bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4668: Human CYP1B1 prevents TRAIL-DR4-mediated cancer cell apoptosis through downregulation of miR-375
Authors: Kwon Yeo-Jung , Ye Dong-Jin , Baek Huoung-Seok , Shin Sangyun , Kwon Tae-Uk , Cho Eunah , Ahn Hong-Gyu , Chun Youngjin 
Published: September 2020

Abstract
Human cytochrome P450 1B1 (CYP1B1) is an important enzyme that catalyzes metabolism of 17β-estradiol (E2) to catechol estrogens, including carcinogenic metabolite 4-hydroxyestradiol (4-OHE2). CYP1B1 may play a crucial role in estrogen-mediated carcinogenesis since CYP1B1 shows tumor-specific expression pattern in various hormone-responsive tissues. However, the detailed mechanism of CYP1B1-dependent carcinogenesis remains still unclear. Here, we investigated the association between TRAIL, DR4, and CYP1B1 expression in human tumor cells, including MCF-7, MDA-MB-231, and HeLa cells. CYP1B1 can inhibit the expression and release of TRAIL simultaneously with the expression of the death receptor DR4/5, known as TRAIL receptors, to prevent apoptosis. Furthermore, we found that CYP1B1 represses the transcription of DR4 by inducing DNA methylation in the promoter region of DR4. In addition, we revealed that CYP1B1 regulates TRAIL and DR4 through activation of Sp1 transcription factor. CYP1B1 and its enzymatic product, 4-OHE2, promote Sp1 expression levels in both mRNA and protein levels. Interestingly, CYP1B1 elevated Sp1 through downregulation of miR-375, which is a candidate tumor suppressive microRNA and transcriptional inhibitor of Sp1. Taken together, our data suggest that CYP1B1 inhibits TRAIL-DR4-mediated cancer cell apoptosis through induction of Sp1 through repression of miR-375, which promotes cancer cell survival.
Citation Format: Yeo-Jung Kwon, Dong-Jin Ye, Huoung-Seok Baek, Sangyun Shin, Tae-Uk Kwon, Eunah Cho, Hong-Gyu Ahn, Youngjin Chun. Human CYP1B1 prevents TRAIL-DR4-mediated cancer cell apoptosis through downregulation of miR-375 [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 4668.
Abstract 4670: TIP60 regulates alternative splicing of Integrin subunit alpha 6
Authors: Bhatia Shreshtha Sailesh , Koeffler H. Phillip , Jha Sudhakar 
Published: September 2020

Abstract
Differences in RNA processing, specifically RNA splicing, contribute to enormous diversity that can be generated from the eukaryotic genome. Given the increasing evidence to show that splicing can occur co-transcriptionally, chromatin structure and histone modifications have been reported to affect the choice of a splice site. For instance, HDAC inhibitor treatment has been shown to affect alternative splicing. TIP60 is a haploinsufficient tumor suppressor gene that is frequently downregulated in cancers. TIP60 is a lysine acetyltransferase that acetylates histone and non-histone proteins. Since TIP60 is a writer of histone and non-histone modifications, we investigated TIP60's role in modulating alternative splicing. To understand TIP60's role in alternative splicing, RNA sequencing was performed in MCF10A cells that were (a) transiently depleted of TIP60 (b) stably overexpressing siRNA-resistant wild-type TIP60 (MCF10A*WT) and (c) stably overexpressing siRNA-resistant catalytically dead TIP60 (MCF10A*KD). Differential splicing analysis was performed using MISO program. We found 130 genes to be differentially spliced when TIP60 was depleted and 59 genes were differentially spliced in MCF10A*KD compared to MCF10A*WT. For both comparisons, the majority of the differential splicing events were skipped exon events. Upon overlapping the differential skipped exon events, we found significant exon 25 skipping of ITGA6, resulting in an isoform that has a shorter cytoplasmic domain. TIP60 depletion results in an increase in the ITGA6 isoform that lacks exon 25, which has been implicated to promote tumor initiation in breast cancer. To identify the splicing factor that regulates this event, we performed a siRNA screen of over 70 splicing factors and identified ESRP2 to regulate splicing of ITGA6 exon 25. The consequence and biological significance of TIP60-ESRP2 mediated alternative splicing will be discussed at the conference.
Citation Format: Shreshtha Sailesh Bhatia, H. Phillip Koeffler, Sudhakar Jha. TIP60 regulates alternative splicing of Integrin subunit alpha 6 [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 4670.
Abstract 4679: Investigating the role of cryptochrome 2 in human cancer
Authors: Chan Alanna , Lamia Katja 
Published: September 2020

