bluuebunny/crossref_metadata_2025 huggingface dataset:
Multipurpose Watermarking Algorithm for Medical Images
Authors: Xiao Shaozhang , Zhang Zhengwei , Zhang Yue , Yu Changhui
Published: September 2020

Considering the existing medical image watermarking algorithms, a single function often has limitations, and a multipurpose watermarking algorithm for medical images is proposed. First, medical images are divided into regions of interest (ROIs) and regions of noninterest (RONIs). Then, the authentication watermark produced for each subblock of the ROI is embedded into the corresponding mapping subblock. The visible watermark is embedded into the RONI, and, finally, the watermark information and constructed authentication information in each subblock of the ROI are embedded into the corresponding RONI subblock. Simulation results show that the embedded visible watermark can protect and facilitate medical image management. In addition, the proposed algorithm has strong robustness and very good visual quality. It can simultaneously realize copyright protection and content authentication and also has high tamper localization capability.
Reversible Data Hiding for Encrypted 3D Model Based on Prediction Error Expansion
Authors: Li Li , Wang Shengxian , Luo Ting , Chang Ching-Chun , Zhou Qili , Li Hui
Published: September 2020

Since 3D models can intuitively display real-world information, there are potential scenarios in many application fields, such as architectural models and medical organ models. However, a 3D model shared through the internet can be easily obtained by an unauthorized user. In order to solve the security problem of 3D model in the cloud, a reversible data hiding method for encrypted 3D model based on prediction error expansion is proposed. In this method, the original 3D model is preprocessed, and the vertex of 3D model is encrypted by using the Paillier cryptosystem. In the cloud, in order to improve accuracy of data extraction, the dyeing method is designed to classify all vertices into the embedded set and the referenced set. After that, secret data is embedded by expanding direction of prediction error with direction vector. The prediction error of the vertex in the embedded set is computed by using the referenced set, and the direction vector is obtained according to the mapping table, which is designed to map several bits to a direction vector. Secret data can be extracted by comparing the angle between the direction of prediction error and direction vector, and the original model can be restored using the referenced set. Experiment results show that compared with the existing data hiding method for encrypted 3D model, the proposed method has higher data hiding capacity, and the accuracy of data extraction have improved. Moreover, the directly decrypted model has less distortion.
Content Analysis of Essential Economic Values in the Vocational Textbook as Compared to the Saudi Arabian Education Policy Document
Authors: Aldoosry Rashed Z. , Aldahmash Abdulwali H. , Alfaifi Mousa S. , Almutairi Abdullah M. , Aldossari Abdulaziz S. , Alshuaibi Abdulrahman A. , ALabbad Abdullah H.
Published: September 2020

This study explores the extent to which five essential economic values related to the themes of production, savings, moderation in expenditure, labor, and economic development were included in the Saudi Arabian Educational Policy Document and their reflection in a high school vocational textbook. A systematic quantitative descriptive approach was used to analyze the contents of the two documents. Results showed that the Education Policy Document only included the production domain value. The vocational textbook did not significantly include all economic values, except the theme related to respecting and the value of time. This means that the two documents should be revised to include these important economic values, as they are important for students’ future.
Safety Monitoring of Expressway Construction Based on Multisource Data Fusion
Authors: Xiao Dianliang , Zhang Tiantao , Zhou Xudong , Zheng Guangshun , Song Haoran
Published: September 2020

China’s terrain is complex, both plain, microhill (heavy-hill) and mountainous terrain; the hidden dangers of highway construction are prominent. Construction site management, production safety management, and construction personnel management are difficult, and it is necessary to borrow advanced technology to establish information, and it is necessary to borrow advanced technology to establish information system to realize the visualization of safety monitoring. In the construction of highways, mountainous terrain is often complicated due to complex terrain, high mountains, and deep valleys. Excavation of the mountain mass is required to form high and steep slopes. For successful projects, safety monitoring is particularly important. Multisource data fusion is one of the computer application technologies. It is an information processing technology that is automatically analyzed and synthesized under certain criteria to complete the required decision-making and evaluation tasks. This paper analyzes high-speed data in the context of multisource data fusion. Study on highway slope construction safety monitoring. BP neural network fusion technology of multisource data fusion technology is used. A high-speed breccia-bearing silty clay slope is taken as the research object. The feedback information about the deployed monitoring system is fully used in the slope design and construction. The construction design parameters are reversed to predict the stability of the slope and ensure the safety of construction and operation of similar slopes of the entire expressway. The research in this paper finds that the maximum deviation between the slope displacement value and the measured value obtained by the slope monitoring based on multisource data fusion in this paper is 7.53%, which is less than 10%, which verifies the feasibility of the method in this paper. The research methods and ideas of this paper can also provide a reference for similar engineering research.
Representative Elementary Volume of Rock Using X-Ray Microcomputed Tomography: A New Statistical Approach
Authors: Rahman Taufiq , Ramandi Hamed Lamei , Roshan Hamid , Iglauer Stefan
Published: September 2020

