bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4919: Ablation of neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression
Authors: Miyauchi Jeremy T. , Chen Danling , Choi Matthew K. , Shroyer Kenneth , Selwood David , Tsirka Stella E. 
Published: July 2017

Abstract
Gliomas are the most commonly diagnosed primary tumors of the central nervous system (CNS). Median times of survival are dismal regardless of the treatment approach, underlying the need to develop more effective therapies. Modulation of the immune system is a promising strategy as innate and adaptive immunity play important roles in cancer progression. Glioma associated microglia and macrophages (GAMs) can comprise over 30% of the cells in glioma biopsies. Gliomas secrete cytokines that suppress the anti-tumorigenic properties of GAMs, causing them to secrete factors that support the tumor’s spread and growth. Neuropilin 1 (Nrp1) is a transmembrane receptor that in mice both amplifies pro-angiogenic signaling in the tumor microenvironment and affects behavior of innate immune cells. Using a Cre-lox system, we generated mice that lack expression of Nrp1 in GAMs. We demonstrate, using an in vivo orthotopic glioma model, that tumors in mice with Nrp1-deficient GAMs exhibit less vascularity, grow at a slower pace, and are populated by increased numbers of anti-tumorigenic GAMs. Moreover, glioma survival times in mice with Nrp1-deficient GAMs were significantly longer. Treating wild-type mice with a small molecule inhibitor of Nrp1’s b1 domain, EG00229, which we show here is selective for Nrp1 over Nrp2, yielded an identical outcome. Moreover, transplanting bone marrow from mice with Nrp1-deficient macrophages to wild type recipient mice led to reductions in tumor growth, al-be-it not to the extent seen in knockout mice. Nrp1-deficient or EG00229-treated wild-type microglia exhibited a shift towards anti-tumorigenicity as evident by altered inflammatory marker profiles in vivo and decreased SMAD2/3 activation when conditioned in the presence of glioma-derived factors. These results provide support for the proposal that pharmacological inhibition of Nrp1 constitutes a potential strategy for suppressing glioma progression.
Citation Format: Jeremy T. Miyauchi, Danling Chen, Matthew K. Choi, Kenneth Shroyer, David Selwood, Stella E. Tsirka. Ablation of neuropilin 1 from glioma-associated microglia and macrophages slows tumor 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 4919. doi:10.1158/1538-7445.AM2017-4919
Abstract 4949: Longitudinal monitoring of cell-free DNA in patients with small cell lung cancer reveals dynamic insights into treatment efficacy and disease relapse
Authors: Lovly Christine M. , Almodovar Karinna , Iams Wade T. , Meador Catherine B. , York Sally , Horn Leora , Raymond Christopher K. , Hernandez Jennifer , Lim Lee P. 
Published: July 2017

Abstract
Introduction: Small cell lung cancer (SCLC) is a highly lethal neuroendocrine malignancy that accounts for approximately 10-15% of all lung cancers and is responsible for approximately 30,000 deaths annually in the United States and 200,000 deaths worldwide every year1. There is an urgent need to develop novel treatment strategies for patients with this disease. We sought to improve the quality of patient care by establishing a liquid biopsy assay for rapid, noninvasive monitoring of disease burden.
Design: The SCLC assay relies on targeted next-generation DNA sequencing of cell-free DNA (cfDNA) collected from patient plasma. The assay targets a panel of 14 genes that are frequently mutated in SCLC2. We examined a total of 141 plasma samples from a cohort of 27 patients. 11 patients had limited stage SCLC and 16 patients had extensive stage SCLC. The analyzed plasma samples were collected during the course of patient treatment and included time points before and after chemotherapy or immunotherapy.
