bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &gt;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.
Association Between the Onset Pattern of Adult Moyamoya Disease and Risk Factors for Stroke
Authors: Hirano Yudai , Miyawaki Satoru , Imai Hideaki , Hongo Hiroki , Ohara Kenta , Dofuku Shogo , Teranishi Yu , Nakatomi Hirofumi , Saito Nobuhito 
Published: September 2020

Background and Purpose:
Few previous studies have comprehensively explored the relationship between the onset pattern of adult moyamoya disease and risk factors for stroke. We performed a retrospective analysis focusing on risk factors for stroke and related findings on magnetic resonance imaging/angiography with respect to the pattern of disease onset. We also examined whether risk factors for stroke were associated with an increased risk for symptomization in asymptomatic patients.

Methods:
A total of 178 adult patients with moyamoya disease (asymptomatic, n=84; ischemic, n=71; hemorrhagic, n=23) at the University of Tokyo Hospital from 2000 to 2018 were included in this study. Data pertaining to patient background and magnetic resonance imaging findings were analyzed retrospectively. In the asymptomatic group, the effects of stroke-associated risk factors on symptom onset were analyzed.

Results:

Comparisons among the 3 groups revealed no significant difference in the frequency of risk factors for stroke. The proportion of patients with magnetic resonance imaging/angiography findings indicating anterior choroidal artery anastomosis or microbleeds was significantly higher in the hemorrhagic group than in the asymptomatic or ischemic group. Among asymptomatic patients, the hazard ratios for symptomization with hypertension and dyslipidemia were 6.69 ([95% CI, 1.23–36.4]
P
=0.028) and 8.14 ([95% CI, 1.46–45.2]
P
=0.017), respectively.

Conclusions:
The development of anterior choroidal artery anastomosis and microbleeds on magnetic resonance imaging/angiography was significantly associated with hemorrhagic onset. Hypertension and dyslipidemia may increase the risk of cerebrovascular events in asymptomatic patients, and thus, early intervention to these factors may be important.
Mexican American Immigrants Demonstrate Better Functional Stroke Outcomes Compared With Mexican American Nonimmigrants
Authors: Hollenhorst Cecilia N. , Gibbs River , Kim Sehee , Agyemang Charles , Lisabeth Lynda , Morgenstern Lewis B. 
Published: September 2020

Background and Purpose:
We analyzed differences in 90-day poststroke outcomes between Mexican Americans born in the United States (nonimmigrant) compared with those born outside the United States (immigrant).

Methods:
We performed a retrospective analysis of prospective data from the population-based Brain Attack Surveillance in Corpus Christi project. We identified stroke cases from 2008 to 2016 and quantified functional, cognitive, and neurological outcomes. Associations between outcome scores and immigration status were analyzed using weighted linear regression models.

Results:

Eighty-three Mexican American stroke cases (n=935) were immigrants, and 852 stroke cases were nonimmigrants. Average length of stay in the United States for immigrants was 47 years. Immigrants were older (69 versus 66 years), more likely men (60% versus 49%), had less education on average, and were more likely to have atrial fibrillation compared with nonimmigrants. No differences in other comorbidities existed between groups. After adjustment for confounders, immigrants had better functional outcomes (activities of daily living/instrumental activities of daily living; mean difference, −0.22;
P
=0.02; 1–4, higher scores worse) and no difference in neurological outcomes (log-National Institutes of Health Stroke Scale; mean difference, −0.15;
P
=0.15; 0–44, higher scores worse) or cognitive outcomes (3 Mini-Mental State Examination; mean difference, −0.79;
P
=0.64; 0–100, lower scores worse).