Rock heterogeneity is a key parameter influencing a range of rock properties such as fluid flow and geomechanical characteristics. The previously proposed statistical techniques were able to rank heterogeneity on a qualitative level to different extents; however, they need to select a threshold value for determination of representative elementary volumes (REV), which in turn makes the obtained REV subjective. In this study, an X-ray microcomputed tomography (μCT) technique was used to obtain images from different porous media. A new statistical technique was then used to compute REV, as a measure of heterogeneity, without the necessity of defining a threshold. The performance of the method was compared with other methods. It was shown that the calculated sum of the relative errors of the proposed method was lowest compared to the other statistical techniques for all tested porous media. The proposed method can be applied to different types of rocks for more accurate estimation of a REV.
The Literature Review of Platform Economy
Authors: Xue Chen , Tian Wuxu , Zhao Xiaotao
Published: September 2020

Since the 1990s, the increasing development of digital-driven technologies such as the Internet, cloud computing, big data, and the Internet of Things and the popularization of computers and mobile electronic devices have accelerated the evolution of global business organizations, thus making a new form of business organization, platform economy. As the most important form of industrial organization in the new economic era, the development of the platform has received extensive attention from the academia. Through literature analysis and inductive deduction, this paper reviews the connotation of platform economy, the historical context of development, the competition and monopoly (differentiation) of multilateral platforms, the evaluation mechanism of platform, antimonopoly governance, and research methods, and provides theoretical references and new ideas for future research directions.
Utility-Based Multicriteria Model for Screening Patients under the COVID-19 Pandemic
Authors: Roselli Lucia Reis Peixoto , Frej Eduarda Asfora , Ferreira Rodrigo José Pires , Alberti Alexandre Ramalho , de Almeida Adiel Teixeira
Published: September 2020

In this paper, a utility-based multicriteria model is proposed to support the physicians to deal with an important medical decision—the screening decision problem—given the squeeze put on resources due to the COVID-19 pandemic. Since the COVID-19 emerged, the number of patients with an acute respiratory failure has increased in the health units. This chaotic situation has led to a deficiency in health resources. Thus, this study, using the concepts of the multiattribute utility theory (MAUT), puts forward a mathematical model to aid physicians in the screening decision problem. The model is used to generate which of the three alternatives is the best one for where patients with suspected COVID-19 should be treated, namely, an intensive care unit (ICU), a hospital ward, or at home in isolation. Also, a decision information system, called SIDTriagem, is constructed and illustrated to operate the mathematical model proposed.
Crystal Guava (Psidium guajava L. “Crystal”): Evaluation of In Vitro Antioxidant Capacities and Phytochemical Content
Authors: Hartati Rika , Nadifan Hashifah I. , Fidrianny Irda
Published: September 2020

Free radicals can cause many diseases, such as cancer. Antioxidant is a compound that could scavenge free radicals. One of the natural antioxidants is guava. The goals of this research were to investigate the antioxidant activity of leaves and fruit of crystal guava by determining the value of the Antioxidant Activity Index (AAI) using DPPH, CUPRAC, and FRAP; evaluate the total phenolic content (TPC) and total flavonoid content (TFC); analyse the correlation between the TPC and TFC with AAI DPPH, CUPRAC, and FRAP, and analyse the correlation between the 3 methods. Extraction was performed by the reflux method using n-hexane, ethyl acetate, and ethanol. Determination of AAI DPPH, CUPRAC, FRAP, the TPC, and the TFC was performed by UV-visible spectrophotometry. The correlation of the TPC and TFC with AAI DPPH, CUPRAC, and FRAP and, also, the correlation of the 3 methods were investigated by Pearson’s method. The antioxidant activity of leaves and fruit extracts of crystal guava showed AAI DPPH in the range of 0.33–56.46, CUPRAC 0.20–7.31, and FRAP 1.65–59.89. The highest TPC was given by ethanol leaf extracts (49.55 ± 1.45 g GAE/100 g), while the highest TFC was for n-hexane leaf extracts (9.68 ± 0.210 g QE/100 g). The TPC of leaves extract had a significantly positive correlation with AAI DPPH, CUPRAC, and FRAP. AAI DPPH, AAI CUPRAC, and AAI FRAP of leaves and fruit extract of crystal guava showed a significantly positive correlation. In general, leaves extract had strong antioxidant activity by the three methods. For the highest antioxidant activity, ethanol was the best solvent for extraction leaves and ethyl acetate for extraction fruit of crystal guava. The TPC in leaves extract contributed to the antioxidant activity by DPPH, CUPRAC, and FRAP methods. The Antioxidant activity of leaves and fruit extracts of crystal guava was linear by the three methods.
Activity Budget and Feeding Ecology of Geladas (Theropithecus gelada obscurus) around Abogedam Church West of Debre Berhan Town, Ethiopia
Authors: Yazezew Dereje , Bekele Afework , Ibrahim Hussein
Published: September 2020

