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The need to reduce fuel-burn and CO2 emissions, is pushing turbofan engines towards geared architectures with very high bypass-ratios and small ultra-high-pressure ratio core engines. However, this increases the radial offset between compressor spools and leads to a more challenging design for the compressor transition ducts. To minimise weight, these ducts must achieve the radial turning in as short a length, but this leads to strong curvature induced pressure gradients, increased aerodynamic loading and likelihood of flow separation. For the duct connecting the low-pressure fan to the engine core this is further complicated by the poor-quality flow generated at the fan hub which is characterised by low total pressure and large rotating secondary flow structures. In a previous paper the authors numerically designed modifications to an existing test facility such that the rotor would produce these large structures. The current paper presents an experimental evaluation of the new rotor design and examines the effect of the increased loss cores on the performance of a set of engine sector stators (ESS) or outlet guide vanes (OGV) and an engine representative compressor transition duct. Aerodynamic data were collected via miniature five-hole probes, for the time-averaged pressure and velocity field, and phase-locked hot-wire anemometry to capture the rotating secondary flows. Analysis of the experimental data showed that these structures promoted mixing through the ESS increasing the momentum exchange between the core and boundary layer flows. Measurements within the duct showed a continued reduction in the hub-wall boundary layer suggesting that the duct has been moved further from separation. Consequently, a more aggressive duct with 12.5% length reduction was designed and tested with the data confirming that the more aggressive duct remained fully attached. Total pressure loss data suggested a slight increase in loss over the vane row but that was offset by a reduced loss in the duct due to improved flow quality and reduced length. Overall, the 12.5% length reduction represents a significant cumulative effect in terms of reduced fuel burn and CO2 over the operational life of an engine.

The S-shaped duct which transfers flow from the low-pressure fan to the engine core of modern large civil turbofans presents a challenging design problem. Aerodynamically it must accommodate a spatially and temporarily non-uniform inlet in conjunction with a complex flow field which will develop under the combined influence of pressure gradients and streamline curvature. It must also allow for the transfer of structural loads and services across the main gas path. This necessitates the use of structural vanes which can compromise aerodynamics, introduce unwanted component interactions and erode performance. Furthermore, this must all be achieved with minimum length/weight and without flow separation. This paper presents a comprehensive aerodynamic evaluation of three options for a low-pressure compressor transition duct containing (i) a long-chord, structural compressor outlet guide vane, (ii) a more aerodynamically optimal but non-structural outlet guide vane in conjunction with a small number of discrete radial load bearing struts and (iii) a fully integrated outlet guide vane and strut design. Evaluation was performed using a fully annular, low-speed test facility incorporating a 1 ½ stage axial compressor and transition duct representative of an engine design. Aerodynamic data were produced from miniature five-hole probe area traverses conducted at several locations with compressor/duct. The data suggest that all the options were viable. However, the aerodynamic vane and discrete struts produced the lowest system loss with the other two options being comparable. The performance of the structural vane was seen to be sensitive to off-design conditions producing a notably increased loss at a low flow coefficient. The more optimized aerodynamic vanes were much less sensitive to off-design conditions whilst the fully integrated design showed only very small changes in loss.

Ski jumping is a highly competitive sport, where the distance jumped is greatly dependent on the aerodynamic effects of the athlete’s posture. In the current paper a wind tunnel experiment was conducted to generate a parametric database of the effects of posture on aerodynamics and to compute the aerodynamic force coefficients. The parameters considered were varied over ranges representative of modern ski jumping and included the ski incidence angle, the ski V-angle, the leg-to-ski angle, and the hip angle. Measured force data were then used to simulate ski jumping flightpaths via a numerical model, allowing for the effects of posture on jump distance to be investigated. The model was able to simulate single and multi-posture flights to suggest both static and dynamic optimums. It was found that the ski jumping system generated lift in previously unreported, non-linear methods, enabling the flow to stay attached at much larger incidences than traditional wings. When optimizing posture for distance, it was found that neither lift nor efficiency (lift-to-drag ratio) should be maximized, due to the reliance on both qualities for a successful jump. However, when considering multi-posture flight, it was found that the lift-to-drag ratio should be maximized immediately after take-off, to maintain horizontal velocity. Lift should be maximized as the athlete approaches landing, due to the highly curved flightpath reducing the negative impact of drag. Realistic recommendations have been made on the postures that athletes should utilize to improve their performance. This includes a single position optimum, a “safe” optimum which allows some variation in an athlete’s ability to hold posture, and a further optimum should the athlete be skillful enough to dynamically alter posture as the jump progresses.

Background: The murine double minute 2 (MDM2) oncoprotein is a key E3 ubiquitin ligase that degrades the tumor-suppressor p53. Reversible SMIs of the MDM2/p53 interaction have been developed to stabilize p53 and to induce apoptosis in wildtype p53 tumors. However, MDM2 SMIs induce a p53/MDM2 feedback loop, resulting in upregulation of MDM2 protein levels and p53 pathway inhibition, thus drastically limiting their biological activity and clinical application. MDM2 targeted protein degradation suppresses p53-dependent MDM2 protein feedback upregulation and is therefore expected to lead to a superior response compared to SMIs. Objectives: We discovered KT-253, a novel, highly potent heterobifunctional MDM2 degrader. We characterized the activity and molecular mechanism of KT-253 in wildtype p53 cell lines and xenograft models and demonstrated that KT-253 has superior activity compared to SMIs in these models. Methods: We characterized KT-253 in MDM2-dependent cell lines in vitro, as well as in in vivo mouse AML and ALL xenograft models. Methods included in vitro cell proliferation and apoptosis assays, gene expression profiling, and in vivo pharmacological studies. Results: KT-253 selectively depletes MDM2 protein levels with sub-nanomolar cellular potency. We demonstrated in the Acute Lymphoblastic Leukemia (ALL) cell line RS4;11 that KT-253 can overcome the p53-dependent upregulation of MDM2 protein levels as seen for reversible SMIs. In addition, even brief exposures to KT-253 in these cells could more potently stabilize p53 compared to SMIs, leading to apoptosis mediated through p53 target genes. The superior MDM2/p53 pathway inhibition and induction of apoptosis by KT-253 translates into a >200-fold stronger cell growth inhibition, compared to SMIs, across a panel of solid and hematological tumor cell lines. Using mouse xenograft models, we established an intermittent dosing schedule that drives anti-tumor efficacy. Importantly, a single dose of KT-253 at 1 mg/kg resulted in sustained tumor regression in the RS4;11 mouse xenograft model. In this model, KT-253 exposures correlated with induction of apoptotic p53 target genes and tumor growth inhibition. In addition, weekly administration of KT-253 significantly prolonged the survival in a disseminated Acute Myeloid Leukemia (AML) model when compared to vehicle treated animals. Conclusions: In summary, KT-253, our development candidate, has significantly improved potency relative to reversible SMIs leading to potent in vitro and in vivo efficacy that is superior to all clinically active agents. In addition, an intermittent dosing schedule of the highly potent KT-253 degrader can induce rapid apoptosis in MDM2-dependent cancer cells potentially leading to improved efficacy and safety profile. Citation Format: Yogesh Chutake, Michele Mayo, Dapeng Chen, Bradley Enerson, Patricia Cho, Jessica Filiatrault, Crystal Brown, Michael Placke, Madison Adams, Rahul Karnik, James Shaw, Yatao Shi, Dirk Walther, Alice McDonald, Frank Qi, Phillip Liu, Joseph D. Growney, Kirti Sharma, Duncan Walker, Stefanie Schalm, Juliet Williams, Matthew Weiss. KT-253, a highly potent and selective heterobifunctional MDM2 degrader for the treatment of wildtype p53 tumors with superior potency and differentiated biological activity compared to small molecule inhibitors (SMI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3934.

This paper uses computational fluid dynamics to investigate the effect of an engine handling bleed situated on the outer casing downstream of the last rotor stage of a low-pressure compressor and upstream of the outlet guide vane and S-shaped duct. The model, validated against existing experimental data, utilized an unsteady Reynolds-averaging Navier–Stokes (RANS) solver incorporating a Reynolds stress closure to examine the unsteady component interactions. The results showed that at bleed rates less than 25% of the mainstream flow, the bleed effects were negligible. However, at higher bleed rates, performance was significantly degraded. A uniform flow extraction hypothesis was employed to separate the positional bias effects of the bleed from the bulk flow diffusion. This revealed that the bleed-induced radial flow distortion can significantly affect the outlet guide vane (OGV) loading distribution, which thereby dictates the position and type of stall within the OGV passage. Extraction of the rotor tip leakage via the shroud bleed, combined with the radial flow distortion, contributed to a 28% reduction in duct loss at 10% bleed and up to 50% reduced loss at 25% bleed. The actual amount of flow required to be extracted for an OGV stall to develop was 30%. That was independent of the bleed location and the type of stall. For bleeds up to 20%, the S-duct displayed a remarkable resilience and consistency of flow variables at duct exit. However, a stalled OGV deteriorated the radial flow uniformity that was presented to the high-pressure compressor.