Abstract
Through numerous epidemiological studies, The World Health Organization (WHO) deemed disruption of circadian rhythms a probable carcinogen. Circadian rhythms regulate many physiological and cellular processes, while maintaining a ~24hr period. The molecular mechanisms by which disrupted circadian rhythms promote tumorigenesis remain unclear. Recently, our lab found that Cryptochrome 2 (CRY2) acts as an adapter to recruit c-MYC to the E3 ligase complex SKP-CULLIN-FBXL3 (SCFFBXL3) to promote degradation of c-MYC, a known proto-oncogene transcription factor. We identified five recurrent CRY2 mutations (CRY2 D347H, S436R, R460C, D467N and S532L) in a variety of human cancers from The Cancer Genome Atlas (TCGA) (referred to as CRY2 TCGA mutations). We hypothesized that these mutations may disrupt the interactions between CRY2, FBXL3, and c-MYC and thereby promote c-MYC accumulation. We performed several biochemical and functional assays in parallel to investigate the impact of these mutations on CRY2 activities. While three of the mutants tested reduce the association of CRY2 with FBXL3 as expected, we unexpectedly found that one of the CRY2 TCGA mutants abolishes interaction between CRY2, CLOCK, and BMAL1 without affecting its ability to interact with FBXL3 or c-MYC. Thus, this mutation prevents the normal function of CRY2 within the circadian clock and affects two-dimensional colony formation, which could impact cellular transformation as well.
Citation Format: Alanna Chan, Katja Lamia. Investigating the role of cryptochrome 2 in human cancer [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 4679.
Abstract 4696: Endometrial receptivity markers in patients with uterine fibroids and their correlation with air pollution exposure
Authors: Ferreira Dara O. , Maffazioli Giovana D. , Baracat Edmund C. , Carvalho Katia C. 
Published: September 2020

Abstract
Uterine leiomyomas (LM) are the most frequent benign tumors in women of reproductive age. They are associated with infertility, pelvic pain, abnormal uterine bleeding and represent a public health challenge. LM are over 4 times more common in African-descendent women. Additionally, this tumor constitutes a major health and financial burden in several countries. Similar to many pathologies, environmental exposure contributes to their origin and development. Air pollution acts as a disruptor in the hormonal activity and in other key pathways leading to enhanced tumor progression and making possible pregnancies difficult. In this study, we evaluated LM samples from women resident in urban (high exposure area) and no-urban areas (low or negative exposure area) for the expression of genes related to endometrial receptivity. We selected a total of 100 patients and among them twenty fill the specific profile of those exposed or not exposed to air pollution. mRNA expression analysis was performed using an array composed by 84 receptivity-related genes (Array Code: CLAH27251A, Qiagen, USA). Gene expression analyses showed PRLR, LITAF, COL6A3, HOXA11, KLRC1, UBE2A e IGFBP5 with higher fold expression (fold &gt;2) in the exposed group. On the other hand, PENK, CALB2, DUOX1, COMP, CXCL14, CTNNA2, TCN1, S100P, WNT5A, ERBB2, MTNR1B and EFNA1 were dowregulated in these samples (fold &lt; - 4). Several other genes exhibited differential regulation between exposed and non-exposed group of patients, but with lower significance. Our results corroborate the expected for these populations, since it is known that women resident in areas with high air pollution have reproductive complications and higher tendency to tumors development. However, this work is the first evidence of the impairment of endometrial receptivity in uterine LM patients associated to air pollution in Brazil. Further studies are ongoing to validate and elucidate the specific roles of these genes in uterine LM origin and development, as well as their reproductive function in this population.
Citation Format: Dara O. Ferreira, Giovana D. Maffazioli, Edmund C. Baracat, Katia C. Carvalho. Endometrial receptivity markers in patients with uterine fibroids and their correlation with air pollution exposure [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 4696.
Abstract 472: What electric field strength is necessary for maximum tumor-treating fields efficacy
Authors: Carlson Kristen W. , Tuszynski Jack A. , Dokos Socrates , Paudel Nirmal , Bomzon Zeev 
Published: September 2020

