bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Inflammatory Markers in a Large Sample of Obstructive Sleep Apnea Patients without Comorbidities
Authors: Bouloukaki Izolde , Mermigkis Charalampos , Tzanakis Nikolaos , Kallergis Eleftherios , Moniaki Violeta , Mauroudi Eleni , Schiza Sophia E.
Published: July 2017

Systemic inflammation is important in obstructive sleep apnea (OSA) pathophysiology and its comorbidity. We aimed to assess the levels of inflammatory biomarkers in a large sample of OSA patients and to investigate any correlation between these biomarkers with clinical and polysomnographic (PSG) parameters. This was a cross-sectional study in which 2983 patients who had undergone a polysomnography for OSA diagnosis were recruited. Patients with known comorbidities were excluded. Included patients (n=1053) were grouped according to apnea-hypopnea index (AHI) as mild, moderate, and severe. Patients with AHI < 5 served as controls. Demographics, PSG data, and levels of high-sensitivity C-reactive protein (hs-CRP), fibrinogen, erythrocyte sedimentation rate (ESR), and uric acid (UA) were measured and compared between groups. A significant difference was found between groups in hs-CRP, fibrinogen, and UA. All biomarkers were independently associated with OSA severity and gender (p<0.05). Females had increased levels of hs-CRP, fibrinogen, and ESR (p<0.001) compared to men. In contrast, UA levels were higher in men (p<0.001). Our results suggest that inflammatory markers significantly increase in patients with OSA without known comorbidities and correlate with OSA severity. These findings may have important implications regarding OSA diagnosis, monitoring, treatment, and prognosis. This trial is registered with ClinicalTrials.gov numberNCT03070769.
Recent Progress in Synthesis and Application of Low-Dimensional Silicon Based Anode Material for Lithium Ion Battery
Authors: Sun Yuandong , Liu Kewei , Zhu Yu
Published: July 2017

Silicon is regarded as the next generation anode material for LIBs with its ultra-high theoretical capacity and abundance. Nevertheless, the severe capacity degradation resulting from the huge volume change and accumulative solid-electrolyte interphase (SEI) formation hinders the silicon based anode material for further practical applications. Hence, a variety of methods have been applied to enhance electrochemical performances in terms of the electrochemical stability and rate performance of the silicon anodes such as designing nanostructured Si, combining with carbonaceous material, exploring multifunctional polymer binders, and developing artificial SEI layers. Silicon anodes with low-dimensional structures (0D, 1D, and 2D), compared with bulky silicon anodes, are strongly believed to have several advanced characteristics including larger surface area, fast electron transfer, and shortened lithium diffusion pathway as well as better accommodation with volume changes, which leads to improved electrochemical behaviors. In this review, recent progress of silicon anode synthesis methodologies generating low-dimensional structures for lithium ion batteries (LIBs) applications is listed and discussed.
Low Cross-Polarization Gaussian Tapered Post-Wall Slotline Antenna for Short Pulse Applications
Authors: Zhao Hongxin , Li Yufu , Yin Xiaoxing
Published: July 2017

A Gaussian tapered slot antenna based on post-wall structured slotline for improvement of cross-polarization for ultra-wideband applications is proposed and experimentally demonstrated. The antenna is composed of two pairs of Gaussian tapered slotline which have the same structure printed on both sides of the PCB, two metallic via arrays positioned along the slot edges, and two terminal resistors. The metallic via arrays are used to reduce the characteristic impedance of the conventional slotline which form a post-wall slotline and thus can be fed by a coaxial connector directly. More importantly, the balanced symmetrical post-wall structure ensures low cross-polarization levels of the antenna. The Gaussian tapered edges and the terminal resistors diminish reflected signal and thus can enlarge the bandwidth significantly. Good agreements between the simulated and the measured results have been observed. Results show that the proposed antenna exhibits a −10 dB impedance bandwidth from 1.5 GHz to 20 GHz, a maximum realized gain of 12 dBi, and the broadside cross-polarization level is averaged about −32 dB in the lower frequency band and −25 dB in the higher frequency band with a maximum value of −22 dB in the whole working frequency band.
CuO–Water Nanofluid Magnetohydrodynamic Natural Convection inside a Sinusoidal Annulus in Presence of Melting Heat Transfer
Authors: Sheikholeslami M. , Ellahi R. , Fetecau C.
Published: July 2017

Impact of nanofluid natural convection due to magnetic field in existence of melting heat transfer is simulated using CVFEM in this research. KKL model is taken into account to obtain properties of CuO–H2O nanofluid. Roles of melting parameter (δ), CuO–H2O volume fraction (ϕ), Hartmann number (Ha), and Rayleigh (Ra) number are depicted in outputs. Results depict that temperature gradient improves with rise of Rayleigh number and melting parameter. Nusselt number detracts with rise of Ha. At the end, a comparison as a limiting case of the considered problem with the existing studies is made and found in good agreement.
Early Spatiotemporal Patterns and Knee Kinematics during Level Walking in Individuals following Total Knee Arthroplasty
Authors: Wu Xubo , Chu Lixi , Xiao Lianbo , He Yong , Jiang Shuyun , Yang Songbin , Liu Yijie
Published: July 2017

