bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B58: The effect of differential miRNA expression in glioblastoma multiforme molecular subtypes
Authors: Verzola Livia Ferreira Silva , Vidotto Thiago , Squire Jeremy Andrew 
Published: May 2019

Abstract
Glioblastoma multiforme (GBM) is characterized by a distinct profile of specific miRNAs that regulate pathways of therapeutic importance, such as cell proliferation, apoptosis, cell cycle regulation, migration, invasion, and angiogenesis. Recently, the molecular classification of gliomas was updated, and three methylation clusters with distinct prognostic values for GBM were characterized. The aim of this research is to evaluate the expression, the functional roles, and the target genes of the miRNAs that have potential value for diagnosis, prognosis, and treatment in patients within the newest molecular subgroup classification of GBM. First, we performed an in silico analysis 606 GBM samples from the Genome Data Commons (GDC) cohort. Based on the methylation subgroups of gliomas recently published (Cecarelli et al., 2016), we performed a comparison of the miRNA expression between LGm4, LGm5, and LGm6 subgroups through Nexus Expression 3.0 (Biodiscovery). The comparison between LGm4 x LGm6 indicated that eight miRNAs were upregulated, while 17 were downregulated. The LGm5 x LGm4 comparison showed two downregulated miRNAs, and the LGm5 x LGm6 comparison showed one upregulated miRNA. By comparing the differentially expressed miRNAs found in our analysis with two other in silico studies, we found an overlap of 54% of the differentially expressed miRNAs. We will now evaluate the expression levels of the upregulated miRNAs obtained through the in silico analysis of samples of the Hospital of Clinics - Faculty of Medicine of Ribeirão Preto (HCFMRP/USP) through a customized nCounter NanoString panel of 24 miRNA. We will also evaluate the plasma exosomal miRNAs from the same patients using the same 24 miRNA nCounter NanoString panel. By identifying the most significant miRNAs regulating cell proliferation and invasive behavior in this tumor, we will be able to use expression levels of the most informative miRNA to both guide the molecular diagnosis of GBM and facilitate future targeted therapeutics for this aggressive disease.
Citation Format: Livia Ferreira Silva Verzola, Thiago Vidotto, Jeremy Andrew Squire. The effect of differential miRNA expression in glioblastoma multiforme molecular subtypes [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B58.
Abstract B69: Study of superoxide dismutase-2 protein in HPV-mediated cell transformation
Authors: Silva Gabriela Ávila Fernandes , Nunes Rafaella Almeida Lima , Boccardo Enrique , Villa Luisa Lina , Termini Lara 
Published: May 2019

Abstract
Oxidative stress reflects an imbalance in the maintenance of the intracellular redox state resulting in the accumulation of oxidant species that may contribute to tumorigenesis. The superoxide dismutase 2 protein (SOD2) contributes to cell homeostasis by catalyzing the dismutation of superoxide anion radicals in oxygen and hydrogen peroxide, preventing the direct inactivation of biomolecules. SOD2 protein can be induced by the activation of the NF-kB pathway in several cell types following treatment with interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNFα), both proinflammatory cytokines. In addition, previous studies from the group have shown a direct correlation between increased levels of SOD2 protein and severity of uterine cervix lesions. The aim of this study is to elucidate the involvement of SOD2 in the pathogenesis associated with HPV and in the effect of proinflammatory cytokines.
Methods: Primary human keratinocytes transduced with HPV16 oncogenes and cervical cancer derived cell lines were treated with the proinflammatory cytokines TNFα, and IL-1beta. The expression of SOD2 protein involved in IL-1 β and TNFα signaling pathways was determined by Western blot and ELISA.
Results: Preliminary results suggest the presence of higher levels of SOD2 expression in uterine cervix-derived tumor cell lines when compared to normal primary keratinocytes. Treatment with IL-1β and TNFα induces SOD2 protein accumulation in in the HPV16 positive cervical-derived tumor line, SiHa. On the other hand, no SOD2 induction was observed in the HPV-negative cervical cancer derived cell line C33. Further replications and additional experiments are needed for conclusions.
Citation Format: Gabriela Ávila Fernandes Silva, Rafaella Almeida Lima Nunes, Enrique Boccardo, Luisa Lina Villa, Lara Termini. Study of superoxide dismutase-2 protein in HPV-mediated cell transformation [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B69.
Abstract B77: Perillyl alcohol derivatives as anticancer agents
Authors: Chen Thomas C. , Schonthal Axel H. , Hofman Florence H. 
Published: May 2019

