bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5928: Suicide gene therapy of ovarian cancer
Authors: Malekshah Obeid M. , Sarkar Siddik , Hatefi Arash 
Published: August 2018

Abstract
Purpose: The objective of this study was to develop a gene directed enzyme prodrug therapy (GDEPT) method that can effectively kill both differentiating and cancer stem-like cells (CSCs) in ovarian cancer.
Methods: Ovarian cancer cell lines including A2780, A2780-Cis, SKOV-3, OVCAR-3 and OVASC-1 (malignant cells from ascitic fluid of an ovarian cancer patient) were examined to identify the most drug resistant one. Various chemotherapeutic drugs which are used for suicide gene therapy were tested to identify one that is the most effective against ovarian cancer cells. These include 6-Methylpurine, 5-Fluorouracil, and SN-38. Cisplatin was used as a standard of care control. The anticancer activities of the drugs were studied by a cell toxicity assay and clonogenic assay. Flow cytometry was performed to study surface stem markers, such as CD133, CXCR4, HER2. ALDH1 activity in ovarian cancer cells was studied by ALDH assay kit. The ability of the most effective enzyme/prodrug system to kill drug resistant ovarian cancer cells was studied by a cell viability assay.
Results: The results of in vitro dose-response experiments on various ovarian cancer cells showed that SN-38 was the most efficient drug with IC50 in a range of 10 -100 nM, in comparison to 10-500 μM range of all other selected active drugs. OVASC-1 and OVCAR-3 cell lines showed a higher resistance to drug therapy as compared with other cell lines. It was observed that these two cell lines have a higher number of drug resistant cancer cells in their populations. It was also observed that CSCs are strongly associated with resistance to chemotherapy. ALDH assay, clonogenic assay and sphere formation assay showed a direct correlation between the therapy resistance and the percentage of CSCs. OVASC-1 cells in comparison to the other cell lines were found to be a suitable model for therapy resistant studies. After treatment by 100 nM SN-38, no visible colonies of Ascites were observed. Adipose-derived stem cells (ADSCs) were genetically modified to express Carboxylesterase-2 (CE2) and thus could convert CPT-11 to its active form (SN-38). Using this enzyme/prodrug system an effective eradication of highly resistant OVASC-1 ovarian cancer cells was demonstrated.
Conclusions: Our findings suggest that Carboxylesterase/CPT-11 enzyme/prodrug system is the most effective GDEPT method against highly drug resistant ovarian cancer cells.
Citation Format: Obeid M. Malekshah, Siddik Sarkar, Arash Hatefi. Suicide gene therapy of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5928.
Abstract 603: Immune response to the influenza vaccination and heart rate variability in breast cancer survivors
Authors: Seiler Annina , LeRoy Angie S. , Fagundes Christopher P. 
Published: August 2018

Abstract
Background: Cancer treatment dysregulates immune function. These effects can persist long after the cessation of therapy and may diminish the immune system's ability to effectively mount an adequate immune response. Latent herpesvirus reactivation may mark a poor immune response to the influenza vaccination. Cancer treatment can also cause adverse effects on cardiac autonomic function as assessed by heart-rate variability (HRV), which is associated with higher morbidity and decreased survival in patients with cancer. Objective: To determine immune response to seasonal influenza vaccination as measured by human cytomegalovirus (CMV) IgG antibody titers and HRV in breast cancer survivors treated with radiation relative to healthy aged-matched controls. Methods: Serum samples for 13 breast cancer survivors within the first year of post-treatment and 13 healthy age-matched controls (mean age 44.7 years) were assayed for CMV IgG antibody titers and heart-rate variability was assessed using MindWare technologies. Group differences between cancer survivors versus healthy individuals were estimated using analysis of covariance (ANCOVA), with adjustment for age, body mass index (BMI) and race. Results: One-way ANCOVA modeling showed that breast cancer survivors treated with radiation had significantly higher antibody titers to CMV relative to age-matched healthy controls (F = 9.15 ; p &lt;.01). While heart rate did not differ among the two groups (F = .36 ; p = .56), high frequency values were significantly lower in breast cancer survivors relative to the healthy controls (HF: F = 10.40 ; p &lt;. 01). Conclusion: Breast cancer survivors manifested a dampened immune response to influenza vaccination and cardiovascular imbalance compared to healthy age-matched controls. These findings have important implications for long-term treatment outcomes.
Citation Format: Annina Seiler, Angie S. LeRoy, Christopher P. Fagundes. Immune response to the influenza vaccination and heart rate variability in breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 603.
Abstract 612: Nivolumab-induced changes associated with patient outcomes are disparate in metastatic melanoma patient Tregs versus conventional T cells
Authors: Woods David M. 
Published: August 2018