Purpose. With the aim of investigating the spatiotemporal features of early gait pattern and knee kinematics after total knee arthroplasty and analyzing the association between outcomes of gait analyses and knee kinematic parameters, the relationship between walking and dynamic knee deformity at the early period after total knee arthroplasty was assessed in this study. Methods. Eighteen patients including 14 women and 4 men who underwent total knee arthroplasty were analyzed using three-dimensional gait analysis system to observe gait parameters and values of maximum knee flexion angle (MKFA) during swing phase and knee flexion angle (KFA) and knee valgus angle (KVA) at midstance phase. Results. 3D gait analysis showed that operated side exhibited significantly less total support time and single support time as well as significantly longer swing phase compared with the other side. During walking, the operated side had significantly smaller MKFA and greater KFA and KVA than the nonoperated side. There was moderate to significant correlation between gait pattern and the dynamic knee kinematics. Conclusion. The gait abnormality of patients after TKA was associated with inadequate flexion of knees at swing phase and insufficient extension at stance phase as well as increased range of valgus.
Practice and Barriers towards Provision of Health Promotion Services among Community Pharmacists in Gondar, Northwest Ethiopia
Authors: Asmelashe Gelayee Dessalegn , Binega Mekonnen Gashaw , Asrade Atnafe Seyfe
Published: July 2017

Background. Health promotion is now becoming an integral part of community pharmacy practice worldwide. Objectives. This study was intended to determine the level of involvement of community pharmacists in providing health promotion service and to identify the barriers to the practice. Methods. A cross-sectional study was conducted on 48 community pharmacists working in Gondar town, Northwest Ethiopia. Data on sociodemographic factors, practice, and barriers to health promotion service were collected and analyzed using SPSS version 20. Results. The majority of respondents were B.Pharm holders (n=27, 56.3%). Almost all respondents (n=45, 95.8%) were willing and claimed to be well involved in health promotion services. The top 5 services were related to drug misuse, asthma, diabetes, family planning, and cardiovascular diseases. However, involvement in some types of health promotion services significantly differed based on sex, educational level, and pharmacy ownership of respondents. The main barrier reported was lack of training. Conclusion. The community pharmacists in Gondar, Northwest Ethiopia, are engaged in health promotion activities. However lack of training has limited their level of involvement and practice differences were noted based on sex, educational level, and pharmacy ownership status of the respondents.
Uncover the Underlying Mechanism of Drug-Induced Myopathy by Using Systems Biology Approaches
Authors: Li Dong , Li Aixin , Zhou Hairui , Wang Xi , Li Peng , Bi Sheng , Teng Yang
Published: July 2017

Drug-induced myopathy (DIM) is a rare side effect; however, the consequence could be fatal. There are few reports to systematically assess the underlying mechanism of DIM. In this study, we curated the comprehensive DIM drug list based on structured labeling products (SPLs) and carried out the analysis based on chemical structure space, drug protein interaction, side effect space, and transcriptomic profiling space. Some key features are enriched from each of analysis. Specifically, the similarity of DIM drugs is more significant than random chance, which shows that the chemical structure could distinguish the DIM-positive drugs from negatives. The cytochrome P450 (CYP) was identified to be shared by DIM drugs, which indicated the important role of metabolism in DIM. Three pathways including pathways in cancer, MAPK signaling pathway, and GnRH signaling pathway enriched based on transcriptomic analysis may explain the underlying mechanism of DIM. Although the DIM is the current focus of the study, the proposed approaches could be applied to other toxicity assessments and facilitate the safety evaluation.
Dynamic Changes in the Nigrostriatal Pathway in the MPTP Mouse Model of Parkinson’s Disease
Authors: Huang Dongping , Xu Jing , Wang Jinghui , Tong Jiabin , Bai Xiaochen , Li Heng , Wang Zishan , Huang Yulu , Wu Yufei , Yu Mei , Huang Fang
Published: July 2017

The characteristic brain pathology and motor and nonmotor symptoms of Parkinson’s disease (PD) are well established. However, the details regarding the causes of the disease and its course are much less clear. Animal models have significantly enriched our current understanding of the progression of this disease. Among various neurotoxin-based models of PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model is the most commonly studied model. Here, we provide an overview of the dynamic changes in the nigrostriatal pathway in the MPTP mouse model of PD. Pathophysiological events, such as reductions in the striatal dopamine (DA) concentrations and levels of the tyrosine hydroxylase (TH) protein, depletion of TH-positive nerve fibers, a decrease in the number of TH-positive neurons in the substantia nigra pars compacta (SNpc), and glial activation, are addressed. This article will assist with the development of interventions or therapeutic strategies for PD.
A Case Report of Isolated Bilateral Cerebral Peduncular Infarction
Authors: Zhou Chenguang , He Yuanhong , Tian Xiaorui , Chao Zhiwen , Zhu Yinghui , Cheng Du , Li Kui
Published: July 2017

