bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 843: Coffee consumption and risk of renal cell carcinoma: A meta-analysis of cohort evidence
Authors: Rhee Jongeun , Lim Rachel , Purdue Mark P. 
Published: July 2021

Abstract
Background: Coffee consumption has been associated with a reduced risk of some cancers, although for renal cell carcinoma (RCC) the evidence is inconclusive. Several cohort analyses investigating coffee intake and RCC have been conducted, although most have been limited by small case numbers. To summarize the cohort evidence of this relationship, we conducted a meta-analysis.
Methods: A literature search was performed in PubMed, Embase and The Cochrane Library for all studies published up to May 2020 using the key words “cancer”, “tumor”, “carcinoma”, “malignant neoplasm”, “renal cell carcinoma”, “kidney cancer”, “renal cancer” “coffee”, “caffeine” and “beverages”. Additionally, the reference lists of all retrieved articles and previous meta-analysis studies were checked to identify additional studies. From our collection of full-text articles (n=7219) we excluded irrelevant topic articles (n=7125), non-English articles (n=2), systematic reviews or editorial letter (n=46), relevant articles not reporting measure of association (n=9), case-control studies (n=27). Following these exclusions, 10 cohort studies remained. Meta-analyses using a random effects model were conducted for relative risks (RRs) contrasting the highest vs lowest level of coffee intake per day. In addition, meta-analyses were conducted for reported sex-specific findings as well as findings restricted to non-smokers. Between-study heterogeneity was assessed using Cochran Q-statistic and quantified by Higgins I2 statistic.
Results: In a meta-analysis of the 10 identified studies, we found a summary RR of 0.88 (95% CI 0.78-0.99) relating the highest study category of coffee intake (vs. the lowest category or non-drinkers) and renal cancer risk, with no significant between-study heterogeneity observed (I2=35%, p = 0.13). The summary RR was comparable for men and women (0.89 and 0.85 respectively). A slightly stronger inverse association was observed among non-smokers (RR 0.78, 95% CI 0.59-1.03), although with moderate evidence of study heterogeneity (I2=62%, p = 0.07).
Conclusions: In this meta-analysis of cohort evidence, we observed overall evidence suggestive of a weak inverse association between higher coffee consumption and lower renal cancer risk.
Citation Format: Jongeun Rhee, Rachel Lim, Mark P. Purdue. Coffee consumption and risk of renal cell carcinoma: A meta-analysis of cohort evidence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 843.
Abstract 85: Metastasizing melanoma cells exhibit increased dependence on the pentose phosphate pathway to manage oxidative stress
Authors: Aurora Arin B. , Khivansara VIshal , Leach Ashley , Martin-Sandoval Misty , Mathews Thomas , Morrison Sean J. 
Published: July 2021

Abstract
To study distant metastasis we developed a patient-derived xenograft (PDX) assay in which melanoma cells from patients spontaneously metastasize in NOD/SCID IL2Rγnull (NSG) mice in a manner that correlates with metastatic behavior in patients (Sci Transl Med 4:159). Using this assay, we discovered that distant melanoma metastasis is limited by oxidative stress (Nature 527:186). Reactive Oxygen Species (ROS) increase dramatically in melanoma cells as they metastasize through the blood. The rare cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We found that metastatic melanomas had significant increases in metabolites from the pentose phosphate pathway as compared to primary cutaneous melanomas. Metabolites in the oxidative branch of the pentose phosphate pathway, downstream of the NADPH-regenerating enzyme Glucose-6-Phosphate Dehydrogenase (G6PD), were the most dramatically increased in metastatic nodules. We hypothesized that metastasizing melanoma cells increase their dependence on the pentose phosphate pathway in order to manage oxidative stress. We used CRISPR gene editing to create loss-of-function mutations in G6PD in patient-derived melanomas. When transplanted into NSG mice, the tumors formed by G6PD mutant melanomas showed significantly reduced oxidative pentose phosphate pathway activity, increased ROS levels, decreased NADPH/NADP ratios, and reduced metastatic potential as compared to parental control melanomas. Our results demonstrate that metastasizing melanoma cells exhibit increased dependence upon the pentose phosphate pathway as compared to primary cutaneous tumors. Untargeted metabolomics revealed that G6PD mutant melanomas exhibit increased glutamine utilization, perhaps to compensate for increased oxidative stress.
Citation Format: Arin B. Aurora, VIshal Khivansara, Ashley Leach, Misty Martin-Sandoval, Thomas Mathews, Sean J. Morrison. Metastasizing melanoma cells exhibit increased dependence on the pentose phosphate pathway to manage oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 85.
Abstract 93: Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression
Authors: Chen Xi , Wang Jennifer Rui , Henderson Ying , Yan Yuanqing , Bai Shanshan , Kieser Rachel , Hu Min , Wang Jiping , Navin Nicholas , Lai Stephen , Gao Ruli 
Published: July 2021

Abstract
Anaplastic thyroid cancer (ATC) is arguably the most lethal human malignancy, with a median survival of ~12 weeks. About half of ATC tumors arise from within differentiated forms of thyroid cancer types, most commonly papillary thyroid cancer (PTC), suggesting an evolutionary continuum from PTC to ATC. In contrast to the extreme lethality of ATC, PTC are typically indolent with long life-histories. The molecular mechanisms driving ATC progression from PTC have been challenging to resolve, mostly due to the heterogenous cellular populations that are undergoing dynamic changes during ATC progression. In this study, we applied high throughput 3'-scRNAseq in an unbiased analysis of cell populations in thyroid tumors. We analyzed 90,990 single cell transcriptomes from 8 ATC tumors, 8 PTC tumors and 5 normal thyroids. To make the precise inference of tumor cell lineages, we stratified the epithelial cells into 5 categories by calculating genotypes from scRNAseq data that include: (1) normal epithelial cells in normal thyroids, (2) PTC epithelial cells in PTC tumors, (3) PTC tumor cells in PTC tumors, (4) ATC epithelial cells in ATC tumors, (5) ATC tumor cells in ATC tumors. We then constructed the full epithelial cell development trajectories from normal epithelial to PTC and ATC tumor cells. Our results show that co-existing epithelial and mesenchymal phenotypes is a major characteristic of ATC tumor cells and epithelial-mesenchymal transition (EMT) drives ATC developmental trajectory. We further analyzed the transcriptional programs of immune cell types and their interactions with tumor cells. Our data suggested a unique sub-population of helper T cell and a distinct B cell subtype arise in the tumor microenvironment in response to ATC progression. Collectively, our results identify EMT as the major driving force of thyroid cancer aggressiveness and provide novel insights regarding the immunological remodeling in response to ATC progression.
Citation Format: Xi Chen, Jennifer Rui Wang, Ying Henderson, Yuanqing Yan, Shanshan Bai, Rachel Kieser, Min Hu, Jiping Wang, Nicholas Navin, Stephen Lai, Ruli Gao. Single cell transcriptome analysis maps dynamic epithelial mesenchymal transition and immunological remodeling in thyroid cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 93.
Abstract 934: Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors
Authors: Thompson Kristin M. , McGuire Christina , Yuan Jin , Ball Aaron , Sonberg Justin , Wang Yuxun , Zhu Shuhao 
Published: July 2021

Abstract
Aptamers are short oligonucleotides that recognize specific molecular targets due to their folded three-dimensional structures. Aptamers are generated against a target molecule using a process called SELEX. This method allows the in vitro evolution of nucleic acid molecules with highly specific binding to target molecules. Here we describe a nuclease stable, fully modified 2'OMethyl aptamer that recognizes Glypican-3 (GPC3) with high affinity and specificity. GPC3 is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of liver cancers, but not in healthy adult tissues. A conjugate comprising a GPC3 aptamer and Drug Maytansinoid (DM1), a membrane-permeable inhibitor of tubulin which can prevent cell division, is used to specifically target GPC3 expressing cells in vitro and in vivo. The aptamer-drug conjugate (GRX54) is capable of selectively killing a variety of GPC3 expressing liver cells in vitro and has significantly less toxicity in cells not expressing GPC3. The anti-tumor effect of GRX54 was tested in several tumor xenograft mouse models: Hep3B xenograft, Balb/c nude mice and NCI-H446 xenograft, Balb/c nude mice. GRX54 was administered at different doses via intraperitoneal injection (IP). For each group, mice were administered with vehicle or GRX54 once a day (QD) for 3, 5 or 7 days. Tumor weight and growth were measured. An anti-cancer drug Sorafenib Tosylate (30mg/kg, oral administration, once a day - Hep3B xenograft mouse model) or irinotecan (40mg/kg, i.p. twice a day for 4 days - NCI-H446 xenograft mouse model) were used as positive controls. GRX54 decreases Hep3B tumor volume in a Balb/c nude mouse xenograft model by ~30-45% depending on treatment schedule and NCI-H446 tumor volume by ~45-90% depending on treatment schedule. Together, our data show that GRX54 is a novel GPC3-targeting molecule capable of reducing tumor size with IP injection.
Citation Format: Kristin M. Thompson, Christina McGuire, Jin Yuan, Aaron Ball, Justin Sonberg, Yuxun Wang, Shuhao Zhu. Identification of a GPC3 specific RNA aptamer and its use in cell specific targeted killing of GPC3 expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 934.
Abstract 942: ErbB3 overexpression unleashed by miR-205 epigenetic silencing is a therapeutic target in glioblastoma
Authors: De Bacco Francesca , Orzan Francesca , Erriquez Jessica , Casanova Elena , Barault Ludovic , Albano Raffaella , D'Ambrosio Antonio , Bigatto Viola , Reato Gigliola , Patané Monica , Pollo Bianca , Kuesters Geoffrey , Dell'Aglio Carmine , Casorzo Laura , Pellegatta Serena , Finocchiaro Gaetano , Comoglio Paolo M. , Boccaccio Carla 
Published: July 2021

Abstract
In glioblastoma (GBM), the most frequent and lethal brain tumor, targeted therapies suppressing commonly altered signaling pathways has remained so far disappointing. However, in selected patient subsets, specific genetic alterations can confer sensitivity to targeted agents. In this study, by generating an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, we identified a human GBM subset (around 9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. This was driven by inheritable epigenetic or post-transcriptional silencing of the oncosuppressor miR-205 and sustained the malignant phenotype. Unexpectedly, ERBB3, known to be devoid of autonomous signaling properties, was overexpressed in the absence of the other members of the EGFR family, but behaved as a specific signaling platform for FGFRs. ERBB3/FGFR dimerization led to hyperactivation of the PI3K/AKT/mTOR pathway and consequent upregulation of glycolysis, oxidative metabolism and de novo fatty acid biosynthesis. Treatment with a specific antibody (MM121) preventing ERBB3 association with FGFR caused metabolic shutdown and consequent proliferative arrest and apoptosis induction in vitro. Moreover, experimental tumors regenerated through ERBB3 overexpressing stem-like cell transplantation reproduced the features of the original GBMs and, upon treatment with the anti-ERBB3 antibody, significantly regressed. These findings identify a subset of GBM patients where exploitation of an ERBB3-targeted therapy could be effective.
Citation Format: Francesca De Bacco, Francesca Orzan, Jessica Erriquez, Elena Casanova, Ludovic Barault, Raffaella Albano, Antonio D'Ambrosio, Viola Bigatto, Gigliola Reato, Monica Patané, Bianca Pollo, Geoffrey Kuesters, Carmine Dell'Aglio, Laura Casorzo, Serena Pellegatta, Gaetano Finocchiaro, Paolo M. Comoglio, Carla Boccaccio. ErbB3 overexpression unleashed by miR-205 epigenetic silencing is a therapeutic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 942.
Abstract 947: Effects of methadone on ovarian cancer cell-lines and patient-derived tumor-spheroids
Authors: Fiegl Heidelinde , Hagenbuchner Judith , Ausserlechner Michael J. , Kyvelidou Christiana , Seeber Beata , Sopper Sieghart , Tsibulak Irina , Wieser Verena , Roessler Julia , Reiser Elisabeth , Huhtinen Kaisa , Carpén Olli , Parson Walther , Marth Christian , Zeimet Alain G. 
Published: July 2021

Abstract
Background: D,L-Methadone exerts analgesic effects via the mu opioid receptor, encoded by OPRM1 and therefore plays a role in chronic pain management. Although the use of this opioid-receptor agonist as an anti-cancer drug is deemed controversial, this drug is gaining popularity in Europe as an “off-label” therapy despite insufficient research to support its benefits. In preclinical glioblastoma and leukaemia cell culture models D,L-methadone showed apoptotic and chemo-sensitizing effects. Its effects in ovarian cancer (OC) are completely unexplored.
Methods: We analysed the OPRM mRNA expression in six cisplatin-sensitive, two cisplatin-resistant OC cell-lines, 192 OC samples and 12 non-neoplastic control tissues. Pro-angiogenetic, cytotoxic and apoptotic effects of D,L-methadone were evaluated in OC cell-lines and four patient-derived tumor-spheroid models.
Results: OPRM1 was transcriptionally expressed in 69% of OC-tissues and in five of eight OC cell-lines. D,L-methadone exposure significantly reduced cell-viability in five OC cell-lines irrespective of OPRM1 expression. D,L-methadone, applied alone or combined with cisplatin, showed no significant effects on apoptosis or VEGF secretion in cell-lines. Notably, in two of the four spheroid models, treatment with D,L-methadone resulted in significantly enhanced cell growth (by up to 121%), especially after long-term exposure. This is consistent with the observed attenuation of the inhibitory effects of cisplatin in three spheroid models when adding D,L-methadone. The effect of methadone treatment on VEGF secretion in tumor-spheroids was inconclusive.
Conclusions: Our study demonstrates that certain OC samples express OPRM1, which, however, is not a prerequisite for D,L-methadone function. As such, D,L-methadone may exert detrimental effects by stimulating the growth of certain OC-cells and abrogating cisplatin's therapeutic effect.
Citation Format: Heidelinde Fiegl, Judith Hagenbuchner, Michael J. Ausserlechner, Christiana Kyvelidou, Beata Seeber, Sieghart Sopper, Irina Tsibulak, Verena Wieser, Julia Roessler, Elisabeth Reiser, Kaisa Huhtinen, Olli Carpén, Walther Parson, Christian Marth, Alain G. Zeimet. Effects of methadone on ovarian cancer cell-lines and patient-derived tumor-spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 947.
Abstract 954: AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma
Authors: Capoccia Benjamin J. , Donio Michael J. , Richards John O. , Hiebsch Ronald R. , Puro Robyn J. , Kashyap Arun K. , Pereira Daniel S. 
Published: July 2021

Abstract
Overexpression of CD47 by tumor cells exploits an immune checkpoint that prevents tumor recognition and destruction by innate immune cells. Binding of tumor CD47 to SIRPα on macrophages and dendritic cells triggers a “don't eat me” signal that inhibits phagocytosis enabling escape from innate immune surveillance. Blockade of the CD47/SIRPα axis enables immune recognition and phagocytic clearance of tumor cells. We have developed a clinical stage CD47 targeting antibody AO-176, that is highly differentiated among agents in this class. AO-176 not only blocks the CD47/SIRPα interaction to induce tumor cell phagocytosis, but also: a) directly induces solid and hematologic tumor cell cytotoxicity and damage-associated molecular patterns (DAMPs); b) preferentially binds tumor versus normal cells, which is correlated with β1-integrin expression and localization; c) negligibly binds RBC; and d) exhibits improved binding at acidic pH as found in tumor microenvironments.Previously we have shown that AO-176 is efficacious in a variety of solid tumor xenograft models as well as in models of multiple myeloma and AML. Here, we show the therapeutic potential of AO-176 in pre-clinical models of lymphoma where CD47 is upregulated and associated with poor prognosis. Using a variety of cell based and in vivo models we show that AO-176 demonstrates increased binding to lymphoma cells at an acidic versus physiologic pH and that this binding and blocking of the do not eat me signal leads to enhanced phagocytosis of lymphoma cells either alone or in combination with rituximab. In addition, we show that AO-176 induces annexin V positivity in lymphoma cells as well as inducing a variety of DAMPs that ultimately may aid in inducing immunogenic cell death of the lymphoma cells. We also demonstrate that AO-176 is a potent tumor growth inhibitor in lymphoma xenograft models and appears to induce immune infiltrates as well as inflammatory cytokines.Taken together, these data show that AO-176 has strong therapeutic potential in lymphoma. AO-176 is currently being evaluated in clinical trials of select solid tumors (NCT03834948) and multiple myeloma (NCT04445701).
Citation Format: Benjamin J. Capoccia, Michael J. Donio, John O. Richards, Ronald R. Hiebsch, Robyn J. Puro, Arun K. Kashyap, Daniel S. Pereira. AO-176, a highly differentiated clinical stage anti-CD47 antibody, is efficacious in pre-clinical models of lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 954.
Abstract 965: The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis
Authors: Chen Xiang , Hicks John M. , Sarkar Poonam , Gaber Waleed M. , MAN Tsz-Kwong 
Published: July 2021

Abstract
Despite the use of chemotherapy and surgery, the development of metastasis remains to be the leading cause of death in patients with osteosarcoma. LOX encodes for lysyl oxidase, which is an enigmatic molecule in cancer by acting as a tumor suppressor in certain tumors, but a metastatic promoter in other tumors. To investigate the function of LOX, we generated LOX overexpression mutants in two osteosarcoma cell lines and showed that higher LOX expression promoted tumor cell proliferation and invasiveness. Using an orthotopic xenograft mouse model, we further showed that osteosarcoma cells with higher LOX expression produced a higher number of mice with pulmonary metastases than the parental cell line (n=9). To characterize the mechanism of LOX-mediated metastasis, we examined the protein expression of a panel of potential downstream targets. The results demonstrated that phospho-FAK (focal adhesion kinase) expression was increased in the LOX-overexpression mutant relative to the parental cell line. Using a small molecule inhibitor of FAK, we showed that it significantly reduced the LOX-mediated metastasis in the orthotopic xenograft model. To demonstrate the clinical significance of our findings, we analyzed the expression profiling and RNAseq datasets recently generated from the TARGET osteosarcoma study. A Kaplan-Meier analysis showed that a higher level of LOX expression significantly correlated with a poor outcome (p &lt; 0.05) and a multivariate analysis indicated LOX remained to be significant after controlling for initial metastatic status. In addition, we have previously shown that p27 is frequently mislocalized in the cytoplasm of osteosarcoma cells and drives the development of metastasis through interacting with the PAK1-mediated actin cytoskeleton network. Our results showed that the expression of LOX was upregulated in p27-mislocalized osteosarcoma cell lines with high metastatic potential. A tissue microarray analysis showed that cytoplasmic p27 expression significantly correlated with LOX expression (p = 0.003). Together, our findings suggest that a novel link between p27 mislocalization and LOX expression. LOX plays a pivotal role in osteosarcoma metastasis by upregulating FAK phosphorylation. FAK inhibition is a potential therapeutic strategy to reduce the development of metastasis in osteosarcoma with LOX overexpression.
Citation Format: Xiang Chen, John M. Hicks, Poonam Sarkar, Waleed M. Gaber, Tsz-Kwong MAN. The role of LOX-mediated FAK phosphorylation in osteosarcoma metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 965.
Abstract 967: Phosphodiesterase 4D depletion enhances anti-tumor effects of tyrosine kinase inhibitor in renal cell carcinoma involving CRAF-ERK pathway
Authors: Cao Minghua , Ajay Amrandra K. , Gasser Martin , Hsiao Li-LI , Waaga-Gasser Ana Maria 
Published: July 2021

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitors are widely used but are not curative and various resistant mechanisms have been described. Previous studies have indicated a crosstalk between the cAMP pathway and the MAPK pathway, and the elevation of cAMP levels by Phosphodiesterase 4 (PDE4) inhibition can result in growth arrest and/or cell death. In this study we focused on the effects of PDE4 in ccRCC. We showed for the first time that PDE4D is the dominant subtype of PDE4 in kidney. PDE4D depletion in ccRCC, Caki-1 cells, using CRISPR Knock Out (KO) enhanced sensitivity of Tyrosine Kinase Inhibitor (TKI), sorafenib and increased cytotoxicity. We also showed synergistic effects of PDE4 inhibitor, roflumilast and sorafenib, in increasing cytotoxicity of ccRCC in the absence of PDE4D. Our results further demonstrated that PDE4D deficiency increased intracellular cAMP levels and resulted in downregulation of MAPK but not PI3K/AKT signaling in a CRAF dependent manners. In conclusion, we provide a preclinical rationale for dual PDE4/VEGFR inhibition in patients with ccRCC. While the MAPK signaling pathway is activated in ccRCC, dual inhibitions may improve the anti-tumor effects in patients with proven CRAF signaling activation.
Citation Format: Minghua Cao, Amrandra K. Ajay, Martin Gasser, Li-LI Hsiao, Ana Maria Waaga-Gasser. Phosphodiesterase 4D depletion enhances anti-tumor effects of tyrosine kinase inhibitor in renal cell carcinoma involving CRAF-ERK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 967.