bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5892: miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2
Authors: Pan Bin , Wang Xiangmin , Xu Kailin , Ikezoe Takayuki 
Published: August 2018

Abstract
BCR-ABL1 independent mechanisms had been indicated to mediate drug resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). In this study, we observed increased level of pro-oncogenic anterior gradient 2 (AGR2) in TKIs-resistant CML cells. Silencing of AGR2 in dasatinib-resistant K562 (K562DR) cells led to restored sensitivity to dasatinib both in vitro and in vivo. Exposure to dasatinib induced up-regulation of AGR2 in K562 cells, which indicated a probable treatment related drug resistance. We further investigated the potential interaction between microRNA (miRNA) and AGR2 in K562DR cells, and found that down-regulation of miR-217 was associated with over-expression of AGR2 in K562DR cells. Luciferase reporter assay identified that miR-217 negatively regulated expression of AGR2 through binding 3'-untranslated region (3'-UTR) of AGR2. Forced expression of miR-217 led to decreased expression of AGR2 as well as compromised TKIs-resistant potential of K562DR cells. Similarly, over-expression of miR-217 re-sensitized K562DR cells to dasatinib-treatment in a murine xenograft transplantation model. Taken together, TKIs-treatment induced drug-resistance is correlated with decrease of miR-217 and up-regulation of AGR2. miR-217/AGR2 interaction might be a potential therapeutic target in treating CML patients with TKIs-resistant.
Citation Format: Bin Pan, Xiangmin Wang, Kailin Xu, Takayuki Ikezoe. miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2 [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 5892.
Abstract 5894: Snail reduces the antitumor efficacy of mTOR kinase inhibitors by transcriptional repression of 4E-BP1
Authors: Ye Qing , Wang Jun , Cao Yanan , Guo Yubin , Huang Xiuping , Mi Wenting , Liu Side , Wang Chi , Yang Hsin-Sheng , Zhou Binhua , Evers Bernard M. , She Qing-Bai 
Published: August 2018

Abstract
The mTOR inhibitors, including the second generation of mTOR kinase inhibitors, for cancer treatment have been evaluated in clinical trials, but their overall activity as monotherapy is limited. The cap-dependent translation repressor, 4E-BP1, is an important downstream effector of the mTOR kinase in controlling cell proliferation and tumor growth. Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors. However, the molecular mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here, we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to block the transcription of the 4E-BP1 gene. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes the formation of the eIF4F translation initiation complex for active translation in polysomes, and reduces the antiproliferative effect of mTOR kinase inhibitors. Conversely, genetic disruption of Snail or pharmacologic inhibition of Snail activity using the Snail co-repressor HDAC inhibitors restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Together, our findings reveal a novel oncogenic function of Snail in mTOR/4E-BP1-mediated translational control of tumorigenesis, and provide a rationale for targeting Snail to improve mTOR-targeted therapies.
Citation Format: Qing Ye, Jun Wang, Yanan Cao, Yubin Guo, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, Hsin-Sheng Yang, Binhua Zhou, Bernard M. Evers, Qing-Bai She. Snail reduces the antitumor efficacy of mTOR kinase inhibitors by transcriptional repression of 4E-BP1 [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 5894.
Abstract 596: Impact of histologic type on survival in primary thyroid lymphomas
Authors: Al-Juhaishi Taha , Yazbeck Victor 
Published: August 2018

