bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3205: A nanomolar potency small-molecule compound against castration-resistant and bone metastatic prostate cancer
Authors: Mamouni Kenza , Gera Lajos , Li Xin , Wu Daqing 
Published: July 2017

Abstract
A standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that suppresses androgen receptor (AR) signaling axis. Although initially responsive, most patients receiving ADT eventually develop metastatic castration-resistant prostate cancer (CRPC), with more than 90% of them exhibiting bone metastases. A mechanism by which CRPC cells evade ADT is the expression of constitutively active AR variants (AR-Vs), such as the well-characterized AR-V7. Recently we developed GH501, a flurbiprofen-modified small-molecule compound, and investigated its anti-cancer activity and mechanism of action in pre-clinical models of CRPC. At nanomolar range, GH501 effectively induces cell cycle arrest and apoptosis in CRPC cells regardless of their resistance status to enzalutamide treatment. RNA-seq analysis of GH501 combined with Western blotting analysis identified key targets implicated in CRPC progression, including the full-length AR, AR-V7 variant, and other important genes implicated in CRPC progression. Importantly, low doses of GH501 effectively inhibit the skeletal growth of CRPC in a xenograft model without obvious in vivo toxicities. These preclinical results indicate that GH501 is a promising small-molecule compound that can be further developed for the treatment of lethal prostate cancer.
Citation Format: Kenza Mamouni, Lajos Gera, Xin Li, Daqing Wu. A nanomolar potency small-molecule compound against castration-resistant and bone metastatic prostate 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 3205. doi:10.1158/1538-7445.AM2017-3205
Abstract 3234: Development of potent and selective antibody-drug conjugates with pyrrole-based KSP inhibitors as novel payload class
Authors: Lerchen Hans-Georg , Wittrock Sven , Griebenow Nils , Lobell Mario , Rebstock Anne-Sophie , Cancho-Grande Yolanda , Stelte-Ludwig Beatrix , Mahlert Christoph , Greven Simone , Sommer Anette , Berndt Sandra , Terjung Carsten , Apeler Heiner , Kreft Bertolt , Jautelat Rolf 
Published: July 2017

Abstract
The number of cytotoxic payload classes with different modes-of-action which have been successfully employed in antibody-drug conjugates (ADC) is still rather limited. So far, only ADCs with microtubule inhibitors, DNA binding payloads or topoisomerase I inhibitors have been advanced into clinical testing. To this end, the identification of ADC payload classes with a novel mode of action will increase therapeutic options and potentially help to overcome resistance. Inhibitors of kinesin spindle protein (KSP/Eg5) have generated interest due to their high antitumor potency. However, transferring the preclinical potency of small molecule KSP inhibitors (KSPis) into highly efficient clinical regimens with a sufficient therapeutic window has remained challenging. We have investigated a new pyrrole subclass of KSPis which showed subnanomolar potency against a large panel of tumor cell lines for their utility as a novel payload class in ADCs. Towards this goal different attachment sites for linkers have been explored in the KSPi molecule which were found compatible with cleavable and/or non-cleavable linkers. Subnanomolar potency and selectivity of ADCs with antibodies targeting either HER2, EGFR or TWEAKR could be demonstrated in vitro. For selected ADCs, the intracellular trafficking and metabolite formation was investigated and KSP inhibition was confirmed as the ADC mode of action. Depending on the linker composition differential profiles of the ADC metabolites with regard to efflux, cellular permeation, and bystander effect have been achieved. Moreover, specific accumulation in the tumor versus other tissues was demonstrated in biodistribution studies in vivo. In conclusion, KSP inhibitors have been established as a versatile new payload class for the generation of highly potent and selective ADCs.
Citation Format: Hans-Georg Lerchen, Sven Wittrock, Nils Griebenow, Mario Lobell, Anne-Sophie Rebstock, Yolanda Cancho-Grande, Beatrix Stelte-Ludwig, Christoph Mahlert, Simone Greven, Anette Sommer, Sandra Berndt, Carsten Terjung, Heiner Apeler, Bertolt Kreft, Rolf Jautelat. Development of potent and selective antibody-drug conjugates with pyrrole-based KSP inhibitors as novel payload class [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 3234. doi:10.1158/1538-7445.AM2017-3234
Abstract 3253: Targeting G-quadruplex nucleic acids: a series of β-carboline alkaloids with new skeletons from the seeds of Peganum harmala
Authors: wang Kaibo , Hua Huiming , Yang Danzhou 
Published: July 2017

