bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 606: Cisplatin disrupts MDM2-DAXX-HAUSP complex, & induces apoptosis in acute leukemia cells
Authors: Tchounwou Paul B. , Kumar Sanjay 
Published: September 2020

Abstract
Cisplatin (CDDP) is an antitumor drug successfully used in the treatment of various types of human malignancies. It enhances toxicity of arsenic trioxide (ATO) in head and neck squamous cell carcinoma cell, small cell lung cancer, ovarian cancer cells, and oral squamous cell carcinoma cells (, and chronic myelogenous leukemia cells. CDDP induces cytotoxicity, DNA damage, oxidative stress, and apoptosis in acute promyelocytes leukemia (APL) cells. However, the molecular mechanisms of CDDP-induced P53 activation, cell cycle arrest, and apoptosis in APL cells remain poorly understood. We hypothesized that CDDP inhibits proliferation of APL cells through MDM2-DAXX-HAUSP complex disruption, p53 activation leading to cell cycle arrest and apoptosis. To test hypothesis, we used three APL cell lines and a mice model of APL and investigated CDDP effects on cells growth, complex disruption, cell cycle progression, and apoptosis by applying western blotting, immunoprecipitation(IP), gene knockdown techniques, immune/histocytochemistry, and confocal imaging. We found that CDDP induced stress signal transmitted by protein kinase (ATM, ATR) and its downstream targets (CHK1 & CHK2) phosphorylation leading to down-regulation of complex molecules expression and accumulation of p53. CDDP-induced p53 expression modulated cell cycle progression and apoptosis in APL cells, and stimulated the formation of more promyelocytes with dense granules through reduction of MDM2 expression in bone marrow cells. CDDP also activated p53 in APL mice liver tissues. This novel mechanism of action of CDDP in APL cells may help in the design of new anti-leukemic drugs for treatment of APL patients.
Citation Format: Paul B. Tchounwou, Sanjay Kumar. Cisplatin disrupts MDM2-DAXX-HAUSP complex, & induces apoptosis in acute leukemia cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 606.
Abstract 6073: The lipogenic regulator SREBP induces Transferrin in circulating melanoma cells, suppressing their susceptibility to ferroptosis
Authors: Hong Xin , Roh Whijae , Sullivan Ryan J. , Wong Keith H. , Wittner Ben S. , Guo HongShan , Dubash Taronish D. , Sade-Feldman Moshe , Wesley Ben K. , Boland Genevieve M. , Marvin Dieuwke L. , Bonesteel Todd , Lu Chenyue , Horwitz Elad , Aguet François , Freeman Samuel S. , Calhoun Katherine , Jewett Michelle K. , Nieman Linda T. , Hacohen Nir , Näär Anders M. , Ting David T. , Toner Mehmet , Stott Shannon L. , Getz Gad , Maheswaran Shyamala , Haber Daniel A. 
Published: September 2020

Abstract
Circulating tumor cells (CTCs) are shed by cancers into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastatic outgrowth. Clonally derived cultured CTCs from patients with BRAF-mutant melanoma reveal upregulation of lipogenesis and iron homeostasis pathways, correlated with their baseline and acquired drug resistance. In CTCs, the lipogenesis regulator SREBP directly induces transcription of the iron carrier Transferrin (TF), thereby reducing intracellular reactive oxygen species (ROS) and lipid peroxidation, and conferring resistance to BRAF inhibitors and inducers of ferroptosis. Knockdown of endogenous TF impairs tumorigenesis by melanoma CTCs; their associated soft agar clonogenic defect is rescued by the lipophilic anti-oxidants Ferrostatin-1 or Vitamin E, and by cholesterol. Single cell RNA-seq of patient-derived melanoma CTCs identifies a subset with high lipogenic, iron metabolic and proliferative signatures, correlated with adverse clinical outcome. Together, the coordinated regulation of these SREBP-driven pathways contributes to cancer progression, drug resistance and metastasis.