Abstract
The PD1 blocking antibody nivolumab induces durable responses in metastatic melanoma patients. However, many patients do not respond and biomarkers differentiating patient response remain unidentified. To address this need, we investigated the effects of nivolumab on peripheral blood conventional CD4+ (Tcons) and regulatory T-cells (Tregs) of metastatic melanoma patients receiving nivolumab as adjuvant therapy or for metastatic disease. An increased ratio of PD1 expression on Tregs compared with Tcons was found at baseline patients with no evidence of disease (NED), while relapsing patients had a lower ratio (p&lt;0.05). Intriguingly, NED patients had an increase in circulating Treg percentages post-nivolumab (p&lt;0.05), which was not observed in relapsing patients. In vitro treatment of isolated T-cells with αPD1 resulted in increased proliferation (p&lt;0.001). RNA-seq analysis of Tcons and Tregs showed distinct gene expression changes based on cell type and patient outcome. Pathway analysis demonstrated: upregulation of proliferation associated genes in NED Tregs, but not in relapse Tregs; downregulation of oxidative phosphorylation associated genes in NED patient Tregs and upregulation in NED Tcons; upregulation of heme metabolism associated genes in NED Tcons and downregulated in relapsing patient Tcons; and similar differences in MTORC1, heme metabolism and hypoxia pathways (all pathways q&lt;0.01). Both Tcons and Tregs from non-relapsing patients had induction of phosphoSTAT3 (pSTAT3) expression post-nivolumab (p=0.012), which was absent in relapsing patients. This was also observed in a cohort of active disease patients (p=0.022), and the magnitude of change in pSTAT3 was positively correlated with patient survival (R2=0.49, p&lt;0.05). Enhanced pSTAT3 expression was recapitulated in vitro in isolated T-cells (p&lt;0.05). Post-nivolumab Tregs from patients with positive outcomes also had reduced suppressive function in mixed lymphocyte reactions (p&lt;0.05), while patients with negative outcomes had no changes. In vitro treatment of Tregs with PD1 blocking antibodies resulted in a reduction in suppressive function (p&lt;0.0001), while addition of a STAT3 inhibitor enhanced suppressive function (p&lt;0.0001). These results suggest that nivolumab alters Treg signaling and metabolism pathways, hindering immune suppressive function. Collectively, our data demonstrate distinct effects of nivolumab on Tcons vs. Tregs, and highlight several potential biomarkers of patient benefit, warranting further exploration.
Citation Format: David M. Woods. Nivolumab-induced changes associated with patient outcomes are disparate in metastatic melanoma patient Tregs versus conventional T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 612.
Abstract 631: Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8 T-cell immunity that effectively combines with checkpoint inhibitors
Authors: Desbien Anthony L. , Gauthier Kelsey Sivick , Corrales Leticia , Reiner Gabrielle , Glickman Laura Hix , Katibah George , Hudson Thomas E. , Vu Uyen , Surh Natalie H. , Francica Brian , Deng Weiwen , Kanne David B. , Leong Justin J. , Ndubaku Chudi , Metchette Ken , McKenna Jeffery M. , Bender Steven L. , Leong Meredith L. , Dubensky Thomas W. , Elsas Andrea van , McWhirter Sarah M. 
Published: August 2018