Abstract
G-quadruplexes are DNA secondary structures implicated in essential physiological and pathological processes, such as tumorgenesis. Small molecules which can stabilize or induce G-quadruplex formation have potential as antitumor agents through the alteration of oncogene expression levels or the disruption of telomere maintenance. Targeting G-quadruplex nucleic acids, we screened 17 medicinal plants for binding activity to a model G-quadruplex d(TTGGGTT)4 system by 1H NMR experiment. We found that the crude extract of Peganum harmala L. seeds showed the most potential binding activity and specific cytotoxicity against the PC-3 cancer cell line with an IC50 value of 13.65 μg/mL. Subsequently, 1H NMR and bioassay co-guided isolation of the extract of P. harmala L. was performed and obtained 21 new alkaloids, including 10 novel β-carboline alkaloids with unprecedented carbon skeletons, and 12 known analogues. Their structures including the absolute configurations were determined by extensive analysis of spectroscopic data, X-ray crystallography, ECD calculations, and ECD exciton chirality approaches. The antiproliferative activities and G-quadruplex binding activities were evaluated for these newly discovered and previously reported alkaloids. Some of the isolates showed pronounced cytotoxic effects with IC50 values below 10 µM and significant G-quadruplex binding activities. More interestingly, pegaharmine D (4), which showed the strongest G-quadruplex interaction, exhibited significant cytotoxic activity against HL-60, PC-3 and SGC-7901 cell lines, with IC50 values of 3.81 ± 0.32, 11.52 ± 0.62, and 15.16 ± 0.42 µM, respectively. The G-quadruplex interactions positively correlated with antiproliferative activities suggesting these β-carboline alkaloids may exert their anti-cancer effects through G-quadruplex interactions. This work contributed a practical strategy at first time for the discovery of novel G-quadruplex ligands from natural products and provided potential insights for using β-carboline alkaloids as anticancer lead compounds specifically targeting G-quadruplexes.
Citation Format: Kaibo wang, Huiming Hua, Danzhou Yang. Targeting G-quadruplex nucleic acids: a series of β-carboline alkaloids with new skeletons from the seeds of Peganum harmala [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 3253. doi:10.1158/1538-7445.AM2017-3253
Abstract 326: Baseline IL-17 receptor signaling is essential for controlling aberrant JNK-dependent cellular proliferation via maintenance of endogenous level of ubiquitin-editing enzyme A20
Authors: Yan Chi , Lei Yang , Greenshields Anna L. , Hoskin David W. , Lin Tong-Jun , Wang Jun 
Published: July 2017

