Abstract: Granulocyte-macrophage colony-stimulating factor (GMCSF) has a central role in proliferation and differentiation of hematopoetic cells. Furthermore, it influences the proliferation and migration of endothelial cells. GMCSF elicits these functions by activating a receptor consisting of a ligand-specific α-chain and a β-chain, which is common for GMCSF, interleukin-3 (IL-3), and IL-5. It is known that various signaling molecules such as Janus kinase 2 or transcription factors of the signal transducer and activator of transcription (STAT) family bind to the common β-chain and initiate signaling cascades. However, α-chain—specific signal transduction adapters have to be postulated given that IL-3, IL-5, and GMCSF induce partly distinct biologic responses. Using a yeast 2-hybrid system, we identified the α-chain of the GMCSF receptor (GMRα) as putative interaction partner of IκB kinase β, one of the central signaling kinases activating the transcription factor nuclear factor—κB (NF-κB). Using endogenous protein levels of endothelial cell extracts, we could verify the interaction by coimmunoprecipitation experiments. Fluorescence resonance energy transfer (FRET) microscopy confirmed the direct interaction of CFP-IKKβ and YFPGMRα in living cells. Functional studies demonstrated GMCSF-dependent activation of IκB kinase activity in endothelial cells, degradation of IκB, and activation of NF-κB. Further biologic studies using GMCSF-dependent TF-1 cells indicated that GMCSF-triggered activation of NF-κB is important for cell survival and proliferation. (Blood. 2003;102:192-199)

Abstract: We have shown previously that oxidized phospholipids (OxPLs), known to accumulate in atherosclerotic vessels, stimulate angiogenesis via induction of autocrine mediators, such as vascular endothelial growth factor (VEGF). We now address the pathways mediating up-regulation of VEGF in human endothelial cells treated with OxPLs. Analysis of structure-function relationship using individual species of OxPLs demonstrated a close relation between induction of VEGF and activation of the unfolded protein response (UPR). Inducers of UPR up-regulated VEGF, whereas inhibition of UPR by chemical chaperones or knock-down of cochaperone HTJ-1 inhibited elevation of VEGF mRNA induced by OxPLs. OxPLs induced protein expression of activating transcription factor-4 (ATF4), an important effector of UPR. Expression levels of VEGF in OxPL-treated cells strongly correlated with induction of the ATF4 target genes ATF3 and TRB3. Knocking down ATF4 was paralleled by loss of VEGF induction by OxPLs. Chromatin immunoprecipitation demonstrated that OxPLs stimulated binding of ATF4 to a regulatory site in the VEGFA gene. Taken together, these data characterize UPR and more specifically its ATF4 branch as an important mechanism mediating up-regulation of VEGF by OxPLs, and allow hypothesizing that the UPR cascade might play a role in pathologic angiogenesis in atherosclerotic plaques.

Abstract: BCR-ABL1 inhibitors have revolutionized the treatment of CML patients. However several drawbacks remain, including clinical resistance of T315I-mutated CML. Further, the clinical success of ponatinib, a selective inhibitor of T315I-mutated BCR-ABL1 is hampered by vascular side effects. Therefore, novel treatment strategies are warranted especially in T315I-mutated CML. We investigated the relevance of the Gas6-Axl axis in CML patients and the therapeutic potential of the clinically applicable small molecule Axl inhibitor BGB324 in primary CML (stem cell) samples, cell lines and preclinical models. We previously found that Gas6 and Axl represent potential novel targets in this disease and that BGB324 inhibits CML growth in vitro and in vivo (Erdmann et al., ASH meeting 2013, New