Geladas are the most distinctive of Ethiopian endemic mammals, representing the last extant species of primate genus that have a very restricted distribution in the northern Ethiopian plateau. The activity budget and feeding ecology of geladas (Theropithecus gelada obscurus) were studied around Abogedam Church, Ethiopia, from May to October 2014, encompassing dry and wet seasons. The scan sampling method was applied to collect behavioural data on the identified band. Activity scans were collected at 15-minute intervals for up to five minutes duration from 0700 to 1730 h. The activity recorded for each individual was the first activity that lasts for five seconds. During each scan, individuals were recorded as performing activities: feeding, moving, resting, playing, aggression, grooming, sexual activity, and others. On average, geladas devoted 57.19% feeding, 14.82% resting, 14.92% moving, 4.83% playing, 2.53% aggression, 4.14% grooming, 1.23% sexual activity, and 0.34% other activities such as vocalization, defecation, and urination. Forty-one plant species were consumed by geladas that belonged to 18 families of which 53.66% were grasses. This study provides basic information on further studies and motivates conservationists to plan the management of unprotected areas at the vicinity of agricultural lands where such endemic animals dwell.
Abstract A014: Rural-urban differences e-cigarette ever use, the perception of harm, and e-cigarette information-seeking behaviors among U.S. adults in a nationally representative study
Authors: Lewis-Thames Marquita W. ,   Marvin E. LWashington University in St. Louis School of Medicineangston, WashiWashington Lindsay Fuzzella. , Khan Saira , Moore Justin X. , Han Yunan
Published: September 2020

Rural adults are more likely to use some tobacco products and die from tobacco-related diseases than their urban counterparts. The harms and benefits of e-cigarette use are mixed, and similarly, obscure messaging about these harms and benefits have a critical influence on e-cigarette uptake and perceived harms. However, little is known about rural-urban differences in the prevalence of adult e-cigarette daily usage. Using the Health Information National Trends Survey-Food and Drug Administration (HINTS-FDA) cycles 1 and 2, we conducted weighted logistic regressions to assess rural-urban differences in the prevalence of adult e-cigarette daily usage, perceived harm, and e-cigarette information seeking behaviors. This analysis included adults aged 18 and older in the United States. (N=4229). Both rural and urban respondents had a similar history of e-cigarette use. Rural respondents were significantly more likely than urban respondents to trust religious organizations and leaders and tobacco companies for information about e-cigarettes. Rural and urban respondents were equally as likely to believe e-cigarettes are addictive, perceive e-cigarette use as harmful, and believe e-cigarettes are more harmful than smoking cigarettes. They were equally as likely to look for information on e-cigarettes, the health effects of e-cigarettes, and cessation; and, to seek e-cigarette information from healthcare professionals, family and friends, and health organizations and groups. Given our findings, it will be pertinent to continue to research the potential harms of e-cigarette use and develop accurate health communication messages to avoid similar rural-urban disparities observed for cigarette smoking-related outcomes.

Citation Format: Marquita W. Lewis-Thames, Marvin E. LWashington University in St. Louis School of Medicineangston, Lindsay Fuzzella. WashiWashington, Saira Khan, Justin X. Moore, Yunan Han. Rural-urban differences e-cigarette ever use, the perception of harm, and e-cigarette information-seeking behaviors among U.S. adults in a nationally representative study [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A014.
G-Protein-Coupled Estrogen Receptor 1 Promotes Gender Disparities in Hepatocellular Carcinoma via Modulation of SIN1 and mTOR Complex 2 Activity
Authors: Feng Guanying , Cai Jingshu , Huang Yunchuanxiang , Zhu Xianjun , Gong Bo , Yang Zhenglin , Yan Chunhong , Hu Zhuowei , Yang Lu , Wang Ziyan
Published: September 2020

Due to its intricate heterogeneity and limited treatment, hepatocellular carcinoma (HCC) has been considered a major cause of cancer-related mortality worldwide. Increasing evidence indicates that G-protein-coupled estrogen receptor 1 (GPER1) can promote estrogen-dependent hepatocellular proliferation by activating AKT signaling. The mTOR complex 2 (mTORC2), whose integrity and activity are modulated by its subunit Sin1, controls the activation of AKT by phosphorylation at position S473. In this study, we investigate the modulation of Sin1 and how estrogen signaling may influence the mTORC2–AKT cascade in HCC cells and a DEN-induced mouse model. We have found that estradiol-dependent Sin1 expression is transcriptionally modulated by GPER1 as well as ERα. GPER1 is able to regulate Sin1 stability via nuclear translocation, therefore increasing Sin1–mTORC2–AKT activation. Moreover, Sin1 interacts with ERα and further enhances its transcriptional activity. Sin1 is highly expressed in acute liver injury and in cases of HCC harboring high expression of GPER1 and constitutive activation of mTORC2–AKT signaling. GPER1 inhibition using the antagonist G-15 reverses DEN-induced acute liver injury by suppressing Sin1 expression and mTORC2–AKT activation. Notably, SIN1 expression varies between male and female mice in the context of both liver injury and liver cancer. In addition, high SIN1 expression is predictive of good prognosis in both male and female patients with HCC who are free from hepatitis virus infection and who report low alcohol consumption. Hence, here we demonstrate that Sin1 can be regulated by GPER1 both through nongenomic and indirect genomic signaling.

