucleosome stability and chromatin opening, creating sites for the high affinity binding of histone chaperone complex FACT. We named this phenomenon “chromatin trapping of FACT” or c-trapping. Consequences of C-trapping are much more deleterious for tumor, than for normal cells. First, c-trapping is an equivalent of functional inactivation of FACT. FACT is critical for oncogenic transformation and tumor, but not normal cell, viability and growth (REF). FACT is essential for the activity of several transcription factors, such as NF-kappaB, HSF1, MYC etc., with important roles in tumor cell proliferation and survival (REF). Further, deregulation of transcription caused by curaxin-dependent chromatin decondensation leads to upregulation of transcription from heterochromatin. This leads to the formation of double stranded RNAs from centromeric and pericentromeric repetitive elements, which mimics a viral infection and induces an IFN response, a powerful inhibitor of tumor cell growth. Additionally, c-trapping of FACT leads to casein kinase 2 mediated phosphorylation and activation of wild type p53 leading to p53-dependent death of cells. Thus non-DNA damaging DNA binding small molecules compromise cancer cell viability via alteration of nucleosome stability and chromatin organization. This is a novel mechanism of anti-cancer activity of small molecules with broad applicability to different types of cancer while lacking the harmful effects of DNA damaging chemotherapy.

Citation Format: Katerina V. Gurova. Chromatin unfolding small molecules as a novel type of anticancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 13. doi:10.1158/1538-7445.AM2017-13
Abstract 1360: Novel function of p21-activated kinase 3 (PAK3) in regulating Akt phosphorylation and pancreatic cancer stem cell phenotypes
Authors: Wu Hsing-Yu , Yang Ming-Chen , Chu Po-Chen , Kulp Samuel K. , Chen Ching-Shih
Published: July 2017

p21-activated kinases (PAKs) are important effectors of the Rho family GTPases and has been implicated in cytoskelestal remodeling, cell proliferation, apoptosis, and transformation. Based on the sequence, structure homology, and activation mechanism, six PAKs are classified into two groups, PAK 1-3 (group I) and PAK 4-6 (group II). PAK kinases are frequently overexpressed in various human tumors and represent therapeutically relevant targets for cancer treatments. Previous studies have shown that PAK1 and PAK4 are upregulated and/or hyperactivated in pancreatic cancer, and promotes pancreatic cancer cell motility and invasion. In our study, we showed that knockdown of PAK3, but not that of PAK1 or PAK2, inhibited pancreatic cancer cell proliferation in vitro, and tumor growth in vivo. In addition, our data showed that PAK3 regulated the protein stability of β-catenin via Akt/GSK-3β signaling pathway in pancreatic cancer cells. The role of PAK3 in regulating Akt/GSK-3β phosphorylation was further confirmed by the ectopic expression of wild-type versus kinase-dead (K297L) PAK3. Equally important, the mammosphere formation, aldehyde dehydrogenase (ALDH) activity and cancer stem cell-associated markers, were also down-regulated in PAK3 knockdown cells, suggesting the involvement of PAK3 in regulating cancer stem cell-like properties in pancreatic cancer cells. Together, these findings suggested that PAK3 as a primary regulator of Akt/GSK-3β/β-catenin signaling for maintaining cancer stem cell phenotypes and promoting tumor growth, which underlies the potential of targeting PAK3 in fostering new therapeutic strategies for pancreatic cancer.

Citation Format: Hsing-Yu Wu, Ming-Chen Yang, Po-Chen Chu, Samuel K. Kulp, Ching-Shih Chen. Novel function of p21-activated kinase 3 (PAK3) in regulating Akt phosphorylation and pancreatic cancer stem cell phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1360. doi:10.1158/1538-7445.AM2017-1360
Abstract 1443: Identification of enhancer elements at kidney cancer susceptibility loci using MPRA
Authors: Colli Leandro Machado , Jessop Lea , Machiela Mitchell , Choi Jiyeon , Myers Timothy , Chanock Stephen
Published: July 2017