Results: We detected somatic, disease-associated mutations in the cfDNA of 78% of patient samples (21/27). The allele frequency of cfDNA ranged from ≤0.5% to ≥85%. The most commonly mutated genes were TP53 and RB1, which were found in 17/27 and 10/27 samples, respectively. We also detected single nucleotide variants in PIK3CA (3/27) and PTEN (1/27) as well as copy number variants in MYC and MYCL1 (2/27). The observed mutant allele frequencies in longitudinal samples tracked closely with treatment responses. Strikingly, we found instances where the assay detected the reappearance of tumor-associated markers several weeks before clinical evidence of relapse was detected.
Conclusions: cfDNA sequencing allows for improved monitoring of disease burden, depth of responses to treatment, and timely warning of disease relapse in patients with SCLC.
References:
1. Society, A.C., Cancer Facts and Figures 2015. American Cancer Society, Atlanta, Ga, 2015.
2. George, J. et al., Comprehensive genomic profiles of small cell lung cancer, Nature 524:47
Citation Format: Christine M. Lovly, Karinna Almodovar, Wade T. Iams, Catherine B. Meador, Sally York, Leora Horn, Christopher K. Raymond, Jennifer Hernandez, Lee P. Lim. Longitudinal monitoring of cell-free DNA in patients with small cell lung cancer reveals dynamic insights into treatment efficacy and disease relapse [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 4949. doi:10.1158/1538-7445.AM2017-4949
Abstract 5194: Focal radiation enhances paclitaxel therapy in a mouse model of triple negative breast cancer
Authors: Franklin Maryland , Dailey Thomas , Leopold Wilbur 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers in the US. In general, patients have poorer prognosis and therapeutic intervention is more challenging due to insensitivity to hormonal and anti-HER2 therapies. Therapeutic options include chemotherapy and/or radiation (RT) treatment. In this work we utilized HCC70, a human TNBC cell line, grown subcutaneously in NSG mice. We investigated whether the combination of focal RT and paclitaxel would improve anti-tumor activity over paclitaxel alone. RT therapy has typically been delivered in low doses over long periods of time. More recently higher fractions of RT are being given in shorter time intervals. Utilizing the Small Animal Radiation Research Platform (SARRP; Xstrahl, Suwanee, GA) we compared a low dose (2.5Gy) fractionated regimen to a higher dose but less frequent regimen (8Gy, QDx3) either as monotherapy or in combination with paclitaxel (15mg/kg weekly). The total cumulative dose of radiation was 24-25Gy in both radiation regimens. Paclitaxel alone produced moderate activity with a 10 day tumor growth delay and no tumor regressions. Treatment with low dose RT resulted in tumor stasis for ≥68 days, but there were no tumor regressions or tumor free survivors (TFS). Treatment with 8Gy, produced a 75% incidence of confirmed partial regressions (PR) and a 25% incidence of complete regressions (CR) with no TFS. In this group we observed slightly more body weight loss (BWL), more frequent clinical signs, and more frequent need for food and water supplementation than with the fractionated RT regimen. Mean BWL was ~10% with a nadir around 8-10 days post first RT dose. BWL was recovered over the next 1-2 week period. The combination of low dose focal RT with paclitaxel produced activity similar to that with high dose radiation (50% PR, 40% CR, and 1 TFS). Treatment with paclitaxel plus 8Gy RT was highly efficacious, producing an 80% incidence of CRs, all of which remained tumor free at study day 108. The remaining mouse experienced tumor stasis in excess of 63 days. Thus, a higher dose of focal RT given in shorter intervals in combination with systemic paclitaxel resulted in the most efficacious therapeutic strategy but at the cost of increased BWL and clinical signs.