Implications:

This study suggests that Sin1 may be a novel HCC biomarker which is gender-dependent and sensitive to particular risk factor.
Neoplastic–Stromal Cell Cross-talk Regulates Matrisome Expression in Pancreatic Cancer
Authors: Honselmann Kim C. , Finetti Pascal , Birnbaum David J. , Monsalve Christian S. , Wellner Ulrich F. , Begg Sebastian K.S. , Nakagawa Akifumi , Hank Thomas , Li Annie , Goldsworthy Mathew A. , Sharma Himanshu , Bertucci François , Birnbaum Daniel , Tai Eric , Ligorio Matteo , Ting David T. , Schilling Oliver , Biniossek Martin L. , Bronsert Peter , Ferrone Cristina R. , Keck Tobias , Mino-Kenudson Mari , Lillemoe Keith D. , Warshaw Andrew L. , Fernández-del Castillo Carlos , Liss Andrew S.
Published: September 2020

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer–stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells. In vitro cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer–CAF cross-talk. Disrupting this cross-talk in vivo resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long- and short-term PDAC survivors. Importantly, the expression of genes predictive of short-term survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival.

Implications:

These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor–stroma cross-talk as a potential therapeutic avenue.
Abstract A13: Yap activity in bile ducts, but not in hepatocytes, is required for normal liver regeneration
Authors: Verboven Elisabeth , Moya Ivan M. , Halder Georg
Published: September 2020

The Hippo-pathway effectors Yap/Taz are assumed to be master regulators of organ regeneration. In the mouse liver, loss of Yap indeed affects the regeneration potential of hepatocytes. However, we found that this is not due to a requirement for Yap in hepatocytes to drive proliferation and regeneration, but is rather due to non-cell autonomous effects of the bile duct defects that develop in the absence of Yap. Developmental deletion of Yap and Taz in liver progenitors, which develop into hepatocytes and bile epithelial cells (BECs), impaired liver regeneration after toxin-induced injury. However, hepatocyte-specific deletion of Yap/Taz in adult mice revealed that Yap/Taz are dispensable in hepatocytes for liver regeneration. In contrast, deletion of Yap/Taz in mature BECs recapitulated the liver regeneration defects that were observed after knockout in liver progenitor cells. Notably, loss of Yap/Taz in BECs impaired bile duct integrity over time, induced a cholestatic liver phenotype, and increased apoptosis in wild-type hepatocytes after toxic liver injury. Our data show that Yap and Taz are required to maintain bile duct integrity, which is essential to maintain the regenerative capacity of adult hepatocytes.

Citation Format: Elisabeth Verboven, Ivan M. Moya, Georg Halder. Yap activity in bile ducts, but not in hepatocytes, is required for normal liver regeneration [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 A13.
Abstract A15: A balance of yki/sd activator and e2f1/sd repressor complexes controls cell survival and affects organ size
Authors: Zhang Peng , Pei Chunli , Yuan Zengqiang , Edgar Bruce A.
Published: September 2020

The Hippo/Yki and RB/E2F pathways both regulate tissue growth by affecting cell proliferation and survival, but interactions between these parallel control systems are poorly defined. In this study, we demonstrate that interaction between Drosophila E2F1 and Sd disrupts Yki/Sd complex formation and thereby suppresses Yki target gene expression. RBF modifies these effects by reducing E2F1/Sd interaction. This regulation has significant effects on apoptosis, organ size, and progenitor cell proliferation. Using a combination of DamID-seq and RNA-seq, we identified a set of Yki targets that play a diversity of roles during development and are suppressed by E2F1. Further, we found that human E2F1 competes with YAP for TEAD1 binding, affecting YAP activity, indicating that this mode of cross-regulation is conserved. In sum, our study uncovers a previously unknown mechanism in which RBF and E2F1 modify Hippo signaling responses to modulate apoptosis, organ growth, and homeostasis.

Citation Format: Peng Zhang, Chunli Pei, Zengqiang Yuan, Bruce A. Edgar. A balance of yki/sd activator and e2f1/sd repressor complexes controls cell survival and affects organ size [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 A15.
Abstract A26: Classification of glioblastoma tumorsphere depending on the regulatory mechanisms of the Hippo pathway
Authors: Oh Yoojung , Kim Eui Hyun , Lee Dongkyu , Park Junseong , Moon Ju Hyung , Park Hyun Woo , Chang Jong Hee , Kang Seok-Gu
Published: September 2020

Background: Although glioblastoma (GBM) is the most common primary brain tumor, the best available treatment options are still associated with poor prognosis. Recently, the Hippo/YAP signaling pathway has emerged as an important driver of GBM. Nevertheless, extensive studies have not yet been focused on the importance of phosphorylation event in regulating endogenous YAP activity in GBM. Here, we sought to elucidate that the modulation and stabilization of YAP/TAZ in Hippo pathway promote GBM progression.