Citation Format: Xin Hong, Whijae Roh, Ryan J. Sullivan, Keith H. Wong, Ben S. Wittner, HongShan Guo, Taronish D. Dubash, Moshe Sade-Feldman, Ben K. Wesley, Genevieve M. Boland, Dieuwke L. Marvin, Todd Bonesteel, Chenyue Lu, Elad Horwitz, François Aguet, Samuel S. Freeman, Katherine Calhoun, Michelle K. Jewett, Linda T. Nieman, Nir Hacohen, Anders M. Näär, David T. Ting, Mehmet Toner, Shannon L. Stott, Gad Getz, Shyamala Maheswaran, Daniel A. Haber. The lipogenic regulator SREBP induces Transferrin in circulating melanoma cells, suppressing their susceptibility to ferroptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6073.
Abstract 6098: Gut microbiome predicts response to immunotherapy in advanced NSCLC
Authors: Yang Lu , Yin Huihui , Wang Yan , Jiao Yuchen 
Published: September 2020

Abstract
Introduction: It has demonstrated that gut microbiome could affect the response to anti-programmed death 1 (PD-1) immunotherapy in the Western population. And one study has suggested that the diversity of gut microbiome was associated with responses to immunotherapy in China. However, there were some conflicts in these previous studies. This study is aimed to further explore the relationship between gut microbiome and clinical response in advanced non-small cell lung cancer (NSCLC) patients.
Methods: From 30th/January/2018, advanced NSCLC patients with anti-PD-1 immunotherapy were enrolled. Fecal samples were collected prior to starting therapy and serially after immunotherapy. Total DNA was extracted and 16S ribosome RNA gene sequencing was applied to assess gut microbiome composition.
Results: Clinical response rate was determined by radiography according to Response Evaluation Criteria in Solid Tumor Version 1.1. There were sixteen responders (referred to as R, thirteen with stable disease and three with partial response), and thirteen non-responders (NR), yielding a response rate of 55.2%. Firmicutes, Bacteroidetes, Actinobacteria and Proteobacoteria were the main microbial composition in baseline stool samples. Gut microbiome diversity at baseline was not statistically different between responders and non-responders. However, the relative abundance of Akkermansia genus at baseline was significantly enriched in R cohort (p=0.0363). The count of OTUs at progression increased significantly during the treatment. (p=0.012). Of note, Alloprevotellal and Capnocytophaga were overrepresented significantly at progression, indicating that they were associated with unfavorable clinical outcome.
Conclusions: This study illustrated that the relationship between clinical outcomes and gut microbiome by dynamic monitoring. Akkermansia present at baseline feces was related with better clinical response to immunotherapy. The increase of some bacteria abundance, especially Alloprevotellal and Capnocytophaga, may predict disease progression during the immunotherapy. This study will continue to collect fecal samples and further verify these conclusions.
Citation Format: Lu Yang, Huihui Yin, Yan Wang, Yuchen Jiao. Gut microbiome predicts response to immunotherapy in advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6098.
