bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B20: STK3/4-mediated phosphorylation of LC3B regulates directional intracellular transport of autophagic vesicles
Authors: Nieto-Torres Jose L. , Shanahan Sean-Luc , Chassefeyre Romain , Landeras-Bueno Sara , Lee Lee R. , Zaretski Sviatlana , Encalada Sandra , Hansen Malene 
Published: September 2020

Abstract
Autophagy is a fundamental catabolic process that allows the degradation of cytosolic components to supply the cell with nutrients in response to starvation, among other functions. Recently, our lab discovered that the Hippo pathway members, STK3 and STK4, phosphorylate the autophagy protein LC3B, a key component of autophagic vesicles that participates in specifying their content and their intracellular transport. Depletion of STK3/4 kinases or generation of an LC3B phospho-null mutant (T50A) causes a block of the autophagy process evidenced by an accumulation of autophagic vesicles throughout the cell. However, these studies did not clarify which step of the autophagy process was impaired. To address this question, we employed proteomics to analyze LC3B-binding partners affected by LC3B phosphorylation, and identified multiple proteins implicated in intracellular vesicle transport. Accordingly, we hypothesized that LC3B phosphorylation may affect transport of autophagic vesicles. We tested this hypothesis directly by live-cell imaging in multiple cell types and found that the absence of LC3B phosphorylation was accompanied by an aberrantly high transport of LC3B-positive autophagic vesicles toward the periphery of the cell, and a low transport of the vesicles toward the perinuclear area, where the autophagy process is normally completed. Moreover, starvation-induced perinuclear positioning of autophagic vesicles was prevented in the absence of LC3B phosphorylation. Collectively, these findings indicate that STK3/4-mediated phosphorylation of LC3B regulates the directional transport of autophagic vesicles and this may promote autophagy completion. Notably, this regulatory axis may be triggered when the nutrient availability is low and autophagy is induced. Understanding how input signals regulate STK3/4, and in turn control autophagy, may prove important to develop therapies against diseases such as cancer.
Citation Format: Jose L. Nieto-Torres, Sean-Luc Shanahan, Romain Chassefeyre, Sara Landeras-Bueno, Lee R. Lee, Sviatlana Zaretski, Sandra Encalada, Malene Hansen. STK3/4-mediated phosphorylation of LC3B regulates directional intracellular transport of autophagic vesicles [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B20.
Abstract B22: The origin of the Hippo pathway
Authors: Chen Yuxuan , Wang Wenqi 
Published: September 2020

Abstract
First discovered in Drosophila, the Hippo signaling pathway plays a crucial role in organ size control from fly to human. Interestingly, there are many paralog genes in the mammalian Hippo pathway, which were developed through duplication from fly to human. Tracked in evolution, the Hippo pathway originated from unicellular organism. In this study, we primarily focused on how the Hippo pathway evolved to establish its conserved function in tissue/organ homeostasis, which may shed light on its dysregulation in cancer development from a new perspective.
Citation Format: Yuxuan Chen, Wenqi Wang. The origin of the Hippo pathway [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B22.
Abstract B28: Cep55 regulates YAP/TAZ expression and localization during cell cycle progression
Authors: Lin Yen-Ming , Wu Chu-Han , Ouyang Pin 
Published: September 2020

