bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4955: Heterogeneous nuclear ribonucleoprotein C as a novel therapeutic target for acute myeloid leukemia
Authors: Vijay Vindhya , Meacham Amy , Terrell Jesse , Katzell Lauren , Drusbosky Leylah , Cogle Christopher 
Published: August 2018

Abstract
Acute myeloid leukemia (AML) is a highly refractory cancer despite conventional treatment. Previously, we found that blood vessels are sanctuary sites for chemo-refractory AML cells. To target AML cells sequestered in the vascular niche, we developed an in vitro co-culture assay consisting of AML cells on bone marrow- derived endothelial cells (BMECs), mimicking the chemo-protective effect of the vascular niche in the bone marrow microenvironment. Using this assay, we performed high-throughput chemical-phenotypic screening of 31 million compounds and identified a novel polyamine sulfonamide (2470-51) that selectively killed AML cells, while sparing the underlying BMECs. 2470-51 was also cytotoxic to CD34+CD38-CD123+ AML stem cells; however, the compound was non-toxic to hematopoietic stem/progenitor cells and T lymphocytes from healthy volunteers. In vivo AML patient-derived xenograft modeling further validated the efficacy of 2470-51 as a selective anti-leukemic agent compared to cytarabine (conventional control) and vehicle control. Protein target identification experiments using unbiased label-free shotgun proteomic analysis in combination with targeted selected ion monitoring revealed heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) as the covalent target of 2470-51. These findings were further validated by shRNA mediated knock-down of HNRNPC (HNRNPC-kd) in AML cell lines THP-1 and K562. HNRNPC-kd significantly reduced AML cell proliferation as well as AML cell viability by inducing apoptosis, compared to scramble controls. HNRNPC-kd also significantly reduced the clonogenic potential of both AML cell lines. In contrast, normal mesenchymal/fibroblastic (HS5) and endothelial cells (BMECs) were unaffected by HNRNPC-kd, indicating the selective dependence of AML cells on hnRNPC. RNA-Seq analyses revealed alternative splice events associated with HNRNPC-kd. Functional enrichment analyses followed by pathway analyses indicated the involvement of hnRNPC in key oncogenic and cell survival pathways. Depleting hnRNPC significantly altered the post-transcriptional landscape, leading to induction of apoptosis. Clinical studies using TCGA AML datasets showed significant survival advantage associated with lower HNRNPC expression. Collectively, our data indicate that hnRNPC is a critical factor in AML and that inhibiting this splicing repressor may be a new therapeutic strategy.
Citation Format: Vindhya Vijay, Amy Meacham, Jesse Terrell, Lauren Katzell, Leylah Drusbosky, Christopher Cogle. Heterogeneous nuclear ribonucleoprotein C as a novel therapeutic target for 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 4955.
Abstract 4967: HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition
Authors: Chen Jie , Cheng Fengdong , Sahakian Eva , Powers John , Wang Zi , Villagra Alejandro , Pinilla-Ibarz Javier , Sotomayor Eduardo M. 
Published: August 2018

Abstract
In normal myelopoiesis, immature myeloid cells (IMCs) differentiate into macrophages, neutrophils or dendritic cells, a process that is tightly controlled by transcription factors and epigenetic regulators. However, under tumor burden, IMCs differentiate into myeloid derived suppressor cells (MDSCs) and with subsequent up-regulation of immune suppressive factors and a pro-tumor effect. In prior studies, we found that MDSCs from HDAC11 KO mice displayed an increased T-cell suppressive activity that was associated with a more aggressive tumor growth as compared to MDSCs from wild type control mice. Unlike MDSC's in which absence of HDAC11 is associated with a suppressive phenotype, T-cell lacking HDAC11 are hyper-reactive and endowed with strong antitumor activity. To assess which phenotype will be the dominant one in vivo, we performed adoptive immune cell transfer experiments of MDSC and/or T-cells from HDAC11 KO mice into C57BL/6 tumor-bearing mice. The transfer of HDAC11KO MDSCs was able to eliminate, at least partially, the anti-tumor effect elicited by the adoptive transfer of HDAC11KO T cells.
Mechanistically we have found that MDSCs lacking HDAC11 displayed up-regulation of expression and enzymatic activity of arginase 1 and Nos2, two enzymes that are crucial in regulating MDSCs suppressive function. The aberrant enzymatic activities of Arg1 and Nos2 in HDAC11KO MDSCs correlate with over-expression of the lineage-specific transcription factor C/EBPβ, which has been shown to be essential for the differentiation of functional MDSCs. Furthermore, ChIP analysis confirmed that HDAC11 is recruited to the C/EBPβ gene promoter where exerts a negative regulatory effect upon gene transcription.
Taken together, we have uncovered a previously unknown role for HDAC11 as a transcriptional regulator of MDSCs function. A better understanding of this novel role of HDAC11 in myeloid biology will lead to targeted epigenetic therapies to manipulate the suppressive effect of these immunoregulatory cells.
Citation Format: Jie Chen, Fengdong Cheng, Eva Sahakian, John Powers, Zi Wang, Alejandro Villagra, Javier Pinilla-Ibarz, Eduardo M. Sotomayor. HDAC11 function as a transcriptional regulator in immature myeloid cells to myeloid-derived suppressor cells transition [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 4967.
Abstract 4986: Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3
Authors: Ahmed Mohamed A. , O'Callaghan Carol , Vassilopulos Athanasios 
Published: August 2018