To develop a local contrast-enhancing and feature-preserving high dynamic range (HDR) image processing algorithm for multichannel and multisequence MR images of multiple body regions and tissues, and to evaluate its performance for structure visualization, bias field (correction) mitigation, and automated tissue segmentation. A multiscale-shape and detail-enhancement HDR-MRI algorithm is applied to data sets of multichannel and multisequence MR images of the brain, knee, breast, and hip. In multisequence 3T hip images, agreement between automatic cartilage segmentations and corresponding synthesized HDR-MRI series were computed for mean voxel overlap established from manual segmentations for a series of cases. Qualitative comparisons between the developed HDR-MRI and standard synthesis methods were performed on multichannel 7T brain and knee data, and multisequence 3T breast and knee data. The synthesized HDR-MRI series provided excellent enhancement of fine-scale structure from multiple scales and contrasts, while substantially reducing bias field effects in 7T brain gradient echo, T1 and T2 breast images and 7T knee multichannel images. Evaluation of the HDR-MRI approach on 3T hip multisequence images showed superior outcomes for automatic cartilage segmentations with respect to manual segmentation, particularly around regions with hyperintense synovial fluid, across a set of 3D sequences. The successful combination of multichannel/sequence MR images into a single-fused HDR-MR image format provided consolidated visualization of tissues within 1 omnibus image, enhanced definition of thin, complex anatomical structures in the presence of variable or hyperintense signals, and improved tissue (cartilage) segmentation outcomes.

Particle Image Velocimetry (PIV) has been used to study the complex flowfield created by simulated battle damage to a two-dimensional wing. Computational Fluid Dynamics (CFD) predictions have also been used for validation of internal cavity flow. Two damage cases were selected for the study; both cases were simulated using a single hole with diameters equal to 20% and 40% of the chord, located at the wing half-chord. Wind-tunnel tests were conducted at a Reynolds number of 500,000 over a range of incidences from 0 to 10° with two-component PIV measurements made on three chordwise and three spanwise planes. The PIV data were analysed and compared to CFD data of the same damage cases. The PIV data have shown lower velocity ratios and lower vorticity in the jet compared to past Jet in Cross-Flow experiments and CFD was used to describe the flow features inside the cavity of the wing. It was seen that the wing cavity has large effects on the external flow features, particularly for the 20% damage case. Finally, the flow field data have been related to force balance data. At higher incidence angles, the larger force coefficient increments in both lift and drag can be attributed to the larger wakes and higher jet strengths.

To reduce fuel-burn and emissions, there is a drive toward higher bypass ratio and smaller high-pressure ratio core engines. This makes the design of the ducts connecting compressor spools more challenging as the higher radius change increases aerodynamic loading. This is exacerbated at inlet to the engine core by fan root flow which is characterized by a hub-low-pressure profile and large secondary flow structures. Additionally, shorter, lighter nacelles mean that the intake may not provide a uniform inlet flow when the aircraft is at an angle of attack or subject to cross winds. Such inlet distortion can further degrade the flow entering the engine. A combination of experiments and computational fluid dynamics (CFD) has been used to examine the effects on the aerodynamics of an engine section splitter (ESS) and transition duct designed to feed the low-pressure spool of a high bypass ratio turbofan. A test facility incorporating a 1½ stage axial compressor was used to compare system performance for a flat rotor exit profile to one with a hub deficient flow. Validated Reynolds averaged Navier–Stokes (RANS) CFD was then used to further investigate the effects of increased inlet boundary layer thickness and bulk swirl distortion at rotor inlet. These changes were seen to have a surprisingly small effect on the flow at the duct exit. However, increased secondary flows were observed which degraded the performance of the ESS and significantly increased loss. Nevertheless, the enhanced mixing delayed separation in the duct suggesting that overall the design was reasonably robust albeit with increased system loss.

The demand for increased efficiencies in modern aeroengines drives designs to higher pressure ratios, temperatures and shaft speeds. Consequently, higher cycle temperatures and parasitic heat loads are likely to become limiting factors in the design of bearing chambers. These chambers are lubricated and cooled with oil and pressurized using air taken from the main gas path. Historically, the temperature and pressure of the sealing air has been low enough to exclude the risk of bearing chamber oil fires caused by oil auto-ignition. However, temperatures are being driven towards the limits set by current design rules. With respect to oil fire risk assessment, current design rules are very conservative as they pessimistically assume the oil is continuously exposed to the maximum temperature expected in operation when determining the minimum residence time required for oil auto-ignition. Improved bearing chamber designs capable of tolerating higher temperatures could therefore be developed by applying a more rational level of conservatism, based on a more physics-based approach (such as considering the effect of an oil droplet being transported through a varying temperature field). In this paper a numerical methodology is developed to provide a pragmatic approach to addressing conservatism in bearing chamber oil fire risk assessment, with respect to oil auto-ignition. An unsteady Eulerian CFD prediction is used to compute the aerothermal flow field within a stylized bearing chamber. A Lagrangian discrete particle method is then used to track the oil droplet trajectories. The time-dependent droplet temperature histories are then used to compute the fractional accumulation of auto-ignition delay time using an empirically derived relationship. Finally, by defining an ‘auto-ignition (AI) energy’ accumulation factor, the methodology assesses whether an individual oil droplet has satisfied the criteria for auto-ignition. The present contribution examines the effects of various modelling parameters on the ‘AI energy’ accumulation factor. These include one/two-way coupling between the air flow and oil droplets, stochastic turbulence modelling of the droplet behavior, and the effect of droplet size and distribution. The work highlights that two-way coupling is required to ensure the thermal effect of the oil is modelled, despite the increased computational demand. Stochastic modelling of interactions between particles and the flow field is also required to capture the spread of particle trajectories and the resulting distribution of particle temperatures. A representative range of droplet sizes must also be simulated as the propensity for oil AI is a function of droplet diameter; the highest risk occurs for the smallest droplets whilst the largest droplets have greater cooling effect on the air flow. Given the extent of model simplification required to allow the work to be completed with a mid-spec desktop computer and the overall scope of the project, a validation of the findings has not been completed. Instead, an experimental validation is proposed as part of future investigation. The authors imagine that with enough investigation and validation, the understanding developed by the work could be applied as part of a computationally efficient industrial design toolset to inform the early stages of product design.

As aero gas turbine designs strive for ever greater efficiencies, the trend is for engine overall pressure ratios to rise. Although this provides greater thermal efficiency, it means that cycle temperatures also increase. One potential solution to managing the increasing temperatures is to employ a cooled cooling air system. In such a system, a purge flow into the main gas path downstream of the compressor will be required to prevent hot gas being ingested into the rotor drive cone cavity. However, the main gas path in compressors is aerodynamically sensitive and it is important to understand, and mitigate, the impact such a flow may have on the compressor outlet guide vanes, pre-diffuser, and the downstream combustion system aerodynamics. Initial computational fluid dynamics (CFD) predictions demonstrated the potential of the purge flow to negatively affect the outlet guide vanes and alter the inlet conditions to the combustion system. The purge flow modified the incidence onto the outlet guide vane, at the hub, such that the secondary flows increased in magnitude. An experimental assessment carried out using an existing fully annular, isothermal test facility confirmed the CFD results and importantly demonstrated that the degradation in the combustor inlet flow resulted in an increased combustion system loss. At the proposed purge flow rate, equal to ∼1% of the mainstream flow, these effects were small with the system loss increasing by ∼4%. However, at higher purge flow rates (up to 3%), these effects became notable and the outlet guide vane and pre-diffuser flow degraded significantly with a resultant increase in the combustion system loss of ∼13%. To mitigate these effects, CFD was used to examine the effect of varying the purge flow swirl fraction in order to better align the flow at the hub of the outlet guide vane. With a swirl fraction of 0.65 (x rotor speed), the secondary flows were reduced below that of the datum case (with no purge flow). Experimental data showed good agreement with the predicted flow topology and performance trends but the measured data showed smaller absolute changes. Differences in system loss were measured with savings of around 10% at the turbine feed ports for a mass flow ratio of 1% and a swirl fraction of 0.65.

