COX-2 activation is associated with Akt phosphorylation and poor survival in ER-negative, HER2-positive breast cancer

<p>Abstract</p> <p>Background</p> <p>Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation.</p> <p>Methods</p> <p>Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival.</p> <p>Results</p> <p>COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196.</p> <p>Conclusions</p> <p>Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.</p

DPEP1 Inhibits Tumor Cell Invasiveness, Enhances Chemosensitivity and Predicts Clinical Outcome in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. To identify biologically relevant genes with prognostic and therapeutic significance in PDAC, we first performed the microarray gene-expression profiling in 45 matching pairs of tumor and adjacent non-tumor tissues from resected PDAC cases. We identified 36 genes that were associated with patient outcome and also differentially expressed in tumors as compared with adjacent non-tumor tissues in microarray analysis. Further evaluation in an independent validation cohort (N = 27) confirmed that DPEP1 (dipeptidase 1) expression was decreased (T: N ratio ∼0.1, P<0.01) in tumors as compared with non-tumor tissues. DPEP1 gene expression was negatively correlated with histological grade (Spearman correlation coefficient = −0.35, P = 0.004). Lower expression of DPEP1 in tumors was associated with poor survival (Kaplan Meier log rank) in both test cohort (P = 0.035) and validation cohort (P = 0.016). DPEP1 expression was independently associated with cancer-specific mortality when adjusted for tumor stage and resection margin status in both univariate (hazard ratio = 0.43, 95%CI = 0.24–0.76, P = 0.004) and multivariate analyses (hazard ratio = 0.51, 95%CI = 0.27–0.94, P = 0.032). We further demonstrated that overexpression of DPEP1 suppressed tumor cells invasiveness and increased sensitivity to chemotherapeutic agent Gemcitabine. Our data also showed that growth factor EGF treatment decreased DPEP1 expression and MEK1/2 inhibitor AZD6244 increased DPEP1 expression in vitro, indicating a potential mechanism for DPEP1 gene regulation. Therefore, we provide evidence that DPEP1 plays a role in pancreatic cancer aggressiveness and predicts outcome in patients with resected PDAC. In view of these findings, we propose that DPEP1 may be a candidate target in PDAC for designing improved treatments

Ordered magnetic fields around the 3C 84 central black hole

Context. 3C 84 is a nearby radio source with a complex total intensity structure, showing linear polarisation and spectral patterns. A detailed investigation of the central engine region necessitates the use of very-long-baseline interferometry (VLBI) above the hitherto available maximum frequency of 86 GHz.Aims. Using ultrahigh resolution VLBI observations at the currently highest available frequency of 228 GHz, we aim to perform a direct detection of compact structures and understand the physical conditions in the compact region of 3C 84.Methods. We used Event Horizon Telescope (EHT) 228 GHz observations and, given the limited (u; v)-coverage, applied geometric model fitting to the data. Furthermore, we employed quasi-simultaneously observed, ancillary multi-frequency VLBI data for the source in order to carry out a comprehensive analysis of the core structure.Results. We report the detection of a highly ordered, strong magnetic field around the central, supermassive black hole of 3C 84. The brightness temperature analysis suggests that the system is in equipartition. We also determined a turnover frequency of gamma(m) = (113 +/- 4) GHz, a corresponding synchrotron self-absorbed magnetic field of B-SSA = (2.9 +/- 1.6) G, and an equipartition magnetic field of B-eq = (5.2 +/- 0.6) G. Three components are resolved with the highest fractional polarisation detected for this object (m(net) = (17.0 +/- 3.9)%). The positions of the components are compatible with those seen in low-frequency VLBI observations since 2017-2018. We report a steeply negative slope of the spectrum at 228 GHz. We used these findings to test existing models of jet formation, propagation, and Faraday rotation in 3C 84.Conclusions. The findings of our investigation into di fferent flow geometries and black hole spins support an advection-dominated accretion flow in a magnetically arrested state around a rapidly rotating supermassive black hole as a model of the jet-launching system in the core of 3C 84. However, systematic uncertainties due to the limited (u, v)-coverage, however, cannot be ignored. Our upcoming work using new EHT data, which offer full imaging capabilities, will shed more light on the compact region of 3C 84