Orleans, #1469). We next wished to confirm Axl as specific therapeutic target and therefore down regulated its expression in KCL-22 and K562 cells by means of shRNA. In these experiments blockade of Axl inhibited CML cell proliferation in comparison to control-transduced cells, thereby confirming that Axl promotes CML growth. Subsequently, we added BGB324 to shAxl- and shcontrol-transduced cells. Surprisingly BGB324 inhibited cell growth significantly more in shAxl-transduced cells in comparison to control-treated shAxl-transduced cells (p 〈 0.05). These experiments indicated that BGB324 was inhibiting an additional target which supported CML cell proliferation, besides Axl. In order to identify this target we carried out a Kinome Scan revealing that BGB324 binds to native and mutated ABL1. Interestingly, the affinity of BGB324 for ABL1 carrying different mutations including T315I was 5 to 50 fold higher compared to unmutated ABL1 (Table 1). Next, we incubated BaF3 cells stably transfected with BCR-ABL1p210, BCR-ABL1T315I, BCR-ABL1M351T and BCR-ABL1E255K with various concentrations of BGB324 in order to determine its IC50 in the different cell lines. These experiments showed in concordance with the Kinome Scan that BGB324 was more potently inhibiting growth of mutated BCR-ABL1 compared to BCR-ABL1p210 (IC50 BCR-ABL1p210 1266 ± 126 nM; BCR-ABL1T315I 726 ± 194 nM; BCR-ABL1M351T 847 ± 10 nM and BCR-ABL1E255K 794 ± 39 nM; n=2-3; p 〈 0.05 compared to BCR-ABL1p210). Notably, further experiments revealed that BGB324 inhibited KCL-22 cells and K526 cells to a similar extent compared to the combination of imatinib (IM) and shAxl. Thus, BGB324 is a dual inhibitor of BCR-ABL1 and Axl. As the inhibition of BCR-ABL1T315I is of special clinical interest we wished to confirm this finding further in vivo. Therefore we inoculated BCR-ABL1p210 and BCR-ABL1T315I cells subcutaneously into NSG mice. After the tumors reached a size of 80-100 mm3 mice were randomized to receive either placebo control or 50 mg/kg BGB324 delivered twice daily by oral gavage. This experiment showed potent inhibition of tumor growth after 12 days with higher activity of BGB324 in mice bearing BCR-ABL1T315I tumors (placebo: 1751 ± 606 mm3, BGB324: 614 ± 224 mm3; p=0.001) compared to mice bearing BCR-ABL1p210 tumors (placebo: 1432 ± 403 mm3; BGB324: 632 ± 229 mm3; p=0.05) (Figure 1). Subsequently, tissue harvested at end-stage was subjected to immunohistochemical staining for the proliferation marker phospho-histone H3 and Western Blot analyses of cleaved caspase 3 in order to determine whether reduced proliferation and/or increased apoptosis was responsible for reduced growth of BCR-ABL1T315I tumors upon treatment with BGB324. These analyses revealed that proliferation as determined by histomorphometric analysis of phosho-histone H3 was reduced while cleaved caspase 3 levels were unchanged. These data were further corroborated by the finding that treatment with BGB324 reduced the level of phosphorylated MapK as determined by immunoblotting and densitometry. Thus, BGB324 inhibits proliferation of BCR-ABL1T315I cells in vivo. Altogether, our findings show that BGB324 represents a dual inhibitor of Axl and ABL kinase with therapeutic potential in CML, in particular in BCR-ABL1T315I disease. As BGB324 was shown to be well tolerated in healthy volunteers (Wnuk-Lipinska et al., AACR meeting 2013 San Diego #1747), our findings pave the way for clinical investigation of BGB324 in (T315I-mutated) CML. Table 1 Gene KinomeScan Kd (nM) KinaseProfiler IC50 (nM) Axl 0.4 3 ABL1 51.88 51 ABL1(E255K) 1.15 n/a ABL1(T315I) 10.13 4 ABL1(Y253F) 18.19 26 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Loges: BerGenBio: Research Funding, travel support, advisory boards Other.