Relapsed/refractory DLBCL remains an incurable disease, and single-agent therapies typically show low response rates and/or transient clinical responses. Oncogenic MYD88 mutations occur in ~25% of DLBCL and drive constitutive NFkB activation, promoting proliferation and survival. Despite its role in tumor biology, targeting MYD88MT by inhibiting or degrading IRAK4 alone, a key component of the MYD88 complex, does not drive significant antitumor activity in preclinical models. One potential reason is the frequent redundant NFkB pathway activation by co-mutations, highlighting the need for combination therapies to effectively target the NFkB pathway in DLBCL. To address this challenge, we have developed IRAKIMiDs, heterobifunctional degraders that simultaneously degrade both IRAK4 and IMiD substrates, as a rational therapeutic combination in a single molecule. IRAKIMiDs show increased antitumor activity in vitro and in vivo in MYD88MT cells as compared to IMiD or IRAK4-targeting alone, highlighting suggesting their potential as single agents in R/R DLBCL.Our lead IRAKIMiD, KT-413, is a potent degrader of IRAK4 (DC50 6nM) and IMiD substrates (Ikaros/Aiolos DC50 2nM), inducing rapid and potent cell killing in vitro and complete and sustained tumor regressions in vivo in MYD88MT models of DLBCL. This activity is superior to the IMiD CC-220, which has similar activity against IMiD substrates (Ikaros/Aiolos DC50 1 nM), supporting the synergistic role of IRAK4 degradation in the context of IMiD biology. We show here that the combined activity of these 2 mechanisms drives a synergistic effect on NFkB and IRF4 signaling with greater downstream effect on NFkB and type 1 interferon (IFN) signaling and cell cycle gene expression than either mechanism alone. In THP1 cells engineered with NFkB and IRF4 reporters, KT-413 but not CC-220 inhibits TLR-stimulated NFkB and IRF4 transcription, supporting a role for IRAK4 but not IMiDs in MYD88-driven survival and proliferation signals. IMiDs have previously been shown to modulate type1 IFN signaling through downregulation of IRF4. We propose that simultaneous targeting of both NFkB and type 1 IFN signaling with KT-413 drives synergistic cell killing in MYD88MT cells. In MYD88MT OCI-Ly10 cells, KT-413 leads to greater IRF4 downregulation, increased type 1 IFN signaling, and preferential downregulation of NFkB pathway and cell cycle transcripts when compared to CC-220. These data support the hypothesis that the synergistic activity of targeting IRAK4 and IMiD substrates by KT-413 in MYD88MT DLBCL is a result of dual targeting of NFkB and IRF4/Type1 IFN through degradation of both IRAK4 and IMiD substrates,driving significantly greater cell killing as compared to either mechanism alone, supporting the potential for the first single agent targeted therapy in MYD88MT DLBCL. KT-413 is on track for initiation of a Phase 1 trial in B cell lymphoma in 2H 2021. Citation Format: Christine R. Klaus, Scott F. Rusin, Kirti Sharma, Samyabrata Bhaduri, Matthew M. Weiss, Alice A. McDonald, Michele F. Mayo, Duncan Walker, Rahul Karnik. Mechanisms underlying synergistic activity in MYD88MTDLBCL of KT-413, a targeted degrader of IRAK4 and IMiD substrate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB118.

Introduction: MYD88 mutations are found in 25% of DLBCL and are associated with an inferior survival. MYD88 is an adapter molecule, forming the core of the Myddosome complex. MYD88 mutations constitutively activate pathways such as NFқB, leading to lymphomagenesis. Essential to the Myddosome-dependent signaling pathway is the recruitment of IRAK4 which complexes with MYD88 to activate downstream effects. Targeting IRAK4 is therefore a rational therapeutic approach in MYD88-mutant lymphomas. First-in-class IRAKIMiDs, novel heterobifunctional degraders that target IRAK4 as well as the IMiD substrates Ikaros and Aiolos to enable the inhibition of both the NFkB and IRF4 pathways activated by MYD88 mutations, demonstrate potent efficacy in MYD88-mutant lymphomas (KTX-475, KTX-582, Walker D et al. AACR 2020). Herein, we compare the activity of IRAKIMiDs to IRAK4 kinase inhibitors and IMiDs alone in MYD88-mutant DLBCL, and evaluate rational combinations of IRAKIMiDs and other active agents in DLBCL for synergy. Methods: MYD88-mutant (n=4) and wild type (n=4) DLBCL cell lines were exposed to a panel of single agents (KTX-475, KTX-582, BAY1830839, CA-4948, CC-220, lenalidomide, pomalidomide, ibrutinib, umbralisib, venetoclax) in order to establish the drug concentration:cytotoxicity effect relationship. Cell viability was assessed using Celltiter-Glo assay at 24-hour intervals. IC50 values were computed. MYD88-mutant DLBCL cells were co-exposed to combinations of KTX-475 with venetoclax, ibrutinib, or umbralisib at concentrations representing their respective IC10-40 in order to determine synergy using the excess over bliss (EOB) method. Venetoclax, ibrutinib, and umbralisib were selected for combinational studies in order to target adverse pathways known to be associated in DLBCL biology. To confirm IRAK4 degradation, western blot and flow cytometry was performed. Apoptosis was evaluated with flow cytometry. Pre-treatment RNA-seq libraries were developed for the purpose of identifying GSEA and mutational analysis to predict response to IRAKIMiDs. Results: Exposure to IRAKIMiDs led to potent activity in MYD88-mutated DLBCL with IC50s in the low nanomolar range. IRAK4 degradation occured in a dose- and time-dependent manner and was observed as early as four hours after exposure. IRAKIMiDs induced superior cytotoxicity compared to two IRAK4 kinase inhibitors, including CA-4948 (Curis), which is currently under clinical investigation for relapsed/refractory NHL, as determined by lower IC50s in all cell lines. IRAKIMiD IC50s were also lower compared to pomalidomide, lenalidomide, and CC-220. KTX-475 was selected for synergy assessments based on IC50 values. Synergy was observed after exposure to KTX-475 in conjunction with venetoclax, ibrutinib, or umbralisib as determined by EOB >0 in the MYD88-mutant OCI-LY10 model, with maximum values peaking at 72-96 hours. After dual drug exposure, IRAK4 degradation was validated by flow cytometry demonstrating that the addition of venetoclax, ibrutinib or umbralisib to KTX-475 did not impair IRAK4 degradation capabilities. RNA-seq interpretation is currently underway. Conclusions: Collectively, our results demonstrate that dual-function degraders targeting both IRAK4 and the IMiD substrates Ikaros and Aiolos can serve as a potential therapeutic option for poor prognosis MYD88-mutant DLBCL. Our data thus far demonstrate improved efficacy of IRAKIMiDs compared to IRAK4 kinase inhibitors or IMiDs alone in vitro, as well as synergy with other active agents in combination regimens. A promising lead IRAKIMiD candidate has been identified, with initiation of a first-in-human clinical trial in B-cell lymphomas planned for 2021. Disclosures Lue: Daiichi Sankyo: Honoraria; AstraZeneca: Speakers Bureau; Astex Pharmaceuticals: Honoraria; Kymera Therapeutics: Honoraria, Research Funding; Kura Oncology: Honoraria. Klaus:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kanik:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Walker:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. O'Connor:Kymera Therapeutics: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Servier: Consultancy; Mundipharma: Other: Consulting; Astex Pharmaceuticals: Honoraria, Research Funding; Merck: Research Funding; Nomocan: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Data Safety Monitoring Committee, Research Funding. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

An important goal of cancer therapy is to improve patient outcomes by driving to deep and durable tumor responses. The activity of single-agent targeted therapies, such as BTK inhibitors or IMiDs alone, has been modest in relapsed and refractory DLBCL, necessitating the use of combination therapy. Targeted protein degraders are heterobifunctional small molecules that co-opt the endogenous ubiquitin-proteasome system to drive the selective degradation of target proteins. Degraders of IRAK4, a key component of the myddosome complex, show potent and selective IRAK4 degradation and preferential activity in MYD88-mutant (MYD88MT) DLBCL models. Notably, the activity of IRAK4 degradation is superior to IRAK4 kinase inhibition, supporting the essential scaffolding role of IRAK4 in myddosome signaling. We have previously described IRAKIMiDs, novel IRAK4 degraders that utilize an IMiD as a pharmacologically active cereblon binder. These degraders simultaneously degrade both IRAK4 and IMiD substrates and show synergistic antitumor activity over either IRAK4 degraders or IMiDs alone, enabling a therapeutically relevant biological combination within a single small molecule. Here we describe KTX-120, a novel IRAKIMiD development candidate. KTX-120 is an equipotent degrader of both IRAK4 and the IMiD substrates Ikaros and Aiolos in lymphoma model systems with low single-digit nM DC50 for degradation of all substrates. The cell activity of KTX-120 has shown a high dependence on MYD88MT status: across a panel of MYD88MT cell lines, KTX-120 showed consistent and potent cell activity, with IC50 ranging from 7-29nM, whereas in MYD88WT lines, cell activity was poor ranging from 1800-3400nM. In the OCI-Ly10 ABC DLBCL cell line that harbors a MYD88L265P mutation, the cell activity of KTX-120 was associated with degradation of both IRAK4 and Ikaros, supporting the combined IRAK4 and IMiD targeting of this molecule as contributing to cell activity. Notably, the onset of cell death in OCI-Ly10 cells with KTX-120 treatment was rapid, with cells becoming committed to cell death within 72h of exposure, suggesting that continuous exposure to KTX-120 may not be necessary for antitumor activity. We explored the pharmacological activity of KTX-120 in several in vivo model systems. KTX-120 is orally bioavailable and shows dose-proportional exposure in several species. A single oral dose of KTX-120 (10 mg/Kg or 30 mg/Kg) showed significant degradation of both IRAK4 and Ikaros in a dose and time-dependent manner, with degradation of both substrates being sustained for >96h, further supporting the potential for intermittent dosing. To assess this, we have explored the antitumor efficacy of KTX-120 in intermittent dosing schedules. KTX-120 was well tolerated and showed potent antitumor activity in several CDX models of MYD88MT DLBCL, including OCI-Ly10, TMD8 and SUDHL2, achieving regressions in all models in as little as once every 2 weeks. As an example, in OCI-Ly10, a 30mpk dose Q2W drove >80% degradation of both IRAK4 and Ikaros and showed regressions (including CR) by D28. Similar activity and tolerability were seen with both PO and IV dosing at doses that achieve active exposure, enabling the potential for both oral and parenteral dosing. We have further explored the activity of KTX-120 in a collection of DLBCL patient derived xenograft models. KTX-120 shows robust activity (>85% TGI) in 4/5 models of MYD88MT DLBCL and shows no or modest activity in 2/2 models of MYD88WT DLBCL, supporting the preferential activity of this mechanism in patient samples harboring MYD88 activating mutations. Importantly, activity was observed in models with a variety of co-mutations that activate the NFkB pathway, including alterations in, CD79B and TNFAIP3, suggesting that KTX-120 has the potential for activity in MYD88MT lymphoma regardless of other mutations. Collectively, these data support the combined IRAK4 degradation and IMiD activity of KTX-120 has the potential to achieve robust and durable regressions in MYD88MT lymphomas with the increased convenience of an intermittently administered single agent and decreased potential for drug combination challenges. Disclosures Walker: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mayo:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Klaus:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chen:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Bhaduri:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rusin:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Weiss:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