First M87 Event Horizon Telescope results. IX.: detection of near-horizon circular polarization

Galaxie

First Very Long Baseline Interferometry Detections at 870 μ m

The first very long baseline interferometry (VLBI) detections at 870 μm wavelength (345 GHz frequency) are reported, achieving the highest diffraction-limited angular resolution yet obtained from the surface of the Earth and the highest-frequency example of the VLBI technique to date. These include strong detections for multiple sources observed on intercontinental baselines between telescopes in Chile, Hawaii, and Spain, obtained during observations in 2018 October. The longest-baseline detections approach 11 Gλ, corresponding to an angular resolution, or fringe spacing, of 19 μas. The Allan deviation of the visibility phase at 870 μm is comparable to that at 1.3 mm on the relevant integration timescales between 2 and 100 s. The detections confirm that the sensitivity and signal chain stability of stations in the Event Horizon Telescope (EHT) array are suitable for VLBI observations at 870 μm. Operation at this short wavelength, combined with anticipated enhancements of the EHT, will lead to a unique high angular resolution instrument for black hole studies, capable of resolving the event horizons of supermassive black holes in both space and time

First M87 Event Horizon Telescope results. IX. Detection of near-horizon circular polarization

Event Horizon Telescope (EHT) observations have revealed a bright ring of emission around the supermassive black hole at the center of the M87 galaxy. EHT images in linear polarization have further identified a coherent spiral pattern around the black hole, produced from ordered magnetic fields threading the emitting plasma. Here we present the first analysis of circular polarization using EHT data, acquired in 2017, which can potentially provide additional insights into the magnetic fields and plasma composition near the black hole. Interferometric closure quantities provide convincing evidence for the presence of circularly polarized emission on event-horizon scales. We produce images of the circular polarization using both traditional and newly developed methods. All methods find a moderate level of resolved circular polarization across the image (〈|v|〉 < 3.7%), consistent with the low image-integrated circular polarization fraction measured by the Atacama Large Millimeter/submillimeter Array (|vint| < 1%). Despite this broad agreement, the methods show substantial variation in the morphology of the circularly polarized emission, indicating that our conclusions are strongly dependent on the imaging assumptions because of the limited baseline coverage, uncertain telescope gain calibration, and weakly polarized signal. We include this upper limit in an updated comparison to general relativistic magnetohydrodynamic simulation models. This analysis reinforces the previously reported preference for magnetically arrested accretion flow models. We find that most simulations naturally produce a low level of circular polarization consistent with our upper limit and that Faraday conversion is likely the dominant production mechanism for circular polarization at 230 GHz in M87*.ACKNOWLEDGEMENTS : The Event Horizon Telescope Collaboration thanks the following organizations and programs: the Academia Sinica; the Academy of Finland (AKA, projects 274477, 284495, 312496, 315721); the Agencia Nacional de Investigación y Desarrollo (ANID), Chile via NCN19_058 (TITANs), Fondecyt 1221421 and BASAL FB210003; the Alexander von Humboldt Stiftung; an Alfred P. Sloan Research Fellowship; Allegro, the European ALMA Regional Centre node in the Netherlands, the NL astronomy research network NOVA, and the astronomy institutes of the University of Amsterdam, Leiden University, and Radboud University; the ALMA North America Development Fund; the Astrophysics and High Energy Physics program by MCIN (with funding from European Union NextGenerationEU, PRTR-C17I1); the Black Hole Initiative, which is funded by grants from the John Templeton Foundation and the Gordon and Betty Moore Foundation (although the opinions expressed in this work are those of the author(s) and do not necessarily reflect the views of these Foundations); the Brinson Foundation; “la Caixa” Foundation (ID 100010434) through fellowship codes LCF/ BQ/DI22/11940027 and LCF/BQ/DI22/11940030; Chandra DD7-18089X and TM6-17006X; the China Scholarship Council; the China Postdoctoral Science Foundation fellowships (2020M671266, 2022M712084); Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico, projects