Abstract
Activation of the STING pathway by intratumoral (IT) injection of synthetic cyclic dinucleotides (CDNs) induces stable tumor regression in preclinical models, yet the underlying immune correlates are not fully understood. ADU-S100, a CDN under clinical evaluation, was administered IT with an optimized dosing regimen to explore the immune requirements for antitumor efficacy in mouse syngeneic tumor models. We show that CD8+ T cells are necessary and sufficient for durable antitumor immunity elicited by ADU-S100 and that activation of STING in hematopoietic cells mediates CD8+ T cell induction. Both type I IFN and TNFα, which are induced by STING pathway activation, influence the antitumor immune response. The combination of ADU-S100 and anti-PD1 treatment enhances CD8+ T cell-dependent, noninjected tumor control that correlates with an enhanced effector profile of CD8+ T cells in the tumor. Combination of ADU-S100 with checkpoint inhibition also enhances durable immunity in a poorly immunogenic tumor model. Together, these results elucidate the immune correlates to STING-mediated antitumor efficacy and highlight the potential of combining STING agonists with checkpoint inhibition in the clinic.
Citation Format: Anthony L. Desbien, Kelsey Sivick Gauthier, Leticia Corrales, Gabrielle Reiner, Laura Hix Glickman, George Katibah, Thomas E. Hudson, Uyen Vu, Natalie H. Surh, Brian Francica, Weiwen Deng, David B. Kanne, Justin J. Leong, Chudi Ndubaku, Ken Metchette, Jeffery M. McKenna, Steven L. Bender, Meredith L. Leong, Thomas W. Dubensky Jr., Andrea van Elsas, Sarah M. McWhirter. Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8 T-cell immunity that effectively combines with checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 631.
Abstract 635: Characterizing PD-L1 expression in tumor-associated cells and CTC using IncellDx and Celsee molecular diagnostic technologies
Authors: Fazeli Fariba , Sharma Vishal Premdev , Chow William Chiro , Chargin Amanda , Gogoi Priya , Handique Kalyan , Patterson Bruce 
Published: August 2018

Abstract
Detection of PD-L1 expression in NSCLC cancer patients is increasingly becoming a widely used molecular diagnostic tool. Evidence also suggests that PD-L1 can be induced with radiotherapy and may be an immune escape mechanism in cancer. Current methods analyze PD-L1 expression in either solid tumor biopsies or circulating tumor cells (CTC), independent of each other. In order to design a comprehensive PD-L1 treatment regime, it is imperative to look at the PD-L1 expression in cancer cells of the tumor as well as in CTCs. In this study we present a comprehensive profiling of PD-L1 expression in solid tumor biopsy and CTC of 10 lung cancer patients. We further extend the study by evaluating the co-relation of the PD-L1 expression with other immune cell infiltration markers in the lung biopsy samples. There is no single technology that can provide a comprehensive profiling of PD-L1 expression in lung biopsies as well as the CTCs isolated from the peripheral blood. Using two very different and unique molecular diagnostic technologies, IncellDx OncoTect iO Single Cell Quantitative PD-L1 assay and automated CTC analysis Celsee C-PREP GENESIS, we present the first report discussing the PD-L1 expression in tumor cells of the solid and liquid biopsies and its correlation with DNA content and infiltrating immune cell markers. Nine out of the ten patient samples evaluated showed strong correlation between DNA content and PD-L1 expression in tumor-associated cells and CTC. One aneuploid patient sample showed very low expression of PD-L1 in tumor-associated cancer cells; however, it still showed a positive staining for PD-L1 in CTC. Obtaining a comprehensive PD-L1 expression and associated immune cell marker profile in solid tumor biopsy and circulating tumor cells may be needed to design a more effective and lasting immunotherapy to treat NSCLC lung cancer patients. The results discussed in this study will strongly impact the current understanding and implementation of the molecular diagnostics tools to evaluate cancer patients in order to define a robust therapeutic regimen.
Citation Format: Fariba Fazeli, Vishal Premdev Sharma, William Chiro Chow, Amanda Chargin, Priya Gogoi, Kalyan Handique, Bruce Patterson. Characterizing PD-L1 expression in tumor-associated cells and CTC using IncellDx and Celsee molecular diagnostic technologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 635.
Abstract 638: Microbubble enrichment of CTCs
Authors: Jones Thomas , Ostruszka Leo J. , Fouladdel Shamileh , Azizi Ebrahim , Slamecka Jaroslav , McNaughton Brandon H. , Younger John , Wicha Max , McClellan Steven 
Published: August 2018