Abstract
Cell cycle regulation plays a pivotal role in controlling cell proliferation and survival. Aberrant expression of cell cycle-associated genes generally afflicts cells with tumor-prone characteristics and promotes chromosome instability. Cep55 (Centrosome Protein 55kDa; also known as c10orf3 and FLJ10540) was identified as an important regulator of cytokinesis involved in cell growth and proliferation. It is associated with central spindle and midbody during cell cycle progression and cooperates with members of endosomal sorting complex required for transport (ESCRT) machinery to constrict intracellular bridge for cell abscission. In addition to cytokinesis, Cep55 is involved in regulating the PI3K/AKT pathway as well as promoting tumorigenesis. In search of novel Cep55 interplayers that may abrogate their expression upon loss of cep55 expression, we set out experiments with cultured cells exogenously expressed Flag-tagged wild type (wt) Cep 55 versus shRNAs against Cep55 and subjected immunoprecipitates to LC-MS/MS. The Hippo pathway components YAP and its paralogue TAZ were found to be diminished apparently in Cep55 null sample compared with wt counterpart. To confirm if Cep55 knockdown affects expression of Hippo pathway, we transfected 293T cells with Cep55 shRNAs and detected expression of Hippo core components with Western blots. Hippo components such as Merlin, Mst, and Lats are without effect in expression level, with the exception of YAP/TAZ whose expression was decreased extensively. Immunofluorescent microscopy reveals YAP/TAZ colocalized with Cep55 at central spindle and midbody during mitosis; however, depletion of Cep55 results in diffusion of YAP/TAZ at midbody, suggesting cep55 is required for midbody localization of YAP/TAZ. In contrast, knockdown of YAP/TAZ did not significantly alter Cep55 localization to the midbody ring but displays phenotype, such as multinuclear cells and micronuclei, similar to that observed in Cep55-depleted cells. Together our data provide evidence that Cep55-YAP/TAZ interaction plays an important role in cytokinesis and may support a biologic interplay between the Hippo-YAP and PI3K-AKT-mTOR pathways.
Note: This abstract was not presented at the conference.
Citation Format: Yen-Ming Lin, Chu-Han Wu, Pin Ouyang. Cep55 regulates YAP/TAZ expression and localization during cell cycle progression [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B28.
Abstract B35: FLT3-TAZ signaling induces drug resistance in leukemia
Authors: Shin Ji Eun , Park Hyun Woo 
Published: September 2020

Abstract
YAP/TAZ, the transcriptional coactivators of TEAD and major transducers of the Hippo pathway, has been studied only in solid tumors. Interestingly, YAP/TAZ are consistently upregulated in adherent tumor cell lines, but hardly expressed in hematologic malignancies including lymphoma and leukemia. However, we identified significant upregulation of TAZ in specific leukemia mouse models driven by FLT3 (AML) or Bcr-Abl (blast crisis-CML; bc-CML). We observed strong correlation between TAZ and FLT3 induction in bc-CML patients as well as leukemia cells, which led us to investigate the role of FLT3-TAZ signaling in imatinib-induced drug resistance in CML. FLT3 expression induced imatinib resistance (IR) in K562 CML cells. In K562-IR cells, transcription of TAZ mRNA is significantly increased, but not YAP. Our data show that target gene induction by TAZ-TEAD interaction promotes imatinib resistance. Importantly, inhibition of FLT3-TAZ signaling resensitized K562-IR cell to imatinib treatment and caused cell death. Therefore, we propose that combination therapy targeting both FLT3-TAZ and Bcr/abl signaling could trigger synthetic lethality in bc-CML cells.
Citation Format: Ji Eun Shin, Hyun Woo Park. FLT3-TAZ signaling induces drug resistance in leukemia [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B35.
Abstract IA10: Inhibition of the Hippo pathway by AMPK-family kinases
Authors: Attisano Liliana 
Published: September 2020

Abstract
Inactivation of the Hippo pathway is a common feature in numerous cancers, yet mutations in pathway components are relatively rare. To uncover novel Hippo pathway regulators, we conducted multidimensional high-throughput screens. These efforts uncovered two AMPK family kinases, MARK4 and NUAK2, as negative regulators of the Hippo pathway. MARK kinases, including MARK3 and MARK4, phosphorylate both SAV1 and MST1/2 and inhibit MST1/2-dependent activation of LATS. Moreover, we showed that DLG5 acts as a scaffold to promote MARK-mediated phosphorylation of MST. In contrast to MARKs, NUAK2 interacts with and phosphorylates LATS. Interestingly, NUAK2 is induced by YAP/TAZ in cooperation with AP-1 and this is required for robust YAP/TAZ signaling. Inhibition or loss of NUAK2 reduces the growth of cultured cancer cells and mammary tumors in mice. In human patient samples, NUAK2 expression is elevated in aggressive, high-grade bladder cancer and strongly correlates with a YAP/TAZ gene signature. Thus, we identified a positive feed-forward loop in the Hippo pathway that establishes a key role for NUAK2 in enforcing the tumor-promoting activities of YAP/TAZ.
Citation Format: Liliana Attisano. Inhibition of the Hippo pathway by AMPK-family kinases [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA10.
Abstract IA21: The Hippo pathway in cancer
Authors: Guo Xiaocan , Liu Huan , Cao Xiaolei , Zhao Bin 
Published: September 2020

