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Résumé La neuropathie optique ischémique antérieure non artéritique (NOIA-NA) est une maladie multifactorielle qui constitue le type le plus courant de neuropathie optique ischémique. La NOIA-NA apparait dans un oeil et peut se développer plus tard dans l’autre oeil. La récurrence ipsilatérale de la NOIA-NA est rare et plusieurs théories ont été proposées pour l’expliquer. Le présent rapport de cas décrit un patient chez qui une récurrence unilatérale de la NOIA-NA est survenue, examine les étiologies proposées et met l’accent sur les symptômes visuels à la suite de sa résolution.

Nonarteritic anterior ischemic optic neuropathy (NA-AION) is a multifactorial disease that represents the most common type of ischemic optic neuropathy. NA-AION develops in one eye and can occur in the fellow eye at a later date.1The recurrence of ipsilateral NA-AION is rare and a multitude of theories have arisen to explain this infrequent recurrence.2 This case report describes an incident of unilateral recurrence of NA-AION, explores the proposed etiologies, and will emphasize visual symptoms following its resolution. Key words. optic nerve edema Ÿ recurrent Ÿ nonarteritic ischemic optic neuropathy Ÿ contrast sensitivity Ÿ peripapillary retinal nerve fiber layer (pRNFL)

[Image: see text] The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.

About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.

John McDowell’s position on the metaphysics of thought combines an identity conception of truth, the view that if one thinks truly that p, then what one thinks is the fact that p, with a Tractarian conception of the world as the totality of facts. In response to the charge that it is incoherent, William Fish and Cynthia Macdonald have recently (2007, 2009, 2011) defended a novel way of developing McDowell’s position. I argue that their interesting proposal doesn't work, owing to the fact that it can accommodate neither false thought nor, it seems, certain cases of true thought.

Breast cancer is the most frequently diagnosed cancer among women and remains the second leading cause of cancer death in women. An estimated 70% of all breast cancers express estrogen receptor alpha (ERα); and endocrine therapies have validated ERα as a target for the treatment of breast cancer. Despite effective endocrine therapies, many patients eventually relapse and become resistant to standard of care treatments. Endocrine resistant tumors often remain dependent on ERα for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor degrader (SERD), fulvestrant. However, fulvestrant may be limited in achieving maximal target occupancy due to pharmaceutical and pharmacokinetics properties which necessitates intramuscular route of administration. Consequently, SERDs with superior drug-like properties were sought to allow consistent and rapid achievement of maximal therapeutic exposure. GDC-0810 and GDC-0927 as first and second generation orally bioavailable SERDs were discovered through a prospective lead optimization on ERα degradation. The evolution from GDC-0810 to GDC-0927 will be described and provides new insights into ERα biology and biochemistry. By shifting away from the acrylic acid moiety in GDC-0810, GDC-0927 achieved increased potency and more consistent, complete suppression of ER signaling. Co-crystal structures of both GDC-0810 and GDC-0927 with ERα will be shared. Subsequent optimization of GDC-0927 resulting in improved pharmacokinetic properties will also be highlighted. Citation Format: Mehmet Kahraman, Steven P. Govek, Johnny Y. Nagasawa, Andiliy Lai, Celine Bonnefous, Karensa Douglas, John Sensintaffar, Nhin Lu, KyoungJin Lee, Anna Aparicio, Josh Kaufman, Jing Qian, Gang Shao, Rene Prudente, James D. Joseph, Beatrice Darimont, Daniel Brigham, Richard Heyman, Peter J. Rix, Jeffrey H. Hager, Nicholas D. Smith, Robert A. Blake, Jae Chang, Edna Choo, Anneleen Daemen, Lori S. Friedman, Jane Guan, Steven Hartman, Ellen Ingalla, James R. Kiefer, Tracy Kleinheinz, Sharada Labadie, Ciara Metcalfe, Vidhi Mody, Michelle Nannini, Deepak Sampath, Amy Young, Maia Vinogradova, Wei Zhou, Jun Liang, Xiaojing Wang. Discovery and evolution of orally bioavailable selective estrogen receptor degraders for ER+ breast cancer: From GDC-0810 to GDC-0927 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1648.