Abstract
The use of the monoterpene perillyl alcohol (POH) for intranasal delivery to brain tumors was first popularized in Brazil. As monotherapy, POH has been found to be nontoxic, and to have anticancer activity in a subset of patients with malignant gliomas. The presumed route of delivery is presumed to be a cranial nerve (olfactory, trigeminal) to brain delivery, bypassing the blood-brain barrier. POH, itself, as a monoterpene is a clear liquid that we have found to be lipophilic in its consistency. We have explored the possibility of taking drugs that are out of patent, but with antibrain tumor activity, chemically conjugating them to POH, and creating a new drug. The process of drug discovery consisted of preclinical determination of: 1) feasibility of chemical conjugation, 2) determination of increased BBB penetrance using a BBB permeability program, 3) determination of functional activity via MTT and colony formation assays, 4) determination of mechanism of action, 5) determination of pharmacokinetic and pharmacodynamics action, and 6) functional activity against intracranial tumors (gliomas, metastatic breast carcinoma, medulloblastomas) demonstrated using established in vivo syngeneic and immune-deficient rodent models. Once these six preclinical steps are validated, formal application for IND status can be prepared by: 1) GMP production of drug, 2) formal toxicity testing using large and small animal models under acute and chronic administration, and 3) clinical trial indication for Phase I/IIa. This method has been successfully employed using temozolomide (TMZ) to create TMZ-POH linked via a carbamate bond (TMZ-POH; NEO212). The same method has been performed for the phosphodiesterase type IV inhibitor rolipram (RP-POH, NEO214), valproic acid (VA-POH; NEO216), 3 bromopyruvate (3BP-POH; NEO218). In each case, we were surprised by the mechanistic differences observed from the native compound to the new drug after POH conjugation. For instance, NEO212 is a DNA-alkylating agent, but with 3x the BBB penetration, 10x the cytotoxic potency, and 3x the stability. This presentation will demonstrate our discovery process using our POH conjugates, and our current IND process for NEO212, which we hope to bring to the clinic in the next 6 months.
Citation Format: Thomas C. Chen, Axel H. Schonthal, Florence H. Hofman. Perillyl alcohol derivatives as anticancer agents [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B77.
Abstract IA11: Epigenetic mechanisms in pathogenesis and targeted therapy for B-cell lymphomas
Authors: Melnick Ari 
Published: May 2019

Abstract
Recent genome sequencing studies have revealed that somatic mutation of genes that control the epigenome are the most common class of genetic lesion in DLBCLs and FLs. The epigenome is composed of hundreds of distinct chemical modifications of DNA, histones, RNA, and other molecules. Collectively, the epigenome functions as cellular “software”: instructions that encode and determine the phenotype of every type of normal and malignant cell. The fact that mutations in epigenetic modifiers are so common in DLBCL and FL points to the significance of the epigenome in these tumors. The four most common mutations in epigenetic modifiers in DLBCL and FL affect the following genes: KMT2D (also called MLL2), CREBBP, EP300, and EZH2. Eighty percent of lymphoma patients have at least one of these four mutations and often have more than one. Moreover, these mutations usually occur very early during lymphomagenesis and so represent important “founder” events. One fascinating insight that has recently emerged is that these genes play critical roles in germinal center B cells, which are the cells from which DLBCL and FL arise. This is interesting because in many ways germinal center B cells already manifest tumor-like phenotypes. Indeed, it appears that much of the effect of mutations in KMT2D, CREBBP, EP300, and EZH2 is to “lock” B cells into the germinal center mode, which essentially means that it maintains B cells in a highly proliferative, mutagenic state that is hidden from immune surveillance. Fortunately, novel small-molecule inhibitors have been developed that can correct the abnormal epigenomic programs caused by these mutations, and some of these drugs are already showing efficacy in clinical trials. In addition to suppressing lymphoma cells, this kind of treatment may enhance antilymphoma response by restoring immune surveillance. In my talk I will explain how these mechanisms work, and how we can design and implement novel therapeutic regimens that can suppress lymphoma cells with minimal toxicity to other tissues.
Citation Format: Ari Melnick. Epigenetic mechanisms in pathogenesis and targeted therapy for B-cell lymphomas [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA11.
Abstract IA15: Overcoming drug resistance and tumor heterogeneity in gastrointestinal cancers
Authors: Corcoran Ryan B. 
Published: May 2019