Abstract
Despite numerous new cell analysis technologies, contaminating red- and white blood cells remain a central barrier to the efficient characterization of circulating tumor cells. Microbubbles, which capture and separate cells by flotation, recently have been described as an alternative or adjunct to magnetic beads or microfluidic methods for CTC sample preparation. This technology may find particular value in applications where mechanical force needs to be minimized or magnetization of cells needs to be avoided. Here, we evaluate novel RBC-targeting microbubbles for buoyancy-based enrichment of CTCs. Cultured human pancreatic cancer cells (line CFPAC-1, ATCC CRL 1918) were spiked into standardized samples representative of common CTC workflows (106 RBC : 5x104 WBC : 1.5x102 tumor cells). Microbubbles bearing antibodies to human erythrocytes were added at various Bubble:RBC ratios and mixed via trituration for 1 minute. Samples were then centrifuged, the microbubble-captured RBCs removed, and the remaining pelleted cells analyzed for the fraction of RBCs removed and the extent of off-target depletion of tumor cells. Cells were quantified with an automated cell counter, and all experimental conditions were performed in at least triplicate. RBC removal rose with increasing Bubble:RBC ratio ( p &lt; 0.001 ). At a ratio of 1:1, 92 +/- 1% of RBCs were removed with one minute of mixing; at a ratio of 1.5:1, 97 +/- 1% of RBCs were removed. Off-target binding of CFPAC-1 cells was minimal at a Bubble:RBC ratio of 1:1, with 0 +/- 6% of tumor cells captured. Off-target capture increased at a Bubble:RBC ratio of 2:1, with 12 +/- 9% tumor cell loss from the experimental samples. Using a standardized blood sample with a clinically relevant low concentration of cultured tumor cells, microbubbles targeting RBCs and dosed at a ratio of one bubble per target erythrocyte were able to achieve &gt; 90% removal without statistically detectable loss of a cultured cancer line. Higher bubble concentrations resulted in more exhaustive RBC removal, but with some loss of cultured cells. Microbubble-based cell separation may have a useful role in CTC purification protocols.
Citation Format: Thomas Jones, Leo J. Ostruszka, Shamileh Fouladdel, Ebrahim Azizi, Jaroslav Slamecka, Brandon H. McNaughton, John Younger, Max Wicha, Steven McClellan. Microbubble enrichment of CTCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 638.
Abstract 643: An ultra-sensitive multiplex allele-specific real-time PCR (Udx-PCR) assay for detection of KRAS/BRAF/NRAS mutations in colorectal cancer
Authors: Zhai Jianxin , Wu Youmin , Luo Xuan , Li Xinsheng , Yu De-Hua 
Published: August 2018