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.

A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

The majority of breast cancers express estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance emerges and disease progression ensues. Importantly, the majority of these tumors continue to depend on ERα for growth and survival via both ligand-dependent and ligand-independent pathways. The emerging evidence that ERα can be activated in the absence of estrogens via point mutations in ERα or cellular signaling pathways supports the development of agents that are not only competitive ERα antagonists but also reduce steady state levels of the receptor and thus limit both ligand dependent and independent signaling. Here we disclose the discovery of ARN-810, also known as GDC-0810. ARN-810 is an oral, potent antagonist of ER that also induces degradation of ERα at picomolar concentrations. ARN-810 treatment results in significant reduction in steady state ERα protein levels in breast cancer cell lines. Using peptide-based conformational profiling, we show ARN-810 induces ERα conformations that are distinct from both fulvestrant and tamoxifen indicating novel mechanism of action. In vitro, ARN-810 is active on wild-type and the constitutively active ERα mutants found in endocrine resistant breast cancer patients. Importantly, ARN-810 is active in cell-line and in vivo models of ESR1 wild-type and mutant, primary and endocrine-resistant breast cancers including patient derived xenograft (PDX) models. These preclinical data indicate that ARN-810, a novel Selective Estrogen Receptor Degrader (SERD), holds promise as a next generation therapy for the treatment of ER+ breast cancer as monotherapy, as well as in combination with agents that target other pathways involved in both intrinsic and acquired endocrine resistance. ARN-810 is in clinical development for the treatment of ER+ breast cancer. Citation Format: James Joseph, Steven Govek, Beatrice Darimont, Daniel Brigham, Anna Aparicio, Eric Bischoff, Mehmet Kahraman, Michelle Nannini, Joshua Kaufman, Andily Lai, Kyoung-Jin Lee, Jason Oeh, Nhin Lu, Wei Zhou, Michael Moon, Jing Qian, John Sensintaffar, Gang Shao, Deepak Sampath, Lori S. Friedman, Peter Rix, Richard A. Heyman, Nicholas Smith, Jeffrey H. Hager. Discovery of GDC-0810 a novel, non-steroidal selective estrogen receptor degrader with robust activity in pre-clinical models of endocrine-resistant breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5053. doi:10.1158/1538-7445.AM2015-5053

The majority of breast cancers express and rely on ERα for tumor growth, thus endocrine therapy is the mainstay of ER-positive breast cancer treatment. Despite the effectiveness of current therapies, many patients relapse with tumors still dependent on ER for growth via both estrogen-dependent and estrogen-independent mechanisms. Acquired mutations in ESR1 were recently identified in the ligand-binding domain of ERα in patients who progressed after aromatase inhibitors and tamoxifen. It is estimated that more than 20% of relapsed ER-positive breast cancer patients acquire activating mutations in ESR1. We created a variety of model systems to study the functional consequences of ESR1 mutations. In stable overexpressing cell lines, the mutant ER protein eventually becomes down-regulated, thus we generated cell lines with dox-inducible and CRISPR engineered ESR1 hotspot mutations. We confirmed ligand-independent transcriptional activity of ESR1 hotspot mutations including Y537S and D538G. Cell lines and patient derived xenograft (PDX) models were utilized in ER ChIP-seq studies. Additionally, we investigated therapeutic response and resistance in the context of ESR1 activating mutations for tamoxifen, fulvestrant, and next generation oral SERDs including ARN-810, also known as GDC-0810. ARN-810 is efficacious in MCF7 ESR1 Y537S xenografts and WHIM20 Y537S PDX tumors, indicating that SERDs may be effective for ER mutants. Citation Format: Wei Zhou, Robert A. Blake, Jim Nonomiya, Jing Qian, Lorna Kategaya, Ingrid Wertz, Anneleen Daemen, Thomas O'Brien, John Sensintaffar, Michael Moon, Michelle A. Nannini, Jason Oeh, Deepak Sampath, Xiaojing Wang, Nicholas Smith, Daniel Brigham, James Joseph, Jeffrey H. Hager, Lori S. Friedman. Selective estrogen receptor degrader (SERD) activity in ESR1 mutant models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1864. doi:10.1158/1538-7445.AM2015-1864