Abstract
Lifestyle factors, especially diet, affects health and lifespan. Dietary restriction (DR) has
been shown as a beneficial regimen to increase longevity and protect from cancer. On the other
hand, high fat intake has been found to be associated with greater risk of several cancer types.
In this regard, several studies suggest that the beneficial effect of calorie restriction (CR) is
mediated by the increased activity of sirtuins, a family of NAD-dependent deacetylases that plays
a role in aging and age-related diseases. However, the specific role of individual family members
in the inhibitory role of CR in tumorigenesis has not been elucidated. With the exception of SIRT1,
there is no evidence for the contribution of other sirtuins in the diet-induced effects on
tumorigenesis. In this study, we investigated, for the first time, the role of SIRT2 and SIRT3, which
are found predominantly in the cytoplasm and mitochondria respectively, in this context. To do
this, Sirt2-/- and Sirt3-/- mice were crossed with p53-/- mice to generate: p53+/-, (Sirt2-/-; p53+/-),
(Sirt3-/-; p53+/-), p53-/-, (Sirt2-/-; p53-/-), and (Sirt3-/-; p53-/-) mice. Subsequently, mice with the
different genotypes were subjected to 3 dietary regimes; ad libitum control diet, 30% calorie
restriction diet (CR), and high-fat diet (HFD). As expected, CR reduced tumor incidence and
increased survival of mice wild type for both SIRT2 and SIRT3. In contrast, HFD significantly
increased body weight, tumor incidence and decreased overall survival. Interestingly, the
protective effect of CR was enhanced in (Sirt3-/-; p53-/-) compared to (Sirt3+/+; p53-/-) mice, as
evidenced by delayed tumor incidence (median age 257 days vs 189 days) and increased survival.
On the other hand, Sirt2 deletion in both p53+/- and p53-/- backgrounds abolished the protective
effect of CR. In addition, loss of Sirt2 decreased tumor incidence age (111 days vs 184 days) and
accelerated the death of p53 deficient mice on HFD. Our results highlight a new role of SIRT2 in
mediating the diet-induced effect on tumorigenesis.
Citation Format: Mohamed A. Ahmed, Carol O'Callaghan, Athanasios Vassilopulos. Association of sirtuins and diet in cancer development: Studying the roles of SIRT2/3 [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 4986.
Abstract 5031: Organotypic brain explant culture as a drug evaluation system for malignant brain tumors
Authors: Minami Noriaki 
Published: August 2018

Abstract
Background: Inhibition of major metabolic pathways is being assessed for several intractable tumors, including glioblastoma. Following screening in 2D-systems, evaluating metabolic inhibitors in assays that include both tumor and normal brain tissue is indispensable for selecting compounds that can affect gliomas within their microenvironment. Here we asked whether organotypic brain slices from adult mice can be used to evaluate the effects of metabolic inhibitors on malignant glioma cells. Methods: Retroviral expression of H-RasV12 and dsRed in Ink4a/Arf-/- neural stem / progenitor cells was adopted to establish glioma initiating cells (GICs). GICs with different extracellular acidification potential were derived by single cell cloning and used after one in vivo passage. GICs or their clones were implanted into the forebrain of 6-weeks-old wild-type mice. Tumor-bearing brain explants were established as 200 µm coronal brain slices, treated with cisplatin, dichloroacetate or phenformin. The effects of the drugs were assessed by fluorescence microscopy of the live explants, as well as immunohistochemical staining at the end of the treatment. Results: The feasibility of assessing drug effects in brain tumor explants from adult mice was confirmed with the use of the DNA-damaging agent cisplatin. Treatment of brain slices carrying tumors formed by GICs with 50 μM cisplatin for 4 days effectively decreased the tumor burden, as shown by a significant reduction of the tumor area on fluorescence imaging and a marked increase in tumor cells positive for cleaved caspase 3 on immunohistochemical analysis. The action of metabolic inhibitors was assessed in explants with tumors formed by GIC-derived populations that predominantly use either glycolysis or mitochondrial respiration. Treatment of the brain slices with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase, resulted in a marked increase in cleaved caspase 3-positive cells in glycolytic tumors. In contrast, phenformin, which inhibits respiratory complex I, had a pronounced pro-apoptotic effect in tumors formed by cells with a high mitochondrial activity. Conclusion: Inhibitors of both glycolysis and oxidative phosphorylation effectively and selectively induced apoptosis of the targeted tumor cells in cultured brain slices. Our results suggest that brain explants from adult mice can be used to assess the effects of anti-metabolic drugs on the survival of glioma initiating cells within a syngeneic microenvironment. Explants could thus be useful in the evaluation of new metabolic inhibitors.
Citation Format: Noriaki Minami. Organotypic brain explant culture as a drug evaluation system for malignant brain tumors [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 5031.
Abstract 5044: Molecular analysis of HBV in histologically confirmed hepatocellular carcinoma in a tertiary hospital in Ghana
Authors: Duduyemi Babatunde M. , Asante Du-bois , Titiloye Nicholas , Afihene Mary 
Published: August 2018