Isolated bilateral cerebral peduncular infarctions (BCPI) presenting as acute pseudobulbar palsy are rarely reported and, to the best of our knowledge, most of the previous reports of BCPI were related to locked-in syndrome and disturbance of consciousness. Herein, we described a case of a 55-year-old man who presented with acute pseudobulbar palsy and mild tetraparesis, but preserved eye movements, with no consciousness disturbance. DWI revealed an acute infarction involving the central portion of the cerebral peduncle with a characteristic “traditional Chinese eight character” sign. The relationship between the infarcted range in the cerebral peduncle and the clinical manifestation was discussed in our report.
Abstract 100: Pancreatic cancer cells rely on the NADPH producing enzyme, IDH1, for adaptive survival against acute metabolic stress
Authors: Vaziri-Gohar Ali , Zarei Mahsa , Brody Jonathan R. , Winter Jordan M.
Published: July 2017

We recently demonstrated that pancreatic cancer cells adapt to low nutrient conditions and chemotherapeutic stress through an adaptive response where HuR (ELAVL1) protects cells from oxidative damage induced by metabolic stress. RNA sequencing data and a series of protein-RNA interaction assays proved that HuR stabilizes transcript levels of the NADPH producing enzyme, isocitrate dehydrogenase 1 (IDH1). HuR-knockout cells had near-complete loss of IDH1 expression (manuscript under review). In light of the fact that IDH1-null mice are particularly sensitive to oxidative damage, we hypothesize that this enzyme plays a critical role in PDA survival of acute stress. We examined the expression levels of all eight well-characterized NADPH-generating enzymes in pancreatic cancer cells in vitro, and demonstrate that only IDH1 and phosphogluconate dehydrogenase (PGD) are upregulated by >2-fold after incubation in low glucose (5 mM) for 48 hours. IDH1-knockout MiaPaCa2 cells were generated through CRISPR gene editing, such that mRNA expression was detected at <5% of control levels. ROS levels detected by DCFDA measurements were increased by 55% in IDH1-knockout cells compared to isogenic controls under normal culture conditions, with even higher levels under low glucose and chemotherapy stress for 48 hours. Additionally, IDH1-knockout cells were more sensitive to chemotherapy under both high and low glucose conditions, compared to IDH1-proficient control cells. Taken together these results suggest that IDH1 expression is important for acute antioxidant defense in pancreatic cancer cells in the face of metabolic stress, and represents a potential therapeutic target.

Citation Format: Ali Vaziri-Gohar, Mahsa Zarei, Jonathan R. Brody, Jordan M. Winter. Pancreatic cancer cells rely on the NADPH producing enzyme, IDH1, for adaptive survival against acute metabolic stress [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 100. doi:10.1158/1538-7445.AM2017-100
Abstract 1000: Estrogen receptor coactivator MED1 in breast tumorigenesis and therapeutic resistance
Authors: Zhang Xiaoting
Published: July 2017

Recent studies have established Mediator Subunit 1 (MED1) as a key ER transcriptional coactivator for in both normal mammary gland development and breast cancer. Significantly, the MED1 gene is located at the chromosome 17q12 region, also known as the HER2 amplicon, and co-amplifies with HER2 in almost all instances. Importantly, we found that MED1 serves as a key crosstalk point for the HER2 and ER pathways in anti-estrogen resistance of breast cancer. Significantly, MED1 expression highly correlates with poor disease-free survival of breast cancer patients; and most recent studies have discovered increased frequency of MED1 mutations in circulating tumor cells of human patients following anti-estrogen and anti-HER2 treatments. To determine the role of MED1 in HER2-driven tumorigenesis, we have crossed the MMTV-HER2 mammary tumor model with our established MED1 mutant knockin and newly generated MED1 mammary specific overexpression mouse models. Collectively, our studies revealed critical roles for MED1 in tumor progression, metastasis, cancer stem cell formation and therapeutic resistance in HER2-mediated mammary tumorigenesis. These studies not only for the first time reported key roles for a HER2 amplicon co-amplified gene in HER2-driven tumorigenesis but also support MED1 as a potential therapeutic target. To test that, we have assembled highly innovative RNA nanotechnology-based pRNA-HER2apt-siMED1 nanoparticles. We found these RNA nanoparticles have a very high Tm value, and is ultra-stable under RNase A, 8 M urea, serum and PBS conditions. Importantly, pRNA-HER2apt-siMED1 nanoparticles could specifically target HER2+ human breast cancer, efficiently deplete the expression of MED1 and decrease ER-mediated gene transcription both in vitro and in vivo. Most significantly, pRNA-HER2apt-siMED1 nanoparticles not only greatly reduce the growth, metastasis and cancer stem cell formation of HER2+ breast cancer, but are also able to overcome their therapeutic resistance. (This work is supported by Susan G. Komen for the Cure Foundation Career Catalyst Grant, American Cancer Society Research Scholar Grant and NIH/NCI Grant Number R01CA197865).