Citation Format: Maryland Franklin, Thomas Dailey, Wilbur Leopold. Focal radiation enhances paclitaxel therapy in a mouse model of triple negative breast 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 5194. doi:10.1158/1538-7445.AM2017-5194
Abstract 5264: Chemoprevention of rat oral carcinogenesis by black raspberry phytochemicals
Authors: Oghumu Steve , Knobloch Thomas , Ahn-Jarvis Jennifer , Weghorst Logan , Horvath Kyle , Geuy Paul , Weghorst Christopher 
Published: July 2017

Abstract
It is expected that in 2016, there will be an estimated 48,330 new cases and 9,570 deaths due to oral cancer in the US, which is about one person every hour every day. Due to the epithelial field defects associated with oral carcinogenesis, tumor recurrence and second primary tumor incidence are common. Recently conducted Phase I Clinical trials demonstrate the ability of black raspberries (BRBs) to modulate inflammatory biomarkers of molecular efficacy that supports a chemopreventive strategy against oral cancer. From these human trials we have established a molecular signature of BRB responsive biomarkers. However, it is essential that a preclinical animal model of BRB chemoprevention which recapitulates the fundamental features of human oral carcinogenesis be developed, so that we can evaluate potential mechanisms of action and validate molecular biomarkers of BRB efficacy. We therefore established the ability of BRB to inhibit oral lesion formation in a rat model of 4-nitroquinoline 1-oxide (4NQO) induced oral carcinogenesis and examined molecular efficacy using a clinically relevant transcriptional signature. Oral cancer was induced in F344 rats using 4NQO in drinking water for 10 weeks followed by regular drinking water for 16 weeks. Rats were administered a diet containing 5 or 10 percent lyophilized BRBs. Tongue tissues were examined for lesion multiplicity, incidence and histopathological features. Clinically derived pro-inflammatory and pro-survival molecular biomarkers were also determined by real-time PCR and ELISA. Dietary administration of 5 and 10 percent BRBs reduced combined lesion incidence and multiplicity by -39.3% and -28.6% respectively. Histopathological analyses of tongue sections further demonstrate the chemopreventive ability of dietary BRB administration in the rat model. Pro-survival and pro-inflammatory biomarkers were downregulated in BRB administered 4NQO induced rats compared to untreated 4NQO induced rats. Our study shows that dietary administration of BRB inhibits oral carcinogenesis in the rat 4NQO model. The rat 4NQO model is suitable for interrogating mechanisms of action of BRB-mediated oral cancer chemoprevention.
Citation Format: Steve Oghumu, Thomas Knobloch, Jennifer Ahn-Jarvis, Logan Weghorst, Kyle Horvath, Paul Geuy, Christopher Weghorst. Chemoprevention of rat oral carcinogenesis by black raspberry phytochemicals [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 5264. doi:10.1158/1538-7445.AM2017-5264
Abstract 5269: Cryptotanshinone activate Nrf2 expression through microRNA regulations
Authors: Dongoran Rachmad A. , Wu Tien-Yuan 
Published: July 2017

Abstract
Cryptotanshinone is a diterpene quinone derived from the roots of Salvia miltiorrhiza Bunge. An increasing number of studies have demonstrated that cryptotanshinone has the pharmacological activities such as anti-oxidative stress, anti-bacteria, anti-inflammation, and anti-cancer. Cryptotanshinone has been found to increase the ARE expression level induced by the Nrf2 and decrease Keap1 expression. This study investigated Nrf2 and Keap1-related microRNA to understand the mechanisms of cryptotanshinone in antioxidant activities. HepG2 cells were treated with cryptotanshinone 2.5 μM in DMEM medium with 1% FBS for 5 days. Total RNA was obtained for small RNA sequencing and real-time PCR analyses. The analyses revealed that Cryptotanshinone had the potential to inhibit miR-27a-5p, miR-142-5p, miR-28 and miR-93-5p levels, which subsequently increased the Nrf2 mRNA level. On the other hand, the Keap1 mRNA level was suppressed through up-regulation of miR-23a and down-regulation of miR-7-5p. Moreover, Nrf2 and its related downstream anti-oxidant enzymes such as NQO1 and UGT were increased and the Keap1 protein level was decreased. These findings suggest that cryptotanshinone possesses the cancer chemoprevention activity in up-regulation of Nrf2 mRNA and protein levels through the suppression of inhibitory microRNA. Future investigations that extend the current study can focus on pharmacological mechanism of cryptotanshinone as a cancer chemoprevention agent, and the safety of long-term uptake of cryptotanshinone for cancer prevention.