Abstract
Background: Hepatocellular carcinoma (HCC) is a leading cause of death in Africa. Viral hepatitis B is a leading cause of hepatocellular cancer in Ghana and most African countries except Egypt where hepatitis C virus is more prevalent. This study aims at reviewing the histopathological patterns of HCC and its association with hepatitis B virus in our environment.
Method: Demographics and histological diagnosis were retrieved from the surgical daybook and archival FFPE tissue samples with histopathologically confirmed HCC were used for this study. Sections (10µm) were taken from the tissues and digested to obtain DNA lysates. The DNA lysates were used in polymerase chain reaction (PCR) to determine the prevalence of HBV in the biopsies.
Result: Of the 24 confirmed cases of HCC seen in the 5 year period, there were 17 males and 7 females with M:F ratio of 2.4:1. The mean age of our patients was 39.92 ± 1.98 years with age range 13-85 years. 50% of the cases were moderately differentiated while 25% each were well and poorly differentiated. Out of the 24 archival HCC biopsies screened, HBV DNA PCR amplification was achieved in 11 after the restriction fragment length polymorphism PCR reaction. Out of the 24 archival HCC biopsies screened, HBV DNA PCR amplification was achieved in 11 (45.83%) after the restriction fragment length polymorphism PCR reaction. Eight of the 11 cases were found in the male and 3 in females. Of the 11 (45.83%) samples that were positive for HBV DNA, 3 were above 40 years and 8 were 40 years and below.
Conclusion: The overall prevalence of HBV DNA in our study was 45.83% and a greater proportion seen in less than 40 years. This suggests that most of our patients are infected with HBV early in life in our environment.
Citation Format: Babatunde M. Duduyemi, Du-bois Asante, Nicholas Titiloye, Mary Afihene. Molecular analysis of HBV in histologically confirmed hepatocellular carcinoma in a tertiary hospital in Ghana [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 5044.
Abstract 5060: Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA
Authors: chen Lechuang , Feng Zhimin , Yue Hong , Sieg Scott , Wang Bingcheng , Huang Alex Y. , Jin Ge 
Published: August 2018

Abstract
Background: Residual and persistent HIV replication plays key roles in the development and progression of non-AIDS-defining cancers (NADCs), including head and neck as well as lung cancers. However, the underlying mechanisms remain elusive. HIV-infected T cells produce immunologically active exosomes to influence intercellular communication and regulate immune response at both local and distant sites, thus potentially contribute to enhanced risk for tumorigenesis. We investigated the role of exosomes derived from HIV-infected T cells in growth and progression of head and neck cancer (HNC) and lung cancer cells. Methods: Exosomes were isolated from conditioned media of HIV-1-infected J1.1 cells and non-infected control Jurkat cells using the ultracentrifugation protocol. Exosomes were validated by western blotting for tetraspanins (CD9, CD63 and CD81) and transmission electron microscope. The acetyl-CoA acetylcholinesterase (AChE) enzyme activity was used to quantify exosomes. HNC cells UM-SCC-104, TR146, HSC3, SCC9 and lung cancer cells NCI-H1299, NCI-H1437 were treated with exosomes for cell growth, migration and gene expression in vitro and in vivo. Exosome HIV RNA was determined by quantitative RT-PCR. Results: Exosomes isolated from HIV-1-infected T cells, but not those from normal control T cells, significantly stimulated HNC and lung cancer cell proliferation, migration and invasion in vitro. Exosomes purified from plasma of HIV-positive individuals also stimulated proliferation of cancer cells. HNC and lung cancer cells co-inoculation with exosomes from HIV-1-infected T cells into nude mice promoted tumor growth compared to those from non-HIV control T cells. Mechanistically, we found that the HIV trans-activation response (TAR) element RNA, which exists in excess of other HIV RNAs in exosomes from HIV-1-infected T cells, enhanced cancer cell proliferation and stimulated EGF- and TLR3-inducible gene expression. The TAR RNA mutant with nucleotide replacements in the loop/bulge region failed to induce gene expression. Moreover, co-transfection of the TAR RNA aptamer blocked induction of gene expression induced by HIV-positive T-cell exosomes. Conclusion: HIV TAR RNA-containing exosomes derived from HIV-1-infected T cells promote growth and progression of NADCs through interaction with EGFR and TLR3.
Citation Format: Lechuang chen, Zhimin Feng, Hong Yue, Scott Sieg, Bingcheng Wang, Alex Y. Huang, Ge Jin. Exosomes derived from HIV-infected T cells promote cancer cell growth and progression via the HIV TAR RNA [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 5060.
Abstract 5072: Immunohistochemical expression of CC-chemokine receptor-like 2/CCRL2 in a prostate cancer tissue microarray
Authors: Reyes Niradiz , Benedetti Ines , Geliebter Jan 
Published: August 2018