Citation Format: Xiaoting Zhang. Estrogen receptor coactivator MED1 in breast tumorigenesis and therapeutic resistance [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 1000. doi:10.1158/1538-7445.AM2017-1000
Abstract 1015: Directionality of T-cell-mediated cross-protection against the same tumor in lungs versus skin
Authors: O'Konek Jessica J. , Ambrosino Elena , Bloom Anja , Izhak Liat , Berzofsky Jay A. , Terabe Masaki
Published: July 2017

Immunotherapy is a new pillar of cancer therapy. One theoretical advantage of immunotherapy of cancer is that effector cells induced at one site should be able to kill metastatic cancer cells in other sites or tissues. On the other hand, it has been recognized that each tissue has unique immune components that play critical roles in protection against pathogens. However, very little is known whether effector T cells induced against tumors in one tissue can work against the same tumors in other tissues. To address this question, we compared the effect of effector cells induced against the same tumor cells growing in either the skin or the lung by using CT26 murine tumor models. Rejection of s.c. CT26 tumors was achieved by pretreatment with anti-CD25, which blocks the function of Treg cells. Both CD4 and CD8 T cells were necessary for the protection. When anti-CD25-pretreated mice challenged with s.c. CT26 were simultaneously inoculated i.v. with CT26, they also rejected tumors in the lung, while anti-CD25-pretreated mice without s.c. CT26 did not. This observation suggested that T cell mediated anti-tumor protective immunity induced against s.c. tumors can also protect against lung metastases of the same tumors. In contrast to Treg depletion which allowed for the induction of protective immunity in the s.c. tumor model, NKT cell-deficiency in CD1d KO mice induced significant CD8 T cell-mediated protection against lung metastasis of CT26 but had no effect on the growth of s.c. CT26 tumors. When CD1d KO mice rejecting i.v. CT26 were simultaneously challenged with s.c. CT26, the development of s.c. tumors was not affected, indicating that tumor rejection induced against the CT26 in the lung did not confer protection for the same tumor cells in the skin. Since the protection against CT26 in the lung in CD1d KO mice is mediated by CD8 T cells, we transferred T cells from CD1d KO mice inoculated i.v. with CT26 into RAG1 KO recipients, and challenged the recipient mice with the CT26 tumor cells. The recipient RAG1 KO mice were highly resistant to CT26 inoculated i.v. but not s.c. confirming that the CD8 T cells protective in the lung are not protective in the skin. These data

indicate the effector cells against the same tumor do not work in all tissues, and the induction site of the effector T cells is critical to control metastasis.

Citation Format: Jessica J. O'Konek, Elena Ambrosino, Anja Bloom, Liat Izhak, Jay A. Berzofsky, Masaki Terabe. Directionality of T-cell-mediated cross-protection against the same tumor in lungs versus skin [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 1015. doi:10.1158/1538-7445.AM2017-1015
Abstract 1025: Controlled and endogenous depletion of a synthetic lethal target in human cancer cell lines via SMASh degron engineering
Authors: Rago Florencia , Dimare Matthew T. , Bushold Geoffrey , Kapoor Avnish , Bhang Hyo-eun C. , Jagani Zainab
Published: July 2017

The SWI/SNF multi-subunit complexes play an important role in regulating processes such as gene transcription through ATP-dependent remodeling of chromatin. The importance of this role is highlighted by the prevalence of mutations in various SWI/SNF subunits across approximately 20% of cancers encompassing various lineages and subtypes. Functional genomics screening via pooled shRNAs has led to the discovery of distinct vulnerabilities of SWI/SNF mutant cancers to loss of mutually exclusive subunits. In particular, cancer cells with BRG1 loss become exquisitely dependent on the remaining BRG1 counterpart, BRM. To further understand the synthetic lethal relationship between BRM and BRG1, we have adapted a recently described degron, the small molecule assisted shutoff (SMASh) tag, showing for the first time the ability to apply this system to control endogenous levels of target protein, in this case BRM. We used the SMASh tag to target the endogenous BRM locus in both a BRG1 wild-type and mutant cancer cell line. Using these engineered cell lines, we were able to show that we can achieve tunable protein levels by varying the concentration of the effector molecule. The ability to tune BRM depletion allowed us to investigate the nature of the BRG1/BRM synthetic lethal relationship. Our data interestingly suggests that while modest depletion of BRM is sufficient to observe changes in the expression of a target gene regulated by SWI/SNF in a dose-dependent manner, a higher level of BRM depletion is required to elicit a growth arrest phenotype in the BRG1-mutant non-small cell lung cancer line. Together these results uncover a novel relationship between the catalytic SWI/SNF subunit and gene expression, where we find that the latter responds in a dose dependent manner to BRM levels. Additionally, we elucidate the level of BRM depletion required to observe the synthetic lethal phenotype, providing insight and informing on strategies for therapeutic targeting whether by protein degradation approaches, such as PROTAC, or other small molecule approaches. Finally, having provided a proof-of-concept, such tools can be readily adapted for application to endogenous degradation of other target proteins in different systems.