Abstract
The molecular mechanisms underlying aberrant activation of NF-κB and JNK in cancer remain incompletely understood. Here, we demonstrate that baseline IL-17 receptor (IL-17R) signaling is essential for controlling aberrant NF-κB and JNK activation, and restraining JNK-dependent homeostatic cellular proliferation. Using a shRNA knockdown approach, we demonstrated in B16 melanoma and 4T1 breast carcinoma murine cell lines that IL-17RA silencing markedly enhanced tumor cell growth in vitro and in vivo. Through mapping IL-17R signaling pathways, we further demonstrated that baseline IL-17A/IL-17R signaling actively restrained JNK phosphorylation in vitro and in vivo via the maintenance of basal expression of the ubiquitin-editing enzyme A20, a negative regulator of NF-κB and JNK. Remarkably, IL-17RA reconstitution evidently restored the A20 level, and suppressed cell proliferation and JNK activity in tumor cells. The reconstitution of A20 in IL-17RA knockdown subclones was able to restore the normal rate of cellular proliferation and associated JNK/c-Jun activity. Finally, meta-analysis of human cancer microarray and RNA-Seq datasets confirmed significant co-expression of IL-17RA and A20. Furthermore, alterations (mutation, upregulation or downregulation) of IL-17RA level in melanoma, ER+ breast cancer and colorectal cancer patients were associated with poorer overall survival compared to the respective patients with normal baseline IL-17RA expression. Together, our data demonstrates a previously unrecognized molecular mechanism underlying aberrant activation of NF-κB and JNK in cancer cells. This work highlights the unique biological role of proinflammatory IL-17R signaling in the maintenance of A20 to regulate the pathogenesis of human cancer, which draws caution on the utility of IL-17A neutralizing antibody in cancer therapy.
CY is a PhD student supported by the graduate student scholarship from the IWK Health Centre and received a trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by the Cancer Research Training Program as part of The Terry Fox Foundation Strategic Health Research Training Program in Cancer Research in CIHR.
Citation Format: Chi Yan, Yang Lei, Anna L. Greenshields, David W. Hoskin, Tong-Jun Lin, Jun Wang. Baseline IL-17 receptor signaling is essential for controlling aberrant JNK-dependent cellular proliferation via maintenance of endogenous level of ubiquitin-editing enzyme A20 [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 326. doi:10.1158/1538-7445.AM2017-326
Abstract 3260: Training for cancer surgery in Sub Saharan Africa
Authors: Jalloh Mohamed , Gueye Serigne Magueye 
Published: July 2017

Abstract
BACKGROUND: Low- and middle-income countries (LMICs) face both training and infrastructural challenges for surgical care, particularly for cancer. Practitioners charged with caring for these patients have few options for basic or advanced training.
OBJECTIVES: To describe the training options for cancer surgery in Sub Saharan Africa
METHODS: The different methods of training are described and the advantages and limits of each methods is highlighted.
RESULTS: Training during residency and onsite fellowship are a good option but requires an appropriate number and capacity of training programme. International fellowships have the limitation of readjustment back home for the trained fellow. Onsite International training missions like IVUmed’s missions have the advantage of “Teach One, Reach Many” outcome where a whole team in trained in accordance of local needs and the participation of all stakeholders.
CONCLUSIONS: Long-term program commitments; effective communication; and a shared vision among the program site, the coordinating nongovernmental organization, and supporting organizations facilitate the development of thriving surgical teaching programs capable of serving local communities and conducting outreach training.
Citation Format: Mohamed Jalloh, Serigne Magueye Gueye. Training for cancer surgery in Sub Saharan Africa [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 3260. doi:10.1158/1538-7445.AM2017-3260
Abstract 3266: Oral rinse point of care test to predict head and neck cancer
Authors: Donovan Michael J. , Curtis Kris , Ginn Greg , Franzmann Elizabeth J. 
Published: July 2017

Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cause of cancer mortality throughout the world affecting some 50,000 people in the US and 600,000 worldwide each year. The ability to detect the disease in a potentially malignant phase and earlier stage could have significant impact on overall outcome. Previous studies have demonstrated that a combined salivary CD44, a tumor-initiating marker, and total protein assay was able to aid in the diagnosis of HNSCC. We sought to understand the performance characteristics of these biomarkers in a prospective population using a qualitative, point-of-care assay (POC) which consists of a cassette with a colorimetric read-out based on a pre-determined threshold for both CD44 and total protein. We also performed results from same samples with a quantitative lab-based test.
Methods: Saline oral rinse specimens (~5ml) from 134 patients (84 HNSCC cases; 50 controls) were obtained from biorepositories. Samples were thawed, gently swirled, placed in a standard collection cup. 600ul were removed for lab assay prior to POC test. The tapered end of the POC cassette was submerged in rinse for 20’; levels of CD44 and total protein (TP) were evaluated by two operators. POC test results were compared between operators and with lab test results using Cohen’s kappa coefficient and McNemar’s test, sensitivity(Se), specificity(Sp), NPV and PPV.
Results: 95% HNSCC patients (cases) were mean 60 years of age, 60% male, 97% white and 74% smokers vs. 43 years, 28%, 96% and 0% respectively, for controls. POC was positive with either CD44 or TP above threshold. Weighted kappa yielded 75% and 72% for CD44 and TP respectively between operators. With a prevalence of 9.27: POC: NPV 94%, PPV 10%; variable TP cut-off produced Se71-84% and Sp30%-50%. McNemar and Kappa for both lab CD44 and TP vs POC indicated moderate agreement; independently both POC and lab produced NPV &gt;90%.
Conclusions: Concordance of the POC assay between operators and moderate agreement with a quantitative lab assay provides supportive evidence for clinical application of the POC assay as an aid in the diagnosis for HNSCC. Additional studies are underway to confirm these observations.
Citation Format: Michael J. Donovan, Kris Curtis, Greg Ginn, Elizabeth J. Franzmann. Oral rinse point of care test to predict head and neck 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 3266. doi:10.1158/1538-7445.AM2017-3266
Abstract 3267: Combined effect of multiple gene polymorphisms on cancer risk stratification
Authors: Andavolu Radhika Gade , Rodriguez Olivia , Rubakovic Anastasia Al , Stafford Catherine , Andavolu Murthy V. 
Published: July 2017