STAT3 (signal transducers and activators of transcription 3) is a transcription factor and a member of the STAT protein family that is activated through a variety of different cytokine and growth factor receptors via JAKs, as well as through oncogenic fusion proteins and gain-of-function (GoF) mutations in STAT3 itself. STAT3 hyperactivation and GoF mutations are found in numerous cancers, including clinically aggressive hematologic malignancies with high unmet medical need, such as peripheral T cell lymphomas (PTCLs) (Andersson et al., 2020). We have previously shown that a potent and selective STAT3 heterobifunctional degrader, KTX-201, strongly represses cell growth in models of STAT3-dependent heme malignancies (Csibi et al., 2019). Herein, we report on the cellular mechanisms underlying the anti-tumor effect of STAT3 degradation in PTCL and provide a model for the relationship between pharmacokinetics/ pharmacodynamics (PK/PD) and activity of KTX-201 in vivo. The relationship between STAT3 degradation by KTX-201, anti-tumor mechanism of action and in vivo activity were investigated in anaplastic large T cell lymphoma (ALCL) models, a subset of PTCLs. In vitro, a decrease of STAT3 by 90% for 48hr was required for ALCL cells to commit to death. To identify anti-tumor mechanism(s) of KTX-201 at the systems level, we performed a time-resolved analysis of the proteomic changes of SU-DHL-1 cells undergoing growth inhibition mediated by KTX-201 at GI95. We measured the abundance of 10,000 proteins and confirmed selective degradation of STAT3 by KTX-201 after 8h of treatment. Significant changes in several marker proteins known to be involved in STAT3-mediated proximal signaling in ALCL including SOCS3, Myc and Granzyme B were observed after 16h. Functional annotation analysis of proteins identified pathways that were significantly enriched in at least one time point. Using unsupervised hierarchical clustering of annotations, we found that proteins that increased in abundance over 48h of exposure to KTX-201 were associated with markers of apoptosis and those that decreased in abundance by 24h and 48h were associated with cytokine signaling and cell cycle, respectively. Based on these data, this study identifies inhibition of cytokine signaling, G1 cell cycle arrest and induction of apoptosis as key anti-tumor mechanisms associated with KTX-201 consistent with observed cell phenotypes. STAT3 degradation in tumor was characterized in mice bearing SU-DHL-1 tumors following single dose IV administration. The STAT3 PD response in tumor was correlated with exposures in tumor. At the dose of 25 mg/kg weekly where complete tumor regression was achieved, KTX-201 achieves >90% STAT3 degradation at 24h post dosing in SUDHL1 xenografts. STAT3 degradation was maintained at 90% at 4 days post dosing. The results from the PK/PD study suggests that STAT3 degradation in tumor of >90% is necessary for anti-tumor efficacy in vivo of KTX-201, but only for a limited duration, such as 4 days out of a weekly dosing cycle. Collectively, our data demonstrate that significant STAT3 degradation for a limited time during dosing interval with KTX-201 in ALCL promotes early changes in key signaling nodes involved with proliferation and cytokine stimulation, followed by profound changes in apoptotic proteins. By integrating mechanistic biology with a deep understanding of PK/PD and efficacy, this study provides a foundation for the clinical development of STAT3 degraders using intermittent dosing regimen for treatment of PTCL and other STAT3-dependent heme malignancies. Disclosures Rong: Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sharma:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Csibi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Yang:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rusin:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Dey:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Karnik:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mayo:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Yuan:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chutake:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. McDonald:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhu:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ji:Kymera Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Liu:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Li:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Walker:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gollob:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Mainolfi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company. Desavi:Kymera Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Targeted protein degraders (TPD) are heterobifunctional small molecules that employ the ubiquitin degradation system to drive the selective degradation of target proteins. In approximately one third of B-cell lymphomas, gain of function mutations in MYD88 constitutively activate the myddosome and drive proliferation and survival through NFkB and AP1 signaling. IRAK4, is a key component of the myddosome and IRAK4 TPD show potent and selective IRAK4 degradation and preferential activity in MYD88 mutated B cell lymphoma models. Notably, the activity of IRAK4 degraders is superior to kinase inhibition, supporting the essential scaffolding role of IRAK4 in Myddosome signaling. An important goal of cancer therapy is to drive to deep and durable responses in patients, and this is frequently achieved by combination therapy. It has been suggested that blocking NFkB while simultaneously inducing a Type 1 IFN response with an IMiD (e.g. Lenalidomide Yang et al. (2012) Cancer Cell 21, 6, p723) may drive additive or synergistic antitumor activity. We have developed novel degraders that utilize an IMiD as a cereblon binder. These compounds simultaneously degrade both IRAK4 and IMiD substrates, enabling a therapeutically-relevant biological combination within a single small molecule. Here we show that dual IRAK4 and IMiD based degraders have potent antiproliferative activity across MYD88 mutant, but not MYD88WT lymphoma cell lines, with increased and broader antiproliferative and apoptosis activity relative to selective IRAK4 degraders or IMiDs alone. Several lines of evidence suggest that both IRAK4 and IMiD activity contribute to the overall superior activity of the dual degraders. Proteomic analysis demonstrates degradation of both both IRAK4 and key IMiD substrates, including Ikaros and Ailolos. This activity results in an enhanced Type 1 IFN response signature compared to selective IRAK4 degraders or IMiD alone, suggesting cooperative biological activity. Degradation of both IRAK4 and IMiD substrates corelates with cell activity, consistent with a requirement for both activities to drive cell death. In xenograft models of MYD88 mutant DLBCL, daily oral dosing of lead dual - degraders demonstrates strong antitumor activity in xenograft models of MYD88 mutant lymphoma, including durable complete regressions that can be maintained for several weeks following cessation of dosing. Regressions are associated with degradation of both IRAK4 and IMiD substrates, consistent with the dual-targeting activity of these molecules. Collectively, these data support a strategy to combine IRAK4 degradation and IMiD activity in a single molecule that will have the potential benefits of enhanced therapeutic activity, increased convenience and decreased potential for drug combination challenges, such as DDI. Lead degraders based on this synergistic profile are being advanced towards IND in 2020. Citation Format: Duncan H. Walker, Michele Mayo, Christine Klaus, Haojing Rong, Scott Rusin, Kirti Sharma, Alice McDonald, Veronica Campbell, Joseph Kelleher, Jared Gollob, Nello Mainolfi, Matt Weiss. Degraders targeting both IRAK4 and IMiD substrates show combinatorial effects leading to broader activity with durable and complete regressions in MYD88 mutant lymphoma xenografts in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5222.