Abstract
Background:
Primary Thyroid Lymphoma (PTL) is a rare disease constituting less than 2% of all extranodal lymphomas; and approximately 2-8% of all thyroid malignancies. In this study, we sought to describe the impact of histologic types on survival.
Methods:
The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients (≥18 years) diagnosed with PTL between 1973 and 2014. B-cell and T-cell lymphomas of all stages were included. Overall survival (OS) was estimated using the Kaplan-Meier method, and compared using Log-Rank test. Cox proportional hazards models were used for adjusted survival analyses.
Results:
Total of 2397 patients were included. Median age was 65 years (56-77); majority were female (n=1734, 72%) and caucasian (n=2178, 91%). Diffuse large B cell lymphoma was the most common histology (DLBCL, N=1351, 56%), followed by marginal zone (MZL, N=334, 14%), follicular (FL, N= 214, 8.9%), Burkitt (BL, N=43, 1.8%), chronic/small lymphocytic leukemia/lymphoma (CLL/SLL, N=41, 1.7%), Hodgkin lymphoma (HL, N=33, 1.4%), T cell lymphomas (TCL, N=14, 0.6%), Lymphoplasmocytic lymphoma (LPL, N=11, 0.4%), and Mantle cell (MCL, N=8, 0.3%). 349 patients (14.6 %) were reported with unclear histology. Total of 1502 (63%) had surgery, 1417 (59%) had chemotherapy and 1153 (48%) had radiation. At a median follow-up of 10.5 years, 1187 (50%) patients died. Median overall survival was 11.4 [10.6-12.3; 95% CI] years. Survival was different by histology type (table, P&lt;0.001). Compared with DLBCL, follicular lymphoma (HR 0.72 [0.57-0.92], P=0.008) and MZL (HR 0.62 [0.48-0.78], P&lt;0.001) were associated with lower mortality, independently of age, sex, race, surgery, chemotherapy, radiation and year of diagnosis. Adjusted mortality decreased by a relative 1% annually (HR 0.99 [0.98-0.99], P&lt;0.001).
Conclusion:
PTL is a rare disease mostly affecting elderly caucasian women. Outcomes vary depending on histologic type. Follicular, MZL and Hodgkin's lymphoma seem to have a favorable prognosis.
Overall Survival by HistologyHistologyNumber (%)Mean Survival in Years (95% CI)1-year survival5-year survivalDLBCL1351 (66%)12.6 [11.7-13.4]80%66%Burkitt43 (2.1%)15.9 [13.5-18.3]79%79%CLL/SLL41 (2%)13 [9.5-16.5]78%67%Follicular214 (10.4%)17.8 [15.1-20.6]97%83%Hodgkin33 (1.6%)25 [20-30]94%84%LPL10 (0.5%)14.2 [7.4-21]100%76%MZL334 (16.3%)13 [11.9-14.1]95%83%Mantel-Cell8 (0.4%)8.7 [3.9-13.5]87%56%T-cell14 (0.7%)10.7 [3.9-17.5]70%53%
Citation Format: Taha Al-Juhaishi, Victor Yazbeck. Impact of histologic type on survival in primary thyroid lymphomas [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 596.
Abstract 607: Inhibition of CDK4/6 and Pi3Kγ modulates mammary tumor immune microenvironment to enhance response to immunotherapy
Authors: Mont Stacey , Black Kevin , Chen Sheau-Chiann , Ayers Gregory D. , Richmond Ann , Vilgelm Anna E. 
Published: August 2018

Abstract
An antitumor immune response is critical in achieving immunotherapy-driven tumor regression. Despite remarkable clinical advances in immunotherapies, patients with breast cancer have been only moderately responsive. In this study, we tested whether CDK4/6 inhibition in combination with Pi3Kγ inhibition can augment the immunotherapy response. Tumor growth was inhibited in the MMTV-PyMT breast cancer model when treated with palbociclib (CDK4/6i) in combination with anti-CD137, an antibody agonist of T cell co-stimulatory receptor 4-1BB. We also assessed the effect of palbociclib alone in a postsurgical model, where treatment began 5 days after injecting 37,000 MMTV-PyMT cells into the mammary fat pad, and show a significant inhibition of both average tumor weight and volume. In addition, we demonstrate that palbociclib can be effective in reducing total tumor burden in the PyMT-FVB spontaneous breast cancer model. Furthermore, mice treated with palbociclib in this model had an increase in CD3+ cell infiltrate in tumor lung metastasis. We used the Pi3Kγ-null mice treated with palbociclib or vehicle control to assess the effect of dual inhibition of CDK4/6 and Pi3Kγ on MMTV-PyMT tumors. We found an increase in CD45+ cells within the tumor microenvironment and an increase in MHC class II+, antigen-presenting macrophages upon palbociclib treatment. Additionally, gene expression analysis of chemokines in palbociclib-treated MCF-7 cells showed an increased expression of CCL4, CCL5, CXCL9, CXCL10, and CXCL11, each of which is implicated in T-cell tumor-homing. Overall, our results suggest that dual inhibition of CDK4/6 and Pi3Kγ may enhance tumor immunogenicity. Drugs targeting CDK4/6 and Pi3Kγ are of high clinical relevance and our findings indicate that they may be used in combination with immunotherapies for the treatment for breast cancer.
Citation Format: Stacey Mont, Kevin Black, Sheau-Chiann Chen, Gregory D. Ayers, Ann Richmond, Anna E. Vilgelm. Inhibition of CDK4/6 and Pi3Kγ modulates mammary tumor immune microenvironment to enhance response to immunotherapy [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 607.
Abstract 622: Differential impact of pembrolizumab and ipilimumab on IFNgamma and IL-10 production from in-vitro monocyte-derived DC and T cell co-cultures
Authors: Tang Tina , Stewart Fay , Roberts Alexander , Gordon John , Curnow John , Barnes Nicholas , Qureshi Omar 
Published: August 2018