GWAS is an important tool for discovering regions in the genome associated with cancer susceptibility. For renal cell carcinoma (RCC), only two loci have had their functional basis explained (11q13 and 12p12). Here, we used a massively parallel reporter assay (MPRA) to investigate enhancer activity in 20 GWAS regions that had an RCC association p-value of at least 10-7. We selected 784 SNPs with an r2>0.4 or D’>0.5 and MAF<0.05 that had evidence for enhancer activity based on available ENCODE transcription factor or histone ChIP-seq, FAIRE, and DNase I hypersensitive data. The MPRA library was composed of 47461 oligonucleotides 201 bp in length, compelled of 145 bps contained the SNP in the forward or reverse orientation followed by 10 bp of barcode sequence to allow for identification. Each of the 784 SNPs tested were tagged 10 separate times for both orientations. Controls were constructed by randomizing the 10 nucleotides centered on the SNP. The MPRA library was the cloned into a luciferase reporter vector that was transfected into HEK293T and ACHN cell lines. NGS was performed on 5 replicates using the the Illumina HiSeq 2500. After correcting for multiple comparisons, 50 SNPs from 16 regions showed significant p-values. From these 50 SNPs, 29 showed enhancer activity that was independent of the forward/reverse orientation and had the same effect in both cell lines. This analysis has identified possible functional variants at RCC risk loci and opens opportunities to discover new molecular mechanisms of genetic susceptibility of RCC.

Citation Format: Leandro Machado Colli, Lea Jessop, Mitchell Machiela, Jiyeon Choi, Timothy Myers, Stephen Chanock. Identification of enhancer elements at kidney cancer susceptibility loci using MPRA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1443. doi:10.1158/1538-7445.AM2017-1443
Abstract 146: The PI3K inhibitor, taselisib, has a unique mechanism of action that leads to enhanced potency in PIK3CA mutant models
Authors: Song Kyung W. , Edgar Kyle A. , Kirkpatrick Donald S. , Phu Lilian , Schmidt Stephen , Nannini Michelle , Hong Rebecca , Cheng Eric , Crocker Lisa , Young Amy , Sampath Deepak , Friedman Lori
Published: July 2017

Activating mutations in PIK3CA are commonly found in a wide variety of human cancers, and the dysregulation of the phosphoinositide-3 kinase (PI3K) signaling pathway has been implicated in tumor cell growth and survival. Taselisib (GDC-0032), a novel, oral, selective inhibitor of p110alpha, sparing inhibition of p110beta, is more potent in cancer cells bearing PIK3CA mutants than those with wildtype PIK3CA. Preclinical studies demonstrate that taselisib induces more apoptotic cell death in PIK3CA mutant cancer cells than other PI3K inhibitors.

We have discovered that taselisib has a dual mechanism of action, both blocking PI3K signaling, and inducing a decrease in p110a protein levels. Mass spec analysis reveals that taselisib treatment leads to the specific depletion of mutant p110alpha without significant change in wildtype p110alpha protein levels. This drug-induced p110a protein depletion is rescued by E1 inhibitors and by proteasome inhibitors. Other clinical PI3K inhibitors, including p110alpha selective and pan-PI3K inhibitors, are unable to induce the depletion of mutant p110 alpha protein. Furthermore, we have discovered that taselisib more effectively maintains pathway suppression in PIK3CA mutant cells at 24 hrs in response to feedback. In comparison to other clinical-stage PI3K inhibitors administered at a maximum tolerated dose, taselisib has superior efficacy with increased tumor regressions in PIK3CA mutant xenograft models. In summary, these preclinical studies indicate that PI3K inhibitors, which have the ability to trigger degradation of mutant p110a protein, can more effectively suppress the signaling pathway, which may result in greater anti-tumor activity and improved therapeutic index in PIK3CA mutant tumors.

Citation Format: Kyung W. Song, Kyle A. Edgar, Donald S. Kirkpatrick, Lilian Phu, Stephen Schmidt, Michelle Nannini, Rebecca Hong, Eric Cheng, Lisa Crocker, Amy Young, Deepak Sampath, Lori Friedman. The PI3K inhibitor, taselisib, has a unique mechanism of action that leads to enhanced potency in PIK3CA mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 146. doi:10.1158/1538-7445.AM2017-146
Abstract 1483: Alteration of miR-186 expression modifies inflammatory markers in normal epithelial and prostate cancer cell models
Authors: Suman Suman , Jones-Reed Dominique Z. , Schmidt M. L. , Clark Geoffrey J. , Klinge Carolyn , Barve Shirish , Kimbro Kevin S. , Kidd La Creis R.
Published: July 2017