Abstract
RAS and BRAF gene mutation assessment is essential for therapy decision in metastatic colorectal cancer patients with anti-EGFR monoclonal antibody treatment. However the currently approved assays in clinic is mainly focusing on tissue samples with detecting sensitivity lower than 1% in 10ng genomic DNA background. The emerging analysis of ctDNA offers advantages in clinical diagnosis as a feasible method, which requires much more sensitive methodology due to low abundance in plasma samples. Herein, we developed a multiplex allele-specific real-time (ARMS) PCR assay for detection fourteen mutations of KRAS/BRAF/NRAS in an 8-tube PCR strip. The reagent and format of mutation detection were particularly optimized to reach high specificity and sensitivity. Performance evaluation showed that the assay is remarkably sensitive with lower detection limit of 0.1% in a background of 10ng wild-type genomic DNA. A total of 136 CRC FFPE samples were screened by using the assay. Sixty-two samples were positive for KRAS/BRAF/NRAS mutations, and fifty-eight were confirmed by the Sanger sequencing. The four discrepant samples were tested further by ddPCR and the results revealed that the allelic frequencies in these samples were as low as 0.1% to 5%. The evaluation of ctDNA detection is being carried in metastatic colorectal cancer patients. The multiplex allele-specific real-time PCR assay provides a rapid, reliable and low-cost diagnostic tool for accurate detection of KRAS/BRAF/NRAS mutations for clinical application.
Citation Format: Jianxin Zhai, Youmin Wu, Xuan Luo, Xinsheng Li, De-Hua Yu. An ultra-sensitive multiplex allele-specific real-time PCR (Udx-PCR) assay for detection of KRAS/BRAF/NRAS mutations in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 643.
Abstract 666: Gut microbiota SCFA modulates DCs antigen presentation and impacts tumor response to radiotherapy
Authors: Facciabene Andrea , Rafail Stavros , Gomez Luis Gil de , Pierini Stefano , Uribe-Herranz Mireia , Bittinger Kyle 
Published: August 2018

Abstract
Alterations in gut microbiota modulate host physiologic functions, including immune responses, and they play a role in the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. Herein, we tested whether the gut microbiota modulates antitumor immune response following RT. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on tumor-associated antigen cross-presentation enanchement, cytolytic CD8+ T cells and on IFN-g. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, gram-positive bacteria depletion by vancomycin enhances the antitumor activity of RT, which has important clinical ramifications.
Citation Format: Andrea Facciabene, Stavros Rafail, Luis Gil de Gomez, Stefano Pierini, Mireia Uribe-Herranz, Kyle Bittinger. Gut microbiota SCFA modulates DCs antigen presentation and impacts tumor response to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 666.
Abstract 669: The regulation of ALOX15 expression in colorectal cancer to overcome the resistance to radiation therapy
Authors: Na Yoo Jin , Lee Dae-Hee , Kim Bo Ram , Kim Jung Lim , Jeong So Yeon , Park Seong Hye , Jo Min Jee , Jeong Yoon A , Yun Hye Kyeong , Oh Sang Cheul 
Published: August 2018

Abstract
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of 'cancer related death' world-wide. In case of CRC patients who have large sized tumor, radiation therapy is essential to decrease tumor size without having to eliminate the anus. However, radiation effects vary according to patients. Also, the association between genes and radiation sensitivity is still rarely researched. In this study, we elucidated that the expression level of ALOX15 regulates radiation sensitivity by TNFα signaling pathway in CRC cells. ALOX15 is known as the main metabolic enzyme for linoleic acid and arachidonic acid. Interestingly, stable cells which express low ALOX15 inhibit radiation-induced apoptosis. Mechanistically, inhibition of ALOX15 increases NF-kB under radiation therapy condition. NF-kB that plays a key role in the cellular response to DNA damage is a reason for ALOX15 to act as a radiation sensitizer. Taken together, our results indicate that ALOX15 is suggested as a prediction marker for radiation therapy. In addition, screening natural compound for elevating ALOX15 would be used for the purpose of combination therapy in radiation-resistant CRC cells.
Citation Format: Yoo Jin Na, Dae-Hee Lee, Bo Ram Kim, Jung Lim Kim, So Yeon Jeong, Seong Hye Park, Min Jee Jo, Yoon A Jeong, Hye Kyeong Yun, Sang Cheul Oh. The regulation of ALOX15 expression in colorectal cancer to overcome the resistance to radiation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 669.