bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3720: Augmented loading efficiency of doxorubicin into glioma-derived exosomes by an integrated microfluidic device
Authors: Thakur Abhimanyu , Zou Heng , Yang Mengsu , Lee Youngjin 
Published: August 2018

Abstract
Glioma is a lethal brain cancer in the central nervous system (CNS). The therapeutic usage of potent anticancer drugs for glioma is restricted by their poor penetration across the blood-brain barrier (BBB). Current reports have revealed that cell-derived exosomes can cross the BBB, suggesting their prospective use as drug delivery vehicles for targeting glioma as well as neurological disorders. However, conventional isolation of intact, specific, and optimal exosomes for drug delivery from various donor cells is laborious and time-consuming. Particularly, increasing loading efficiency of non-hydrophobic anticancer drugs, such as doxorubicin, into exosomes has been challenged. Therefore, a single integrated microfluidic device has been developed, based on the principles of immunocapture and density-gradient-free centrifugation, using soft lithography for efficient exosome isolation and drug loading consecutively. The isolated glioma-exosomes were characterized by transmission electron microscopy (TEM), immunogold-EM, and nano tracking analyzer. The loading efficiency of doxorubicin into glioma-exosomes was evaluated by UV-visible spectrophotometer as well high performance liquid chromatography (HPLC). Furthermore, the doxorubicin loaded glioma-exosomes were treated to autologous and heterologous glioma cells, followed by evaluation with confocal microscopy. The present study has shown that our integrated microfluidic device isolates pure exosomes from glioma cells, and it dramatically increases loading efficiency of doxorubicin into the exosomes, supporting its usefulness to study the exosome-mediated drug delivery for glioma therapy.
Citation Format: Abhimanyu Thakur, Heng Zou, Mengsu Yang, Youngjin Lee. Augmented loading efficiency of doxorubicin into glioma-derived exosomes by an integrated microfluidic device [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 3720.
Abstract 3731: Deciphering the transcriptional role of estrogen receptor alpha in ovarian cancer
Authors: Lee Irene , Brown Myles 
Published: August 2018

Abstract
Ovarian cancer is the leading cause of death among gynecologic malignancies. Despite years of research, the 5-year survival rate for ovarian cancer patients has remained poor and the standard of care is largely the same as it was decades ago. Epidemiological evidence and previous studies have suggested a role for steroid hormones in the pathogenesis of ovarian cancer, however, the role of steroid hormones in ovarian cancer remains understudied. We hypothesized that Estrogen Receptor α (ERα) is transcriptionally active and drives a transcriptional program that is sufficient to promote ovarian cancer cell proliferation and survival in a subset of ER+ ovarian cancers. Preliminary data generated in our laboratory has suggested that estradiol (E2) treatment increases cell proliferation in PEO1 cells, an ERα+ ovarian cancer cell line. This increase in cell proliferation can be inhibited by co-administration with the selective estrogen receptor modulator, Tamoxifen, and the selective estrogen receptor degrader, Fulvestrant. To further interrogate the mechanism of action of ERα in ovarian cancer, we performed RNA-seq on PEO1 cells treated with Vehicle, 10 nM E2, 100 nM Fulvestrant, and E2+Fulvestrant for 24 hours. We identified 659 significantly differentially expressed genes following E2 treatment. Fulvestrant inhibited the majority of E2-induced differentially expressed genes, confirming that these genes are dependent upon ERα. Gene Set Enrichment Analysis (GSEA) indicated that the Hallmark early and late estrogen responses are enriched in the E2 dataset, confirming that classical ER activity is intact in these cells. Furthermore, we identified G2/M checkpoint as positively enriched in our dataset, indicating that proliferation genes are upregulated by ERα in these cells. Additionally, we found that apoptosis was negatively enriched in our dataset, indicating that apoptosis pathway genes are suppressed by E2 treatment. Future investigation in this project will center on exploring the mechanisms of ERα transcriptional activity through examining the ERα-dependent cistrome, regulation of target genes, and its interactions with other cofactors. These data will give us insight into how ER is regulated and what pathways and processes ER is driving. Additionally, we will use CRISPR/Cas9 screening to uncover the key genes downstream of ER that are executing the estrogen-dependent effects on proliferation and survival. We believe that these studies will provide additional drug targets that may suggest a combinatorial therapeutic approach in conjunction with endocrine therapies for the treatment of ovarian cancer.