Citation Format: Florencia Rago, Matthew T. Dimare, Geoffrey Bushold, Avnish Kapoor, Hyo-eun C. Bhang, Zainab Jagani. Controlled and endogenous depletion of a synthetic lethal target in human cancer cell lines via SMASh degron engineering [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 1025. doi:10.1158/1538-7445.AM2017-1025
Abstract 1027: Development of orthotopically grafted organoid models to study pancreatic cancer progression
Authors: Hwang Chang-Il , Lee Eunjung , Silva Brandon Da , Wright Kevin , Park Youngkyu , Tuveson David A.
Published: July 2017

Pancreatic ductal adenocarcinoma (PDA) is one of the most difficult human malignancies to treat. The 5-year survival rate of PDA patients is 7% and PDA is predicted to become the second leading cancer-related cause of death in the USA. A subset of potential tumor suppressor genes was identified by genome-wide analysis of human PDA and insertional mutagenesis in genetically engineered mouse models (GEMMs). Since the functional validation of these genes in GEMMs is time-consuming and labor-intensive, we have developed a rapid and efficient ‘orthotopically grafted organoid’ (OGO) models in conjunction with RNAi and CRISPR/Cas9 technology to study PDA progression. Previously, we showed that OGO model represents the full spectrum of PDA progression in vivo upon orthotopic engraftment. Here, as a proof-of-concept experiment, we demonstrate that ablation of Trp53 by viral introduction of shRNA or gRNA in PanIN-derived organoids accelerates PDA progression upon transplantation. In addition, we engineered tetracyclin-inducible shRNA against Trp53 in ColA1 locus by Flpe recombinase-mediated cassette exchange in organoids derived from Kras +/G12D ; Rosa26-rtTA ; ColA1-homing cassette mouse. Orthotopic transplantation followed by doxycycline administration resulted in rapid PDA progression with metastases. Isolated tumor organoids were re-transplanted to evaluate the effect of p53 restoration in PDA progression. Restoration of p53 by doxycycline withdrawal led to reduced liver metastases, although there was no difference in survival and primary tumor growth. This will provide a new insight how p53 regulates PDA metastasis. Therefore, OGO models should provide an excellent platform to study the functional role of genes in PDA progression in vivo.

Citation Format: Chang-Il Hwang, Eunjung Lee, Brandon Da Silva, Kevin Wright, Youngkyu Park, David A. Tuveson. Development of orthotopically grafted organoid models to study pancreatic cancer progression [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 1027. doi:10.1158/1538-7445.AM2017-1027
Abstract 1028: Genetic disruption of Kras sensitizes lung cancer cells to Fas-mediated apoptosis
Authors: Mou Haiwei , Moore Jill , Malonia Sunil , Li Yingxiang , Ozata Deniz , Hough Soren , Song Chunqing , Smith Jordan , Yin Has , Fisher Andrew , Anderson Daniel , Weng Shipping , Green Michael , Xue Wen
Published: July 2017

Genetic lesions that activate KRAS account for ~30% of the 1.6 million annual cases of lung cancer. Despite clinical need, KRAS is still undruggable using traditional small molecule drugs/inhibitors. When oncogenic Kras is suppressed by RNA interference, tumors initially regress but eventually recur and proliferate despite suppression of Kras. Here we show that tumor cells can survive CRISPR-mediated knockout of oncogenic Kras, indicating the existence of Kras-independent survival pathways. Thus even if clinical KRAS inhibitors were available, resistance would remain an obstacle to treatment. Kras-independent cancer cells exhibit decreased colony formation in vitro but retain the ability to form tumors in mice. Comparing the transcriptomes of oncogenic Kras cells and Kras knockout cells, we identified 603 genes that were specifically upregulated in Kras knockout cells, including the Fas gene, which encodes a cell surface death receptor involved in physiological regulation of apoptosis. Antibodies recognizing Fas-receptor efficiently induced apoptosis of Kras knockout cells but not oncogenic Kras expressing cells. Increased Fas expression in Kras knockout cells was attributed to decreased association of repressive epigenetic marks at the Fas promoter. Concordant with this observation, treating oncogenic Kras cells with histone-deacetylase inhibitor and Fas-activating antibody efficiently induced apoptosis, thus bypassing the need to inhibit Kras. Our results suggest that activation of Fas could be exploited as an Achilles’ heel in tumors initiated by oncogenic Kras.

Citation Format: Haiwei Mou, Jill Moore, Sunil Malonia, Yingxiang Li, Deniz Ozata, Soren Hough, Chunqing Song, Jordan Smith, Has Yin, Andrew Fisher, Daniel Anderson, Shipping Weng, Michael Green, Wen Xue. Genetic disruption of Kras sensitizes lung cancer cells to Fas-mediated apoptosis [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 1028. doi:10.1158/1538-7445.AM2017-1028
Abstract 103: Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted therapy
Authors: McLaughlin Ronan P. , He Jichao , Noord Vera van der , Redel Jevin , Smid Marcel , Dorssers Lambert , Martens John , Foekens John , Zhang Yinghui , Water Bob van de
Published: July 2017