Signal transducer and activator of transcription 3 (STAT3) has been implicated in multiple aspects of tumorigenesis. In addition to increasing cancer cell proliferation and survival, constitutively activated STAT3 is proposed to regulate cross-talk between tumor, stroma and immune cells to promote immune-evasion. STAT3 activity in tumors promotes the production of immune-suppressive factors that activate STAT3 in diverse immune-cell subsets. Mechanistically, genetic studies support a direct role of activated STAT3 in regulating myeloid cell differentiation to contribute to an immune-suppressed tumor microenvironment (TME) (Kortylewski et al.; Nat. Med. 2005 and Curr. Opin. Immunol. 2008) Therefore, STAT3 is a highly attractive target for immune-oncology. Here, we demonstrate that the degradation of STAT3 with a potent and selective STAT3 degrader reverses immune suppression in preclinical models. KYM-003 is a heterobifunctional molecule that hijacks the ubiquitin-proteasome system (UPS) for rapid STAT3 degradation. KYM-003 robustly degraded STAT3 in both human peripheral blood mononuclear cells (hPBMC)-derived monocytes and lymphocytes with DC50 < 100 nM. Degradation in hPBMCs was highly selective for STAT3 vs >10,000 other detected proteins (including all other STAT family members) as evaluated by deep tandem mass tag proteomics. IL-6 treatment of hPBMCs upregulates STAT3 phosphorylation, resulting in transcription of genes involved in myeloid cell-mediated immune suppression, such as IL-10 and CD163, a marker of M2 macrophage differentiation. Treatment of cells with KYM-003 at DC90 for 6 hours abrogated the IL-6 induced up-regulation of immune-suppressive gene signatures consistent with a role of STAT3 in mediating an immune suppressive environment by regulating macrophages and other myeloid cells. In several tumor cell lines, degradation of STAT3 by KYM-003 led to strong downregulation of PD-L1. Importantly, in the BioMap StroNSCLC (DiscoverRx), a co-culture system composed of NCI-H1299 lung cancer cells, hPBMCs and primary human fibroblasts that models immune-suppressed TME biology, KYM-003 treatment decreased angiogenic and immune-suppressive cytokines, including VEGF and IL-10, and promoted the pro-inflammatory anti-tumor cytokines IL-2, IFNg and TNFa. Lastly, administration of KYM-003 to mice bearing syngeneic tumors exhibited anti-tumor activity as monotherapy in the CT26 syngeneic model. We have shown that targeting STAT3 for degradation may have a role in restoring an immune-permissive environment in tumors by both rescuing the suppressed immunologic microenvironment and directly downregulating immune checkpoint signals in tumor cells. These data support STAT3 degraders as a promising new therapeutic modality as immune-oncology agents.Citations: Kortylewski et al (2005) Nat. Med, 11(12):1314-21. Kortylewski et al (2008) Curr. Opin. Immunol, 20(2):228-33 Citation Format: Alfredo Csibi, Bin Yang, Yogesh Chutake, Karen Yuan, Michele Mayo, Veronica Campbell, Alice McDonald, Scott Rusin, Kirti Sharma, Hari Kamadurai, Henry Li, Mike Sintchak, Sean Zhu, Sharon Townson, Anthony Slavin, Haojing Rong, Phillip Liu, Chris De Savi, Jared Gollob, Duncan Walker, Nan Ji, Nello Mainolfi. A STAT3 selective targeted protein degrader decreases the immunesuppressive tumor microenvironment and drives antitumor activity in preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-088.

Impingement cooling is commonly employed in gas turbines to control the turbine tip clearance. During the design phase, computational fluid dynamics (CFD) is an effective way of evaluating such systems but for most turbine case cooling (TCC) systems resolving the small scale and large number of cooling holes is impractical at the preliminary design phase. This paper presents an alternative approach for predicting aerodynamic performance of TCC systems using a “smart” porous media (PM) to replace regions of cooling holes. Numerically CFD defined correlations have been developed, which account for geometry and local flow field, to define the PM loss coefficient. These are coded as a user-defined function allowing the loss to vary, within the calculation, as a function of the predicted flow and hence produce a spatial variation of mass flow matching that of the cooling holes. The methodology has been tested on various geometrical configurations representative of current TCC systems and compared to full cooling hole models. The method was shown to achieve good overall agreement while significantly reducing both the mesh count and the computational time to a practical level.

OBJECTIVES To assess the safety, short-term efficacy and early functional results of prostate artery embolisation (PAE), an emerging minimally invasive treatment for symptomatic benign prostate hyperplasia (BPH). PATIENTS AND METHODS In all, 51 men with BPH (prostate size >40 mL) causing moderate-severe lower urinary tract symptoms, who had either failed or ceased medical therapy and had declined or were considered unsuitable for surgical intervention, were recruited to this study. All men underwent baseline clinical assessment, PAE, and 3-month follow-up. The primary endpoints of this study were safety and feasibility. Safety was measured by the incidence of post-PAE adverse events and feasibility was defined by technical success. Secondary endpoints were changes in the International Prostate Symptom Score (IPSS) and quality of life (QoL) score at 3 months after PAE. RESULTS There were no serious adverse events and all procedures were technically successful. For non-catheterised patients, improvement in IPSS and QoL was reported in 95.1% of cases (P < 0.001). The mean reductions in IPSS and QoL were 18.8 points (80.7%) (P < 0.001) and 3.8 points (80.6%) (P < 0.001), respectively. Of the 30 non-indwelling-catheter-dependent men on medical therapy, 23 men were able to completely cease all medications, with all but one of the remaining men reporting significant improvements in IPSS and QoL score. CONCLUSION PAE is a technically feasible and safe procedure, with excellent short-term efficacy. High rates of patient satisfaction were achieved in this study, along with significant reductions in prostate symptoms and improvements in QoL. PAE may be an alternative to long-term use of medical therapy for symptoms due to BPH.

It has been known for a sometime that the compressor exit profile can have a significant effect on the overall performance of the fuel injector. This effect has been increased recently with the advent of larger leaner injection systems. With a modern gas turbine combustion system the fuel injectors are presented with a non-uniform feed generated by the upstream compressor and OGV/pre-diffuser assembly. For generic lean burn combustion systems previous experimental and numerical work highlighted a complex interaction between the compressor efflux and the upstream diffuser. Circumferential non-uniformities in the flow presented to the fuel injector can amount up to ±10% of the mean velocity. Previous investigations examined only the isothermal flow field and the effects of this level of non-uniformity on reacting performance are not known. There are potential impacts on local fuel atomisation, air/fuel mixing and hence emissions performance. The main aim of this paper is to observe and assess the effect of these upstream conditions using a reacting flow test facility. In the initial design phases reacting flow experiments are generally conducted in simple, single sector plenum fed test facilities. Since this does not capture the effects of non-uniformities modifications were made to the facility to produce an aerodynamically representative feed. CFD was used in the design process to ensure that the aerodynamic features present in engine geometries would be faithfully reproduced by the test rig modifications. The CFD also highlighted changes in the downstream isothermal flow field. This included differences in the overall effective area of the fuel injector and, importantly, a redistribution of mass flow between the various fuel injector passages. Additionally, the cone angle, and the flow structure downstream was observed to change. Back-to-back tests were then conducted in a reacting flow test facility for various pilot-mains fuel flow splits and air-to-fuel ratios. Visualisation of the flame showed notable qualitative differences in the structure and stability of the flame. Quantitative measurements indicated that, compared to a plenum feed, a representative feed produced changes in the production of carbon monoxide, unburned hydrocarbons and oxides of nitrogen. Emission results were used to calculate the extent of the mass flow redistribution between passages. From this a correction was applied to the estimated AFRs. This correction did not fully collapse the emissions data, suggesting that while the mass flow redistribution contributes to the change in emissions it is not fully responsible. Covered in this paper are initial observations. However, further work is required to fully understand how the changes to the aerodynamic flow field alter the emissions performance, but it is clear that having a representative fuel injector feed is important in low TRL testing.

To develop an automated approach for 3D quantitative assessment and measurement of alpha angles from the femoral head-neck (FHN) junction using bone models derived from magnetic resonance (MR) images of the hip joint.Bilateral MR images of the hip joints were acquired from 30 male volunteers (healthy active individuals and high-performance athletes, aged 18–49 years) using a water-excited 3D dual echo steady state (DESS) sequence. In a subset of these subjects (18 water-polo players), additional True Fast Imaging with Steady-state Precession (TrueFISP) images were acquired from the right hip joint. For both MR image sets, an active shape model based algorithm was used to generate automated 3D bone reconstructions of the proximal femur. Subsequently, a local coordinate system of the femur was constructed to compute a 2D shape map to project femoral head sphericity for calculation of alpha angles around the FHN junction. To evaluate automated alpha angle measures, manual analyses were performed on anterosuperior and anterior radial MR slices from the FHN junction that were automatically reformatted using the constructed coordinate system.High intra- and inter-rater reliability (intra-class correlation coefficients > 0.95) was found for manual alpha angle measurements from the auto-extracted anterosuperior and anterior radial slices. Strong correlations were observed between manual and automatic measures of alpha angles for anterosuperior (r = 0.84) and anterior (r = 0.92) FHN positions. For matched DESS and TrueFISP images, there were no significant differences between automated alpha angle measures obtained from the upper anterior quadrant of the FHN junction (two-way repeated measures ANOVA, F

As aero gas turbines strive for higher efficiencies and reduced fuel burn, the trend is for engine overall pressure ratio to increase. This means that engine cycle temperatures will increase and that cooling of various engine components, for example the high pressure turbine, is becoming more difficult. One solution is to employ a cooled cooling air system where some of the compressor efflux is diverted for additional cooling in a heat exchanger fed by air sourced from the by-pass duct. Design of the ducting to feed the heat exchangers with coolant air is challenging as it must route the air through the scenery present in the existing engine architecture which leads to a convoluted and highly curved system. Numerical predictions using ANSYS Fluent demonstrated that a baseline design was unsuitable due to large amounts of flow separation in the proximity of the heat exchangers. This paper is mainly concerned with the aerodynamic design of this component of the duct. In order to produce a viable aerodynamic solution a numerical design methodology was developed which significantly enhances and accelerates the design cycle. This used a Design of Experiments approach linked to an interactive design tool which parametrically controlled the duct geometry. Following an iterative process, individually optimized 2D designs were numerically assessed using ANSYS Fluent. These designs were then fed into an interactive 3D model in order to generate a final aerodynamic definition of the ducting. Further CFD predictions were then carried out to confirm the suitability of the design. RANS CFD solutions, generated, using a Reynolds stress turbulence model, suggested that the new design presented significant improvement in terms of diffusion and flow uniformity.