Abstract 6152: Characterizing cancer stem cells in diffuse intrinsic pontine glioma
Authors: Ferris Sarah F. , Surowiec Rachel K. , Espinoza Carlos , Galban Stefanie 
Published: September 2020

Abstract
Diffuse Intrinsic Pontine Glioma (DIPG) is a lethal pediatric brain cancer with a five-year survival rate of less than 1%. This is reflective of a 100% tumor reoccurrence emphasizing the need for efficacious therapies. Previous studies have identified Aldehyde dehydrogenase expression (ALDH) as a marker for stemness and an indicator of tumor aggression and therapeutic resistance in many malignancies including adult glioma. Understanding the role of cancer stem-cells in gliomagenesis of DIPG is critical for developing therapies targeting resistance and averting 200-400 pediatric deaths in the US per year. We identified a subpopulation of cells expressing the ALDH cancer stem-cell marker in patient-derived DIPG cell lines with high variability in ALDH expression among the cell lines likely indicating previous treatment and resistance. As expected, proliferation and neurosphere formation as well as neurosphere size were dramatically increased in ALDH+ CSC compared to ALDH- CSC supporting our hypothesis of a tumor initiating, aggressive subpopulation likely conferring therapeutic resistance. To evaluate tumor initiation properties of ALDH+ CSC subpopulation in vivo, implantation of SU-DIPG-7 luciferase expressing cells into the pons of immunocompromised mice (NSG) was performed after sorting for ALDH by FACS. Our results demonstrate tumor initiation and tumor growth in ALDH+ mice as assessed by Bioluminescence imaging (BLI) as well as histological analysis. Furthermore, survival of mice implanted with ALDH+ CSCs was significantly reduced compared to mice implanted with ALDH- cells indicating tumor initiating and ‘stem cell' properties of this subpopulation. In summary, we have identified and characterized ALDH+ cancer stem-cells in DIPG which are more aggressive than the non-cancer stem-cell population (ALDH-). These results highlight the need to develop therapies targeting this highly aggressive cancer stem-cell population. Future studies investigating the gene regulation response to treatment in these stem-cell subpopulations could provide valuable insight to co-targeted therapies to address treatment resistance in DIPG.
Citation Format: Sarah F. Ferris, Rachel K. Surowiec, Carlos Espinoza, Stefanie Galban. Characterizing cancer stem cells in diffuse intrinsic pontine glioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6152.
Abstract 620: The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock
Authors: Trebucq Laura Lucia , Cardama Goergina A. , Menna Pablo Lorenzano , Golombek Diego A. , Chiesa Juan J. , Marpegan Luciano 
Published: September 2020

Abstract
Glioblastomas (GBM) account for almost half of the malignant central nervous system tumors and have the highest mortality rates with only about 5% of the adult patients surviving 5 years after diagnosis. Current therapy for GBM is generally very aggressive, combining chemotherapy, radiotherapy, and surgical removal and increased the life expectancy only from 11 to 14 months, but, almost no significant advances were made in the last decades. Taking this into account, more effective compounds and new strategies, such as chronotherapeutic ones, need to be developed.
The novel drug 1A-116 specifically blocks the interaction of the Rho GTPase Rac1 with some of its activators (GEFs proteins, such as Tiam1) inhibiting cell motility and proliferation of GBM. To optimize the effectiveness of 1A-116 a chronotherapeutic approach was implemented in vitro by applying the drug at different circadian times to synchronized LN-229 human GBM cells. Cell cultures displayed a functional circadian clock measured by Bmal1-luc activity and BMAL1 protein expression. Expression of Tiam1 was also assessed, finding circadian expression rhythms. The effects of 1A-116 on either cell proliferation, motility and toxicity, were dependent on the circadian cellular clock. The preliminary in vivo studies consisted on treating nude mice with 1A or control at ZT3 or 12. We found that the median survival of the mice treated at ZT3 was 82 days and at ZT12 was 78 days. These results suggest that a chronopharmacological approach based on the drug 1A-116 is a feasible strategy to improve GBM treatment outcomes.
Citation Format: Laura Lucia Trebucq, Goergina A. Cardama, Pablo Lorenzano Menna, Diego A. Golombek, Juan J. Chiesa, Luciano Marpegan. The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 620.