A Chemical-structure-based PolyUrethane Foam (CPUF) decomposition model has been developed to predict the fire-induced response of rigid, closed-cell polyurethane foam-filled systems. The model, developed for the B-61 and W-80 fireset foam, is based on a cascade of bondbreaking reactions that produce CO2. Percolation theory is used to dynamically quantify polymer fragment populations of the thermally degrading foam. The partition between condensed-phase polymer fragments and gas-phase polymer fragments (i.e. vapor-liquid split) was determined using a vapor-liquid equilibrium model. The CPUF decomposition model was implemented into the finite element (FE) heat conduction codes COYOTE and CALORE, which support chemical kinetics and enclosure radiation. Elements were removed from the computational domain when the calculated solid mass fractions within the individual finite element decrease below a set criterion. Element removal, referred to as ?element death,? creates a radiation enclosure (assumed to be non-participating) as well as a decomposition front, which separates the condensed-phase encapsulant from the gas-filled enclosure. All of the chemistry parameters as well as thermophysical properties for the CPUF model were obtained from small-scale laboratory experiments. The CPUF model was evaluated by comparing predictions to measurements. The validation experiments included several thermogravimetric experiments at pressures ranging from ambient pressure to 30 bars.more » Larger, component-scale experiments were also used to validate the foam response model. The effects of heat flux, bulk density, orientation, embedded components, confinement and pressure were measured and compared to model predictions. Uncertainties in the model results were evaluated using a mean value approach. The measured mass loss in the TGA experiments and the measured location of the decomposition front were within the 95% prediction limit determined using the CPUF model for all of the experiments where the decomposition gases were vented sufficiently. The CPUF model results were not as good for the partially confined radiant heat experiments where the vent area was regulated to maintain pressure. Liquefaction and flow effects, which are not considered in the CPUF model, become important when the decomposition gases are confined.« less

Differential fluorescence induction technology was used to identify promoters of Streptococcus pneumoniae genes that are expressed during lung infection of the mouse. Among the promoter clones that were identified multiple times was the psa promoter, which drives expression of the psaBCA operon. These genes have been identified previously and shown to encode a manganese permease system as well as play a role in the virulence of this organism. Mutations in psaB, psaC or psaA result in growth limitation in low manganese. The expression of the psa operon was examined in vivo and the virulence of deletion mutants of psaB, psaC, psaA and psaBCA was assessed in four different animal models of infection. The psa promoter was induced more than ten-fold in vivo using an intraperitoneal chamber implant model. The psaB, psaC and psaA mutants were completely attenuated in systemic, respiratory tract and otitis media infections. In addition, these mutants were unable to grow in an implanted peritoneal chamber, but growth was restored by the addition of manganese to the chambers.

Differential fluorescence induction (DFI) technology was used to identify promoters of Streptococcus pneumoniae induced under various in vitro and in vivo conditions. A promoter-trap library using green fluorescent protein as the reporter was constructed in S. pneumoniae , and the entire library was screened for clones exhibiting increased gfp expression under the chosen conditions. The in vitro conditions used were chosen to mimic aspects of the in vivo environment encountered by the pathogen once it enters a host: changes in temperature, osmolarity, oxygen, and iron concentration, as well as blood. In addition, the library was used to infect animals in three different models, and clones induced in these environments were identified. Several promoters were identified in multiple screens, and genes whose promoters were induced twofold or greater under the inducing condition were mutated to assess their roles in virulence. A total of 25 genes were mutated, and the effects of the mutations were assessed in at least two different infection models. Over 50% of these mutants were attenuated in at least one infection model. We show that DFI is a useful tool for identifying bacterial virulence factors as well as a means of elucidating the microenvironment encountered by pathogens upon infection.