Abstract
Despite the success with checkpoint inhibitors in-vivo, demonstrating efficacy in-vitro using human primary immune cells remains a challenge. Our aim was to determine the impact of pembrolizumab and ipilimumab on proliferation, as well as IFNγ and IL-10 production, from monocyte-derived dendritic cell and T cell co-cultures.
CD14+ monocytes from the peripheral blood of healthy donors were isolated before differentiating into immature dendritic cells (iDC) with IL-4 and GM-CSF. Immature dendritic cells were subsequently matured (mDC) by exposure to IL-1β, IL-6, TNFα and PGE2. Allogeneic purified CD4+ T cells (from healthy donors) were co-cultured with either iDC or mDC in the absence (media alone or isotype control) or presence of either pembrolizumab or ipilimumab. T cell proliferation and IFNγ and IL-10 secretion were subsequently assessed.
Whilst there was no consistent impact of either pembrolizumab or ipilimumab on the proliferation of CD4+ T cells in co-culture with iDC or mDC, IFNγ secretion by CD4+ T cells was increased in iDC- and mDC-co-cultures by pembrolizumab (percentage increase at 1μg/ml compare to isotype control: 524.5±196.1, P=0.037; 200.7±80.6, P=0.047, respectively, n=7) and reduced in iDC cultures with ipilimumab (percentage increase at 1μg/ml compared to isotype control: -63.4±11.7, P=0.012, n=4). IL-10 secretion was also impacted upon by pembrolizumab, whereby it increased in both iDC and mDC cultures with CD4+ T cells (percentage increase at 1μg/ml compare to isotype control: 175.3±27.0, P=0.003; 183.2±16.7, P&lt;0.001, respectively, n=4). Ipilimumab however, whilst having no evident effect in iDC-T cell co-cultures, reduced IL-10 production of mDC co-cultures (percentage decrease at 1μg/ml compare to isotype control: -27.7±6.3, P=0.022, n=4).
These data support the positive in-vivo results with pembrolizumab and ipilimumab, and demonstrates a reliable method for investigating the impact of checkpoint inhibitors in immune cells.
Citation Format: Tina Tang, Fay Stewart, Alexander Roberts, John Gordon, John Curnow, Nicholas Barnes, Omar Qureshi. Differential impact of pembrolizumab and ipilimumab on IFNgamma and IL-10 production from in-vitro monocyte-derived DC and T cell co-cultures [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 622.
Abstract 632A: Microbiome diversity in sputum and circulating exosomes of women with breast cancer and nontuberculous mycobacterial lung disease
Authors: Philley Julie V. , Griffith David E. , Dasgupta Santanu 
Published: August 2018

Abstract
The nontuberculous Mycobacterial lung disease, primarily caused by Mycobacterium avium complex is an alarming health problem in the United States and worldwide. Being prevalent among Caucasian women with a history or current diagnosis of breast cancer, Nontuberculous Mycobacterial lung disease poses a significant challenge towards treatment. A large community of resident microbes, including bacteria, virus, Archeas and Fungi living in the human body are being increasingly recognized as the key components of controlling human health and disease. In this study, we examined microbiome diversity in sputa and circulating exosomes derived from women with both breast cancer and nontuberculous Mycobacterial lung disease, women with nontuberculous Mycobacterial lung infection only and healthy women by 16S rDNA sequencing. Our study identified a diverse microbiome community in the sputa and the exosomes dominated by Streptococcus, Haemophillus, Veillonella, Neisseria, Prevotella, Fusobacterium, Bacteroides, Allistipes, Faecalibacterium and Staphylococcus in women with both breast cancer and nontuberculous Mycobacterial lung disease and nontuberculous Mycobacterial lung disease only. Some of these genera, including Fusobacterium, Bacteroides, Allistipes have estrobolome activity and are associated with the development of breast and other neoplasm. This work confirms the presence of a distinct microbiome other than the Mycobacteriome in the sputa and the circulating exosomes of these patients. Further studies investigating the role of the sputa and exosome microbiome linking nontuberculous Mycobacterial pathogenesis and breast cancer are warranted.
Citation Format: Julie V. Philley, David E. Griffith, Santanu Dasgupta. Microbiome diversity in sputum and circulating exosomes of women with breast cancer and nontuberculous mycobacterial lung disease [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 632A.
Abstract 650: Effect of antigen retrieval on immuno-based microdissection methods
Authors: Tangrea Michael , Liu Meeiyueh , Roberge Adam , Noyes Kristen , Sanders Kennedy , Emmert-Buck Michael , Johann Donald J. 
Published: August 2018