The treatment of Triple-Negative Breast Cancer (TNBC) still represents a profound clinical challenge, the disease being disproportionately responsible for breast cancer-associated deaths. As a consequence, the identification of targeted agents, which synergize with current therapeutic options, is paramount. Resistance to EGFR-tyrosine kinase inhibitors (TKIs), despite frequent EGFR overexpression and reliance on downstream signalling pathways in TNBC, remains endemic. Recent data has also suggested that kinase-inhibition of EGFR in itself is insufficient, given the kinase-independent functions of the protein in transcriptional regulation and DNA-repair may permit prolonged EGFR-mediated signalling in the presence of inhibitors. We performed a kinase inhibitor drug screen (378 kinase inhibitors targeting ~40 different cancer-related kinases) to identify synergistic activity with EGFR inhibition in TNBC. We demonstrate that the dual cdc7/CDK9 inhibitor PHA-767491 synergizes with multiple EGFR-TKIs (Erlotinib, Gefitinib and Lapatinib) in vitro to overcome resistance to EGFR-targeted therapy in various TNBC cell lines. Combined inhibition of EGFR and cdc7/CDK9 resulted in reduced cell proliferation, accompanied by induction of apoptosis and G2-M cell cycle-arrest. Combination therapy inhibited crucial components of the DNA-replicative machinery and also proteins involved in CDK9-mediated transcriptional elongation. Moreover, higher expression of cdc7 and POLR2A was found to be significantly correlated with poorer survival rates in breast cancer patients. Additionally, this synergistic combination effectively inhibited the growth of cells isolated from patient-derived TNBC xenografts under ex vivo culture conditions, highlighting the utility of targeting common transcriptional nodes in cancers addicted to growth factor-mediated signalling pathways.

Citation Format: Ronan P. McLaughlin, Jichao He, Vera van der Noord, Jevin Redel, Marcel Smid, Lambert Dorssers, John Martens, John Foekens, Yinghui Zhang, Bob van de Water. Blockage of Cdc7/CDK9 signaling sensitizes triple negative breast cancer to EGFR-targeted 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 103. doi:10.1158/1538-7445.AM2017-103
Abstract 1040: LIN28B-mediated let-7 independent activation of AKT promotes neuroblastoma pathogenesis
Authors: Tao Ting , Powers John T. , Shi Hui , Missios Pavlos , Perez-Atayde Antonio R. , Zhu Shizhen , Daley George Q. , Look Thomas A.
Published: July 2017

LIN28 is well known as a RNA-binding protein and a suppressor of microRNA biogenesis, by selectively blocking the processing of let-7 precursors. It plays diverse functions in cellular reprogramming, development, metabolism and tumorigenesis. Many of these functions are executed through its ability to inhibit let-7 maturation. However, little is known about its function independent of let-7. Here we made zebrafish transgenic lines expressing high levels of either wild-type or mutant LIN28B (does not block the maturation of let-7) in the peripheral sympathetic nervous system driven by the dopamine beta-hydroxylase promoter. We bred these lines with a transgenic zebrafish line overexpressing the MYCN oncogene in these cells. Either wild-type or mutant LIN28B overexpression accelerated the onset and increased the penetrance of MYCN-induced neuroblastoma, despite the fact that only wild-type LIN28B blocked let-7 maturation compared to MYCN-only tumors. Mechanistically, both wild-type and mutant LIN28B overexpression enhanced MYCN-induced hyperplasia by increasing cell proliferation in the sympathoadrenal lineage. Further studies revealed that overexpression of either wild-type or mutant LIN28B resulted in hyperphosphorylation of AKT on both Ser473 and Thr308 in zebrafish tumors and also serum-deprived human neuroblastoma cell lines. Both wild-type and mutant LIN28B interacted with IGF2BP1, a known interactor that increases stability and translation of a subset of RNAs. We found IGF2 RNA levels to be increased in response to either form of LIN28B. Coincident with IGF2 overexpression, IGF1R was phosphorylated, providing an explanation for PI3K-AKT activation in LIN28B overexpressing cells. Finally, overexpression of a constitutively active, myristoylated murine Akt2 (myr-mAkt2) alone in zebrafish induced ganglioneuroma in the interregnal gland (the zebrafish equivalent of the human adrenal medulla), without a requirement for MCYN overexpression. Thus, our studies indicate that overexpression of LIN28B leads to AKT activation mediated through its interaction with IGF2BP1 and subsequent upregulation of IGF2. This pathway provides a mechanism underlying enhanced transformation in LIN28B overexpressing neuroblastomas, which is independent of the inhibitory activity of LIN28B on let-7 maturation.

Citation Format: Ting Tao, John T. Powers, Hui Shi, Pavlos Missios, Antonio R. Perez-Atayde, Shizhen Zhu, George Q. Daley, Thomas A. Look. LIN28B-mediated let-7 independent activation of AKT promotes neuroblastoma pathogenesis [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 1040. doi:10.1158/1538-7445.AM2017-1040
Abstract 1043: CSF-1R inhibitor prevented pre-metastatic lung niches in metastatic mammary tumor
Authors: Borin Thaiz F. , Angara Kartik , Rashid Mohammad , Shankar Adarsh , Iskander Asm , Ara Roxan , Jain Meenu , Achyut Bhagelu R. , Arbab Ali S.
Published: July 2017