Citation Format: Irene Lee, Myles Brown. Deciphering the transcriptional role of estrogen receptor alpha in 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 3731.
Abstract 3783: Mitochondrial metabolism in tumor-associated macrophages: The role of MIF and tumor-derived lactate
Authors: Noe Jordan , Rendon Beatriz , Kim Eun Jung , Mitchell Robert 
Published: August 2018

Abstract
Purpose: Within the tumor microenvironment, tumor-associated macrophages (TAMs) polarized to an "M2" phenotype promote angiogenesis, metastasis, and the suppression of anti-tumor immune responses. Previously, we have found that macrophage migration inhibitory factor (MIF) promotes lactate-enhanced M2-polarization, however the underlying mechanisms were not elucidated. As cancer cells that exhibit the Warburg Effect secrete copious amounts of lactate into the tumor microenvironment, highly glycolytic cancers may promote tumor progression by producing lactate to support an immunosuppressive tumor microenvironment. The goal of this study is to investigate the mechanism by which MIF and tumor-derived lactate support pro-tumorigenic M2-TAMs.
Methods: Using primary bone marrow-derived macrophages (BMDMs), we explored the mechanisms of MIF and lactate-enhanced M2 polarization using metabolic inhibitors and gene expression assays. To investigate the role of MIF in mitochondrial metabolism, we conducted extracellular flux analysis to determine mitochondrial OCR and ECAR in macrophages polarized to an M0 and M2 phenotype.
Results: Blocking mitochondrial pyruvate uptake reduces both M2 polarization and HIF1α stabilization. Blocking mitochondrial metabolism and respiration inhibits M2 polarization. MIF deficiency decreases mitochondrial OCR, NRF2 stability, and M2 polarization. Increasing CSN5 activity "rescues" the loss of M2 polarization with MIF deficiency.
Conclusions: Tumor-derived lactate per se does not promote M2 polarization but instead requires subsequent metabolism to pyruvate. Additionally, we have identified that mitochondrial pyruvate metabolism is a previously undetermined requirement for M2 macrophages. Further, we have found a potential link between MIF and metabolism, where MIF likely regulates CSN5 activity and NRF2 stability to increase mitochondrial respiration. As inhibiting mitochondrial respiration blocks M2 polarization, MIF may promote lactate-enhanced M2 polarization by enhancing mitochondrial metabolism. Subsequent studies will be conducted to further investigate the metabolic pathways and mechanisms required for the mitochondrial metabolism of tumor-derived lactate in promoting M2-TAM polarization.
Citation Format: Jordan Noe, Beatriz Rendon, Eun Jung Kim, Robert Mitchell. Mitochondrial metabolism in tumor-associated macrophages: The role of MIF and tumor-derived lactate [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 3783.
Abstract 3797: Chromosome instability as a prognostic factor& an immunotherapeutic target in acute myeloid leukemia
Authors: Jin Ning , Burkard Mark 
Published: August 2018

Abstract
Chromosome instability (CIN) is an increased rate of chromosome mis-segregation due to errors in mitosis. CIN generates genetic and karyotypic diversity and is common in hematological malignancies. Low to moderate levels of CIN are well tolerated, and moderate levels can promote cancer proliferation by generating genetic diversity for tumor evolution. However, very high levels of CIN are lethal and enhancing CIN can be therapeutic. Therefore, CIN status could be prognostic for clinical outcomes as well as a therapeutic target. Despite its promise, little is known about CIN in AML.
We first determined if CIN is correlated with clinical outcome in patients with acute myeloid leukemia (AML). We quantified the chromosome mis-segregation frequency (lagging chromosomes and chromatin bridges) in dividing AML cells on bone marrow core biopsies. Our study reveals a wide distribution of CIN in AML core biopsy specimens, ranging from 20% to 67%. High CIN correlates with a better overall survival in patients with AML.