Abstract
Cyclin D1 (CCND1) G870A polymorphism has been known to be a risk factor in multiple cancers. Cyclin D1 is a cell cycle regulator frequently mutated, amplified and overexpressed in a variety of tumors. Activation and over expression of CCND1 have been found in variety of tumors and alterations in CCND1 are thought to be involved in carcinogensis. CCND1 polymorphism A870G interferes with splicing and studies showed DNA damage in cells from subjects with ‘A’ allele to bypass G1/S check point of the cell cycle control mechanism more easily than damage in cells with G allele (wild type). A single base pair polymorphism (exon 4, G870A) in the CCND1 gene affects gene splicing. This identification and validation of contributing genetic factors such as single-nucleotide polymorphisms (SNPs) represents a critical step in the advance toward personalized medicine. Several gene expression correlation studies have been done but to our knowledge studies have not been reported on SNP’s of ERBB2 gene, ESR gene and CCND1 combined effect correlating with high risk. In this study, we examined the relationship between ERBB2 (codon 655), Estrogen receptor (ER Intron1 T&lt;C) and cyclin D1 (Exon 4) polymorphic additive effect in cancers more specific to breast cancer. Genomic DNA was extracted from whole blood samples collected on study. The SNPs were tested by the PCR-restriction fragment length polymorphism (PCR-RFLP) method. Our results show individuals carrying CCND1 ‘A allele in combination with variant ERBB2/BsmAI uncut allele are significantly high (P&lt;0.004) in cancer patients (N=232) as compared to controls. (N=222). Similarly individuals carrying CCND1 Variant ‘A ‘ allele in combination with ESR ‘C’ Allele showed high frequency with p&lt;0.009. Both these combinations showed a strong and significant association with cancer but individually, ERBB2 variant did not show any significant association, ESR gene showed a borderline association and CCND1 showed strong association independent of these two gene polymorphisms. Earlier few studies have shown no association of ERBB2 mutation in agreement with the previous reports. In conclusion our data suggests that in complex diseases a single gene may not contribute to show its effect but in combination may show a profound effect in evaluating the risk.
Citation Format: Radhika Gade Andavolu, Olivia Rodriguez, Anastasia Al Rubakovic, Catherine Stafford, Murthy V. Andavolu. Combined effect of multiple gene polymorphisms on cancer risk stratification [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 3267. doi:10.1158/1538-7445.AM2017-3267
Abstract 3300: Inhibition of autophagy by 3-MA enhances the effect of ursolic acid-induced apoptosis in hepatoma SK-Hep-1 cells
Authors: Wan-Ling Chuang , Ping-Yi Lin , Yao-Li Chen 
Published: July 2017