Dysregulation of miRNAs and chronic inflammation are strongly implicated in the development of various malignancies, including prostate cancer (PCa). Previously, our lab identified several inflammatory and immune response sequence variants in CCL5 and CCR5 significantly modified PCa risk. Recently, we propose an oncogenic role for miR-186-5p based on its up-regulation in serum from PCa patients and metastatic PCa cell lines. Moreover, miR-186-5p inhibition reduced proliferation, anchorage independent growth and invasion in metastatic PC cells (PC3, MDA-PCA-2b). We hypothesize dysregulation of inflammatory and immune response markers may enhance immune surveillance leading to a reduced aggressive tumor phenotype. Following modulations in miRNA-186 levels in normal prostate epithelial (RWPE1) and metastatic PCa (PC3) cell lines, we evaluated alterations in mRNA expression using micro-array analysis. Ectopic expression of miRNA-186 in the RWPE1 resulted in a 1.3-2.6-fold down-regulation in TLR2, IRAK2, CCL20, IL1RAP, IL1RAP, IL15, and IL17RD (FDR p-value ≥7.8x10-06). Whereas, inhibition of miR-186 in PC3 cells corresponded with a 1.4-fold up-regulation of IL18R1 (p=0.0095). Notably, these inflammatory markers are involved in cell invasion (TLR2), apoptosis (IL17RD), tumorigenesis (TLR2, IRAK2) and autoimmune diseases (CCL20). Validation of these targets is underway using qRT-PCR, western blots and luciferase reporter assays. We will assess the mechanism by which these miR-186 targets suppress aggressive cancer behavior using knock-out and knock-in cell and ultimately animal models. Future studies may identify inflammatory targets that may guide immune therapies for the effective treatment of aggressive prostate cancer.

Citation Format: Suman Suman, Dominique Z. Jones-Reed, M. L. Schmidt, Geoffrey J. Clark, Carolyn Klinge, Shirish Barve, Kevin S. Kimbro, La Creis R. Kidd. Alteration of miR-186 expression modifies inflammatory markers in normal epithelial and prostate cancer cell models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1483. doi:10.1158/1538-7445.AM2017-1483
Abstract 1541: The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation
Authors: Kuznetsov Jeffim N. , Aguero Tristan , Kurtenbach Stefan , Field Matthew G. , King Mary Lou , Harbour J William
Published: July 2017

Introduction: Our lab discovered that mutations in the tumor suppressor BAP1 are strongly associated with metastasis and death in patients with uveal melanoma. Subsequently, other cancers have been found to harbor BAP1 mutations, including skin melanoma, kidney cancer, mesothelioma and others. Germline BAP1 mutations are responsible for a newly described genetic cancer syndrome. Therapeutic molecules that reverse the effects of BAP1 mutations could represent a potent new treatment strategy for BAP1-mutant cancers. Unfortunately, there are several obstacles to developing such therapies. First, BAP1 is a tumor suppressor that is inactivated by mutations, such that targeted therapy would need to be directed against downstream effectors that are deregulated by BAP1 loss. Second, the effectors of BAP1 that are relevant to cancer are not known. Interestingly, most known proteins that interact with Bap1 are developmental epigenetic regulators such as Asxl1/2, Cbx1/3 and Kdm1b. Third, BAP1 is difficult to study in cultured cells because BAP1 loss results in cell cycle exit and stem cell-like behavior. These obstacles led us to shift to Xenopus laevis as an in vivo developmental model to study the functions of BAP1. Results and conclusions: Loss of BAP1 during embryo development results in a failure to turn off pluripotency genes such as ventx 1, ventx2 (Xenopus orthologues of the mammal gene nanog), oct 25, oct 91 (Xenopus orthologues of the mammal gene oct3/4) and pax3, and a failure to induce lineage specification genes such as the prospective epidermis marker keratin1 and the melanocyte precursor marker sox10. This block in the shift from pluripotency to differentiation programs results in a delay in gastrulation, neural crest specification and migration, mesodermal differentiation and other phenotypes. The BAP1-deficient phenotype can be rescued by Xenopus or human wildtype BAP1 or by the histone deacetylase inhibitor SAHA (vorinostat). We conclude that BAP1 is a fundamental regulator of multiple developmental lineages, including the neural crest from which melanomas arises, and that this in vivo model can be used to screen for novel therapeutic compounds that reverse the phenotypic effects of BAP1 loss.