Recent data suggest that chromosome mis-segregation promotes senescence and initiates immune clearance. Our hypothesis is that chromosome instability is immunogenic due to DNA damage, proteotoxic/oxidative stress with a high mutagenic potential, which can be recognized by immune system. To test this, we used an inhibitor of Monopolar spindle 1 (Mps1) to enhance CIN and tested if that altered immunogenicity. Mps1 is a key component of the mitotic checkpoint and is also involved with chromosome alignment. Inhibition of Mps1 by AZ3146 results in severe chromosome mis-segregation, micronuclei formation, and apoptosis in AML cell lines. In addition, AZ3146 treatment causes activation of γH2AX due to DNA damage, and calreticulin exposure from endoplasmic reticulum stress. This generates danger signals to activate innate immune system (natural killer cells and dendritic cells) and induces immunogenic cell death (ICD) through priming of cytotoxic T cells. This effect is mainly seen in synchronized mitotic cells, suggesting AZ3146 acts specifically on mitosis. Additionally, we observed the overexpression of programed death ligand-1 (PD-L1) after the treatment of AZ3146 in AML cells. As evidence showed, PD-L1 participates in the immune evasion and protects AML blasts from cytotoxic T cells in mouse models of leukemia.
Taken together, our observations in Mps1 inhibitor treatment indicate the immunogenicity of CIN in AML. Additionally, these data support combination treatment of mitotic checkpoint inhibitor with immunotherapy to improve therapeutic efficacy in AML patients.
Citation Format: Ning Jin, Mark Burkard. Chromosome instability as a prognostic factor& an immunotherapeutic target in acute myeloid leukemia [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 3797.
Abstract 3831: Development of near-infrared photoimmunotherapy targeting GD2-positive neuroblastoma
Authors: Nouso Hiroshi , Tazawa Hiroshi , Tanimoto Terutaka , Tani Morimichi , Oyama Takanori , Sato Hiroaki , Noma Kazuhiro , Kagawa Shunsuke , Kobayashi Hisataka , Noda Takuo , Fujiwara Toshiyoshi 
Published: August 2018

Abstract
Background: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. Despite the recent advances in the treatment of NB, patients with high-risk NB still have poor prognosis. Immunotherapy using anti-GD2 monoclonal antibody (mAb), which binds to disialoganglioside GD2 on the surface of NB cells, has recently become a standard treatment for high-risk NB. However, the therapeutic efficacy of anti-GD2 mAb is insufficient in many clinical trials. Therefore, the enhancement of therapeutic potential of anti-GD2 mAb is needed to improve the clinical outcome of patients with high-risk NB. Near-infrared photoimmunotherapy (NIR-PIT) is a promising antitumor strategy to enhance the therapeutic potential of immunotherapy using an antibody-photoabsorber conjugate (APC). In this study, we investigated the therapeutic efficacy of anti-GD2-based NIR-PIT using anti-GD2 mAb conjugated to the photoabsorber IR700 (anti-GD2-IR700) in human NB cells.
Methods: We used 3 human NB cell lines, including IMR-32, CHP-134 and SK-N-SH. The expression of GD2 on the cell surface of NB cells was analyzed by flow cytometric analysis. Anti-GD2-IR700 was synthesized by incubating anti-GD2 mAb and IR700. The mixture was purified with a Sephadex G50 column. The antitumor effect of anti-GD2-IR700 was evaluated using XTT assay. NB cells were incubated with anti-GD2-IR700, anti-GD2 mAb or PBS and NIR light was irradiated at 2.0J/cm2.
Results: IMR-32 and CHP-134 cells, but not SK-N-SH cells, expressed GD2 protein on the cell surface. In GD2-positive IMR-32 and CHP-134 cells, administration of anti-GD2-IR700 significantly suppressed the cell viability compared to anti-GD2 mAb or PBS when combined with NIR light irradiation. In contrast, in GD2-negative SK-N-SH cells, anti-GD2-IR700 showed no significant inhibition of cell viability in combination with NIR light irradiation.
Conclusion: These results suggest that NIR-PIT using an anti-GD2-IR700 is a promising antitumor strategy to promote the therapeutic efficacy of anti-GD2 immunotherapy for high-risk NB.