Abstract
Why Is 4 V/cm Electric Field Strength Necessary for Maximum Tumor-Treating Fields Efficacy? INTRODUCTION: Tumor Treating Fields (TTFields) extend overall survival in glioblastoma patients. Threshold field strength for TTFields is typically cited as 2V/cm. Yet plots of cell death vs. field strength in vitro indicate a power law relationship asymptotic to 4 V/cm for 100% efficacy. The mechanisms of action (MoA) of TTFields underlying this relationship are currently under investigation. TTFields are suspected of disrupting critical mitotic processes performed by large polar cellular molecules such as microtubules (MT). METHODS: Using the power law relationship for the energy (intensity, I) carried by an electric field and its amplitude (Eq. 1), we calculated energy vs. TTFields amplitude. (1) RESULTS: We suggest Eq. 1 is a likely source of the relationship between TTFields' amplitude and cell death proportion that has been demonstrated empirically. Further, Table 1 shows energy transmitted per unit MT surface area per TTFields cycle, specifically, the energy per MT dimer band around an MT helix per TTFields period of 5 µs.
TTFields Field Strength (V/cm)Radiant Flux Density (W/nm2)Energy/(Cycle-Area) (J/nm2)Energy/MT Dimer/Cycle (J)Energy/MT Dimer Band/Cycle (J)113.3 × 10−186.63 × 10−234.01 × 10−224.17 × 10−20253.1 × 10−1826.6 × 10−231.60 × 10−211.67 × 10−193119 × 10−1859.7 × 10−233.61 × 10−213.75 × 10−194212 × 10−18106 × 10−236.42 × 10−216.67 × 10−195332 × 10−18166 × 10−231.00 × 10−201.04 × 10−186478 × 10−18239 × 10−231.44 × 10−201.50 × 10−18
A metric for disruption of cellular processes is 1-2 orders of magnitude greater than the thermal background energy in the cell, kT = 4.3 × 10−21 J. Table 1 shows that the energy absorbed by a MT dimer is insufficient to disrupt cellular processes at 2 V/cm, while due to energy increasing with square of field strength, at 5 V/cm it may be disruptive. For an entire dimer band around the MT helix, 2 V/cm appears to be sufficient, while 4 V/cm seems amply strong to disrupt MT function, in accordance with in vitro experiments. CONCLUSION: Assuming the power law of energy vs. electric field strength and the resulting energy absorbed by microtubule components, we found a correlation between typical TTFields' amplitudes and estimated disruption thresholds of MT function. TTFields MoA. 4 V/cm, not 2V/cm, should be the target field strength to realize the full efficacy of TTFields.
Citation Format: Kristen W. Carlson, Jack A. Tuszynski, Socrates Dokos, Nirmal Paudel, Zeev Bomzon. What electric field strength is necessary for maximum tumor-treating fields efficacy [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 472.
Abstract 480: Molecular mechanism of action of photoimmunotherapy with antibody-IR700 dye conjugates
Authors: Heim Roger , Makings Lew , Wiemann Torsten , Manibusan Anthony , Garcia-Guzman Miguel 
Published: September 2020