As aero gas turbine designs strive for ever greater efficiencies the trend is for engine overall pressure ratios to rise. Although this provides greater thermal efficiency it means that cycle temperatures also increase. Traditionally turbines have been the focus of cooling schemes to enable them to survive high temperatures. However, it is envisaged that the compressor delivery air will soon reach temperatures which mean they may require similar cooling strategies to the turbine. One such concept is akin to that of a turbine “rim purge flow” which ensures that hot, mainstream flow does not get ingested into rotor cavities. However, the main gas path in compressors is generally more aerodynamically sensitive than in turbines and introduction of a purge flow may be more penalizing. It is important to understand the impact such a flow may have on the primary gas path flow of a compressor and the downstream combustion system aerodynamics. This paper presents a preliminary investigation into the effects of a purge flow which enters the main gas path immediately upstream of the high pressure compressor outlet guide vane (OGV) row. Initial, simplified, CFD predictions clearly demonstrated the potential of the purge flow to negatively affect the OGV/pre-diffuser and alter the inlet conditions to the combustion system. Consequently, an experimental assessment was carried out using an existing fully annular, isothermal test facility which incorporated a bespoke 1.5 stage axial compressor, engine relevant outlet guide vanes, pre-diffuser and downstream combustor geometry. Using CFD to guide the process the test rig was modified to allow a metered airflow to be introduced upstream of the outlet guide vanes. Importantly the flow was directed up the face of the rotor such that it picked up a representative swirl component prior to injection into the main gas path. The experimental data confirmed the CFD results and importantly demonstrated that the degradation in the combustor inlet flow resulted in an increased combustion system loss. At the proposed purge flow rate, equal to ∼1% of the mainstream flow, these effects were small with the system loss increasing by ∼4%. However, at higher purge flow rates (up to 3%) these effects became notable and the OGV/pre-diffuser flow degraded significantly with a resultant increase in the combustion system loss of ∼13%.

Transcatheter hepatic arterial administration of irinotecan-loaded drug-eluting beads (DEBIRI) is used to treat liver-only or liver-dominant metastatic disease from colorectal cancer (CRC). Eligibility for DEBIRI should be established in each individual patient by a multidisciplinary team based on comprehensive clinical, imaging, and laboratory assessment. Standardization of DEBIRI technique and protocols would be expected to lead to improved efficacy and safety. The present article provides a set of technical recommendations for the use of DEBIRI in the treatment of hepatic CRC metastases.

Purpose: Targeted protein degradation is a novel therapeutic modality that holds the promise to target previously “undruggable” proteins by harnessing the innate ubiquitin proteasome system in cells. In this study we describe the discovery and characterization of KYM-003, a novel, selective degrader of the oncogenic transcription factor STAT3 that shows potent antitumor activity in vitro and in vivo in STAT3-dependent models. Introduction: STAT3 is a transcription factor downstream of several signaling events including the IL-6-JAK pathway. Activating mutations and aberrant STAT3 activation are found in numerous cancers and STAT3 activation has been directly linked to the promotion of cancer cell survival, proliferation and immune evasion, making it a highly attractive target for oncology. Potent and selective agents specifically and directly targeting STAT3 have remained elusive, however. Herein we report the discovery of a potent and selective STAT3 degrader, KYM-003, which displays strong anti-tumor activity in models of heme malignancies. Methods: The binary binding of KYM-003 to STAT3 and the E3 ligase were characterized in fluorescence polarization assays. An AlphaLISA immunoassay was used to measure the formation of the E3-KYM-003-STAT3 ternary complex. Ubiquitination of endogenous STAT3 was evaluated in human cell lysates in the presence of KYM-003. STAT3 levels in multiple primary cells, cell lines, and xenograft tumor tissues were quantified by immunoassays. STAT3 signaling was monitored through its target gene levels by RT-qPCR. Cell viability was monitored by CellTiter-Glo. Tumor xenograft studies were conducted by implanting human cancer cell lines into immune-compromised mice and assessment of tumor volume changes. Key data: KYM-003 degrades STAT3 via an E3 ligase-dependent mechanism. KYM-003 potently binds to and demonstrated strong cooperativity in promoting the formation of the STAT3-KYM-003-E3 ligase ternary complex. In a biochemical assay with A549 cell lysates, KYM-003 potently induced ubiquitination of endogenous STAT3. KYM-003 robustly degraded STAT3 in numerous primary cells or cell lines with DC50 < 100 nM. Degradation was highly selective for STAT3 vs >10,000 other detected proteins (including all other STAT family members) in A549 and hPBMCs. Degradation of STAT3 by KYM-003 led to strong downregulation of STAT3 targets gene expression, such as SOCS3, MYC, and PIM1 Importantly, total STAT3 and pSTAT3 levels in tumors were reduced by >90% for at least 24 hours after a single dose of KYM-003 and repeated dosing of KYM-003 showed dose-dependent antitumor activity in xenograft models of heme maliganancies. Conclusion: KYM-003 is a potent and selective STAT3 degrader that demonstrated strong anti-tumor activity in heme cancer models. These data support STAT3 degraders as a promising new therapeutic opportunity. Citation Format: Fred Csibi, Nan Ji, Bin Yang, Karen Yuan, Michele Mayo, Haojing Rong, Scott Rusin, Kirti Sharma, Christine Loh, Henry Li, Sharon Townson, Hari Kamadurai, Jesse Chen, Duncan Walker, Jared Gollob, Nello Mainolfi. Discovery of KYM-003, a potent and selective STAT3 degrader with antitumor activity in heme malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C054. doi:10.1158/1535-7163.TARG-19-C054

Targeted protein degradation mediated by small molecule degraders represents a new and exciting therapeutic modality to target difficult-to-drug oncogenic proteins including transcription factors. These molecules bind to both the target protein and an E3 ligase, enabling the formation of a ternary complex that leads to ubiquitination and subsequent degradation of the target protein by the proteasome. STAT3 (signal transducers and activators of transcription 3) is a transcription factor and a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated serine/threonine kinases, and phosphylated STAT3 (pSTAT3) then forms dimers that translocate into the nucleus, binds to DNA, and regulate transcription. STAT3 is frequently mutated and activated in numerous cancers including clinically aggressive hematologic malignancies with high unmet medical need. Mechanistically, aberrant activation of STAT3 has been directly linked to the promotion of cancer cell survival, proliferation and immune evasion, thus making it a highly attractive target for oncology. Potent and selective agents specifically and directly targeting STAT3 have remained elusive, however. Herein we report the discovery of a potent and selective STAT3 heterobifunctional degrader, KYM-003, which displays strong anti-tumor activity in models of STAT3-dependent heme malignancies. KYM-003 degrades STAT3 via an E3 ligase-dependent mechanism. It strongly binds to STAT3 and a E3 ligase, leading to the formation of the a productive ternary complex, which leads to ubiquitination of STAT3 and subsequent proteasomal degradation. KYM-003 robustly degraded STAT3 in a number of primary cells or cell lines with DC50 < 100 nM. Degradation was highly selective for STAT3 vs >10,000 other detected proteins (including all other STAT family members) in cell lines and human PBMCs. Degradation of STAT3 by KYM-003 led to significant downregulation of STAT3 target genes, such as SOCS3, MYC, and PIM1. Importantly, total STAT3 and pSTAT3 levels in tumors were reduced by >90% for at least 24 hours after a single dose of KYM-003 and repeated dosing of KYM-003 showed dose-dependent antitumor activity in xenograft models of heme malignancies. Collectively, our data demonstrates that KYM-003 is a potent and selective STAT3 degrader that exhibited strong anti-tumor activity in vitro and in vivo. These data support STAT3 degraders as a new and exciting therapeutic opportunity in heme malignancies. Disclosures Csibi: kymera Therapeutics: Employment, Equity Ownership. Ji:Kymera Therapeutics: Employment, Equity Ownership. Yang:Kymera Therapeutics: Employment, Equity Ownership. Yuan:Kymera Therapeutics: Employment, Equity Ownership. Mayo:kymera Therapeutics: Employment, Equity Ownership. Rong:Kymera Therapeutics: Employment, Equity Ownership. Rusin:Kymera Therapeutics: Employment, Equity Ownership. Sharma:kymera Therapeutics: Employment, Equity Ownership. Loh:Kymera Therapeutics: Employment, Equity Ownership. Li:Kymera Therapeutics: Employment, Equity Ownership. Townson:Kymera Therapeutics: Employment, Equity Ownership. Chen:kymera therapeutics: Employment, Equity Ownership. Kamadurai:Kymera Therapeutics: Employment, Equity Ownership. Walker:Kymera Therapeutics: Employment, Equity Ownership. Gollob:Kymera Therapeutics: Employment, Equity Ownership. Mainolfi:Kymera Therapeutics: Employment, Equity Ownership.