Methods: A core gene expression signature reflecting Silence of Hippo pathway (SOH) was developed in GBM patient samples to determine whether SOH enhances the tumor progression. In GBM tumorsphere (TS), mRNA levels of YAP1 were determined by microarray, and nuclear YAP1 expression level and its correlation with tumor aggressiveness were assessed through nucleus cytosolic fractionation, quantitative confocal microscopy, Western blot, and TEAD4 reporter assay. Cell proliferation, stemness, and invasive properties were also measured after treatment of YAP siRNA or its inhibitor verteporfin (VP).

Results: GBM patients with SOH signature associated with poor prognosis and shorter survival. GBM TSs exhibited various phosphorylation states of YAP and could be distinguished by its phosphorylation status. GBM TSs with reduced YAP phosphorylation, including TS15-88, and other GBM TSs with higher YAP phosphorylation, which includes TS13-64, showed aggressive or less-aggressive cancer phenotypes, respectively. The siRNA-mediated knockdown of YAP1 significantly suppressed proliferation of TSs, and the results were confirmed using VP. Knockdown of YAP1 not only attenuated the invasiveness and stemness of TSs.

Conclusion: We showed that reduced phosphorylation of endogenous YAP contributes to GBM progression. Moreover, we found that GBM TSs can be classified into two groups based on their YAP phosphorylation. These associations emphasize the YAP signaling network as new therapeutic opportunities in diagnosing and treating GBM.

Citation Format: Yoojung Oh, Eui Hyun Kim, Dongkyu Lee, Junseong Park, Ju Hyung Moon, Hyun Woo Park, Jong Hee Chang, Seok-Gu Kang. Classification of glioblastoma tumorsphere depending on the regulatory mechanisms 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 A26.
Abstract B17: Hyperactivating the Hippo pathway effector TAZ distorts the immune microenvironment in promoting the mesenchymal transformation in glioblastoma
Authors: Yee Patricia , Wei Yiju , Liu Zhijun , Li Wei
Published: September 2020

Glioblastoma (GBM), the deadliest and most common primary brain malignancy in adults, is highly heterogeneous with variable prognoses and treatment responses. The mesenchymal subtype of GBM is associated with the worst prognosis and highest treatment resistance. It is still not clear how GBM mesenchymal differentiation is achieved. Hyperactivity of transcriptional coactivator with PDZ-binding motif (TAZ) was linked to the GBM mesenchymal transformation, although its role in this process remains unclear. Here, by using orthotopic xenograft mouse GBM models, we found that hyperactive TAZ in tumor cells promotes myeloid cells to infiltrate into tumors. Such enhanced myeloid cell infiltration is associated with the mesenchymal transformation and tumor progression. We demonstrated that these TAZ-induced tumorigenic properties rely on its interaction with the transcription factor, TEA domain family member (TEAD). Such interaction induces the transcription of chemokines that are able to recruit the myeloid cells. Specific depletion of the infiltrated myeloid cells is able to slow down the tumor progression. Our studies suggested that recruiting myeloid cells by hyperactive TAZ contributes the mesenchymal transformation and tumor progression in glioblastoma.

Citation Format: Patricia Yee, Yiju Wei, Zhijun Liu, Wei Li. Hyperactivating the Hippo pathway effector TAZ distorts the immune microenvironment in promoting the mesenchymal transformation in glioblastoma [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 B17.
Abstract B25: An actionable AXL-ABL2-TAZ signaling axis promotes lung adenocarcinoma metastasis to the brain
Authors: Hoj Jacob P. , Mayro Benjamin J. , Pendergast Ann Marie
Published: September 2020

Despite recent work to uncover the biologic mechanisms governing tumor cell metastasis to the brain, new therapeutic approaches for treating patients with brain-metastatic disease have remained elusive. Through the use of in vivo models of brain metastasis and relevant in vitro molecular biology techniques, we identify a novel and targetable autocrine signaling axis required for lung adenocarcinoma metastasis to the brain centered upon the transcriptional coactivator TAZ. Nuclear localization of TAZ drives transcription of target genes AXL and ABL2, which in turn engage in bidirectional tyrosine kinase signaling at the protein level. Activation of ABL2 in turn increases TAZ stability and promotes its nuclear localization, establishing an autocrine feed-forward signaling loop and revealing a previously undescribed mechanism of TAZ nuclear localization dependent on tyrosine kinase activity of ABL2. We further reveal that the Neural Adhesion Molecule L1 (L1CAM), previously identified as a critical mediator of brain metastasis, is a direct target gene of TAZ whose expression is regulated by activation of AXL-ABL2-TAZ signaling. Our findings provide evidence for AXL and ABL2 kinase inhibitors as potential therapeutic strategies for the treatment of brain metastases.