Abstract
INTRODUCTION: Cancer cell-targeted photoimmunotherapy (PIT) is a platform technology under development for the treatment of various cancers. PIT is a drug and device combination that utilizes an antibody conjugated to the IR700 (IRDye 700DX®) light-excitable dye, which upon antigen binding and illumination with non-thermal red light, leads to necrotic cell death. The objective of these studies was to characterize the molecular pharmacology and the underlying mechanism of action of PIT.
METHODS: In vitro PIT studies using human and mouse cancer cells were performed to evaluate conjugate (antibody + dye) binding, dose response and light dosimetry response. Mouse xenograft experiments assessed necrotic markers in tumor tissue and surrounding normal tissue post-PIT treatment. Oxidative damage to lipids was detected with a reporter dye. Mass spectrometry analysis was performed to assess protein oxidation, crosslinking and axial ligand dissociation from the dye.
RESULTS: Binding of the conjugate to the target cancer cells was required for PIT treatment to induce cell death as measured by antibody competition studies, however, internalization of the conjugate was not required for cytotoxic effects. Administration of non-thermal red light to the target cells bound with the conjugate led to morphologic changes and membrane disruption within minutes, and necrotic cell death was observed in a conjugate- and light-dose dependent manner. Requirement of conjugate binding to the cancer antigen provided high level of tumor specificity as demonstrated by lack of damage to normal surrounding tissue after PIT treatment. Light excitation of the conjugate generated 1O2 with high quantum yield. In vitro PIT treatment led to cell membrane lipid peroxidation, mediated by 1O2 as shown by abrogation with sodium azide, a selective 1O2 quencher. In addition, protein oxidation, cross-linking and aggregation of the conjugate was observed. In low oxygen concentrations and in the presence of ascorbate, photo-induced dissociation of axial ligands from the dye was detected.
CONCLUSIONS: These studies suggest the molecular mechanism of action of PIT includes generation of 1O2 that leads to lipid peroxidation and cell membrane disruption. Additional mechanisms may include protein oxidation and non-oxygen dependent mechanisms such as axial ligand loss of the IR700 dye. These results describe a biophysical process that damages and disrupts the cell membrane integrity resulting in necrotic cell death and immunogenic cell death.
Citation Format: Roger Heim, Lew Makings, Torsten Wiemann, Anthony Manibusan, Miguel Garcia-Guzman. Molecular mechanism of action of photoimmunotherapy with antibody-IR700 dye conjugates [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 480.
Abstract 4803: Mitochondrial response to temozolomide treatment in glioma cells
Authors: Lenz Luana S. , Silva Mardja M. , Bristot Ivi J. , Klamt Fabio , Lenz Guido 
Published: September 2020

Abstract
Mitochondria are a central organelle to metabolism and apoptosis control, it means that their functionality is essential to cellular homeostasis. We investigated the mitochondrial alterations in respose to the chemotherapeutic Temozolomide (TMZ) in glioma cells.We transduced A172 and U87 cells with a fluorescent protein targeted to mitochondria (Addgene #50057), treated these cell with TMZ 100 uM during 3 hours and analyzed them by cytometry, microscopy and high resolution respirometry at days 3, 5 and 7 after treatment.Once tolerance is a dynamic process that can lead to different responses even between related cells, we first asked how related cells respond to TMZ in terms of mitochondria amount. Closely related sisters and cousins cells were not different to random pairs, indicating that mitochondria amount is not inherited and that this feature is very dynamics. Population analysis reveal that five days after TMZ the cells showed an increase in mitochondrial mass and mitochondrial swelling. The PGC-1 expression was reduced by half on day 3, suggesting that increase in mitochondrial mass must be due to accumulation of mitochondria instead of biogenesis. Five days after treatment we observed an increase in mitochondrial membrane potential measure by JC1 and an increase in mitochondria ATP linked respiration. To test if increased mitochondria respiration is a therapeutically targetable adaptation of these cells treated with TMZ, we treated the cells that survived five days after TMZ with KCN, a cytochrome c oxidase inhibitor. As expected, the TMZ-treated cells were more sensitive to the blockage of mitochondrial respiration than untreated cells. On the other hand, cells treated at day five after TMZ with 2-DG, a glycolysis inhibitor, were less affected, indicating that the oxidative phosphorylation is important to tolerance to TMZ.Our results indicate that treatment induce a metabolic reprogramming with increase in oxidative state, and strategies to overcome this tolerance mechanism could be explored.
Citation Format: Luana S. Lenz, Mardja M. Silva, Ivi J. Bristot, Fabio Klamt, Guido Lenz. Mitochondrial response to temozolomide treatment in glioma 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 4803.
Abstract 482: Multiple chemical action cancer therapeutics
Authors: Papineni Rao , Adhikary Amithava 
Published: September 2020