Citation Format: Jeffim N. Kuznetsov, Tristan Aguero, Stefan Kurtenbach, Matthew G. Field, Mary Lou King, J William Harbour. The tumor suppressor BAP1 promotes a developmental switch from pluripotency to differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1541. doi:10.1158/1538-7445.AM2017-1541
Abstract 1718: RT-qPCR gene expression analysis of CTCs isolated through an epitope-independent enrichment microfluidic device in patients with head and neck squamous cell carcinoma
Authors: Zavridou Martha , Strati Areti , Koutsodontis George , Psyrri Amanda , Lianidou Evi
Published: July 2017

Background: Molecular characterization of circulating tumor cells (CTCs) is very challenging since these cells are rare, and the amount of available sample for their analysis is very limited. Moreover, CTC are highly heterogeneous and enrichment technologies based on EpCAM expression present the risk of missing EpCAM-negative CTCs. The Parsortix system (ANGLE plc, UK), is a novel microfluidic technology platform designed for marker-independent capture of CTCs. In this study we used for the first time the Parsortix system to isolate CTCs from patients with Head and Neck Squamous Cell carcinoma (HNSCC), and proceeded to downstream molecular characterization through RT-qPCR gene expression analysis.

Methods: Peripheral blood samples (10 mL) from head and neck squamous cell carcinoma (HNSCC) patients (n=19) and healthy donors used as a control group (n=10) were used for the isolation of CTCs using the Parsortix device. Enriched CTCs were harvested in Trizol reagent, followed by extraction of total RNA and cDNA synthesis. RT-qPCR was performed in the LightCycler (Roche) for the following gene targets: PD-L1, VIM, TWIST, EGFR, and B2M (used as a reference gene). The expression levels of PD-L1, VIM, TWIST and EGFR were normalized using the 2-ΔΔCt approach in respect to the expression of B2M.

Results: All samples analyzed were of excellent RNA quality as this was evaluated by B2M expression. According to our results, PD-L1 overexpression was detected in 5/19(26.3%) samples, VIM was overexpressed in 3/19 (15.7%) and TWIST-1 in 1/19 (5.3%) sample, while EGFR expression was not detected in any patient (0/19, 0%). These are preliminary results and these percentages may change, since the number of samples that we are analyzing is continuously increasing.

Conclusions: This preliminary study is showing for the first time that RT-qPCR can be successfully used for the molecular characterization of CTCs isolated by the label-free Parsortix microfluidic device in HNSCC. Overexpression of individualized immunotherapy important biomarkers such as PD-L1 in CTCs of HNSCC patients could be of significant clinical importance for the selection and follow up of these patients.

Citation Format: Martha Zavridou, Areti Strati, George Koutsodontis, Amanda Psyrri, Evi Lianidou. RT-qPCR gene expression analysis of CTCs isolated through an epitope-independent enrichment microfluidic device in patients with head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1718. doi:10.1158/1538-7445.AM2017-1718
Abstract 1811: A PEAK1/GATA2 signaling axis controls VEGFR2 expression to mediate angiogenesis
Authors: Klemke Richard L.
Published: July 2017