Abstract
Introduction - Immunohistochemical staining (IHC) of histological sections is a well-established and useful technique for a large number of research studies and clinical applications, and is increasingly used as a targeting strategy for procurement of labeled cells via tissue microdissection, including immuno-LCM, immuno/computer-LCM, expression microdissection, and other techniques. The antigen retrieval (AR) process employed at the beginning of most IHC protocols increases epitope availability and improves staining characteristics; however, the procedure can damage DNA to an unknown extent.
Experimental Procedures - To better understand the effects of AR on DNA quality and quantity, model system samples (lung cancer PDX tissue) and clinical specimens (KRAS gene mutation positive cases) were subjected to commonly employed AR methods [heat induced epitope retrieval (HIER), protease digestion] and the effects on DNA were assessed by Qubit, Fragment Analyzer, agarose gels, kappa qPCR, digital droplet PCR, NGS library preparation, and targeted sequencing.
Data Summary - The results showed that HIER resulted in optimal staining characteristics, but induced significant damage to DNA, producing extensive fragmentation and decreased yields. Variation in the HIER protocol mitigated but did not eliminate the negative effects. In contrast, the consequences of protease treatment on DNA were relatively minor and immunostaining quality was acceptable, although diminished in intensity compared to HIER treated sections. Apart from the AR procedure, the IHC process itself also resulted in a decreased yield of DNA. However, in spite of the observed deleterious effects on DNA, none of the AR methods combined with IHC negatively affected PCR amplification of small amplicons, and KRAS gene mutations were successfully identified in the clinical cases under all conditions.
Conclusions - The data indicate that DNA recovered from histology slides after standard AR and IHC processing can be successfully employed for the majority genomic applications, but studies that require larger DNA fragments such as long-read sequencing should avoid the use of HIER.
Citation Format: Michael Tangrea, Meeiyueh Liu, Adam Roberge, Kristen Noyes, Kennedy Sanders, Michael Emmert-Buck, Donald J. Johann. Effect of antigen retrieval on immuno-based microdissection methods [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 650.
Abstract 659: A novel manganese MRI contrast agent (PyC3A) for the evaluation of hepatic neoplasms
Authors: Erstad Derek J. , Ramsay Ian , Sojoodi Mozhdeh , Farrar Christian , Rotile NIcholas J. , Li Shen , Ghoshal Sarani , Michael Lanuti , Caravan Peter , Tanabe Kenneth K. , Fuchs Bryan C. , Gale Eric 
Published: August 2018