Citation Format: Rachmad A. Dongoran, Tien-Yuan Wu. Cryptotanshinone activate Nrf2 expression through microRNA regulations [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 5269. doi:10.1158/1538-7445.AM2017-5269
Abstract 5360: DNA repair increases sequencing accuracy without altering actual mutation frequency in clinical samples
Authors: Liu Pingfang , Chen Lixin , Ettwiller Laurence , Dimalanta Eileen , Davis Theodore B. , Evans Thomas C. 
Published: July 2017

Abstract
Targeted cancer therapy based on genomic alterations can be remarkably effective. Currently, cancer genome profiling using next generation sequencing (NGS) is routinely applied in cancer care to guide personalized treatment. The accuracy of this profiling directly impacts therapeutic choices and the outcomes of patient care. We previously showed that false positive variants are abundant and can account for a major fraction of identified somatic variations in publicly available datasets (doi: http://dx.doi.org/10.1101/070334). These false positive variants show signs of mutagenic DNA damage. We further demonstrated that enzymatic DNA repair increases sequencing quality by lowering damage-induced background noise. Therefore, enzymatic DNA repair has the potential to improve sequencing accuracy, avoiding incorrect somatic variant calls and consequently reducing incorrect diagnostic conclusions. In this study, we investigated whether enzymatic DNA repair introduces any bias to NGS libraries using analysis by droplet digital PCR (ddPCR) and deep sequencing. DNA Reference Standards containing multiple common cancer mutations (Horizon Discovery, Inc.) were spiked into formalin-fixed paraffin-embedded (FFPE) DNA isolated from tumor samples from different tissue types at defined frequencies (0.5-10% quantified by ddPCR). Genotyping of the FFPE DNA ensured that they were free of any of the spiked-in mutations. After DNA repair and library preparation, mutation frequencies were quantified by ddPCR, and compared to the mutation levels in input DNA and control libraries without repair. Deep sequencing of 151 cancer genes including these spike-ins showed no difference in mutation frequency for the spiked-in mutations between the control and repair groups. However, the number of false positive variant calls was reduced in the repair group. Our data demonstrates that DNA repair significantly increases sequencing accuracy without altering the frequency of actual mutations in tumor samples.
Citation Format: Pingfang Liu, Lixin Chen, Laurence Ettwiller, Eileen Dimalanta, Theodore B. Davis, Thomas C. Evans. DNA repair increases sequencing accuracy without altering actual mutation frequency in clinical samples [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 5360. doi:10.1158/1538-7445.AM2017-5360
Abstract 5383: Non-invasive diagnosis of early-stage lung cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA)
Authors: Cai Xuyu , Gao Yangbin , Shen Hui , Laird Peter , Fan Jian-bing , Xu Weihong , Liang Wenhua , He Jianxing 
Published: July 2017

Abstract
Current state-of-the-art lung cancer early screening involves using low-dose CT scan to identify lung nodules smaller than 3cm in diameter. However, it’s still a clinical dilemma to differentiate between malignant and benign nodules.
We took the approach of methylation profiling by high-throughput bisulfite DNA sequencing in tissue samples to identify specific methylation signatures. We learned methylation patterns that differentiate malignant vs. benign lesions from tissue samples by in-depth data mining, and then used pattern matching to classify plasma samples. Given the usual low amount of ctDNA in plasma, we also developed an ultra-sensitive library preparation method to perform targeted bisulfite DNA sequencing from as low as 1ng of cfDNA or 1mL of plasma.