Citation Format: Jacob P. Hoj, Benjamin J. Mayro, Ann Marie Pendergast. An actionable AXL-ABL2-TAZ signaling axis promotes lung adenocarcinoma metastasis to the brain [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 B25.
Abstract B31: YAP1-induced cervical carcinogenesis challenges the HPV dogma
Authors: Wang Cheng
Published: September 2020

Aims: HPV infections are common in women but only rarely cause cervical cancer, suggesting that individual genetic susceptibility may play a critical role in the establishment of persistent HPV infection and development of cervical cancer. The molecular mechanisms underlying cervical cancer development remain unclear. Although our previous in vitro studies have shown that YAP1 plays a role in the malignant transformation of cervical epithelial cells, whether YAP1 contributes to the cervical carcinogenesis in vivo is unknown. This study aims to determine whether YAP1, alone or interacting with HPV, contributes to cervical carcinogenesis in vivo.

Methods: Cellular and transgenic mouse models were developed to evaluate the role of YAP1 in cervical carcinogenesis.

Results: Keratin-14 promoter-driven expression of constitutively active YAP1 (YAPS127A) in mouse cervical epithelial cells induced invasive cervical cancer, suggesting that hyperactivation of YAP1 is sufficient to induce cervical cancer development. Cervical epithelial cell-specific HPV and YAP1 double knockin mouse models showed that HPV synergizes with YAP1 to promote the initiation and progression of cervical carcinogenesis. Our mechanistic studies demonstrated that hyperactivation of YAP1 in cervical epithelium not only increased the putative HPV receptor molecules and cellular susceptibility to HPV infection, but also disrupted the host cell innate immune system, resulting in failure of HPV viral recognition, suppression of type I IFN production, inhibition of the IFNRs/JAKs/STATs pathway, and blockage of production of antiviral interferon-stimulated genes.

Conclusion: Our results indicated that the YAP1 oncogene plays a central role in cervical cancer development. The synergism between hyperactivated YAP1 and high-risk HPV may be a key driver of cervical cancer initiation and progression. Our finding challenges the dogma that HPV is a necessary agent for the development of cervical cancer, uncovers a novel mechanism for the cervical carcinogenesis, and provides new targets for developing strategies to improve prevention and treatment of cervical cancer.

Note: This abstract was not presented at the conference.

Citation Format: Cheng Wang. YAP1-induced cervical carcinogenesis challenges the HPV dogma [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 B31.
Abstract B36: Therapy-induced YAP hyperactivation is a mechanism driving the evolution of residual disease and resistance to targeted cancer therapy
Authors: Zaman Aubhishek , Bivona Trever
Published: September 2020

Initial profound responses of precision medicines against cancer are limited in duration in part due to residual disease states that are therapy refractory and serve as a prelude to acquired drug resistance and tumor relapse. A prominent clinical example is in the collection of BRAF mutant cancers, including lung cancer and melanoma, which often respond initially, but incompletely and temporarily, to targeted RAF and MEK inhibition. The Hippo pathway transcriptional coactivator, Yes-associated protein (YAP), is a chief mediator of RAF and MEK inhibitor response in BRAF mutant cancers. However, the underlying mechanism for YAP-driven resistance is not fully understood. Here, we modeled the kinetics of patient-derived and isogenic BRAF mutant (V600E) cell lines in response to BRAF inhibitor and MEK inhibitor treatment. Our analysis indicated that in response to drug treatment the cells evolve through a “persister,” residual disease state that is distinct from therapy-naive cells or cells with acquired resistance. We observed that drug treatment induced early nuclear translocalization of YAP and this response peaked at the “persister” cell state before returning towards baseline upon acquired resistance. Additionally, our functional analysis of the proteomic and transcriptional landscape of the “persister” cells demonstrated drug-dependent reversible and concomitant activation of AKT, YAP target gene expression, and an epithelial mesenchymal transition (EMT). These programs underlay acquired vulnerabilities, as pharmacologic perturbation of AKT and genetic ablation of YAP was lethal specifically in the “persister” cells. Remarkably, AKT was required and sufficient for drug-induced nuclear localization of YAP, indicating that therapy-mediated hyperactivation of AKT is required for YAP induction and YAP-mediated residual disease. Current studies are focused on characterizing the molecular events causing AKT-mediated hyperactivation of YAP in response to MAPK pathway inhibition. Overall, this work aims to deconvolute a novel molecular mechanism of YAP activation in cancer cells and establish the functional implications of YAP signaling on “persister” cell biology and the evolution of targeted cancer therapy resistance.