Abstract
Introduction:
Magnetic resonance imaging (MRI) is routinely used to diagnosis hepatic neoplasms. However, Gadolinium (Gd) is contraindicated in patients with severe renal impairment, and recent evidence also suggests Gd accumulates in brain tissue after repeated contrast injections. Manganese (Mn2+) is a paramagnetic ion that is cleared via biliary excretion, and provides an ideal alternative to Gd-based MR contrast agents. We present a novel Mn-based contrast agent, [Mn(PyC3A)(H2O)]- (referred to as PyC3A), and compare its efficacy to gadoxetic acid (Eovist) by imaging orthotopically implanted colorectal cancer hepatic metastases in mice.
Methods:
Male BALB/c mice (n = 8) were injected in the left lobe of the liver with 5x104 MC26/MCA-26 murine colon carcinoma cells, and were imaged on postoperative day 10 using a 4.7T MR scanner with PyC3A and gadoxetic acid (Eovist) 24 hrs apart. Signal contrast-to-noise ratio (CNR) was calculated for normal liver relative to tumor for each probe and compared.
Results:
Relaxivity of PyC3A in blood plasma was shown to be comparable to commercial Gd contrast agents. Biodistribution analysis confirmed that PyC3A clears via a mixed renal/hepatobiliary pathway with greater than 99% clearance within 24 hours. For imaging hepatic metastases, all mice survived to the study endpoint and developed radiographically discernible tumors (5 ± 2 mm diameter) without evidence of carcinomatosis. Calculated CNRs for liver relative to tumor for all recorded times are shown in Table 1. There was no difference in CNR between gadoxetic acid and PyC3A for all time points, suggesting near-equivalent enhancement of normal liver and tumor by both probes.
Conclusions:
PyC3A provides resolution of metastatic liver metastases that is comparable to gadoxetic acid. PyC3A may provide a safe and effective alternative to Gd constrast agents for imaging hepatic neoplasms in patients with renal impairment.
Table 1. Contrast-to-Noise Ratio (CNR) of Normal Liver Relative to TumorTime (minutes post injection)Gadoxetic AcidPyC3Ap-value02.61 ± 1.082.60 ± 1.640.9237.72 ± 4.677.53 ± 3.020.9387.85 ± 3.898.85 ± 4.430.66138.02 ± 3.987.62 ± 5.490.88189.79 ± 4.175.60 ± 3.080.06238.72 ± 4.167.03 ± 2.060.36
Citation Format: Derek J. Erstad, Ian Ramsay, Mozhdeh Sojoodi, Christian Farrar, NIcholas J. Rotile, Shen Li, Sarani Ghoshal, Lanuti Michael, Peter Caravan, Kenneth K. Tanabe, Bryan C. Fuchs, Eric Gale. A novel manganese MRI contrast agent (PyC3A) for the evaluation of hepatic neoplasms [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 659.
Abstract 683: SOS1 allosterically linked conformational changes modulate KRas4B activation
Authors: Liao Tsung-Jen , Jang Hyunbum , Fushman David , Nussinov Ruth 
Published: August 2018

Abstract
Son of sevenless homology 1 (SOS1) is a robust guanine nucleotide exchange factor (GEF) that exchanges GDP by GTP and activates Ras. SOS1 is a large multidomain protein with molecular weight of ~153 kDa. The C-terminal catalytic region, composed of RAS exchanger motif (REM) and CDC25 domains, is responsible for Ras activation. SOS1 offers two Ras binding sites; one at the allosteric site in REM and the other at the catalytic site in CDC25. Experimental studies provided a Ras-SOS1-Ras ternary complex and suggested that Ras binding to REM allosteric site is essential to activate GDP-bound Ras at the CDC25 catalytic site. However, details of SOS1 conformational changes due to different binding modes of Ras at the allosteric and catalytic sites in Ras activation are not well understood. Here, using molecular dynamics (MD) simulations, we examine Ras activation mechanism for SOS1 systems containing GDP- and GTP-bound, and nucleotide-free KRas4B. Among the three Ras isoforms, including HRas, NRas, and KRas (with two splice variants of KRas4A and KRas4B), KRas4B is highly oncogenic, the most frequently mutated in RAS-driven cancers. We observed that the REM domain inherently and sterically obstructs the Ras binding site of CDC25 domain. Upon binding to the REM allosteric site, KRas4B-GTP relieves the steric occlusion, making the CDC25 catalytic site capable of associating with KRas4B-GDP, leading to the nucleotide exchange. Allosteric effects lead to the dislocation of the helix-hairpin motif at the CDC25 catalytic site. This large movement of the helix-hairpin motif causes the Ras catalytic site to open and liberates GDP. Allosteric signals propagating through the REM-CDC25 tandem domains of SOS1 can explain the communication between two Ras proteins modulating the large conformational changes. Our simulations provide insight into the structural correlation of KRas4B-SOS1 as well as the allosteric effect. The conformational changes of SOS1 correspond to the allosteric signaling between two KRas4B at REM and CDC25 domains, promoting Ras activation.
Citation Format: Tsung-Jen Liao, Hyunbum Jang, David Fushman, Ruth Nussinov. SOS1 allosterically linked conformational changes modulate KRas4B activation [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 683.