From a training set of 88 tissue samples, which includes 60 malignant specimens with different subtypes (invasive adenomas, IA; minimally invasive adenomas, MIA; atypical adenomatous hyperplasia, AAH; adenocarcinoma in situ, AIS; carcinoid; lymphoepithelioma-like carcinoma of the lung, LELC; squamous carcinoma, SC; as well as 28 benign specimens in different categories including hematomas, granuloma, tuberculosis, inflammatory pseudotumor (IPT), sclerosing hemangiomas (SHL) and infections, we were able to achieve a sensitivity of 95% for identification of malignant lesions, with a specificity of 78.6%. From an independent validation set of 45 plasma samples, we achieved a sensitivity of 94.7% and a specificity of 85.7% for differentiating patients with malignant tumor from patients with benign lesions. Specifically, our assay is demonstrated to be highly sensitive towards early-stage lung cancer detection, with a sensitivity of 93.3% in a total of 15 patients with stage IA/B lung cancer.
In summary, we have developed a highly sensitive blood-based non-invasive diagnostic assay for identification of early stage lung cancer, which can aid clinical decisions for patients with a CT scan positive for lung nodules. This approach can also be extended to non-invasive early screening for various cancer types.
Citation Format: Xuyu Cai, Yangbin Gao, Hui Shen, Peter Laird, Jian-bing Fan, Weihong Xu, Wenhua Liang, Jianxing He. Non-invasive diagnosis of early-stage lung cancer via targeted high-throughput DNA methylation sequencing of circulating tumor DNA (ctDNA) [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 5383. doi:10.1158/1538-7445.AM2017-5383
Abstract 5443: Developing a novel miR-15a mimic as a potential therapeutic molecule to eliminate resistant colorectal cancer stem cells
Authors: Fesler Andrew T. , Liu Hua , Wu Ning , Ju Jingfang 
Published: July 2017

Abstract
In the last 15 years, it has become well established that microRNA play important roles in cancer biology. Due to their ability to regulate the expression of important target genes, aberrant expression of miRNAs has been linked to cancer development and progression. Based on these important functions, there is great interest in developing miRNA based therapeutics. In colorectal cancer, treatment using 5-flurouracil (5-FU) based chemotherapy has improved patient outcomes. However, there remain challenges associated with chemoresistance and recurrence for patients with advanced stage colorectal cancer. miRNA based therapeutics may represent an potential novel therapeutic option for colorectal cancer therapy either alone or in combination with 5-FU based chemotherapy. miR-15a was of the first miRNAs identified to be associated with cancer, and has been shown to have important roles in several tumor types. miR-15a is downregulated in colon cancer and associated with poor patient prognosis. We have identified several important cancer related targets of miR-15a in colon cancer, including YAP1, DCLK1, BMI1 and BCL2. Through the regulation of these targets, miR-15a expression can be used as a potent inhibitor to reduce colon cancer cell proliferation, invasion and improve sensitivity to 5-FU, as well as decreasing tumor growth in vivo mouse colon tumor models using colon cancer stem cells. In the interest of developing miR-15a based colon cancer therapeutics, we have made a modified miR-15a mimic that shows enhanced abilities to disrupt resistant colon cancer cell proliferation and induction of cell cycle arrest when compared to unmodified miR-15a. Following transfection with miR-15a mimic, cell number was reduced by 84% compared to control and 66% compared to miR-15a precursor. Cell cycle analysis showed that G1/S ratio was increased from 1.07 for control to 2.87 for precursor miR-15a and 7.07 for miR-15a mimic. This miR-15a mimic also maintains its ability to regulate these important target genes in colon cancer stem cells. In mouse models using colon cancer stem cells, miR-15a mimic has demonstrated therapeutic potential by reducing tumor growth. Based on these findings, there is potential that modified miR-15a could be adapted for treatment of patients to improve survival of advanced stage colorectal cancer patients.
Citation Format: Andrew T. Fesler, Hua Liu, Ning Wu, Jingfang Ju. Developing a novel miR-15a mimic as a potential therapeutic molecule to eliminate resistant colorectal cancer stem 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 5443. doi:10.1158/1538-7445.AM2017-5443