U0004- 246083, U0004-259839, F0003-272050, M0037-279006, F0003-281692, 104497, 275201, 263356); the Colfuturo Scholarship; the Consejería de Economía, Conocimiento, Empresas y Universidad of the Junta de Andalucía (grant P18-FR-1769), the Consejo Superior de Investigaciones Científicas (grant 2019AEP112); the Delaney Family via the Delaney Family John A. Wheeler Chair at Perimeter Institute; Dirección General de Asuntos del Personal Académico- Universidad Nacional Autónoma de México (DGAPA-UNAM, projects IN112417 and IN112820); the Dutch Organization for Scientific Research (NWO) for the VICI award (grant 639.043.513), grant OCENW.KLEIN.113, and the Dutch Black Hole Consortium (with project No. NWA 1292.19.202) of the research program the National Science Agenda; the Dutch National Supercomputers, Cartesius and Snellius (NWO grant 2021.013); the EACOA Fellowship awarded by the East Asia Core Observatories Association, which consists of the Academia Sinica Institute of Astronomy and Astrophysics, the National Astronomical Observatory of Japan, Center for Astronomical Mega-Science, Chinese Academy of Sciences, and the Korea Astronomy and Space Science Institute; the European Research Council (ERC) Synergy Grant “BlackHoleCam: Imaging the Event Horizon of Black Holes” (grant 610058); the European Union Horizon 2020 research and innovation program under grant agreements RadioNet (No. 730562) and M2FINDERS (No. 101018682); the Horizon ERC Grants 2021 program under grant agreement No. 101040021; the Generalitat Valenciana (grants APOSTD/ 2018/177 and ASFAE/2022/018) and GenT Program (project CIDEGENT/2018/021); MICINN Research Project PID2019- 108995GB-C22; the European Research Council for advanced grant “JETSET: Launching, propagation and emission of relativistic jets from binary mergers and across mass scales” (grant No. 884631); the FAPESP (Fundação de Amparo á Pesquisa do Estado de São Paulo) under grant 2021/01183-8; the Institute for Advanced Study; the Istituto Nazionale di Fisica Nucleare (INFN) sezione di Napoli, iniziative specifiche TEONGRAV; the International Max Planck Research School for Astronomy and Astrophysics at the Universities of Bonn and Cologne; DFG research grant “Jet physics on horizon scales and beyond” (grant No. FR 4069/2-1); Joint Columbia/ Flatiron Postdoctoral Fellowship (research at the Flatiron Institute is supported by the Simons Foundation); the Japan Ministry of Education, Culture, Sports, Science and Technology (MEXT; grant JPMXP1020200109); the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for JSPS Research Fellowship (JP17J08829); the Joint Institute for Computational Fundamental Science, Japan; the Key Research Program of Frontier Sciences, Chinese Academy of Sciences (CAS, grants QYZDJ-SSW-SLH057, QYZDJ-SSW-SYS008, ZDBS-LY-SLH011); the Leverhulme Trust Early Career Research Fellowship; the Max-Planck-Gesellschaft (MPG); the Max Planck Partner Group of the MPG and the CAS; the MEXT/JSPS KAKENHI (grants 18KK0090, JP21H01137, JP18H03721, JP18K13594, 18K03709, JP19K14761, 18H01245, 25120007, 23K03453); the Malaysian Fundamental Research Grant Scheme (FRGS) FRGS/1/2019/STG02/ UM/02/6; the MIT International Science and Technology Initiatives (MISTI) Funds; the Ministry of Science and Technology (MOST) of Taiwan (103-2119-M-001-010-MY2, 105-2112-M-001-025-MY3, 105-2119-M-001-042, 106-2112- M-001-011, 106-2119-M-001-013, 106-2119-M-001-027, 106- 2923-M-001-005, 107-2119-M-001-017, 107-2119-M-001- 020, 107-2119-M-001-041, 107-2119-M-110-005, 107-2923- M-001-009, 108-2112-M-001-048, 108-2112-M-001-051, 108- 2923-M-001-002, 109-2112-M-001-025, 109-2124-M-001- 005, 109-2923-M-001-001, 110-2112-M-003-007-MY2, 110- 2112-M-001-033, 110-2124-M-001-007, and 110-2923-M- 001-001); the Ministry of Education (MoE) of Taiwan Yushan Young Scholar Program; the Physics Division, National Center for Theoretical Sciences of Taiwan; the National Aeronautics and Space Administration (NASA, Fermi Guest Investigator grant 80NSSC20K1567, NASA Astrophysics Theory Program grant 80NSSC20K0527, NASA NuSTAR award 80NSSC20K0645); NASA Hubble Fellowship grants HSTHF2- 51431.001-A and HST-HF2-51482.