Abstract
Personalized cancer medicine approaches, inhibiting kinases in tumors driven by defined genomic alterations, have demonstrated striking efficacy in many cancer types. However, the development of drug resistance is a major limitation to the efficacy of targeted therapies in oncology. Identifying and understanding the molecular mechanisms driving resistance may foster opportunities to develop therapeutic strategies to overcome resistance. For example, in the ~10% of colorectal cancer patients whose tumors harbor BRAF V600 mutations, we have found that feedback reactivation of MAPK signaling, often mediated by EGFR, underlies the relative insensitivity of these cancers to RAF inhibitors. The development of targeted therapy combination strategies to block feedback reactivation of MAPK signaling has led to marked improvements in response rates for these patients from ~5% to &gt;30% over the past few years. However, in patients who respond to these targeted combinations, the rapid development of acquired resistance still limits clinical benefit. Acquired resistance in BRAF mutant colorectal cancer and in other molecularly defined tumor types can be marked by the development of extensive molecular heterogeneity due to the selection of sub-clonal tumor cell populations, capable of growing under drug pressures, which poses significant diagnostic and therapeutic challenges. We will present data demonstrating how a single-lesion biopsy at disease progression to diagnose the mechanism of acquired resistance can vastly underrepresent the molecular heterogeneity of resistant tumor clones in an individual patient, and may fail to detect the existence of distinct but important resistance mechanisms that can drive mixed or lesion-specific responses and treatment failure to subsequent targeted therapy. By contrast, liquid biopsy approaches analyzing circulating tumor DNA have the potential to detect the presence of simultaneous resistance mechanisms residing in separate metastases in a single patient and to monitor the effects of subsequent therapies on specific sub-clonal tumor cell populations. These findings highlight the critical role of tumor heterogeneity in driving therapeutic resistance and how convergent targeted therapy strategies blocking common signaling nodes capable of overcoming multiple resistance mechanisms may be needed.
Citation Format: Ryan B. Corcoran. Overcoming drug resistance and tumor heterogeneity in gastrointestinal cancers [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA15.
Abstract IA21: PARP trapping and Schlafen 11 to kill cancer cells
Authors: Pommier Yves G. , Murai Junko 
Published: May 2019

Abstract
Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARP inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small-cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs.
Citation Format: Yves G. Pommier, Junko Murai. PARP trapping and Schlafen 11 to kill cancer cells [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA21.
Abstract A10: Withaferin-A, a natural compound inhibits AKT-induced metastatic colorectal cancer
Authors: Suman Suman , Das Trinath P. , Damodaran Chendil 
Published: May 2019

Abstract
The survival rate of metastatic colorectal carcinoma (CRC) is less than 5%. Use of 5-fluorouracil (5-FU), radiation, and surgery are the primary treatments; however, most metastatic cancers eventually cause death. Developing approaches to prevent progression to metastasis could therefore be part of an important therapeutic strategy, especially for high-risk patients, including those patients already diagnosed with high grade polyps or localized colon cancer. In our preclinical and clinical data, we hypothesized that accumulation of AKT (protein kinase-B) is a critical step in the aggressive phenotype of disease. The metastatic cascade of CRC involves the crucial process of the epithelial–mesenchymal transition (EMT), which endows cancer cells with migratory and invasive capabilities via acquisition of a mesenchymal phenotype. These characteristics also contribute to cellular resistance to chemotherapeutic drugs.
Withaferin-A (WA) is a potent herbal molecule from withania sominefera herbal plant, inhibited CRC growth by down regulating AKT signaling. Furthermore, over expression of AKT significantly increased cell proliferation, aggressiveness and angiogenesis of colon tumors in xenograft models. However, WA overcomes AKT mediated growth in both cell culture and animal models by transcriptionally down regulating Epithelial Mesenchymal Transition (EMT) related transcription factors and genes such as Snail, Slug and β-catenin. We also found AKT expression is steadily increased in CRC patients in a stage specific manner, suggesting accumulation of AKT could be a critical step for CRC metastasis. We found that WA binds to AKT with a predicted affinity of -10.6 kcal/mol and inhibited its activation. We have identified several novel WA–derived analogs which may be more potent than the parental compound with high AKT binding affinity. We have identified a potent analog which inhibited AKT kinase activity and induced growth arrest (~30 times potent) more significantly than WA. Currently, we are testing the invivo efficacy of the potent analog of WA, which could be a used as a novel agent for chemoprevention and/or chemotherapy of colon cancer.
Citation Format: Suman Suman, Trinath P. Das, Chendil Damodaran. Withaferin-A, a natural compound inhibits AKT-induced metastatic colorectal cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A10.
Abstract A31: Omega-3 fatty acids may regulate levels of pAkt through a mechanism independent of PI3K
Authors: Zhu Lingji , Marsacarinas Windel Emman T. , Principe Daniel R. , Grippo Paul J. 
Published: May 2019