The aim of this research was to improve the understanding of the complex flow features found around a wheel and wheelhouse and to examine how the lateral displacement of the wheel affects these features and the production of exhibited pressures and forces. A bespoke rotating wheel rig and accompanying wheelhouse with a fully-pressure-tapped wheel arch was designed and manufactured at Loughborough University. Wind tunnel tests were performed where force and pressure measurements and Particle Image Velocimetry (PIV) data were obtained. The experimental data was used to validate unsteady CFD predictions where a k- ω SST Improved Delayed Detached Eddy Simulation (IDDES) turbulence model was used in STAR-CCM+ (10.04.009, Siemens). The CFD showed good agreement with all trends of the experimental results providing a validated numerical methodology. For both methodologies, a lower amount of wheelhouse drag was found generated when the wheel was rotating. However, the CFD showed that whilst this was the case, total configuration drag had increased. This was attributed to an increase of the wheel and axle drag, illustrated by the change in separation over the wheel itself when located within a wheelhouse and so overcompensating the reduction in body and stand drag. Differences in vortex locations when comparing to previously-attained results were due to differences in housing geometry, such as blockage in the cavity or housing dimensions. Experimental and computational results showed that up until a 10 mm displacement outboard of the housing, overall drag decreased. The reduction in housing drag was credited to a reduction in the size of outboard longitudinal vortex structures. This led to the lateral width of the shear layer across the housing side being narrower. Overall, this study identified that there were potential benefits to be gained when offsetting a wheel outboard of the longitudinal edge of a model housing.

Purpose: This work assessed the antitumor activity of selective small molecule IRAK4 degraders in human ABC DLBCL cell lines in vitro and in tumor xenograft models in vivo, alone and in combination with BTK inhibition. Introduction: ABC DLBCL comprises approximately 45% of DLBCL and has a worse outcome with R-CHOP chemotherapy compared to GCB DLBCL. Activating mutations in MYD88 occur in 30-40% of ABC DLBCL; L265P, the most prevalent MYD88 mutation, causes constitutive assembly and activation of the Myddosome. IRAK4 kinase and scaffolding functions are essential for full signaling through the Myddosome to NFκB and MAPK pathways. Kymera Therapeutics is using a chemical knockdown strategy to develop heterobifunctional small molecule IRAK4 degraders, exemplified by KYM-001, for the treatment of MYD88-driven lymphomas. Methods: IRAK4 in human PBMC, ABC DLBCL cell lines and xenografts was quantified by immunoassays or targeted MS/MS. Myddosome signaling was monitored by mRNA and phosphoprotein endpoints. Cell viability and cell cycle were monitored by flow cytometry. Tumor xenograft studies were conducted by implanting human ABC DLBCL lines into immunocompromised mouse strains and assessing tumor volume. Key data: KYM-001 led to potent E3 ligase-dependent degradation of IRAK4. Notably, KYM-001 more effectively inhibited TLR-activated Myddosome signaling compared to IRAK4 kinase inhibitors in human PBMC. Degradation was highly selective for IRAK4 vs >10,000 other detected proteins in the MYD88 L265P mutant ABC DLBCL line OCI-LY10. IRAK4 degradation by KYM-001 resulted in cell cycle inhibition and apoptosis within 48-72 h in ABC DLBCL, with preferential activity in MYD88-mutant vs MYD88-WT cell lines. Oral dosing of KYM-001 showed dose-dependent antitumor activity in several mouse xenograft models of human MYD88-mutant ABC DLBCL at tolerated doses and schedules. In the OCI-LY10 model, tumor regression was associated with >80% degradation of IRAK4, establishing the pharmacodynamic effect required for maximal efficacy. Since alterations in BCR signaling and MYD88 frequently co-occur in B-cell malignancies, we investigated the potential for combined activity of IRAK4 degradation and BTK inhibition. In the OCI-LY10 xenograft model, which has activating mutations in both CD79B and MYD88, BTK inhibition with ibrutinib had an additive effect on KYM-001 antitumor activity. Conclusions: KYM-001 is a first-in-class, potent, selective and orally active IRAK4 degrader that causes tumor regression in ABC-DLBCL models. Degradation of IRAK4 removes both the kinase and scaffolding functions of IRAK4, and may be superior to kinase inhibition alone. These data support IRAK4 degraders as a promising new therapeutic opportunity for MYD88-driven lymphoma, both alone and in combination with other targeted approaches such as BTK inhibition. Citation Format: Joseph F. Kelleher, Veronica Campbell, Jesse Chen, Jared Gollob, Nan Ji, Hari Kamadurai, Christine Klaus, Henry Li, Christine Loh, Alice McDonald, Haojing Rong, Scott Rusin, Kirti Sharma, Dominico Vigil, Duncan Walker, Matt Weiss, Karen Yuan, Yi Zhang, Laurent Audoly, Nello Mainolfi. KYM-001, a first-in-class oral IRAK4 protein degrader, induces tumor regression in xenograft models of MYD88-mutant ABC DLBCL alone and in combination with BTK inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-272.

Numerical methods are invaluable in the initial phase of a project for evaluating potential design solutions. The design of aircraft gas turbine combustor external aerodynamics is one example where such methodology is applied. The system is geometrically complex and requires a high fidelity mesh to resolve small geometric features, such as the injector swirl vanes. Typically the injector alone accounts for approximately 20% of the mesh cells of the entire domain. This makes it expensive to model in terms of both requisite computational resource and run time. This paper presents a numerical method for replacing the injector swirl vane passages with mathematically porous volumes which replicate the required pressure drop. This is preferential to modelling the fully featured injector as it allows a significant reduction in the cell count. This in turn allows significant time savings that serve to expedite the initial design of the combustor external aerodynamics. It also makes the geometry easier to change, scale and re-mesh during development. This method has been rigorously tested through a range of approach conditions to ensure that it is robust enough for use in the design process. The loss in accuracy owing to the simplification has been demonstrated to be less than 4.4%, for all tested flowfields. This error is dependent on the flow conditions and is generally much less for passages fed with representative levels of upstream distortion.

To manage the increasing turbine temperatures of future gas turbines a cooled cooling air system has been proposed. In such a system some of the compressor efflux is diverted for additional cooling in a heat exchanger (HX) located in the bypass duct. The cooled air must then be returned, across the main gas path, to the engine core for use in component cooling. One option is do this within the combustor module and two methods are examined in the current paper; via simple transfer pipes within the dump region or via radial struts in the prediffuser. This paper presents an experimental investigation to examine the aerodynamic impact these have on the combustion system external aerodynamics. This included the use of a fully annular, isothermal test facility incorporating a bespoke 1.5 stage axial compressor, engine representative outlet guide vanes (OGVs), prediffuser, and combustor geometry. Area traverses of a miniature five-hole probe were conducted at various locations within the combustion system providing information on both flow uniformity and total pressure loss. The results show that, compared to a datum configuration, the addition of transfer pipes had minimal aerodynamic impact in terms of flow structure, distribution, and total pressure loss. However, the inclusion of prediffuser struts had a notable impact increasing the prediffuser loss by a third and consequently the overall system loss by an unacceptable 40%. Inclusion of a hybrid prediffuser with the cooled cooling air (CCA) bleed located on the prediffuser outer wall enabled an increase of the prediffuser area ratio with the result that the system loss could be returned to that of the datum level.

The development of radical new aero engine technologies will be key to delivering the step-changes in aircraft environmental performance required to meet future emissions legislation. Intercooling has the potential for higher overall pressure ratios, enabling reduced fuel consumption, and/or lower compressor delivery air temperatures and therefore reduced NOx. This paper considers the aerodynamics associated with the complex ducting system that would be required to transfer flow from the core engine path to the heat exchanger system. The cycle benefits associated with intercooling could be offset by the pressure losses within this ducting system and/or any detrimental effect the system has on the surrounding components. A suitable branched S-shaped duct system has been numerically developed which diffuses and delivers the flow from the engine core to discrete intercooler modules. A novel swirling duct concept was used to locally open larger spacing between certain duct branches in order to provide engine core access whilst hiding the resultant pressure field from the upstream turbomachinery. The candidate duct system was experimentally evaluated on a bespoke low speed, fully annular isothermal test facility. Aerodynamic measurements demonstrated the ability of the design to meet the stringent aerodynamic and geometric constraints.