Abstract
Background: CCRL2 is a presumed member of the atypical chemokine receptor family, whose members are increasingly recognized as key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies. Recent studies have reported the expression of CCRL2 in different human cancer cell lines and tissues. However, its function and expression in prostate cancer has not been previously addressed. The aim of this work was to determine the protein expression profile of the atypical chemokine receptor CCRL2 in human prostate cancer tissue using a tumor microarray approach.
Methods: A tissue microarray was constructed using 231 cores of matched prostate cancer and benign prostatic tissue from 47 patients with a previous diagnosis of localized prostate cancer, which underwent surgical resection as their primary treatment. CCRL2 expression was evaluated by immunohistochemistry using a monoclonal, anti-human-CCRL2 antibody. An H score was calculated in each spot as the sum of expression intensity (0-3+) by extent (0%-100%). Differences in CCRL2 protein expression were assessed by comparing H-Scores between benign and cancerous tissues using Mann-Whitney test for non-Gaussian distribution.
Results: Immunohistochemical evaluation of CCRL2 at the protein level in a prostate tissue microarray constructed with clinical specimens confirmed its overexpression in malignant prostatic tissue. CCRL2 staining was present predominantly in the cytoplasm of prostate cancer tumor cells. Compared to benign epithelial cells, CCRL2 expression was significantly higher in epithelial tumor cells in cores with prostate cancer compared to cores with benign tissue (p=0.0001).
Conclusions: Immunohistochemistry of prostate cancer tissue specimens arrayed in a tissue microarray revealed that CCRL2 expression was significantly stronger in epithelial cells in cancerous acini compared to epithelial cells in matched adjacent benign acini from the same patient. To this point, the physiological effects of CCRL2 expression in epithelial cancer cells are unclear.
Citation Format: Niradiz Reyes, Ines Benedetti, Jan Geliebter. Immunohistochemical expression of CC-chemokine receptor-like 2/CCRL2 in a prostate cancer tissue microarray [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 5072.
Abstract 5080: ADAM10 promotes breast cancer via CXCL16 constitutive cleavage and CXCR6 signaling
Authors: Gales Dominique N. , Mir Hina , Kapur Neeraj , Lillard James W. , Singh Shailesh 
Published: August 2018

Abstract
Despite the survival of breast cancer (BrCa) patients, there is still demand to better understand metastasis as the obvious mark for most aggressive breast cancers. Recent evidence highlighted the possible involvement of chemokines and their cognate receptors in BrCa progression and metastasis. Expression and functional role of CXCR6 and CXCL16 have been investigated in different types of cancer. ADAM10 is also known to regulate the metastatic process by the proteolytic shedding of CXCL16 creating a soluble form of CXCL16. High levels of soluble CXCL16 could support tumor progression by promoting migration and invasion of CXCR6 expressing BrCa cells. Here, we demonstrate the significance of CXCR6-CXCL16 axis in BrCa progression. In addition to increased CXCR6 expression, our tissue microarray analysis (TMA) showed increased expression of CXCL16 and ADAM10 in BrCa tissues. BrCa cell lines (MCF-7 and MBA-231) also showed higher expression of ADAM10 as compared to the normal epithelial cells (MCF-10A). Further, these BrCa cells showed increased migration and invasion towards CXCL16 gradient that is due to high expression of CXCR6 and ADAM10. Hence, our findings suggest the clinical and biological significance of ADAM10 and soluble CXCL16 in BrCa progression. We also highlight the potential of ADAM10 and soluble CXCL16 as prognostic markers and new therapeutic target for BrCa.
Citation Format: Dominique N. Gales, Hina Mir, Neeraj Kapur, James W. Lillard, Shailesh Singh. ADAM10 promotes breast cancer via CXCL16 constitutive cleavage and CXCR6 signaling [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 5080.