Abstract
The effects of dietary factors on pancreatic cancer have been proposed to augment etiology of disease, yet the mechanisms involved are poorly understood. Our previous work demonstrated that omega-6 fatty acid rich diets have been associated with increased severity of pancreatic neoplasia, but conversely, omega-3 fatty acid rich diets have chemoprotective effects against Kras-induced pancreatic neoplasia. Also, our more recent data indicates that docosahexaenoic acid (DHA, omega-3 fatty acid) and linoleic acid (LA, omega-6 fatty acid) have opposing effects on protein kinase B (Akt)-mediated mitogenic signaling in Human Pancreatic Duct Epithelial cells in vitro. Furthermore, published studies suggest that one mechanism of action may be through cyclooxygenase (COX)-2 derived prostaglandin E2 (PGE2) secretion leading to cell proliferation. In our current work, we demonstrate that DHA treated HPDE cells do not generate a change in phosphorylated Akt (pAkt) levels and proliferation between cells with or without COX-2 inhibition. As a major maker of proliferation, Akt is often activated by phosphatidylinositol 3 kinase (PI3K), which facilitates conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol trisphosphate (PIP3), and PIP3 phosphorylates Akt. Yet the effects of DHA are not directly at the level of PI3K, as HPDE cells treated with a PI3K inhibitor (LY294002), a significantly further reduction in DHA-induced decrease of pAkt. Therefore, it is likely that DHA may not mediate pAkt through PI3K, and we propose that due to its high lipid solubility, DHA may interact with membrane-tethered targets including PIP2.
Citation Format: Lingji Zhu, Windel Emman T. Marsacarinas, Daniel R. Principe, Paul J. Grippo. Omega-3 fatty acids may regulate levels of pAkt through a mechanism independent of PI3K. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A31.
Abstract A33: The novel ways to inhibit atrophy of thymus and reconstructing the immune function in preventing the advance of tumor
Authors: Xu Jie , Xu Ze , Tovanich Sitthipol , Wu Bin 
Published: May 2019

Abstract
Objective: The objective of this research was to search the new ways to reconstruct the immune function.
Methods: 200 Kunming mice, 5 to 6 weeks old, divided into 8 Groups: control group bearing tumors (Group B, n=9);observation group for combined transplantation of fetal liver, spleen and thymus cells(Group CI, n=15); observation group(Group CII, n=15; carry on combined transplantation to this group once a week for successive 5 weeks and then execute the mice);treatment group with transplantation of fetal liver cells (Group F);treatment group with transplantation of fetal spleen cells (Group G); treatment group with transplantation of fetal thymus cells (Group H); treatment group with combined transplantation of fetal liver and spleen cells (Group I);treatment group with combined transplantation of fetal liver and thymus cells (Group K), nF=nG=nH=nI=nJ=nK= 12. First, prepare mice of ascitic type after the anabiosis of the root of Ehrlich ascites tumor; when the ascites are formed, draw out the ascites of the cancer cells and collect them to inoculate the experimental mice under the skin of the right hollow viscera to make the subcutaneous solid tumor model bearing Ehrlich Ascites tumor. When the model is prepared, carry out correspondent cell transplantation once a week for each group. After prepared of the suspension of fetal liver, spleen and thymus, they were transplanted into above animal models to record the tumor growth, disappear, survival time, the immune function and the tissue pathology change and compared each experimental group number.
Results: The results showed that in three experimental groups the rate which the tumors were completely disappeared is 40% in the early stages and the rate which the tumors were completely disappeared in the later stage is 46.67%. After the tumors completely disappeared, the animals can survive for a long time. The partial disappeared rate is 26.67% in the early group and is 13.33% in the long-term group. In the partial group the average survival time is above one month which the immune function increase and immune organ enlarge. The immune organ histology slides showed that the organ cells proliferation increased.
Conclusion: Reconstitution of immune system organ completely and partially can help the host to fight the tumor and to improve the treatment effects.
Citation Format: Jie Xu, Ze Xu, Sitthipol Tovanich, Bin Wu. The novel ways to inhibit atrophy of thymus and reconstructing the immune function in preventing the advance of tumor. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A33.