Abstract
Radiation-produced quasi-free electrons (i.e., low energy electrons in solutions) causes DNA damage. However, there are no evidence that radiation-produced partially solvated electrons (i.e., presolvated or, prehydrated electrons) and fully solvated electrons (i.e., aqueous or solvated electrons) cause strand breaks. However, recent work on azidoDNA-model systems show that radiation-produced electrons can be converted to highly damaging aminyl radicals (RNH•) which do have the potential to cause strand breaks. Experimental studies in our labs (both in vitro and in vivo) have shown that 2-deoxy-D-glucose (2-DG), a glucose mimic and glycolytic inhibitor, enhances radiation-induced damage selectively in tumor cells while protecting normal cells and against infection. Thereby suggesting that 2-DG can be used as a differential radiomodifier to improve the efficacy of cancer radiotherapy. Based on these experimental results and data mining models, we show that the azido derivative of 2DG; 2-Azido-2-deoxy-D-glucose (2-AZ-2-DG) has unique azido chemistries. The neutral aminyl radical produced from 2-AZ-2-DG under reductive environment undergoes facile conformational change from the stable chair form to the reactive boat form. Subsequently, this aminyl radical causes H-atom abstraction from C5 of the sugar moiety via proton-coupled electron transfer process. Further, a promise as multivalent drug to augment multipronged cellular damage including site-specific DNA radiation damage and also counter infections persisting in several cancer cases. Our long range goals are to harness these unique chemistries in gold based nanotools for X-PDT (X-ray induced photodynamic therapy).
Citation Format: Rao Papineni, Amithava Adhikary. Multiple chemical action cancer therapeutics [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 482.
Abstract 4844: CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance
Authors: Zhang Juan , Tang Liang , Li Zhenhu , Lu Liang , Bao Yuanwu , Ren Zhaoxiang , Ma Jingshu , Huang Yaling , Xu Zhaobing , Xia Yuanfeng , Ding Charles Z. , Hu Lihong , Chen Shuhui , Xie Archie N. , Wang Xinzhong Jon 
Published: September 2020

Abstract
The G1 restriction point is critical for regulating the cell cycle and is controlled by the retinoblastoma protein (Rb) pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). Selective CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib have been approved by US FDA as single agent or in combination with endocrine therapy to treat patients with HR+/Her2- breast cancer. Here, we disclose the preclinical development of CS3002 and its characterization as a novel CDK4/6 inhibitor with unique kinase inhibition spectrum. Similar to the three approved CDK4/6 inhibitors, CS3002 is highly selective for and potent against CDK 4 and 6, a feature that is expected to overcome the toxicity issues of pan-CDK inhibitors. Cell-based assays confirmed the biological activities of CS3002 by showing anti-proliferative effect, significant Rb phosphorylation inhibition, and G1 cell cycle arrest in a set of Rb-positive cancer lines. Furthermore, CS3002 showed excellent in vivo activity as a single agent, and in combinations with either endocrine therapy (fulvestrant) or PD-1 blockade (CS1003) in a set of tumor models, together with desirable ADME/PK and safety profile. CS3002 was further tested against 196 kinases in a Carna panel. In addition to CDK4 and CDK6, FLT3 and TRKA were also potently inhibited with IC50 values &lt;50nM. To this end, CS3002 demonstrated high activity in cell lines harboring NTRK1 fusion that were otherwise insensitive to CDK4/6 inhibitors. Across a panel of 19 AML cell lines, CS3002 demonstrated a similar sensitivity profile to gilteritinib (an approved FLT-3 inhibitor), but overall higher sensitivity compared to palbociclib. Interestingly, when MCF-7 breast cancer cell line was treated continuously with CS3002 in vitro, the emergence of drug-resistance was much delayed compared to treatment with palbociclib or abemaciclib. Given the encouraging preclinical properties as well as the unique potential in allowing indication expansion and delaying drug resistance to CDK4/6 inhibition, CS3002 is selected for clinical exploration in a Phase 1 study for advanced solid tumors (NCT04162301).
Citation Format: Juan Zhang, Liang Tang, Zhenhu Li, Liang Lu, Yuanwu Bao, Zhaoxiang Ren, Jingshu Ma, Yaling Huang, Zhaobing Xu, Yuanfeng Xia, Charles Z. Ding, Lihong Hu, Shuhui Chen, Archie N. Xie, Xinzhong Jon Wang. CS3002, a novel CDK4/6 inhibitor with unique kinase inhibition spectrum which may expand indications beyond breast cancer and delay acquired drug resistance [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 4844.