Preliminary thermal decomposition experiments with Ablefoam and EF-AR20 foam (Ablefoam replacement) were done to determine the important chemical and associated physical phenomena that should be investigated to develop the foam decomposition chemistry sub-models that are required in numerical simulations of the fire-induced response of foam-filled engineered systems for nuclear safety applications. Although the two epoxy foams are physically and chemically similar, the thermal decomposition of each foam involves different chemical mechanisms, and the associated physical behavior of the foams, particularly ''foaming'' and ''liquefaction,'' have significant implications for modeling. A simplified decomposition chemistry sub-model is suggested that, subject to certain caveats, may be appropriate for ''scoping-type'' calculations.

Using two different animal models of Streptococcus pneumoniae infection, we have demonstrated that this organism is able to spread to the central nervous system and cause meningitis by bypassing the bloodstream. Following respiratory tract infection induced via intranasal inoculation, bacteria were rapidly found in the bloodstream and brains in the majority of infected mice. A similar pattern of dissemination occurred following otitis media infection via transbullar injection of gerbils. However, a small percentage of animals infected by either route showed no bacteria in the blood and yet did have significant numbers of bacteria in brain tissue. Subsequent experiments using a galU mutant of S. pneumoniae , which is impaired in its ability to disseminate to the bloodstream following infection, showed that this organism is able to spread to the brain and cerebrospinal fluid. These results demonstrate that, unlike many bacterial pathogens that cause meningitis, S. pneumoniae is able to do so independent of bloodstream involvement upon different routes of infection. This may address the difficulty in treating human infections caused by this organism.

Fms-like tyrosine kinase 3 (FLT3) is thought to be a major driver in the pathogenesis of acute myeloid leukemia (AML). FLT3-activating mutations are found in ∼ 30% of AML patients and are associated with poor outcome in this patient population. AC220 is a small molecule kinase inhibitor with potent and selective FLT3 inhibitory activity. Here we characterize the effect of AC220 on FLT3 autophosphorylation, activation of downstream signaling pathways (STAT5, ERK and AKT), cell cycle distribution, and apoptosis endpoints in multiple leukemia cell lines expressing either wild type FLT3 (FLT3-WT, SEM-K2 cells (FLT3-WT overexpression) and RS4;11 cells (FLT3-WT)) and/or ITD-mutated FLT3 (FLT3-ITD, MV4-11 (FLT3-ITD), MOLM-14 (FLT3-ITD/FLT3-WT)). Across each of these parameters we also compare the effects of AC220 to those of other known FLT3 inhibitors including, sorafenib, sunitinib, lestaurtinib, and midostaurin. AC220 inhibited FLT3 autophosphorylation in both FLT3-WT and FLT3-ITD cells with roughly equal potency, while other FLT3 inhibitors showed differential pFLT3 inhibition across several cell lines. Although AC220-mediated inhibition of FLT3 autophosphorylation was observed in all cell lines, subsequent cell death was only detected in the cell lines with activated FLT3. This contrasts with other FLT3 inhibitors, where potent inhibition of cell proliferation in the non-FLT3 activated RS4;11 cells was observed, highlighting the lack of FLT3 selectivity of these compounds. Consistent with FLT3 inhibition, AC220 also inhibited constitutively activated STAT5, ERK and AKT in these cell lines, suggesting that one or more of these pathways play a role in FLT3-mediated cell growth and survival. Furthermore, the inhibition of these downstream markers correlated with the inhibition of FLT3 across each of the FLT3 inhibitors tested. Lastly, in an MV4-11 murine xenograft model, AC220 administration resulted in the reduction of phosphorylated FLT3 and downstream signaling molecules concomitant with tumor reduction. Together, these data suggest that selective FLT3 inhibition is sufficient to inhibit the growth and induce cell death of FLT3-driven leukemia cells. AC220 is currently being evaluated in a phase II clinical trials in relapsed or refractory AML patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3619.