Abstract
The Hippo pathway plays a critical role in organ size control in development. Deregulation of the Hippo pathway leads to drastic enlargement of organs due to increased cell proliferation, inhibition of apoptosis, and dedifferentiation of differentiated cells. Interestingly, deregulation of the Hippo pathway also plays a critical role in tumorigenesis. However, precise roles of the Hippo pathway in tumorigenesis are unclear. By generating genetically defined liver tumor-initiating cells (TICs) with Hippo pathway inactivation or YAP activation, we found that the Hippo pathway unexpectedly mediates a crosstalk between TICs and the immune system. Via cytokines induced by YAP, TICs actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages (TICAMs) abolishes tumorigenesis in a manner dependent on the immune system. Furthermore, YAP activation has been observed in TICs induced by pathologically relevant oncogenes in murine livers and in human hepatocellular carcinoma (HCC) precancerous lesions. These results demonstrate for the first time that macrophages play a decisive role in the survival of single TIC in vivo and provide a proof of principle for TIC elimination by targeting YAP or M2 macrophages. Furthermore, we found that YAP induces leukocyte-specific integrin β2 (ITGB2) expression in cancer cells, thereby promoting cell invasion through the endothelium in a manner mimicking leukocytes. Through independent biochemical purification and a functional screen, we further identified PR/SET domain 4 (PRDM4) as a transcription factor interacting with the WW domains of YAP to mediate ITGB2 expression and cell invasion. Consistently, ITGB2 and PRDM4 mRNA levels are significantly increased in metastatic prostate cancer. In addition, PRDM4 contributes to YAP-induced tumorigenesis, possibly via mediating the expression of other YAP target genes. Our results demonstrate that YAP promotes cell invasion by inducing leukocyte-specific integrin expression and identify PRDM4 as a novel transcription factor for YAP targets.
Citation Format: Xiaocan Guo, Huan Liu, Xiaolei Cao, Bin Zhao. The Hippo pathway in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA21.
Abstract IA11: Reversal of immunotherapy resistance through hypoxia reduction
Authors: Jayaprakash Priyamvada , Ai Midan , Curran Michael A. 
Published: September 2020

Abstract
Across multiple cancers, we find that T cells fail to accumulate in regions of hypoxia that can occupy as much as 50% of the volume of some solid tumors. In mouse models of both prostate cancer and head and neck cancer, we find that the hypoxia-activated prodrug TH-302 (evofosfamide) can reduce hypoxia by triggering a tissue-remodeling process that culminates in revascularization with organized, functional vessels. In the TRAMP-C2 model of prostate cancer, combining TH-302 with blockade of the T-cell immune checkpoint receptors CTLA-4 and PD-1 cures nearly all mice of 7-day established tumors and the majority of larger, 2-week established malignancy. TRAMP transgenic mice, which do not respond at all to immunotherapy alone, treated with the combination of TH-302 and either CTLA-4 and PD-1 blockade or CTLA-4 blockade and 4-1BB agonist show exceptional tumor control at 36 weeks of age. Mechanistically, hypoxia favors accumulation of myeloid-derived suppressor cells (MDSC), and reduction of hypoxia using TH-302 significantly decreases both their frequency and density in prostate tumors. In addition, the capacity of MDSC from mice receiving hypoxia reduction and checkpoint blockade to suppress T-cell proliferation is significantly diminished. Tumor-infiltrating T cells benefit both directly and indirectly from hypoxia reduction as evidenced by increased proliferation, cytotoxicity, effector cytokine production, and survival. Immunofluorescence reveals a lack of T-cell infiltration of hypoxic zones even in the context of CTLA-4 and PD-1 blockade. In contrast, coadministration of TH-302 with checkpoint blockade promotes nearly equivalent T-cell densities across normoxic and hypoxic tumor areas. Clinically, we are evaluating the combination of TH-302 and ipilimumab in patients with checkpoint refractory melanoma, HPV- head and neck cancer, metastatic prostate cancer, and pancreatic cancer (NCT03098160). Correlative studies in these patients reveal advantageous skewing of the tumor immune microenvironment in tumors where hypoxia is reduced on therapy. Further studies of the response of patient cancers to this therapy are ongoing. In addition, we seek to understand the molecular mechanisms linking hypoxia to impaired suppression in stromal myeloid and fibroblast compartments, and to identify additional pharmacologic interventions capable of disrupting hypoxia.
Citation Format: Priyamvada Jayaprakash, Midan Ai, Michael A. Curran. Reversal of immunotherapy resistance through hypoxia reduction [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA11.
Abstract B28: Optimizing DNA processing and ovarian cancer methylation-specific PCR assays for the detection of early-stage ovarian cancer
Authors: Warton Kristina , Yuwono Nicole , Henry Claire , Hacker Neville , Ford Caroline 
Published: September 2020