Exosomes are small vesicle cellular products originating from the endocytic pathway abundantly secreted by tumor cells. These exosomes have the ability to alter their immediate microenvironment (ME) through cell-cell interaction by fusion with plasma membrane and subsequent endocytosis or release of their cargo. Exosomes are critical modulators of pre-metastatic niche creation by increasing the recruitment of inflammatory cells. In breast cancer, tumor-derived exosomes recruit myeloid derived suppressor cells in the creation of an immunosuppressive pro-tumorigenic lung niches. Colony stimulating factor 1-receptor (CSF1R), which is a key regulator of myeloid cell proliferation, survival, and differentiation can be blocked by a selective inhibitor GW2580. Overexpression of CSF-1 has been implicated in the creation of increased number of metastatic niches in numerous cancers. In our study, we have demonstrated that the exosomes secreted under hypoxic conditions can initiate early pre-metastatic niche creation in lungs in a metastatic breast cancer model compared to normoxia-secreted exosomes. Exosomes were injected intravenously into Balb/c female mice three days after the implantation of 4T1 breast tumor and continued for a week with injections on alternated days. The animals were pre-treated with GW2580 the day before tumor implantation and continued for a week concomitantly with exosomes on alternate days. Lungs, bone marrow, spleen and brain tissues were collected and analyzed by flow cytometer to detect myeloid and angiogenic cells populations. GW2580 was able to prevent myeloid cell infiltration in lungs and bone marrow. Further, we observed significant increase in anti-tumorigenic M1-macrophage population in the lungs of exosome treated animals pre-treated with GW2580. However, these findings were not observed in the bone marrows of the same group. Vasculogenic leukocyte and angiogenic myeloid cell populations were significantly decreased in the lung of exosome treated animals pre-treated with GW2580. A similar decrease in these populations of cells was not seen in the lungs of animals pre-treated with GW2580 only. These surprising results have led us to hypothesize that GW2580 treatment can prevent the effects of exosomes, which causes infiltration of myeloid cells in the lung to create metastatic niche. These observations indicate a role of CSF1R inhibitor in preventing the distant metastatic niche formation.

Citation Format: Thaiz F. Borin, Kartik Angara, Mohammad Rashid, Adarsh Shankar, Asm Iskander, Roxan Ara, Meenu Jain, Bhagelu R. Achyut, Ali S. Arbab. CSF-1R inhibitor prevented pre-metastatic lung niches in metastatic mammary tumor [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 1043. doi:10.1158/1538-7445.AM2017-1043
Abstract 1044: Development of a miRNA-based signature to predict human cancer metastasis
Authors: Willetts Lian , Stoletov Konstantin , Jovel Juan , Woolner Emma , Lewis John D.
Published: July 2017

Metastasis is the primary cause of death for cancer patients, and invasive cancer cell migration is required at multiple steps during metastasis (e.g. intravasation and extravasation). Since microRNAs (miRNAs) have been implicated as key regulators of metastatic spread of cancer cells, we sought to develop a miRNA signature that can be used to predict cancer metastasis. We hypothesized that the miRNAs that are functionally required for invasive cell migration could serve as biomarkers to predict human cancer metastasis.

We developed an intravital imaging-based approach combined with NGS to screen for miRNAs that are required for invasive cell migration of human HT1080 fibrosarcoma cells. The screen-identified miRNAs were validated in a panel of in vitro and in vivo assays for invasive migration. Microarray analysis identified genes downregulated in transfected HT1080 cells. Publically available databases were used to correlate the expression of screen-identified miRNAs and the progression of multiple human cancers. We used a qRT-PCR approach combined with machine learning to develop a miRNA signature to predict metastasis in a 66-patient cohort of prostate cancer.

We identified over twenty novel miRNAs that regulate directional cancer invasion. Microarray analysis in HT1080 cells revealed that the altered expression of metastasis-regulating miRNAs is associated with 50% reduction in gene expression of migration and adhesion gene network components such as integrin a4, CDC42, and transgelin).

We evaluated the potential of screen-identified miRNAs to serve as biomarkers to predict cancer metastasis. Using publically available databases, we found that majority of screen-identified miRNAs are dysregulated in multiple human cancer types (e.g. prostate, breast, ovarian and lung) and the expression of these miRNAs correlate directly with patient disease progression. We analyzed the expression of the top two screen-identified miRNAs in plasma samples from the PCa patient cohort. A signature was generated using a weighted K-nearest neighbor algorithm that provided a ROC area under the curve of 0.79 for predicting metastatic disease.

We identified a panel of novel metastasis-regulating miRNAs that is functionally involved in human cancer metastasis. These miRNAs have the potential to serve as both biomarkers to predict metastasis and potentially as therapeutic targets to block metastasis.

Citation Format: Lian Willetts, Konstantin Stoletov, Juan Jovel, Emma Woolner, John D. Lewis. Development of a miRNA-based signature to predict human cancer metastasis [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 1044. doi:10.1158/1538-7445.AM2017-1044
Abstract 1052: Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiomyopathy
Authors: Sonowal Himangshu , Pal Pabitra B. , Srivastava Satish K. , Ramana Kota V.
Published: July 2017