Conclusions:
Long-term Mexican American immigrants in this community display better stroke functional outcomes than nonimmigrant Mexican Americans and comparable neurological and cognitive outcomes.
Effects of Wave Streaming and Wave Variations on Nearshore Wave-Driven Circulation
Authors: Wang Peng , McWilliams James C. , Uchiyama Yusuke , Chekroun Mickaël D. , Yi Daling Li 
Published: September 2020

AbstractWave streaming is a near-bottom mean current induced by the bottom drag on surface gravity waves. Wave variations include the variations in wave heights, periods, and directions. Here we use numerical simulations to study the effects of wave streaming and wave variations on the circulation that is driven by incident surface waves. Wave streaming induces an inner-shelf Lagrangian overturning circulation, which links the inner shelf with the surf zone. Wave variations cause alongshore-variable wave breaking that produces surf eddies; however, such eddies can be suppressed by wave streaming. Moreover, with passive tracers we show that wave streaming and wave variations together enhance the cross-shelf material transport.
Meta-Analysis on the Effect of Pasireotide for Prevention of Postoperative Pancreatic Fistula
Authors: Dalton Elissa C. , Johns Michael S. , Rhodes Lori , Merritt William T. , Petrelli Nicholas J. , Tiesi Gregory J. 
Published: September 2020

Background A randomized controlled trial of routine administration of pasireotide demonstrated decreased incidence of clinically significant postoperative pancreatic fistula (POPF). Recent studies have not replicated these results. A meta-analysis was performed to evaluate its efficacy in this setting. Methods Prospective trials utilizing pasireotide prophylactically after pancreatectomy were reviewed. The primary outcome was clinically significant POPF. Secondary outcomes included length of stay (LOS), readmission rates, and mortality. Study heterogeneity was assessed. Results Five studies totaling 1571 patients were identified. There was no difference in age, sex, or cancer rates. Pasireotide patients had smaller pancreatic ducts ( P < .001) and softer glands ( P = .04). For all pancreatectomies, there was no difference in POPF rates (odds ratio [OR] 0.84; 95% CI 0.60-1.16, P = .29). Patients undergoing distal pancreatectomy (OR 0.70; 95% CI 0.30-1.63, P = .41) had similar rates of POPF versus pancreaticoduodenectomy (PD) patients who experienced a lower incidence of POPF (OR 0.60; 95% CI 0.42-0.86, P = .006). Mortality rates and LOS were similar. Readmission rates were decreased with pasireotide (OR 0.61; 95% CI 0.44-0.85). Conclusions Routine administration of pasireotide did not decrease POPF rates for all pancreatectomies, but was associated with lower rates for PD, and decreased readmission rates. Further prospective, randomized studies are warranted.
The role of MRI texture analysis based on susceptibility-weighted imaging in predicting Fuhrman grade of clear cell renal cell carcinoma
Authors: Sun Jun , Pan Liang , Zha Tingting , Xing Wei , Chen Jie , Duan Shaofeng 
Published: September 2020

Background The Fuhrman nuclear grade system is one of the most important independent indicators in patients with clear cell renal cell carcinoma (ccRCC) for aggressiveness and prognosis. Preoperative assessment of tumor aggressiveness is important for surgical decision-making. Purpose To explore the role of magnetic resonance imaging (MRI) texture analysis based on susceptibility-weighted imaging (SWI) in predicting Fuhrman grade of ccRCC. Material and Methods A total of 45 patients with SWI and surgically proven ccRCC were divided into two groups: the low-grade group (Fuhrman I/II, n = 29) and the high-grade group (Fuhrman III/IV, n = 16). Texture features were extracted from SWI images. Feature selection was performed, and multivariable logistic regression analysis was performed to develop the SWI-based texture model for grading ccRCCs. Receiver operating characteristic (ROC) curve analysis and leave-group-out cross-validation (LGOCV) were performed to test the reliability of the model. Results A total of 396 SWI-based texture features were extracted from each SWI image. The SWI-based texture model developed by multivariable logistic regression analysis was: SWIscore = –0.59 + 1.60 * ZonePercentage. The area under the ROC curve of the SWI-based texture model for differentiating high-grade ccRCC from low-grade ccRCC was 0.81 (95% confidence interval 0.67–0.94), with 80% accuracy, 56.25% sensitivity, and 93.10% specificity. After 100 LGOCVs, the mean accuracy, sensitivity, and specificity were 90.91%, 91.83%, and 89.89% for the training sets, and 77.29%, 80.52%, and 71.44% for the test sets, respectively. Conclusion SWI-based texture analysis might be a reliable quantitative approach for differentiating high-grade ccRCC from low-grade ccRCC.