Abstract
Background: Ovarian cancer screening has the potential to greatly reduce mortality by shifting the time of diagnosis to an early stage when the tumor is confined to a single site and can be completely cured by surgical removal. Ovarian cancer DNA is present in blood and has a distinct methylation profile that distinguishes it from healthy blood cells, thus making it a target for ovarian cancer diagnosis via a blood test. However, while the presence of this DNA in the blood of cancer patients is well established, low abundance and DNA fragmentation present a barrier to developing clinical applications that target it.
Methods: We are systematically evaluating and optimizing each step of DNA extraction, processing, and analysis to increase the sensitivity of cancer DNA detection by PCR. At the same time, we are developing PCR assays to detect ovarian cancer specific methylation based on a previous tumor and blood screen that identified 73 methylated candidate biomarker regions.
Results: We have found that inhibitors of the PCR reaction introduced into the sample during DNA extraction and bisulphite treatment limit the total amount of DNA that can be analyzed, and thus the sensitivity of the test. Precipitation of the DNA samples prior to PCR analysis removes the inhibitors and increases useable sample volume and thus sensitivity. We have also developed methylation-specific PCR assays for DNA regions that are methylated in ovarian tumor tissue, and unmethylated in white blood cells.
Conclusions: We are progressing our candidate methylated DNA ovarian cancer biomarkers closer to testing in clinical samples. Our results on sample processing and DNA analysis methods to enable ovarian cancer DNA detection are relevant to all cancer types for which cell-free tumor DNA has clinical applications.
Citation Format: Kristina Warton, Nicole Yuwono, Claire Henry, Neville Hacker, Caroline Ford. Optimizing DNA processing and ovarian cancer methylation-specific PCR assays for the detection of early-stage ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B28.
Abstract PR12: Genetic aberrations dictate distinct tumor immune landscape and chemosensitivity in HGSOC
Authors: Zhang Shuang , Iyer Sonia , Ran Hao , Wei Wei , Weinberg Robert A. , Neel Benjamin G. 
Published: September 2020

Abstract
High-grade serous ovarian cancer (HGSOC) is the most common and deadly subtype of ovarian epithelial cancer and is known for its aggressiveness, high recurrence rate, metastasis to other sites, development of resistance to conventional chemotherapy, and general lack of response to immune checkpoint inhibitors. The absence of genomically relevant, immune-competent HGSOC models represents a major barrier to developing new therapies. Taking advantage of a mouse fallopian tube organoid system that we developed, along with lentiviral gene transduction and/or CRISPR/Cas9 technology, we generated multiple new HGSOC models containing combinations of mutations seen in human HGSOC, including homologous recombination (HR)-proficient (Tp53-/-;Ccne1amp;Akt2ampand Tp53-/-;Ccne1amp;Krasamp) and -deficient (Tp53-/-;Brca1-/-;Pten-/-and Tp53-/-;Brca1-/-;Mycamp), and poorly characterized (Tp53-/-;Pten-/-;Nf1-/-) models. These models differ in proliferation, differentiation, and polarity/organoid structure in vitro, as well as tumorigenic capacity and behavior upon orthotopic injection into syngeneic mice. Organoids bearing different mutational spectra show differential sensitivity to conventional HGSOC chemotherapies, signal transduction inhibitors and DDR inhibitors, and evoke distinctly different immune microenvironment in vivo. In particular, the immune microenvironment induced by HR-deficient tumors shows more T-cell infiltration/Treg cells, whereas HR-proficient lines show lower T-cell infiltration but higher levels of myeloid-derived suppressor cells and macrophages. The results of these studies suggest novel, genotype-informed combination therapies for this devastating disease.
This abstract is also being presented as Poster B19.
Citation Format: Shuang Zhang, Sonia Iyer, Hao Ran, Wei Wei, Robert A. Weinberg, Benjamin G. Neel. Genetic aberrations dictate distinct tumor immune landscape and chemosensitivity in HGSOC [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR12.
Trends in Left Ventricular Ejection Fraction for Patients With a New Diagnosis of Heart Failure
Authors: Tisdale Rebecca L. , Haddad François , Kohsaka Shun , Heidenreich Paul A. 
Published: September 2020