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555; the National Institute of Natural Sciences (NINS) of Japan; the National Key Research and Development Program of China (grants 2016YFA0400704, 2017YFA0402703, 2016YFA0400702); the National Science Foundation (NSF, grants AST-0096454, AST-0352953, AST-0521233, AST-0705062, AST-0905844, AST-0922984, AST-1126433, AST-1140030, DGE-1144085, AST-1207704, AST-1207730, AST-1207752, MRI-1228509, OPP-1248097, AST-1310896, AST-1440254, AST-1555365, AST-1614868, AST-1615796, AST-1715061, AST-1716327, OISE-1743747, AST-1816420, AST-1935980, AST-2034306, AST-2307887); NSF Astronomy and Astrophysics Postdoctoral Fellowship (AST-1903847); the Natural Science Foundation of China (grants 11650110427, 10625314, 11721303, 11725312, 11873028, 11933007, 11991052, 11991053, 12192220, 12192223, 12273022); the Natural Sciences and Engineering Research Council of Canada (NSERC, including a Discovery Grant and the NSERC Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program); the National Youth Thousand Talents Program of China; the National Research Foundation of Korea (the Global PhD Fellowship Grant: grants NRF-2015H1A2A1033752; the Korea Research Fellowship Program: NRF-2015H1D3A1066561; Brain Pool Program: 2019H1D3A1A01102564; Basic Research Support Grant 2019R1F1A1059721, 2021R1A6A3A01086420, 2022R1 C1C1005255); Netherlands Research School for Astronomy (NOVA) Virtual Institute of Accretion (VIA) postdoctoral fellowships; Onsala Space Observatory (OSO) national infrastructure, for the provisioning of its facilities/observational support (OSO receives funding through the Swedish Research Council under grant 2017-00648); the Perimeter Institute for Theoretical Physics (research at Perimeter Institute is supported by the Government of Canada through the Department of Innovation, Science and Economic Development and by the Province of Ontario through the Ministry of Research, Innovation and Science); the Princeton Gravity Initiative; the Spanish Ministerio de Ciencia e Innovación (grants PGC2018-098915-BC21, AYA2016-80889-P, PID2019-108995GB-C21, PID2020- 117404GB-C21); the University of Pretoria for financial aid in the provision of the new Cluster Server nodes and SuperMicro (USA) for a SEEDING GRANT approved toward these nodes in 2020; the Shanghai Municipality orientation program of basic research for international scientists (grant No. 22JC1410600); the Shanghai Pilot Program for Basic Research, Chinese Academy of Science, Shanghai Branch (JCYJ-SHFY-2021-013); the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award for the Instituto de Astrofísica de Andalucía (SEV-2017-0709); the Spanish Ministry for Science and Innovation grant CEX2021-001131-S funded by MCIN/AEI/10.13039/501100011033; the Spinoza Prize SPI 78-409; the South African Research Chairs Initiative, through the South African Radio Astronomy Observatory (SARAO, grant ID 77948), which is a facility of the National Research Foundation (NRF), an agency of the Department of Science and Innovation (DSI) of South Africa; the Toray Science Foundation; the Swedish Research Council (VR); the US Department of Energy (USDOE) through the Los Alamos National Laboratory (operated by Triad National Security, LLC, for the National Nuclear Security Administration of the USDOE, contract 89233218CNA000001); and the YCAA Prize Postdoctoral Fellowship. We thank the staff at the participating observatories, correlation centers, and institutions for their enthusiastic support. This paper makes use of the following ALMA data: ADS/JAO.ALMA#2016.1.01154.V. ALMA is a partnership of the European Southern Observatory (ESO; Europe, representing its member states), NSF, and National Institutes of Natural Sciences of Japan, together with National Research Council (Canada), Ministry of Science and Technology (MOST; Taiwan), Academia Sinica Institute of Astronomy and Astrophysics (ASIAA; Taiwan), and Korea Astronomy and Space Science Institute (KASI; Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, Associated Universities, Inc. (AUI)/NRAO, and the National Astronomical Observatory of Japan (NAOJ). The NRAO is a facility of the NSF operated under cooperative agreement by AUI. This research used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under contract No. DE-AC05-00OR22725; the ASTROVIVES FEDER infrastructure, with project code IDIFEDER-2021- 086; and the computing cluster of Shanghai VLBI correlator supported by the Special Fund for Astronomy from the Ministry of Finance in China. We also thank the Center for Computational Astrophysics, National Astronomical Observatory of Japan. This work was supported by FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) under grant 2021/01183-8. APEX is a collaboration between the Max-Planck-Institut für Radioastronomie (Germany), ESO, and the Onsala Space Observatory (Sweden). The SMA is a joint project between the SAO and ASIAA and is funded by the Smithsonian Institution and the Academia Sinica. The JCMT is operated by the East Asian Observatory on behalf of the NAOJ, ASIAA, and KASI, as well as the Ministry of Finance of China, Chinese Academy of Sciences, and the National Key Research and Development Program (No. 2017YFA0402700) of China and Natural Science Foundation of China grant 11873028. Additional funding support for the JCMT is provided by the Science and Technologies Facility Council (UK) and participating universities in the UK and Canada. The LMT is a project operated by the Instituto Nacional de Astrófisica, Óptica, y Electrónica (Mexico) and the University of Massachusetts at Amherst (USA). The IRAM 30 m telescope on Pico Veleta, Spain, is operated by IRAM and supported by CNRS (Centre National de la Recherche Scientifique, France), MPG (Max-Planck- Gesellschaft, Germany), and IGN (Instituto Geográfico Nacional, Spain). The SMT is operated by the Arizona Radio Observatory, a part of the Steward Observatory of the University of Arizona, with financial support of operations from the State of Arizona and financial support for instrumentation development from the NSF. Support for SPT participation in the EHT is provided by the National Science Foundation through award OPP-1852617 to the University of Chicago. Partial support is also provided by the Kavli Institute of Cosmological Physics at the University of Chicago. The SPT hydrogen maser was provided on loan from the GLT, courtesy of ASIAA. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), supported by NSF grant ACI-1548562, and CyVerse, supported by NSF grants DBI- 0735191, DBI-1265383, and DBI-1743442. The XSEDE Stampede2 resource at TACC was allocated through TGAST170024 and TG-AST080026N. The XSEDE JetStream resource at PTI and TACC was allocated through AST170028. This research is part of the Frontera computing project at the Texas Advanced Computing Center through the Frontera Large-Scale Community Partnerships allocation AST20023. Frontera is made possible by National Science Foundation award OAC-1818253. This research was done using services provided by the OSG Consortium (Pordes et al. 2007; Sfiligoi et al. 2009), which is supported by the National Science Foundation award Nos. 2030508 and 1836650. Additional work used ABACUS2.0, which is part of the eScience center at Southern Denmark University. Simulations were also performed on the SuperMUC cluster at the LRZ in Garching, on the LOEWE cluster in CSC in Frankfurt, on the HazelHen cluster at the HLRS in Stuttgart, and on the Pi2.0 and Siyuan Mark-I at Shanghai Jiao Tong University. The computer resources of the Finnish IT Center for Science (CSC) and the Finnish Computing Competence Infrastructure (FCCI) project are acknowledged. This research was enabled in part by support provided by Compute Ontario (http://computeontario. ca), Calcul Quebec (http://www.calculquebec.ca), and Compute Canada (http://www.computecanada.ca). The EHTC has received generous donations of FPGA chips from Xilinx Inc., under the Xilinx University Program. The EHTC has benefited from technology shared under opensource license by the Collaboration for Astronomy Signal Processing and Electronics Research (CASPER). The EHT project is grateful to T4Science and Microsemi for their assistance with hydrogen masers. This research has made use of NASAʼs Astrophysics Data System. We gratefully acknowledge the support provided by the extended staff of the ALMA, from the inception of the ALMA Phasing Project through the observational campaigns of 2017 and 2018. We would like to thank A. Deller and W. Brisken for EHT-specific support with the use of DiFX. We thank Martin Shepherd for the addition of extra features in the Difmap software that were used for the CLEAN imaging results presented in this paper. We acknowledge the significance that Maunakea, where the SMA and JCMT EHT stations are located, has for the indigenous Hawaiian people. FACILITIES : EHT, ALMA, APEX, IRAM:30m, JCMT, LMT, SMA, ARO:SMT, SPT. SOFTWARE : AIPS (Greisen 2003), ParselTongue (Kettenis et al. 2006), GNU Parallel (Tange 2011), eht-imaging (Chael et al. 2016), DIFMAP (Shepherd 2011), Numpy (Harris et al. 2020), Scipy (Virtanen et al. 2020), Pandas (McKinney 2010), Astropy (The Astropy Collaboration et al. 2013, 2018), Jupyter (Kluyver et al. 2016), Matplotlib (Hunter 2007), THEMIS (Broderick et al. 2020a), DMC (Pesce 2021), polsolve (Martí-Vidal et al. 2021), HARM (Gammie et al. 2003; Noble et al. 2006), IPOLE (Noble et al. 2007; Mościbrodzka & Gammie 2018).https://iopscience.iop.org/journal/2041-8205am2024PhysicsNon