Citation Format: Aubhishek Zaman, Trever Bivona. Therapy-induced YAP hyperactivation is a mechanism driving the evolution of residual disease and resistance to targeted cancer therapy [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 B36.
Abstract IA03: The Hippo pathway in melanoma
Authors: Zhang Xiaomeng , Yang Lie , Vergara Ismael , Szeto Pacman , Zhang Youfang , Papenfuss Anthony , Shackleton Mark , Harvey Kieran
Published: September 2020

Melanoma is usually driven by mutations in BRAF or NRAS that trigger hyperactivation of mitogen-activated protein kinase (MAPK) signaling. However, MAPK targeted therapies are not sustainably effective in most patients. Accordingly, characterizing mechanisms that cooperatively drive melanoma progression is key to improving patient outcomes. One possible mechanism is the Hippo signaling pathway, which regulates cancer progression via its central oncoproteins YAP and TAZ, although it is relatively rarely affected by direct mutation. As YAP hyperactivation occurs in uveal melanoma, we investigated this oncogene in cutaneous melanoma. YAP protein expression was elevated in most benign nevi and primary cutaneous melanomas but present at only very low levels in normal melanocytes. In patient-derived xenografts and melanoma cell lines, we observed variable reliance of cell viability on Hippo pathway signaling that was independent of classical melanoma driver mutations such as BRAF and NRAS. YAP activity was enriched in invasive melanoma cell lines and was necessary for their invasive properties in culture. In in vivo studies, we found that expression of hyperactive YAP induced spontaneous melanoma metastasis in mice. Finally, in genotyping studies of melanoma, we observed the first ever hyperactivating YAP mutations in a human cancer, manifest as seven distinct missense point mutations that caused serine to alanine transpositions. Strikingly, these mutate four of five known serine residues targeted by the Hippo pathway, and we show that they lead to hyperactivation of YAP function. Our studies highlight the YAP oncoprotein as a potential therapeutic target in select subgroups of melanoma patients, although successful treatment with anti-YAP therapies will depend on identification of biomarkers other than YAP protein expression.

Citation Format: Xiaomeng Zhang, Lie Yang, Ismael Vergara, Pacman Szeto, Youfang Zhang, Anthony Papenfuss, Mark Shackleton, Kieran Harvey. The Hippo pathway in melanoma [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 IA03.
Abstract IA06: Dysregulated Hippo signaling in childhood rhabdomyosarcoma
Authors: Linardic Corinne M.
Published: September 2020

Rhabdomyosarcoma (RMS) is a mesenchymal cancer of skeletal muscle histogenesis and the most common soft tissue sarcoma of childhood. Survival for children with high-risk disease is less than 30% and has not improved in over four decades, underscoring the need for a deeper understanding of the dysregulated pathways at the molecular level. Recently, we and others have identified Hippo signaling as one of the developmental pathways hijacked by RMS, leading to uncontrolled RMS cell and tumor growth. Here we will describe the nature of dysregulated Hippo signaling in the two most common forms of RMS, known as fusion-negative RMS and fusion-positive RMS (formerly ERMS and ARMS, respectively). Fusion status refers to the absence or presence of RMS-specific PAX-FOXO1 fusion oncogenes, mutant transcription factors that portend a poor clinical outcome. In fusion-negative RMS, we find a critical role for YAP1 in tumor initiation and tumor maintenance, with YAP1 engaged in a feed-forward loop with the Notch pathway to support RMS cancer cell stemness. In fusion-positive RMS, we also find dysregulated canonical Hippo signaling supporting tumorigenic phenotypes. However, there is an additional unanticipated role for PAX3-FOXO1 in restraining noncanonical Hippo signaling. Complementary tumor models used to interrogate Hippo signaling in RMS, including patient-derived cell lines, primary human myoblast-based models, and genetically engineered mouse models, will be presented. Finally, the discrete knowledge gaps to be filled and the therapeutic opportunities that will arise from preclinical harnessing of the Hippo pathway in this and other childhood soft tissue sarcomas will be considered.

Citation Format: Corinne M. Linardic. Dysregulated Hippo signaling in childhood rhabdomyosarcoma [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 IA06.
Abstract IA27: Regulation of Hippo and TAZ signaling in breast cancer
Authors: Lu Yi , Wu Tiantian , Zhu Qingwei , Gutman Orit , Henis Yoav , Luo Kunxin
Published: September 2020

TAZ and YAP are transcriptional coactivators that can contribute to cancer by promoting proliferation, tumorigenesis, and cancer stem cell expansion. Hippo signaling activates the Lats family of kinases, which phosphorylate TAZ and YAP, resulting in cytoplasmic retention and degradation and inhibition of their transcriptional activity. Hippo signaling can be activated by a wide variety of upstream signals and is itself regulated by crosstalk with other intracellular signaling pathways. One such regulator is SnoN. SnoN regulates multiple signaling pathways, including TGF-β/Smad and p53, and displays both pro-oncogenic and antioncogenic activities in human cancer. We have observed previously that both its intracellular localization and expression levels are sensitive to cell density, suggesting that it may crosstalk with Hippo signaling. Indeed, SnoN interacts with multiple components of the Hippo pathway to inhibit the binding of Lats2 to TAZ and the subsequent phosphorylation of TAZ, leading to TAZ stabilization. Consistently, SnoN enhances the transcriptional and oncogenic activities of TAZ, and reducing SnoN decreases TAZ expression as well as malignant progression of breast cancer cells. Interestingly, SnoN itself is downregulated by Lats2 that is activated by the Scribble basolateral polarity protein. Thus, SnoN is a critical component of the Hippo regulatory network that receives signals from the tissue architecture and polarity to coordinate the activity of intracellular signaling pathways. New results from recent investigations will be discussed.