Background:
The left ventricular ejection fraction (LVEF) guides treatment of heart failure, yet this data has not been systematically collected in large data sets. We sought to characterize the epidemiology of incident heart failure using the initial LVEF.

Methods:
We identified 219 537 patients in the Veterans Affairs system between 2011 and 2017 who had an LVEF documented within 365 days before and 30 days after the heart failure diagnosis date. LVEF was obtained from natural language processing from imaging and provider notes. In multivariate analysis, we assessed characteristics associated with having an initial LVEF <40%.

Results:
Most patients were male and White; a plurality were within the 60 to 69 year age decile. A majority of patients had ischemic heart disease and a high burden of co-morbidities. Over time, presentation with an LVEF <40% became slightly less common, with a nadir in 2015. Presentation with an initial LVEF <40% was more common in younger patients, men, Black and Hispanic patients, an inpatient presentation, lower systolic blood pressure, lower pulse pressure, and higher heart rate. Ischemic heart disease, alcohol use disorder, peripheral arterial disease, and ventricular arrhythmias were associated with an initial LVEF <40%, while most other comorbid conditions (eg, atrial fibrillation, chronic obstructive pulmonary disease, malignancy) were more strongly associated with an initial LVEF >50%.

Conclusions:
For patients with heart failure, particularly at the extremes of age, an initial preserved LVEF is common. In addition to clinical characteristics, certain races (Black and Hispanic) were more likely to present with a reduced LVEF. Further studies are needed to determine if racial differences are due to patient or health systems issues such as access to care.
Tax Culture and Trust
Authors: Ogorodnikova Irina Ivanovna , Pecherkina Irina Fedorovna , Baksha Nadezhda Vladimirovna , Tarasova Anna Nikolaevna 
Published: September 2020

Abstract
The purpose of this research is to study the influence of the level of public trust in various social institutions and structures on shaping tax culture. The authors identify three components of tax culture, namely, tax morality, tax literacy, and tax behavior. Institutional trust as the main component of a tax paying culture has a strong impact on tax morality. The groups with a high level of institutional trust have only about a third as many tax deviations as the groups with a low level of institutional trust. Over the past decade, Russia has seen a gradual increase in trust, which contributes to strengthening tax morality and raising the level of tax culture in the population. This is manifested in increased tax collection and reduced tax arrears. Nevertheless, tax opportunism still persists in Russian society. Almost a third of citizens do not consider themselves obliged to pay taxes and are tolerant of tax deviations. This fact may serve as a factor in the reproduction of deviant forms of taxpayer behavior, together with a low level of tax literacy in the population.
Attitudes towards Gender Equality
Authors: Zagrebina Anna 
Published: September 2020

Abstract
This study contributes to a societal vision of contemporary democracy, a subject that is not sufficiently considered in the research literature, by analyzing the mechanisms underlying the production of egalitarian gender attitudes in less democratic and more democratic societies and concluding on the democratic social context. A comparative analysis of gender attitudes in 72 countries shows that citizens of the most democratized countries have more egalitarian gender attitudes in politics, business and access to university education and employment, and that determinants of gender attitudes vary by sex and socio-political context.