Abstract 6239: A novel topical delivery system of carvedilol for skin cancer prevention
Authors: Chen Mengbing , Yeung Steven , Shamim Md Abdullah , Coronel Kaitlyn , Shahid Ayaz , Andresen Bradley , Wang Jeffrey , Huang Ying 
Published: September 2020

Abstract
Solar ultraviolet (UV) light-induced non-melanoma skin cancer is the most common type of cancer diagnosed in the United States and remains one of the major public health concerns. There is an urgent need to develop effective and safe skin cancer chemopreventive agents. We have previously demonstrated that carvedilol, an FDA approved β-blocker for cardiovascular diseases, could prevent UV-induced skin cancer in vitro and in vivo. However, the β-adrenergic blockade effects of carvedilol might be a barrier for its repurposing as a cancer chemopreventive agent. In this study, we designed a novel topical formulation, namely carvedilol-loaded transfersomes (T-CAR), to maintain cancer preventive properties of carvedilol while avoiding systemic cardiovascular effects. T-CAR formulations were prepared using different phospholipids and surfactants at various ratios by the thin-film hydration method. The formulations were characterized in terms of particle size, zeta potential, and encapsulation efficiency. An optimal formulation was identified that composes carvedilol, soy phosphatidylcholine (SPC), and Tween 80 at a ratio of 1:3:0.5 with the particle size of 95.84 ± 3.8 nm, the zeta potential of +11.34 ± 0.7 mV, and the encapsulation efficiency of 93.7 ± 5.1%. The in vitro drug release and ex vivo skin permeation studies were performed using Pur-A-Lyzer mini dialysis kit and Franz diffusion cells, respectively. The optimal formulation showed a relative slow in vitro release profile and it could permeate through the porcine ear skin to the same degree as free carvedilol dissolved in acetone. 200 uL of 10 uM carvedilol dissolved in acetone, T-CAR containing the same amount of carvedilol as in acetone group, or the plain transfersome were topically applied to SKH-1 hairless mice 30 minutes before and immediately after single-dose UV irradiation. Compared to carvedilol solution, T-CAR demonstrated the same inhibitory effects against UV-induced epidermis thickening but exhibited increased inhibitory effects against UV-induced cyclobutane pyrimidine dimer (CPD) formation and mRNA expression of pro-inflammatory cytokines IL-1β and IL-6. In addition, carvedilol was not detectable by LC-MS in plasma after topical administration. These findings suggest that T-CAR could be a promising topical carvedilol formulation to prevent UV-associated skin cancer, with enhanced photoprotective effects but neglectable systemic cardiovascular effects.
Citation Format: Mengbing Chen, Steven Yeung, Md Abdullah Shamim, Kaitlyn Coronel, Ayaz Shahid, Bradley Andresen, Jeffrey Wang, Ying Huang. A novel topical delivery system of carvedilol for skin cancer prevention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6239.
Abstract 6244: Turning poorly vascularized tumors into highly vascularized tumors with nanoparticles: Proof of concept and pharmacometric analysis
Authors: Sicard Guillaume , Rodallec Anne , Correard Florian , Vaghi Cristina , Poignard Clair , Ciccolini Joseph , Benzekry Sébastien , Sergé Arnauld , Fanciullino Raphaelle 
Published: September 2020

Abstract
Combinatorial regimen are a mainstay in oncology. Taxanes and trastuzumab are both gold standards for HER2 positive breast cancer. To what extent they could reshape tumor micro-environment remains to be elucidated. The aim of this study was to compare in breast cancer mice models the antiproliferative efficacy and impact on tumor neo-angiogenesis of trastuzumab stealth immunoliposomes encapsulating docetaxel and stealth liposomal docetaxel associated with free trastuzumab. Nude mice bearing human MDA-MB-231 breast cancer tumors were treated by saline (control), docetaxel liposome (5mg/kg) associated with free trastuzumab (1.9 mg/kg) or trastuzumab immunoliposome (eq. 5 mg/kg docetaxel and 1.9 mg/kg trastuzumab) QW for 4 consecutive weeks. Tumor growth was monitored twice a week by volumetric measurement using a caliper. Blodd vessels density was evaluated in vivo by fluorescence imaging using Angiosense as a vascular probe plus ex-vivo using anti-CD31 antibodies and electronic microscopy at 2, 4 and 6 weeks. A specific algorithm was developed on MatLab for imaging analysis. No treatment-induced toxicities was observed. After 4 weeks of dosing, no difference in efficacy was seen between treatments (p=0.798) and Angiosense imaging did not show differences either (p=0.628). However electronic microscopy showed that both immunoliposomes and liposomes increased tumor vascular density as compared with control. In addition, a difference between treatments was evidenced because a marked increase in vascularization of central tumors VS. peripheral tumors was observed with trastuzumab immunoliposome as compared with standard docetaxel liposome (p=0.00023). A numerical model based on porous medium theory combined with multi-scale approaches has been derived to describe the spatial distribution of the drugs within tissues. Overall our data suggest that trastuzumab stealth immunoliposomes induce a normalization of tumor vessels with an increase in blood vessels density in central tumors. This could pave the way for sequencing combinatorial strategies so as to improve drug delivery into tumors of the associated treatments.