Citation Format: Yi Lu, Tiantian Wu, Qingwei Zhu, Orit Gutman, Yoav Henis, Kunxin Luo. Regulation of Hippo and TAZ signaling in breast 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 IA27.
Abstract PR11: Active YAP as a functional marker of drug-tolerant persister cells in EGFR-mutant and ALK fusion-positive NSCLC
Authors: Haderk Franziska , Allegakoen David , Guan Juan , Wu Wei , Bivona Trever
Published: September 2020

Targeted therapies against clinically actionable oncogenic drivers in lung adenocarcinoma have significantly improved survival of cancer patients, but durable responses are limited due to the emergence of drug resistance. Resistance development is often characterized by the retention of a small subpopulation of cancer cells under drug treatment and their evolution from non-/low-proliferative residual disease to an aggressively growing resistant tumor. Most importantly, drug-tolerant persister cells have been identified as a reservoir for a multitude of drug resistance mechanisms and thus, their characterization and the development of rational combinatorial treatment may delay or prevent resistance development and improve treatment outcome for cancer patients. Using a multitude of in vitro models such as cell culture models and patient-derived organoids, we characterized signaling and transcriptional changes in drug-tolerant persisters. We identified YAP nuclear relocalization and its increased transcriptional activity as a key marker of persisters derived from EGFR-mutant and EML4-ALK fusion-positive specimen under third-generation TKI treatment. Image analysis of cells genetically engineered via CRISPR-Cas9 to express endogenously labeled YAP-mNeonGreen validated these results. Moreover, we were able to prove the functional relevance of YAP activation in drug persistence by overexpressing active mutants of YAP that are lacking inhibitory Hippo phosphorylation sites. The latter resulted in increased nuclear levels and transcriptional activity of YAP and mediated significantly reduced cell death under high-dose drug treatment in different cell line models. Using RNA sequencing, we show a clear evolutionary path from drug-sensitive parental cells to drug-tolerant persisters and long-term derived drug-acquired resistant cells. We are currently profiling vulnerabilities of drug-tolerant EGFR-mutant and EML4-ALK fusion persisters using genetic and pharmacologic approaches. In conclusion, YAP activation is a functional marker of EGFR-mutant and EML4-ALK fusion persisters derived under high-dose drug treatment with third-generation TKIs. Targeting YAP activation either on the level of upstream signaling input, its relocalization between cytoplasm and nucleus, or its action as transcriptional coactivator may represent a promising combinatorial treatment approach to limit resistance development and improve patient survival in lung adenocarcinoma.

Citation Format: Franziska Haderk, David Allegakoen, Juan Guan, Wei Wu, Trever Bivona. Active YAP as a functional marker of drug-tolerant persister cells in EGFR-mutant and ALK fusion-positive NSCLC [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 PR11.
Abstract A03: PrOTYPE (Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE): The development and validation of a clinical-grade consensus classifier for the molecular subtypes of high-grade serous tubo-ovarian cancer
Authors: Talhouk Aline , George Joshy , Wang Chen , Goode Ellen , Ramus Susan , Doherty Jennifer , Bowtell David , Anglesio Michael ,   OTTA Consortium
Published: September 2020

Background: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC) are distinguished by differential immune and stromal infiltration and may provide opportunities for targeted therapies. Integration of molecular subtypes into clinical trials has been hindered by inconsistent subtyping methodology.

Methods: Adopting two independent approaches, we derived and internally validated algorithms for molecular subtype prediction from gene-expression array data in 1,650 tumors. We applied resulting models to assign labels to 3829 HGSOCs from the Ovarian Tumor Tissue Analysis (OTTA) consortium evaluated on NanoString. Using the labeled NanoString data, we developed, confirmed, and validated a minimal gene set, clinical-grade test and prediction tool. We also used the OTTA dataset to evaluate associations between molecular subtype, biologic, and clinical features.

Findings: The locked-down test included a model with 55 genes that predicted HGSOC molecular subtype with >95% accuracy. Subtype varied between primary and metastatic site taken at the time of primary surgery, and was significantly associated with age, stage, CD8+ lymphocyte infiltration, residual disease, and outcome. In multivariable models, molecular subtypes lose their prognostic significance in the presence of risk factors such as residual disease and BRCA1/2 germline mutations.

Interpretation: We validated the Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE, or PrOTYPE, following the Institute of Medicine guidelines for the development of omics-based tests. This simple-to-use, cost-effective, fully defined, and locked-down clinical-grade assay will facilitate molecular subtype stratification into clinical trial design. PrOTYPE will allow for objective assessment of HGSOC molecular subtype predictive value in precision medicine applications.

Citation Format: Aline Talhouk, Joshy George, Chen Wang, Ellen Goode, Susan Ramus, Jennifer Doherty, David Bowtell, Michael Anglesio, OTTA Consortium. PrOTYPE (Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE): The development and validation of a clinical-grade consensus classifier for the molecular subtypes of high-grade serous tubo-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 A03.