Abstract 2053 Poster Board II-30 Activating mutations in the receptor tyrosine kinase FLT3 are present in up to 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a potential target for kinase inhibitor therapy. AC220, a potent and selective FLT3 inhibitor, is currently in Phase II clinical trials in both FLT3-ITD positive and WT patients. Similar to imatinib therapy for CML, it is possible that targeted therapies will be delivered chronically. Therefore, we examined the efficacy of AC220 in a limited versus chronic dosing regimen in the homozygous FLT3-ITD-dependent MV4-11 disseminated mouse disease model. As AML is a heterogeneous disease, we also examined the in vivo efficacy of AC220 in the MOLM-14 disease model. This cell line is heterozygous for a FLT-3 ITD mutation in addition to carrying the MLL-AF9 fusion. In the MV4-11 model, a 30 day dosing regimen was compared to chronic dosing. In the vehicle control group, median survival time following inoculation was 47 days, with mortality preceded by clinical signs of disease and detection of MV4-11 cells in the blood. No specific clinical signs or body weight loss were attributed to the study drug. AC220 demonstrated dose-dependent efficacy from 0.1 mg/kg to 10 mg/kg orally once per day for 30 days. The 0.1 mg/kg group had a marginal (10%) increase in life span (ILS) relative to vehicle control, while a significant increase of survival was observed at the 1.0 mg/kg dose (55% ILS). The 10 mg/kg dose led to 80% survival at study termination, day 172 (>250% ILS). Prolonged survival with AC220 correlated with delayed disease onset as measured by clinical signs and detection of circulating MV4-11 cells. Chronic dosing in the 1.0 mg/kg group further delayed disease onset and mortality with an ILS of 155% relative to vehicle, and 63% relative to 30-day dosing. Similar to the 30-day dosing group, chronic administration of AC220 at 10 mg/kg led to 80% survival at day 172. A separate study was conducted to examine the relationship between bone marrow engraftment, tumor burden in peripheral blood and disease onset. At day 20, engraftment was detected only in the bone marrow. At day 35, when clinical signs of disease are typically apparent, levels of tumor cells as high as 80% and 35% were detected in the bone marrow and peripheral blood, respectively. AC220 given for 28 days at 1.0mg/kg delayed median onset of disease by 24 days (63%), with tumor burden undetectable in the absence of clinical signs of disease. The 28 day dosing at 10.0mg/kg completely inhibited disease onset, with no detectable tumor burden in either blood or bone marrow through the end of the study (terminated on day 130, >200% ILS). In the MOLM-14 model, median survival time of untreated or vehicle treated animals was 22 days. In a 21 day dosing regimen, AC220 demonstrated dose dependent efficacy, providing 9%, 64% and 127% ILS at 0.1, 1.0 and 10 mg/kg respectively. Prolonged survival correlated with a delay in both disease onset and detection of circulating MOLM-14 cells. Similar to the MV4-11 model, temporal analysis confirmed bone marrow engraftment prior to detectable levels in the circulation. At 13 days post-transplant, tumor cells are only detectable in the bone marrow, while by day 19, when clinical signs are apparent, tumor burden in the bone marrow and periphery of vehicle treated animals are as high as 35% and 6%, respectively. Unlike the MV4-11 model, dosing at 10 mg/kg for 21 days did not prevent disease onset after cessation of dosing, indicating that tumor cells were not completely eliminated, although detectable levels are not present in bone marrow or circulation until days 47 and 52, respectively. These data suggest that AC220 is efficacious against both FLT3-ITD homozygous and heterozygous genotypes, and that a chronic dosing regimen may provide greater disease protection than a limited course of therapy. This study is consistent with observed efficacy in AML patients treated continuously with AC220. Disclosures: Brigham: Ambit Biosciences: Employment. Belli:Ambit Biosciences: Employment. Breider:Ambit Biosciences: Employment. Bhagwat:Ambit Biosciences: Consultancy. Wierenga:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment.