bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 348: Efficacy of triple combination treatment with trametinib, mebendazole and CD133 RNA aptamer in recalcitrant NRAS-mutant melanoma cells
Authors: Haribabu Yoga , Chien Raymond , Alobaidi Ryyan , Kuo Li-Wei , Islam Nusrat , Simbulan-Rosenthal Cynthia M. , Rosenthal Dean S. 
Published: June 2022

Abstract
Malignant melanoma is the most aggressive form of skin cancer. Although kinase inhibitors have proven to be efficient with promising clinical results, the development of drug resistance is one of the major issues in targeted therapy. CD133, also known asProminin-1, is a membrane glycoprotein studied extensively as a cell surface marker for cancer stem cells. In our previous studies, mebendazole, a repurposed broad spectrum anti-helminthic agent, inhibited the growth of NRAS mutant melanoma cells in combination with trametinib, a MEK inhibitor. However, a CD133-positive cancer stem cell population remain resistant to this targeted therapy. Use of RNA aptamers in diagnostic as well as therapeutics has been studied recently in different types of cancer cells. Drug delivery of aCD133 aptamer coupled with doxorubicin has been found to inhibit the growth of liver cancer cells. In this study, we targeted the cancer stem cells expressing CD133 with RNA aptamers, in combination with trametinib and mebendazole to sensitize the cells to the combination treatment. Patient derived melanoma cell lines, BAKP and POT, harboring BRAFWT/NRASQ61K and BRAFWT/NRASQ61R driver mutations, were co-transduced with aTet-on vector expressing CD133 and a Tet activator. The doxycycline-induced and uninduced cells were subjected to single agent treatment with 100 nM trametinib, 100 nM mebendazole or 100 nM CD133 RNA aptamer, as well as dual and triple agent combinations for 24 or 48 hours. XTT cell viability and apoptotic assays such as AnnexinV-PI flow cytometry analysis revealed that the triple combination with trametinib, mebendazole and the CD133 aptamer was the most effective in inducing apoptotic cell death, even in the doxycycline-induced CD133-overexpressing melanoma cells. Further studies will use preclinical in vivo mouse xenograft models to investigate the effects on tumor growth of CD133 RNA aptamers in combination treatments, potentially making it available for clinical trials aiming to improve patient response to therapeutics against drug-resistant melanoma cells.
Citation Format: Yoga Haribabu, Raymond Chien, Ryyan Alobaidi, Li-Wei Kuo, Nusrat Islam, Cynthia M. Simbulan-Rosenthal, Dean S. Rosenthal. Efficacy of triple combination treatment with trametinib, mebendazole and CD133 RNA aptamer in recalcitrant NRAS-mutant melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 348.
Abstract 3587: Racial disparity in COVID-19 severity after adjusting for chronic illnesses and sociodemographic factors
Authors: Wu Xiao-Cheng , Yi Yong , Maniscalco Lauren S. , Hsieh Mei-Chin , Gruber DeAnn , Mendoza Lee , Sokol Theresa , Mederos Eileen T. , Ochoa Augusto 
Published: June 2022

Abstract
Background. Research has reported that African American (AA) cancer patients with COVID-19 had a higher hospitalization rate than their white counterparts. Because the severity of COVID-19 is partly related to existing chronic diseases, one of the speculations is that racial differences in COVID-19 severity are attributable to AA cancer patients having a higher prevalence of chronic illnesses. Our study aimed to assess the impact of existing chronic diseases on the racial differences in hospitalization and length of hospitalization in COVID-19 cancer patients in Louisiana.
Methods. We linked cancer cases diagnosed in 2015-2019 from the Louisiana Tumor Registry (LTR) with the statewide COVID-19 data to identify COVID-19 patients who had been previously diagnosed with cancer. We also identified chronic illnesses (i.e., heart disease, peripheral vascular and cerebrovascular diseases, pulmonary disease, renal disease, liver disease, diabetes, and others) from 2012-2020 hospital discharge data and LTR data. Age and census tract level poverty were at the time of COVID-19 diagnosis. Bivariate and multivariable logistic regressions were used to exam the association of race with hospitalization after adjusting for socio-demographic and chronic illnesses. The multivariable Poisson model was used to assess the racial disparity in length (in days) of hospitalization.
Results. Of 6,518 COVID-19 cancer patients, there were 30.8% AA, 68.4% whites, and 0.8% other races. AA, male, older, residing in high poverty, and patients with chronic illnesses were more likely (P&lt;0.05) to be hospitalized. The odds of hospitalization was 87.2% higher among AA patients than white patients in bivariate analysis. After adjusting for age, gender, poverty, obesity, smoking status, and chronic illnesses, the odds of hospitalization was still higher for AA than white patients (OR=1.81;95% CI: 1.55-2.09). The length of hospital stay for AA was more (P&lt;0.05) than whites After adjusting for the same covariates.
Conclusion. Sociodemographic factors and chronic illnesses are associated with the severity of COVID-19 among cancer patients. However, AA COVID-19 cancer patients have significantly higher odds of hospitalization and longer hospital stays even when controlling these factors. More research is warranted to determine underlying factors of the observed racial disparities.
Citation Format: Xiao-Cheng Wu, Yong Yi, Lauren S. Maniscalco, Mei-Chin Hsieh, DeAnn Gruber, Lee Mendoza, Theresa Sokol, Eileen T. Mederos, Augusto Ochoa. Racial disparity in COVID-19 severity after adjusting for chronic illnesses and sociodemographic factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3587.
Abstract 366: Combinatorial effect of fisetin and paclitaxel encapsulated PBM nanoparticles in ovarian cancer therapy
Authors: McFadden Melayshia , Singh Santosh Kumar , Singh Rajesh 
Published: June 2022

Abstract
High-grade Serous Ovarian Cancer (HGSOC) accounts for 68% of Ovarian Cancers (OvCas). It is a clinically aggressive neoplasm that even after treatment, a substantial proportion of advanced OvCas will develop resistance within 18 months. Thus, it is imperative to formulate anti-cancer agents that target cancer cells without affecting normal cells. The proposed study evaluated a novel method for targeted delivery of fisetin alone or combined with paclitaxel (PTX) at desired rates. We have used a natural polysaccharide (starch; FDA approved) as a core for planetary ball milled (PBM) nanoparticles which binds high-affinity folate receptors on OvCa cells via folate conjugated poly (ε-caprolactone)/poly (ethylene glycol) copolymer coating of the PBM nanoparticles. Treatment of OvCa cells (CAOV-3 and OVCAR-3) with PBM-NPs has shown its cytotoxic effect. The cell viability (MTT) assay was performed to determine the optimal IC50 values of fisetin, PTX alone, and in combination. These particles are rapidly internalized and induce significant cancer cell death at lower doses than unformulated fisetin or PTX. Importantly, negative controls showed that PBM nanoparticles without fisetin or paclitaxel have no toxic effects on OvCa cells. The immunofluorescence study confirmed the effectiveness of the combined drug; dead nuclei were found more within the cells treated by the combination than fisetin or PTX alone. The combined drug treatment was most effective in inhibiting proliferation and inducing apoptosis; accordingly, it showed noticeable increases in pro-apoptotic (BAX, BID), apoptotic (PARP, Caspase-3), and decreases in anti-apoptotic genes (BCL-XL and MCL-1) gene in a western blot and RT-PCR analysis. Taken together, we observed that the combination of PTX and fisetin resulted in significant cytotoxicity and apoptosis as compared to alone. Our results suggest that fisetin can be a potential agent in enhancing the efficacy of PTX in OvCa treatment. These finding highlights the promising role of natural bioactive compounds and provide the rationale for further transitional research.
Citation Format: Melayshia McFadden, Santosh Kumar Singh, Rajesh Singh. Combinatorial effect of fisetin and paclitaxel encapsulated PBM nanoparticles in ovarian cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 366.
Abstract 369: Improving the nanomaterial delivery by using cell-penetrating peptides in the bystander manner
Authors: Li Yue-Xuan , Wei Yushuang , Pang Hong-Bo 
Published: June 2022

Abstract
While nanoparticles (NPs) can be useful to improve the diagnosis and treatment of various diseases including cancer, a major limiting factor for their applications is the poor efficiency of cell entry. A common solution to this problem is to covalently link NPs with cell-penetrating peptides (CPPs), such as the transactivator of transcription (TAT) peptide. A few cationic CPPs were previously shown to increase the cellular uptake of co-administered, but not covalently coupled, NP cargo through an endocytic pathway, macropinocytosis. This so-called bystander uptake process is of unique advantage for NP intracellular delivery as it bypasses the requirements of additional chemical modifications. Here, we set out to determine whether other classes of CPPs (e.g. hydrophobic and amphiphilic) exhibit similar bystander activities, and what physico-chemical properties of NPs affect the bystander uptake process. First, we discovered that transportan (TP) peptide, an amphiphilic CPP, can initiate similar bystander uptake process for a variety of NPs and solute tracers. TP-induced bystander uptake relies on macropinocytosis as well, and occurs in a variety of cell types and in physiological tissues. Second, using TAT-functionalized NPs to stimulate the bystander effect, we showed that the bystander activity depends on the size of bystander NPs, with an optimal range around 50 nm in diameter. Compared to rod-like and triangular NPs, spherical NPs showed higher uptake in the bystander manner. Additionally, we investigated how CPP-NPs, once inside cells, get out of one cell and enter another, and found again that NP sizes affect the efficiency of CPP-NP intercellular transport as well. Overall, these efforts lay the foundation to further understand the bystander activity of CPP-assisted cell entry and improve the efficacy of nanomedicine in cancer and other human diseases.
Citation Format: Yue-Xuan Li, Yushuang Wei, Hong-Bo Pang. Improving the nanomaterial delivery by using cell-penetrating peptides in the bystander manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 369.
Abstract 3822: Chromosomal instability shapes the tumor microenvironment through a chronic ER-stress response
Authors: Li Jun , Hubisz Melissa , Earlie Ethan , Duran Mercedes A. , Lettera Emanuele , Phyu Su M. , Amin Amit D. , Deyell Matthew , Kamiya Erina , Budre Karolina , Cavallo Julie-Ann , Garris Christopher , Wen Hannah , Izar Benjamin , Parkes Eileen , Laughney Ashley , Bakhoum Samuel 
Published: June 2022

Abstract
Chromosomal instability (CIN) is a cancer hallmark associated with cancer metastasis and immune evasion. Yet, it is unclear how CIN modulates the tumor-microenvironment (TME). Here we show that CIN results in a protumor TME with enrichment of immune-suppressive macrophages, a granulocytic infiltrate, and exhausted T cells. Using ContactTracing, a newly developed computational tool to infer conditionally dependent cell-cell interactions from single cell RNA sequence data, we identify tumor ligands induced by the ER stress response in cancer cells as central mediators of immune suppression. Mechanistically, CIN-dependent chronic activation of the cytosolic DNA sensing cGAS-STING pathway promotes ER-stress-dependent transcription. Suppression of CIN or depletion of cancer cell STING reduces ER-stress and restores CIN-induced changes on the TME. Correspondingly, chronic STING activation in human breast cancer patients is associated with reduced tumor infiltrating lymphocytes and increased metastasis. Remarkably, pharmacologic inhibition of chronically active STING or depletion of downstream ER stress signaling suppresses metastasis in syngeneic models of melanoma, breast, and colorectal cancers, thereby demonstrating a viable therapeutic strategy for chromosomally unstable cancers.
Citation Format: Jun Li, Melissa Hubisz, Ethan Earlie, Mercedes A. Duran, Emanuele Lettera, Su M. Phyu, Amit D. Amin, Matthew Deyell, Erina Kamiya, Karolina Budre, Julie-Ann Cavallo, Christopher Garris, Hannah Wen, Benjamin Izar, Eileen Parkes, Ashley Laughney, Samuel Bakhoum. Chromosomal instability shapes the tumor microenvironment through a chronic ER-stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3822.
Abstract 3829: Microenvironmental stiffness induces metabolic reprogramming in glioblastoma
Authors: Sohrabi Alireza , Lefebvre Austin , Condro Michael , Kornblum Harley , Digman Michelle , Seidlits Stephanie 
Published: June 2022

Abstract
Glioblastoma (GBM) is the most common and lethal type of brain cancer with 5-year survival of &lt;15%. The unique microenvironment of GBM is a key factor in tumor aggression. Similar to other solid tumors, GBM cells experience different biomechanical forces than do cells in healthy brain tissue. Here, we use atomic force microscopy to perform micro-compression mechanical analysis of xenografted GBM tumors. We show that tumors have a relatively stiff core (5-6 kPa Young’s modulus) and a softer edge (1-2 kPa Young’s modulus), yet all tumor tissue was stiffer than adjacent brain tissue (0.5-0.8 kPa Young’s modulus). To understand the functional implications of this biomechanical landscape, GBM spheroids were encapsulated in 3D culture matrices tuned to mimic the measured stiffnesses of a tumor regions and neighboring, non-cancerous tissue. These 3D matrices are fabricated from hyaluronic acid to promote GBM/matrix interaction through CD44 and RHAMM. RNA-sequencing analysis revealed overexpression of mitochondrial-encoded genes in stiff conditions, specifically genes encoding proteins involved in oxidation phosphorylation (OXPHOS), when compared to soft hydrogels. Using fluorescence-life time imaging microscopy to assess metabolic states at a single-cell level, we found that metabolism in GBM cells cultured in stiff matrices was dominated by OXPHOS while those in softer matrices was dominated by glycolysis (GLY). Furthermore, we show that this stiffness-induced shift towards OXPHOS in stiff matrices was associated with increased proliferation while the shift towards GLY in soft matrices was associated with increased migratory activity. Finally, inhibition of ezrin, an adaptor molecule linking the HA receptor CD44 to the actin cytoskeleton, eliminated the shift towards GLY induced in soft matrices, indicating that HA-CD44 interactions are necessary for these matrix-induced metabolic shifts.
Citation Format: Alireza Sohrabi, Austin Lefebvre, Michael Condro, Harley Kornblum, Michelle Digman, Stephanie Seidlits. Microenvironmental stiffness induces metabolic reprogramming in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3829.
Abstract 3837: The physiological relevance of TIMP dimer formation
Authors: Lazaroff Carolyn , Peeney David , Gurung Sadeechya , Stetler-Stevenson William G. 
Published: June 2022

Abstract
Tissue inhibitors of metalloproteinases (TIMPs) are a family of four paralogous genes that modulate the activity of matrix metalloproteinases (MMPs) and are vital for tissue homeostasis. Additionally, TIMPs display activities that are independent of their MMP inhibitory activities. Dysregulation and perturbations within this system can lead to complex tissue-specific pathologies. TIMP2 is the most abundantly expressed member of the TIMP family and has been shown to display potential therapeutic uses in cancer and other diseases. We have noted the persistent presence of SDS-stable TIMP2 dimers/multimers in SDS-PAGE at a level of ~5% total protein. The goal of this study is to determine the stability and biological relevance of SDS-stable dimer formation of TIMP2 in in vitro and in vivo. We found that TIMP2 dimers display an enhanced ability to inhibit MMP2 activity in reverse zymography assays. Immunoblotting revealed gel extracted TIMP2 dimer entered an equilibrium with monomeric TIMP2, while the extracted monomer did not form new dimer. In addition, MMP2 activity assays do not corroborate the enhanced MMP2 inhibitory activity observed in reverse zymograms but are consistent with the observation that isolated TIMP2 dimers re-equilibrate with monomers. This implies that structural or sequence difference mediates the formation of dimers. Dimer/multimer formation is observed across the TIMP family. Mass spectrometry analysis of gel extracted TIMP monomers and dimers show that monomer and dimer forms of TIMPs display unique post-translation modification (PTM) profiles. We propose that understanding the interplay between TIMP multimers and PTMs will reveal new biological functions within this intriguing family of proteins. We are currently working to resolve the functional differences between monomer and dimer and reveal the underlying mechanisms at play.
Citation Format: Carolyn Lazaroff, David Peeney, Sadeechya Gurung, William G. Stetler-Stevenson. The physiological relevance of TIMP dimer formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3837.
Abstract 3885: USP7 is an interaction partner of EZHIP and potential druggable target in PFA ependymomas
Authors: Jenseit Anne , Camgöz Aylin , Mauermann Monika , Pfister Stefan M. , Kool Marcel 
Published: June 2022

Abstract
Ependymomas (EPN) are tumors of the central nervous system (CNS) that can arise in the supratentorial brain (ST-EPN), hindbrain or posterior fossa (PF-EPN), or anywhere in the spinal cord (SP-EPN), both in children and adults. Molecular profiling has identified distinct subgroups and subtypes in each of the anatomic compartments. In the posterior fossa, three subgroups have been identified: PFA, PFB and PF-SE. Of them, PFA ependymomas are characterized by a young median age at diagnosis, an overall balanced genome and a bad clinical outcome (56% 10-year overall survival). Standard therapy consists of tumor resection and radiotherapy, but working chemo- or targeted therapies will be essential to improve patient outcomes. Recently, we and others identified enhancer of zeste inhibiting protein (EZHIP) as potential main driver of PFA tumorigenicity. By inhibiting EZH2, the catalytic subunit of the polycomb repressive complex 2 (PRC2), EZHIP prevents the distribution of the epigenetic repressor mark H3K27me3. However, since EZHIP does not possess any known enzymatic functions itself, it does not serve as the druggable target urgently needed for PFA tumors. Thus, interaction partners are one main focus of ongoing PFA research. In this project, we focused on the ubiquitin-specific protease 7 (USP7), a well-known regulator of cancer pathways with a variety of inhibitors available, which was observed to interact with EZHIP in non-PFA cell lines before. We were able to confirm this interaction of EZHIP and USP7 in PFA cells in vitro by co-immunoprecipitation and mass spectrometry, and could show that the EZHIP-USP7 interaction is independent of EZH2, a separate interactor of both. Functionally, we are testing the hypothesis that USP7 de-ubiquitinates EZHIP, thereby preventing its proteasomal degradation and thus stabilizing the protein. As EZHIP expression is essential to PFA cell survival, we aim to target EZHIP indirectly by interfering with its stability regulation via USP7. RNAi-based knockdown (KD) experiments have been used to test a susceptibility of PFA cells to a loss of USP7, focusing on effects on cell proliferation and apoptosis, but also investigating gene expression changes provoked by a change in USP7 levels. Moreover, multiple USP7 inhibitors already highly affect the survival of different PFA cell lines in vitro. Ongoing experiments with PFA patient-derived xenograft (PDX) models will hopefully confirm the strong effect of USP7 inhibitors in PFA, and help to improve targeted therapy for PFA patients.
Citation Format: Anne Jenseit, Aylin Camgöz, Monika Mauermann, Stefan M. Pfister, Marcel Kool. USP7 is an interaction partner of EZHIP and potential druggable target in PFA ependymomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3885.
Abstract 3887: β3-adrenergic receptor sustains IFN-γ-dependent PD-L1 expression and impairs anti-tumor immunity in neuroblastoma
Authors: Bruno Gennaro , Nastasi Nicoletta , Subbiani Angela , Boaretto Alessia , Tondo Annalisa , Favre Claudio , Calvani Maura 
Published: June 2022

Abstract
In this study we aimed to investigate the role of the β3-adrenergic receptor (β3-AR) in regulating the immune system response against neuroblastoma (NB) tumor. NB is a very heterogeneous extracranial tumor occurring in childhood. A distinctive feature of NB tumors is their neuroendocrine ability to secrete catecholamines, which in turn, via β-adrenergic receptors ligation, may affect different signaling pathways in the tumor microenvironment (TME). We previously demonstrated that the specific antagonism of the β3-AR on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB (A/J mice inoculated with the murine neuroblastoma cell line Neuro-2a), the β3-AR blockade ability to influence the number of immunoreactive and/or immunosuppressive cells in TME was investigated through flow cytometry analysis. Moreover, the involvement of the immune-checkpoint signaling axis PD-1/PD-L1 in mediating the anti-tumoral effects brought by a β3-AR antagonist administration was analyzed. Results demonstrated that β3-AR antagonism leads to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, β3-AR antagonism was able to increase the number of immune reactive CD8+, natural killer (NK) and dendritic cells (DCs), and to decrease the number of immune suppressive regulatory T cells (Treg) and Myeloid-derived suppressor cells (MDSC) in tumor mass. Moreover, β3-AR blockade on tumor infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ, which in turn reduced the PD-L1 expression on NB tumor cells. Further investigations, through a genomic analysis on NB patients, showed that high ADRB3 gene expression correlates negatively with the patient’s clinical outcome compared to the low expression group, and that ADRB3 gene expression is also related to the expression of different immune-checkpoints. Overall, results indicate that β3-AR in NB TME is able to modulate the interaction between tumor and host immune system, and that its antagonism hits multiple pro-tumoral signaling pathways.
Citation Format: Gennaro Bruno, Nicoletta Nastasi, Angela Subbiani, Alessia Boaretto, Annalisa Tondo, Claudio Favre, Maura Calvani. β3-adrenergic receptor sustains IFN-γ-dependent PD-L1 expression and impairs anti-tumor immunity in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3887.