Citation Format: Hiroshi Nouso, Hiroshi Tazawa, Terutaka Tanimoto, Morimichi Tani, Takanori Oyama, Hiroaki Sato, Kazuhiro Noma, Shunsuke Kagawa, Hisataka Kobayashi, Takuo Noda, Toshiyoshi Fujiwara. Development of near-infrared photoimmunotherapy targeting GD2-positive neuroblastoma [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 3831.
Abstract 3881: Formulating a cell membrane lipid-extracted nanoliposome (CLENS) drug platform for the treatment of prostate cancer
Authors: Omaer Abubker , Alqarni Ali , Randulfe Carlos , Alharbi Hanan , Campbell Robert 
Published: August 2018

Abstract
Background: Liposome-encapsulated doxorubicin has proven to be an effective drug delivery method to cancer cells. Lipid extracts derived from human prostate cancer cells along with conventional components were employed to develop cell membrane lipid-extracted nanoliposomes (CLENs) for prostate cancer treatment. In an effort to balance efficiency of drug loading with cellular targeting efficiency we report on physicochemical characteristics (i.e., particle size, zeta potential, drug loading efficiency) and cellular uptake studies.
Methods: Five preparations of CLENS were prepared consisting of variable concentrations of DOPC and CRL-1740 lipid extract material varying as a function of optimized fixed ratios of conventional components (Cholesterol and DSPE-PEG5000). The controls used to investigate the effect of the different components on drug incorporation efficiency were preparations of DOPC (100%) and CRL-1740 (100%). Doxorubicin hydrochloride (5 mol%) was employed during the preparation of all formulations. Samples were readily prepared by thin film evaporation. For cellular uptake studies CRL-1740 cells were seeded at 1 x 104 mL in 48-well plate and incubated for 24 hours prior to use. The cells were next exposed to various amounts of rhodamine labeled CLENS for 24 hrs. Cellular uptake was determined using fluorescence intensity values determined by a fluorescence microplate reader. Fluorescence microscopy supplement cellular uptake studies.
Results: The DOPC drug-loaded liposome preparation consistently achieved the lowest percent of drug incorporation. Likewise, 100% CRL-1740 CLENs demonstrated a significant degree of formulation instability, resulting in a relatively low percent of drug incorporation compared to preparations that consisted of lipid extract and conventional components. The finding were supported by values determined for zeta potential and particle size. Cellular uptake studies also favored the preparations that consisted of lipid extract material and conventional components compared to each alone. The results collectively support the importance of balancing lipid extract material derived from prostate cancer target cells with cholesterol and DSPE-PEG5000 for formulation development and cellular uptake.
Conclusion: We formulated seven preparations of CLENS as part of the drug platform. The most promising candidates were determined following completion of the study. Future studies should evaluate the cytotoxicity and safety profile of the most promising formulations vivo.
Citation Format: Abubker Omaer, Ali Alqarni, Carlos Randulfe, Hanan Alharbi, Robert Campbell. Formulating a cell membrane lipid-extracted nanoliposome (CLENS) drug platform for the treatment of prostate 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 3881.
Abstract 3889: RPL28 promoter polymorphism rs4806668 is associated with reduced survival in FOLFIRI-treated metastatic colorectal cancer patients
Authors: Labriet Adrien , Lévesque Éric , Mattia Elena De , Cecchin Erika , Jonker Derek , Couture Félix , Simonyan David , Buonadonna Angela , D'Andrea Mario , Villeneuve Lyne , Toffoli Giuseppe , Guillemette Chantal 
Published: August 2018

Abstract
Fluorouracil (5-FU), folinic acid, and irinotecan (FOLFIRI) is a standard treatment of metastatic colorectal cancer (mCRC). Our study aimed to investigate genetic variability in candidate genes in relation to patients' outcomes using two independent cohorts of 417 FOLFIRI-treated mCRC cases recruited in Canada and Italy. We used a haplotype-tagging polymorphism (htSNP) approach to maximize the coverage of genetic variability of the selected genes and genotyping was performed using time-of-flight mass spectrometry iPLEX Sequenom Technology. Associations between polymorphisms and clinical outcomes were tested using Cox proportional hazards model adjusted for covariates. Of the genes tested, RPL28 encodes a ribosomal protein and its silencing was shown to enhance sensitivity to 5-FU and irinotecan in vitro.1 RPL28 rs4806668G&gt;T was associated with a shorter progression-free survival (PFS) in the Canadian (hazard ratio (HR) 3.23, P = 0.013), Italian (HR 3.28, P = 0.021) and combined (HR 3.36, P &lt; 0.001) cohorts. This marker was also associated with a reduced overall survival (OS) in the Canadian (HR 3.09, P = 0.032), Italian (HR 3.05, P = 0.030) and combined (HR 3.07, P = 0.002) cohorts. These carriers of the rs4806668 TT genotype associated with reduced survival represent less than 5% of the population of European ancestry and its frequency varies greatly among ethnic groups. This htSNP, located in the promoter region of RPL28, is in strong linkage disequilibrium with six other polymorphisms and may affect RPL28 gene expression. In support, the rs4806668T allele was associated with increased RPL28 expression in colon tissues of healthy individuals of the GTEx cohort, compared to rs4806668G carriers. Functional investigations are required to elucidate the underlying molecular mechanism. These results suggest a role for the ribosomal RPL28 protein in cancer cell response to FOLFIRI treatment.