Citation Format: Guillaume Sicard, Anne Rodallec, Florian Correard, Cristina Vaghi, Clair Poignard, Joseph Ciccolini, Sébastien Benzekry, Arnauld Sergé, Raphaelle Fanciullino. Turning poorly vascularized tumors into highly vascularized tumors with nanoparticles: Proof of concept and pharmacometric analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6244.
Abstract 6251: Blood brain barrier opening by TTFields: a future CNS drug delivery strategy
Authors: Salvador Ellaine , Kessler Almuth F. , Hörmann Julia , Burek Malgorzata , Brami Catherine T. , Sela Tali V. , Giladi Moshe , Ernestus Ralf-Ingo , Löhr Mario , Förster Carola , Hagemann Carsten 
Published: September 2020

Abstract
Introduction: Although a number of effective drugs are available to treat central nervous system (CNS) disorders, their ability to breach the tight regulation of the blood brain barrier (BBB) still remains a major challenge. Recently, the use of tumor treating fields (TTFields) has become an effective treatment approach for glioblastoma. Furthermore, its combination with chemotherapy significantly improved overall patient survival. Nonetheless, how TTFields could affect the BBB has not yet been studied. Our recent findings exhibit the potential of TTFields administration to open up the BBB in vitro with an optimal frequency of 100 kHz. Consequently, in this study, we therefore aimed to validate our data in vivo.
Experimental procedures: Subsequent to 100 kHz TTFields or heat treatment for 72 h, rats were i.v. injected with Evan´s Blue (EB). Next, they were sacrificed to extract and quantify EB from the brain. In the same manner, rats were injected with TRITC-dextran (TD), after which permeation was visualized in sectioned brains. Cryosections of rat brains were also prepared post-TTFields treatment. These were stained for intercellular junction proteins claudin-5, occludin and PECAM-1 as well as immunoglobulin G (IgG) to assess vessel structure. Finally, serial dynamic contrast-enhanced (DCE) MRI with gadolinium (Gd) contrast agent was performed before and after TTFields administration.
Results: Permeation of both EB and TD was observed in the brain after TTFields application. Moreover, brain cryosections displayed claudin-5 and occludin delocalization but not PECAM-1. Accumulation of IgG in the brain parenchyma was also noted. Confirming these observations, increased Gd in the brain was shown by DCE-MRI post TTFields treatment. A reversion to normal conditions was, however, detected 96 h after end of treatment demonstrated by no difference in contrast enhancement between control and TTFields-treated rats.
Conclusions: Administration of 100 kHz TTFields in rats led to alterations in BBB integrity and permeability, which signal its opening. The subsequent recovery of the BBB at the end of treatment demonstrates transient effects, hence presenting TTFields as a possible novel clinical strategy to open the BBB for enhanced and more effective drug delivery strategy for CNS disorders.
Citation Format: Ellaine Salvador, Almuth F. Kessler, Julia Hörmann, Malgorzata Burek, Catherine T. Brami, Tali V. Sela, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Förster, Carsten Hagemann. Blood brain barrier opening by TTFields: a future CNS drug delivery strategy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6251.