First Sagittarius A* Event Horizon Telescope Results. VII. Polarization of the Ring

The Event Horizon Telescope observed the horizon-scale synchrotron emission region around the Galactic center supermassive black hole, Sagittarius A* (Sgr A*), in 2017. These observations revealed a bright, thick ring morphology with a diameter of 51.8 ± 2.3 μas and modest azimuthal brightness asymmetry, consistent with the expected appearance of a black hole with mass M ≈ 4 × 106 M ⊙. From these observations, we present the first resolved linear and circular polarimetric images of Sgr A*. The linear polarization images demonstrate that the emission ring is highly polarized, exhibiting a prominent spiral electric vector polarization angle pattern with a peak fractional polarization of ∼40% in the western portion of the ring. The circular polarization images feature a modestly (∼5%–10%) polarized dipole structure along the emission ring, with negative circular polarization in the western region and positive circular polarization in the eastern region, although our methods exhibit stronger disagreement than for linear polarization. We analyze the data using multiple independent imaging and modeling methods, each of which is validated using a standardized suite of synthetic data sets. While the detailed spatial distribution of the linear polarization along the ring remains uncertain owing to the intrinsic variability of the source, the spiraling polarization structure is robust to methodological choices. The degree and orientation of the linear polarization provide stringent constraints for the black hole and its surrounding magnetic fields, which we discuss in an accompanying publication