This work is supported by the Canadian Institutes of Health Research.
1Allen et al. Mol Cancer Ther. 2012 Jan;11(1):119-31
Citation Format: Adrien Labriet, Éric Lévesque, Elena De Mattia, Erika Cecchin, Derek Jonker, Félix Couture, David Simonyan, Angela Buonadonna, Mario D'Andrea, Lyne Villeneuve, Giuseppe Toffoli, Chantal Guillemette. RPL28 promoter polymorphism rs4806668 is associated with reduced survival in FOLFIRI-treated metastatic colorectal cancer patients [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 3889.
Abstract 4190: Synergistic anticancer effect of sulforaphane and cisplatin on sirtuins-mediated epithelial-to-mesenchymal signaling in triple negative breast cancer
Authors: SINHA SONAM , Shrivastava Neeta 
Published: August 2018

Abstract
Purpose:
Triple negative breast cancer (TNBC) overexpresses sirtuins (SIRTs), a class III HDACs, which induces epithelial-to-mesenchymal (EMT) transition and facilitates Cisplatin (CIS) resistance. We hypothesized that Sulforaphane (SFN), an HDAC inhibitor, when combined with CIS, could potentiate CIS efficacy against TNBC metastasis and overcome its resistance.
Material and Methods:
The effect of SFN and CIS combination on cellular proliferation and apoptosis of two TNBC cell lines, MDA-MB-231 and MDA-MB-468 were assessed by MTT assay and Annexin and PI method followed by FACS analysis respectively. The anti-metastatic capabilities of the compounds were evaluated using wound healing assay, invasion assay, chemotaxis assay, colony formation and tumorsphere assay. The regulation of key proteins involved in sirtuin-mediated EMT signaling and metastasis was determined by zymography and western blot analysis.
Results:
The results revealed that SFN in combination with CIS synergistically inhibited TNBC cells through inhibition of cellular proliferation, induction of apoptosis, in-silico and in-vitro modulation of SIRTs (1-7) expression. Anti-metastatic capabilities of the combinatorial treatment regimen were associated with inhibition of migratory, invasive, mammosphere forming potential and downregulation of matrix metallopeptidase (MMP-9 and MMP-2) activity of TNBC cells. When TNBC cells were treated with SFN, the expression of epithelial marker, E-cadherin was up-regulated, while the expression of mesenchymal markers, ZEB1, SNAIL, TWIST and associated SIRTs were down-regulated. In contrast, when the cells were treated with CIS, the expressions of mesenchymal markers were up-regulated. Interestingly, the combinatorial treatment of SFN and CIS synergistically inhibited EMT transition in TNBC cells. In-vivo studies are warranted to confirm our results.
Conclusion:
Collectively our findings demonstrated a SIRTs-mediated EMT-suppression leading to synergistic antitumor effect by combination of SFN and CIS in TNBC cells. This combination therapy may serve as a novel therapeutic strategy for TNBC management.
Citation Format: SONAM SINHA, Neeta Shrivastava. Synergistic anticancer effect of sulforaphane and cisplatin on sirtuins-mediated epithelial-to-mesenchymal signaling in triple negative breast 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 4190.