Formation of new blood vessels (angiogenesis) is crucial for proper development, but can also contribute to many diseases including cancer. Vascular endothelial growth factor receptor 2 (VEGFR2) is a receptor tyrosine kinase that mediates angiogenesis in developing vertebrates and is frequently upregulated in many human cancers. However, the underlying mechanisms that regulate VEGFR2 expression in normal and diseased cells are poorly understood. Here we demonstrate that pseudopodium-enriched atypical kinase 1 (PEAK1) mediates developmental and tumor-induced angiogenesis by modulating VEGFR2 expression and downstream signaling. Knockout of peak1 in zebrafish using TALEN technology (Transcription Activator-Like Effector Nucleases) or knockdown by specific peak1 morpholinos (MO) induced severe pericardial edema, blood-pooling defects, and inhibited formation of intersegmental (ISV) and subintestinal vessels (SIV). In Peak1 knockout mice, neonatal retinal vessel development was severely delayed, and the ex vivo angiogenic ability of adult thoracic aorta was greatly reduced. Intravital time-lapse imaging of ISV formation in peak1 knockout zebrafish revealed major defects in endothelial cell migration and proliferation. Similarly, PEAK1 knockdown or overexpression in HUVECs modulated endothelial cell migration, proliferation, and vessel sprouting in vitro. Biochemical studies and quantitative proteomic profiling of PEAK1 knockdown HUVECs revealed a dramatic loss of VEGFR2 mRNA and protein expression, which attenuated downstream signaling to Akt and ERK, leading to loss of VEGF-mediated vessel formation. PEAK1 specifically regulated VEGFR2 levels and did not alter VEGFR1 expression, and reconstitution of PEAK1 knockdown cells with PEAK1 restored VEGFR2 mRNA and protein expression. Mechanistic studies revealed that PEAK1 specifically regulates VEGFR2 mRNA transcription by modulating expression of the transcription factor GATA2. Re-expression of GATA2 in PEAK1 depleted cells restored VEGFR2 mRNA and protein expression as well as downstream signaling, indicating that GATA2 is a necessary downstream component in this response. Also, introduction of gata2 mRNA into PEAK1 knockdown zebrafish restored normal ISV formation and vegfr2 mRNA expression in these animals. Finally, bioinformatics and interrogation of the TCGA RNAseq database revealed significant Pearson’s correlations between PEAK1 and VEGFR2 expression in 17 of 32 different human cancers. Collectively, our findings indicate that PEAK1 regulates developmental and tumor-induced angiogenesis by regulating GATA2-dependent VEGFR2 expression and its downstream signals.

Citation Format: Richard L. Klemke. A PEAK1/GATA2 signaling axis controls VEGFR2 expression to mediate angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1811. doi:10.1158/1538-7445.AM2017-1811
Abstract 188: Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice
Authors: Zhang Qi , Pan Jing , Miller Marker S. , Lubet Ronald A. , Wang Yian , You Ming
Published: July 2017

Lung cancer is the leading cause of cancer-related deaths in the United States. The 5 year survival rate for lung cancer patients has remained a dismal 15% for 3 decades. Thus, the development of chemopreventive agents that could prevent lung cancer could potentially reduce the incidence and mortality of pulmonary neoplasms. Bexarotene has exhibited inhibitory effects in preclinical in vivo models of mammary and lung tumorigenesis, has been approved for clinical use in the treatment of cutaneous T-cell lymphoma, and has shown efficacy in phase I/II trials of non-small cell lung cancer (NSCLC). Preclinical studies have demonstrated that it is highly effective in the prevention of all three major subtypes of lung cancer in mouse models: adenocarcinoma (AD), squamous cell carcinoma (SCC), and small cell lung cancer (SCLC). The major side effects of bexarotene when administered orally to rodents or human patients have been hypertriglyceridemia and hypercholesterolemia. Previous studies in a mouse model of lung AD have demonstrated that aerosol delivery of bexarotene through nasal inhalation exhibited potent chemopreventive activity similar to that observed following oral administration (59 to74% reductions in lung tumor multiplicity). The significant decreases in tumor multiplicity and tumor load were achieved without hypertriglycerides that accompany oral bexarotene administration. In this study, aerosolized delivery of 10-30 mg/ml bexarotene showed a significant chemopreventive effect in all three major subtypes. In the N-nitroso-tris-chloroethylurea (NTCU) induced mouse SCC model, 1 week after the first dose of NTCU a dose dependent decrease in tumor formation was observed, with the highest dose causing 75% (p<0.001) and 42% (p<0.01) decreases in SCC tumor burden and the percentage of SCC tumors, respectively. Tumor load was decreased by 73% in A/Jp53 mouse AD model and by 41% in A/Jp53Rb mouse SCLC model. Aerosol delivery of bexarotene had no effect on animal body weight and other signs of toxicity, and no effect on triglyceride and cholesterol level. Aerosolized bexarotene formulation was effective against all 3 major lung cancer cell types and would be a major advance achieving significant reductions in preventing lung cancer incidence in persons at high risk of lung cancer e.g. former or present smokers.

Citation Format: Qi Zhang, Jing Pan, Marker S. Miller, Ronald A. Lubet, Yian Wang, Ming You. Preventive effect of aerosolized bexarotene in three major subtypes of lung cancer: adenocarcinoma, squamous cell carcinoma and small cell lung cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 188. doi:10.1158/1538-7445.AM2017-188