Abstract
Purpose
The aim of this study is to investigate the autophagic effect of Ursolic Acid (UA) on hepatoma SK-Hep-1 cells.
Methods
The cytotoxicity of UA in hepatoma SK-Hep-1 cells was measured by MTT assay, the accumulation of acidic vesicular organelles was measured by FACS, the protein expression of LC3-II was detected by immunofluorescence staining, and the autophagic protein expression was evaluated by western blotting.
Hepatoma SK-Hep-1 cells treated with a combination of autophagy inhibitor 3-Methyladenine (3-MA) and UA, then use Annexin V/PI Double Staining and western blotting to detect apoptosis and apoptotic protein levels.
Statistical Analyses
Data was expressed as the mean ± standard deviation and were compared using the Student’s t-test. A p value of &lt;0.05 was considered to indicate statistical significance. All statistical analyses were performed using GraphPad Prism software, version 4.0 (GraphPad Software, Inc., La Jolla, CA, USA).
Preliminary Results
SK-Hep-1 cells treated with different concentrations of UA (0, 20, 40, and 60 μM). Regarding the results, the half-maximal inhibitory concentration (IC50) was 45.9 and 36.6 μM for 24 and 48 h, respectively. The FACS results showed that when increase the dose of UA could increase the percentages of autophagic populations. The anti-autophagic proteins such as Beclin, Atg-5, Atg-7, and LC3-II, in our results showed that UA decreased the protein expression of mTOR, PI3K, and p62 and PI3K/Akt/mTOR expression. Immunocytochemistry staining showed that SK-Hep-1 cells treated with UA increased the protein expression of LC3-II. The combination treatment of 3-MA and UA significantly increased the apoptotic cell death as monitored by increased protein expression of Caspase-3 and PAPR.
Conclusions
UA could induced autophagy in hepatoma SK-Hep-1 cells through inhibition of mTOR and PI3K signaling pathways. SK-Hep-1 cells treated with UA exhibited LC3-І/LC3-II conversion, increased protein expression levels of Beclin, Atg-7, and Atg-5 along with reduced protein expression levels of p62. UA-induced apoptosis was enhanced by the treatment of autophagy inhibitor 3-MA. Our findings may assist in the development of novel chemotherapeutic agents for the treatment of malignant types of liver cancer.
Citation Format: Chuang Wan-Ling, Lin Ping-Yi, Chen Yao-Li. Inhibition of autophagy by 3-MA enhances the effect of ursolic acid-induced apoptosis in hepatoma SK-Hep-1 cells [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 3300. doi:10.1158/1538-7445.AM2017-3300
Abstract 3302: Autophagy is required for cell survival under L-asparaginase-induced metabolic stress in acute lymphoblastic leukemia cells
Authors: Inoue Jun , Takahashi Hiroyoshi , Sakaguchi Kimiyoshi , Takagi Masatoshi , Mizutani Shuki , Inazawa Johji 
Published: July 2017

Abstract
L-asparaginase has been used for more than three decades in acute lymphoblastic leukemia (ALL) patients and remains an essential drug in the treatment of ALL. Poor response to L-asparaginase is associated with increased risk of therapeutic failure in ALL. However, both the metabolic perturbation and molecular context of L-asparaginase-treated ALL cells has not been fully elucidated. Here we identify that treatment with L-asparaginase results in metabolic shutdown via the reduction of both glycolysis and oxidative phosphorylation, accompanied by mitochondrial damage and activation of autophagy. The autophagy is involved in reducing reactive oxygen species (ROS) level by eliminating injured mitochondria. Inhibition of autophagy enhances L-asparaginase-induced cytotoxicity and overcomes the acquired resistance to L-asparaginase in ALL cells. The ROS-p53 positive feedback loop is an essential mechanism of this synergistic cytotoxicity. Thus, our findings provide the rationale for the future development of combined treatment of L-asparaginase and anti-autophagy drug in ALL patients.
Citation Format: Jun Inoue, Hiroyoshi Takahashi, Kimiyoshi Sakaguchi, Masatoshi Takagi, Shuki Mizutani, Johji Inazawa. Autophagy is required for cell survival under L-asparaginase-induced metabolic stress in acute lymphoblastic leukemia cells [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 3302. doi:10.1158/1538-7445.AM2017-3302