In engineering applications, diffuser performance is significantly affected by its boundary conditions. In a gas turbine combustion system, the space envelope is limited, the inlet conditions are generated by upstream turbomachinery, and the downstream geometry is complex and in close proximity. Published work discusses the impact of compressor-generated inlet conditions, but little work has been undertaken on designing diffusers to accommodate a complex downstream geometry. This paper considers the design of an annular diffuser in the presence of a large downstream blockage. This is most applicable in the combustion system of a low-emission landbased aero-derivative gas turbine, where immediately downstream of the diffuser approximately 85% of the flow moves outboard and 15% moves inboard to supply the various flame-tube and turbine-cooling features. Several diffuser concepts are numerically developed and demonstrate 1) the interaction between the diffuser and downstream geometry and 2) how this varies with changes in diffuser geometry. A preferred concept is experimentally evaluated on a low-speed facility that simulates the combustion system and provides compressorgenerated inlet conditions. A conventionally designed aero-derivative diffuser system is also evaluated and, with reference to this datum, the system total pressure losses are reduced by between 20 and 35%.

To compare automated segmentation of the quadratus lumborum (QL) based on statistical shape modeling (SSM) with conventional manual processing of magnetic resonance (MR) images for segmentation of this paraspinal muscle.The automated SSM scheme for QL segmentation was developed using an MR database of 7 mm axial images of the lumbar region from 20 subjects (cricket fast bowlers and athletic controls). Specifically, a hierarchical 3D-SSM scheme for segmentation of the QL, and surrounding psoas major (PS) and erector spinae+multifidus (ES+MT) musculature, was implemented after image preprocessing (bias field correction, partial volume interpolation) followed by image registration procedures to develop average and probabilistic MR atlases for initializing and constraining the SSM segmentation of the QL. The automated and manual QL segmentations were compared using spatial overlap and average surface distance metrics.The spatial overlap between the automated SSM and manual segmentations had a median Dice similarity metric of 0.87 (mean = 0.86, SD = 0.08) and mean average surface distance of 1.26 mm (SD = 0.61) and 1.32 mm (SD = 0.60) for the right and left QL muscles, respectively.The current SSM scheme represents a promising approach for future automated morphometric analyses of the QL and other paraspinal muscles from MR images.

Kinesin spindle protein (KSP/Eg5) inhibitors are novel anticancer agents that have thus far shown only modest activity in the clinic. Understanding how to identify patients who may be most sensitive to treatment is clearly needed to improve the development of these molecules. We studied four multiple myeloma cell lines treated with the KSP inhibitor ARRY-520 to identify factors important for initiating apoptosis while cells are arrested in mitosis. The majority (three of four) of cell lines underwent mitotic arrest, with apoptosis occurring in mitosis within 24 to 30 hours. The remaining line (NCI H929) is temporally refractory to ARRY-520 treatment, undergoing mitotic slippage and subsequently peaking in apoptotic markers after 72 hours of treatment, while most cells are in interphase. Interestingly, loss of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) coincided with mitotic cell death. Stabilization of Mcl-1 resulted in a delayed onset of apoptosis, whereas enforced downregulation of Mcl-1 increased cell death in response to KSP inhibition. Thus, variation in responses to KSP inhibition is governed by a balance between survival proteins and spindle checkpoint integrity. Cells relying on short-lived survival proteins during mitosis are more likely to undergo apoptosis in response to KSP inhibition. We propose that patients with hematologic malignancies, which rely on Mcl-1, would therefore be good candidates for treatment with KSP inhibitors. Mol Cancer Ther; 9(7); 2046–56. ©2010 AACR.

Engstrom, C. M., D. G Walker, V. Kippers, and A. J. H. Mehnert. Quadrants Lumborum Asymmetry and L4 Pars Injury in Fast Bowlers: A Prospective MR Study. Med. Sci. Sports Exerc., Vol. 39, No. 6, pp. 910-917, 2007. Purpose: This prospective study examined the association between quadratus lumborum (QL) asymmetry and the development of symptomatic pars interarticularis lesions in the lumbar spine of adolescent cricket fast bowlers. Methods: Annual magnetic resonance imaging was used to measure QL volume asymmetry and for identifying pars lesions of the lumbar vertebrae in fast bowlers (N = 5 1) and a control group of swimmers (N = 18). Manual segmentation of axial images spanning the lumbar spine was performed to calculate percent QL asymmetry relative to the bowling- or throwing- (swimmers) arm side. Asymmetry above 100% indicated a larger QL volume on the bowling- (throwing) arm side. Results: The mean QL asymmetry in bowlers of 110.5% (SD = 12.1%) was significantly different from the 96.6% (SD = 5.0%) asymmetry in swimmers (t = 6.75, P

Particle Image Velocimetry (PIV) has been used to map the complex flow field generated by simulated battle damage to a two-dimensional wing. Previous studies have relied on surface flow visualisation techniques to study the flow but here PIV data has enabled the flow field away from the surface to be analysed for the first time. Damage was simulated by a single hole with a diameter equal to 20% of the chord, located at mid-chord. Wind tunnel tests were conducted at a Reynolds number of 500,000 over a range of incidences from 0-10 with two-component PIV measurements made on three span-wise planes; on the damage centre line and o set by 0.5 and 1.0 hole radii. The PIV data was seen to be in good agreement with existing surface flow visualisation showing strong evidence of the formation of a horse shoe vortex, a counter-rotating vortex pair and reverse flow regions. Large variations in the flow structure were observed over the range of incidences tested as the jet transitioned from weak at lower angles to strong at higher angles. The data also revealed some significant differences in the flow compared to classic Jets In Cross-Flow (JICF) behaviour. Notably in the case of battle damage the jet never fully occupies the hole and jet velocity pro le is highly skewed towards the rear of the hole. Additionally, the measured velocity ratios are much less than would be expected for typical JICF. For example, strong jet behaviour is observed at a velocity ratio as low as 0.22 whereas JICF studies would suggest a much higher ratio (> 2) is required. Increasing velocity ratio has been related to a reduction in lift and an increase in drag. At the highest incidence tested (10 ) the velocity ratio of 0.32 resulted in a reduction of the lift coe fficient by 0.18 and an increase in the drag coeffi cient of 0.035.

The trend for higher overall pressure ratios means that turbine entry temperatures are continually increasing. Furthermore, the development of lean, low-emission combustion systems reduces the availability of cooling air and is accompanied by new problems at the combustor/turbine interface. For example, the exit temperature traverse differs from that found in traditional rich-burn combustors with increased swirl and a much flatter profile. Effectively cooling the turbine components is becoming increasingly difficult. One solution is to employ cooled cooling air (CCA) where some of the compressor efflux is diverted for additional cooling in a heat exchanger located in the by-pass duct. An example CCA system is presented which includes an off-take within the dump cavity and the addition of radial struts within the pre-diffuser through which the cooled air is returned to the engine core. This paper addresses the impact this CCA system has on the combustion system external aerodynamics. This included the development of a fully annular, isothermal test facility which incorporated a bespoke 1.5 stage axial compressor, engine relevant outlet guide vanes, pre-diffuser and combustor geometry. A datum aerodynamic performance was established for a non-CCA configuration with a clean, un-strutted pre-diffuser. Results for this baseline CCA system demonstrated that inclusion of a bleed in the dump cavity had limited effect on the overall flow field. However, the inclusion of struts within the pre-diffuser caused a reduction in area ratio and a notable increase in system loss. Consequently an alternative pre-diffuser was designed (using CFD) with the aim of increasing the area ratio back to that of the un-strutted datum. A so-called hybrid diffuser was designed in which the CCA bleed was moved to the pre-diffuser outer wall. The bleed was then used to re-energize the boundary layer, preventing flow separation, enabling the area ratio to be increased close to the datum value. The mechanisms of the hybrid diffuser are complex; the geometry of the off-take and its location with respect to the OGV and strut leading edge were seen to be critical. Experimental evaluation of the final design demonstrated the effective operation the hybrid diffuser with the result that the system loss returned to a level close to that of the datum. Only small differences were seen in the overall flow field.

In this paper we use experimental measurements to characterize the extent that improved the external aerodynamic performance (reduced total pressure loss, increased flow quality) of a gas-turbine combustion system may be achieved by adopting an integrated OGV/prediffuser technique. Two OGV/prediffuser combinations were tested. The first is a datum design corresponding to a conventional design approach, where the OGV and prediffuser are essentially designed in isolation. The second is an “integrated” design where the OGV blade shape has been modified, following recommendations of earlier CFD work (Final Report No. TT03R01, 2003), to produce a secondary flow/wake structure that allows the prediffuser to operate at a higher area ratio without boundary layer separation. This is demonstrated to increase static pressure recovery and reduce dump losses. Experimental measurements are presented on a fully annular rig. Several traverse planes are used to gather five-hole probe data that allow the flow structure through the OGV, at the inlet and exit of the prediffuser, and in the inner/outer annulus supply ducts to be examined. Both overall performance measures (loss coefficients) and measures of flow uniformity and quality are used to demonstrate that the integrated design is superior.