Chemotherapy is one of the most common option for colorectal cancer (CRC), specifically at the advanced stages and after surgical resection of the tumor. Anthracycline drugs such as doxorubicin, daunorubicin are the most commonly used for the therapy of leukemia, lymphoma and breast cancer. However, doxorubicin is not a very effective drug to kill CRC cells since a high amount of doxorubicin is required for colon cancer therapy, which leads to unwanted side effects like cardiac toxicity and cardiomyopathy. Therefore, better adjuvant therapies are required to increase sensitivity of CRC to doxorubicin as well as to decrease the associated cardiomyopathy. Our recent studies indicate that aldose reductase (AR; AKR1B1) inhibitors such as fidarestat prevent CRC growth as well as metastasis in nude mice xenograft models. We now examined our hypothesis that AR inhibition increases the sensitivity of CRC to doxorubicin and decreases its cardiotoxicity by modulating oxidative stress-mediated signaling pathways. We have investigated the effect of co-administration of doxorubicin along with AR inhibitor fidarestat in in vitro and in vivo CRC cells growth and toxicity. Our results suggest that treatment of CRC cells with fidarestat increases the efficacy of doxorubicin-induced death of HT-29 and SW-480 colon cancer cells. Flow cytometric analysis indicates that in fidarestat + doxorubicin -treated CRC cells, the intracellular accumulation of doxorubicin is increased as compared to doxorubicin alone-treated cells. Further, AR inhibition prevents doxorubicin-induced increase in the expression of drug transporter proteins such as MRP-1 and ABCG-2 in CRC cells. In addition, combination of fidarestat with doxorubicin significantly prevented the growth of CRC cells in nude mice xenografts as compared to doxorubicin alone. Fidarestat also prevented the doxorubicin-induced cardiac toxicity as measured by serum troponin-I levels and inflammatory cytokines and chemokines in the serum and heart of doxorubicin-treated mice in combination with fidarestat. Most importantly, fidarestat protects the cardiac damage and dysfunction in doxorubicin-treated mice. Thus, our results suggest that fidarestat could be used as a novel adjuvant therapy in enhancing doxorubicin sensitivity of CRC cells and to reduce the doxorubicin-associated cardiotoxicity.

Citation Format: Himangshu Sonowal, Pabitra B. Pal, Satish K. Srivastava, Kota V. Ramana. Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiomyopathy [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 1052. doi:10.1158/1538-7445.AM2017-1052
Abstract 106: Traditional medicinal plants effect on five cancer cell lines
Authors: Myles Elbert L.
Published: July 2017

Cancer refers to as a group of numerous diseases that can originate in various parts of the body. From the beginning of human history natural compounds have been used for medical purposes. Many of the most frequently used natural compounds have their origin from plants. Plants are very diverse and responsible for the synthesis of a number different secondary compounds. Scientist and non-scientist have taken advantage of these secondary compounds treatment of a variety of diseases. In the current study, we are investigating the viability of specific cancer cell lines after exposure to methanolic extracts from each of the following plants. The plants are Costus, Fenugreek, and Rhamnus. The cell lines used in this investigation are lung cancer (A549), colon cancer, (SW620 and Colo320), breast cancer (BT549), and cervical cancer (HeLa). The determination of cell viability found inhibition. The three test compounds were methanolic extracts from the plants Costus, Fenugreek, and Rhamnus. All showed different levels of viability and was dependent on the specific cell line.

Citation Format: Elbert L. Myles. Traditional medicinal plants effect on five cancer cell lines [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 106. doi:10.1158/1538-7445.AM2017-106
Abstract 1068: Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid cancer
Authors: Martino Daniela De , Yilmaz Emrullah , Orlacchio Arturo , Cristofano Antonio Di
Published: July 2017

Anaplastic thyroid cancer (ATC) is one of the most lethal malignancies, with a median survival of less than 6 months from the time of diagnosis. Molecular changes that characterize ATC have been recently well defined and involve most often p53 mutations, and activation of PI3K, RAS and BRAF. PLK1, an essential mitotic regulator, has been found overexpressed in ATC.

Previous data from our lab have shown that PLK1 inhibitors are effective in ATC cell lines. However PLK1 inhibition often results in escape from growth arrest through mitotic slippage. This leads to the generation of polyploid, genetically unstable, cell populations.

We have tested the effect of combining PLK1 and PI3K inhibitors in ATC cell lines. Combined treatment with the PLK1 inhibitor BI6727 and the PI3K inhibitor BKM120 resulted in a significant synergistic effect in ATC cell lines with high levels of AKT activity, but not in those with undetectable pAKT. Combination of the two drugs enhanced the G2/M arrest at doses in which the single drugs showed no effect. In addition, it led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment with BI6727 and BKM120 in PI3Khigh cell lines showed a significant induction of apoptosis in a time- and dose-dependent manner.

Combined inhibition of PI3K and PLK1 was extremely effective in inhibiting tumor growth in vivo, in an immunocompetent allograft model of ATC.

Our results show that combination of PLK1 and PI3K inhibitors is an effective treatment for ATC cells with high levels of PI3K signaling. This combination results in cell cycle arrest, inhibition of of tetraploid cell generation, and induction of apoptosis, suggesting a clear therapeutic potential.

Citation Format: Daniela De Martino, Emrullah Yilmaz, Arturo Orlacchio, Antonio Di Cristofano. Driver pathway blockage synergizes with PLK1 inhibition in anaplastic thyroid 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 1068. doi:10.1158/1538-7445.AM2017-1068