Abstract: Background. Literature on the treatment of rrPCNSL is limited to a few retrospective studies and phase II trials addressing new drugs or strategies. Evidence supporting therapeutic choice in patients (pts) with rrPCNSL after modern high-dose-methotrexate (HD-MTX)-based chemotherapy (chemo) followed by consolidative whole-brain irradiation (WBRT) or autologous stem cell transplantation (ASCT) is lacking. We reviewed management and outcome of pts with rrPCNSL in the randomized trials of the IELSG, which included 294 assessable pts, treated with modern approaches, and followed for several years. Herein, we analyse efficacy of salvage options to provide recommendations for routine practice. Methods. Pts enrolled in the IELSG20 or IELSG32 trials who experienced progressive disease (PD) at any time were considered. Pts who died due to toxicity and pts with extra-CNS relapse were excluded. Pts were grouped according to the time to progression after the first-line treatment: refractory (REF; relapse/PD ≤6 months from end of treatment), early relapse (ER; 6-35 months) and late relapse (LR; ≥36 months). Effect of salvage therapy on survival after relapse (SAR) was the primary objective. SAR was estimated from date of PD/relapse to date of death or last visit. Results. 164 pts (median age 58, range: 26-70; 94 males) were considered: 119 (73%) REF, 24 (15%) ER and 21 (13%) LR. First-line chemo included HD-MTX in all pts, alone in 31, +cytarabine in 68, +cytarabine/rituximab in 36, and +cytarabine/rituximab/thiotepa (MATRIX regimen) in 29. Consolidation was part of first-line treatment in 58 (35%) pts: WBRT in 39 and carmustine-thiotepa/conditioned ASCT in 19; 106 pts did not receive consolidation due to PD during first-line chemo (n=96), pt refusal (2), poor conditions (4) or per protocol (4). Treatment of relapsed/PD was WBRT in 47 pts and chemo in 58; 59 pts received only supportive care (BSC) due to rapid neurological impairment or pt refusal. Importantly, except for performance status (ECOG PS 0-1: 49% of BSC pts, 70% of treated pts; p=0.009), pts managed with BSC showed the same characteristics (age, gender, extension of disease, first-line treatment) than pts who received salvage therapy. Salvage chemo consisted of HD-ifosfamide-based chemo (R-IE, RICE, DeVIC) in 20 pts, rechallenging with HD-MTX-based chemo (same regimen or ± other drugs) in 25, direct myeloablative chemo and ASCT in 3, single drugs in 10; 17 pts responsive to salvage chemo received consolidative ASCT (n=12) or WBRT. Pts with LR had a better outcome than REF and ER cohorts, with a 2-year SAR of 64±11%, 11±3% and 13±7% (p= 0.001), respectively. These figures were similar when only treated pts were considered, with 2-year SAR of 80±11%, 17±4% and 23±12% (p= 0.0002), respectively. All untreated pts died of lymphoma within 4 months of progression. Salvage WBRT (n= 45) and chemo (n= 31) were associated with poor outcome in REF pts (2-year SAR 18±5% vs 16±6%; p= 0.76). Salvage treatment after ER or LR consisted of chemo in 27 pts and WBRT in two; HD-MTX retreatment showed a trend to a better outcome with respect to other chemo combinations, with a 2-year SAR of 73±12% and 27±13% (p=0.25), respectively. Importantly, 12 of the 15 pts with a SAR longer than one year were treated with HD-MTX-based chemo, followed by consolidation in 5 of them. A 2-year SAR of 90±9% was observed in the 11 LR pts retreated with HD-MTX-based chemo. At a median follow-up from relapse/PD of 40 (range 3-118) months, 16 (10%) pts are alive and disease-free. Deaths were due to lymphoma in 137 (93%) pts, infections in six (4%), and thromboembolic events in two (1%); cause unknown in two pts. Multivariable analysis showed that ECOG PS 0-1, LR and HD-MTX retreatment were independently associated with better SAR and that outcome was not affected by age, gender, first-line induction and consolidation, and considered trial. Conclusions. Mortality of rrPCNSL is regrettably high (≈90%), even among selected pts enrolled in prospective trials. One-third of pts are considered unsuitable candidates for salvage treatment. WBRT provides a marginal benefit over BSC in REF pts, suggesting that other strategies, including novel agents, should be considered in routine practice. Pts experiencing LR can achieve long-lasting second remission, especially when retreatment with HD-MTX-based chemo is feasible. Efficacy of salvage therapy appears to be independent of the first-line treatment. Disclosures Ferreri: Pfizer: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Genmab: Research Funding; Amgen: Research Funding; Hutchison Medipharma: Research Funding; Beigene: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees; Ospedale San Raffaele srl: Patents & Royalties. Cwynarski: Roche: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Takeda: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Celgene/BMS: Honoraria, Other: Travel / Conference Support; Atara: Honoraria; Gilead, KITE: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Janssen: Honoraria, Other: Travel / Conference Support; Incyte: Honoraria, Speakers Bureau. Pulczynski: Roche: Research Funding. Fox: Abbvie: Honoraria, Research Funding; Astrazeneca: Honoraria; Atarabio: Honoraria; BMS/Celgene: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Incyte: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Beigene: Honoraria, Research Funding. La Rosée: AstraZeneca: Honoraria; Bristol Myers Squib: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen-Cilag: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Schorb: Roche: Research Funding; AbbVie: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Roeth: Roche: Consultancy, Honoraria, Research Funding; Kira: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. Linton: BeiGene: Research Funding; Celgene: Research Funding; University of Manchester: Current Employment; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hartley Taylor: Honoraria; Aptitude Health: Honoraria. Binder: Deutsche Krebsgellschaft, Medconcept GmbH, event Lab. GmbH: Honoraria, Other: Speaker Activity; Amgen GmbH, Janssen-Cilage GmbH, DGHO, Art tempi, Tumorzentrum Anhalt MD, Uniklinikum Hamburg, Sanofi Aventis: Honoraria, Other: Speaker Activity. Hemmaway: Abbvie: Honoraria. Pinto: Takeda: Consultancy; MSD: Honoraria; Bristol Myers Squibb-CELGENE: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau. Zucca: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Gilead, Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Support.

Abstract: We have recently shown that resting human mast cells (MCs) produce tissue-type plasminogen activator (t-PA) without simultaneously expressing plasminogen activator inhibitor 1 (PAI-1). In the present study we have identified the anaphylatoxin rhC5a as a potent inducer of PAI-1 expression in human MCs and basophils. In primary human skin MCs and primary blood basophils, exposure to rhC5a was followed by an increase from undetectable to significant levels of PAI-1. In addition, rhC5a induced a concentration- and time-dependent increase in PAI-1 antigen in the MC line HMC-1 and the basophil cell line KU-812 and increased the expression of PAI-1 mRNA in HMC-1. In conditioned media of HMC-1 treated with rhC5a, active PAI-1 could be detected. A simultaneous loss of t-PA activity in conditioned media from the same cells indicated that rhC5a-induced PAI-1 was capable of inhibiting the enzymatic activity of coproduced t-PA. Correspondingly, the levels of t-PA–PAI-1 complexes increased in rhC5a-treated cells. When HMC-1 cells were incubated with pertussis toxin or anti-C5a receptor antibodies, the effect of rhC5a on PAI-1 production was completely abolished. Treatment of C5a with plasmin resulted in loss of its ability to induce PAI-1 production in MCs. Considering the suggested role for MCs and components of the complement system in the development of cardiovascular diseases, we hypothesize that MCs, by producing t-PA in a resting state and by expressing PAI-1 when activated by C5a, might participate in the modulation of the balance between proteases and protease inhibitors regulating tissue injury and repair in such disease processes.

Abstract: Vascular endothelial cell growth factor (VEGF) is a major regulator of angiogenesis. We report here that treatment of endothelial cells with VEGF leads to upregulation of tissue factor mRNA and protein expression on the cell surface. Reporter gene studies show that transcriptional activation of the tissue factor gene by VEGF is mediated by a GC-rich promoter element containing overlapping binding sites for Sp1 and EGR-1. As shown by immunofluorescence and electrophoretic mobility shift assays, upon VEGF treatment EGR-1 rapidly accumulates in the nucleus and binds to its respective recognition site in the tissue factor promoter. Sp1 occupies this element in unstimulated cells and seems to be partially displaced by increasing amounts of EGR-1. Transfection of endothelial cells with an EGR-1 expression plasmid mimics the upregulation of tissue factor transcription observed after VEGF treatment. In contrast, NFκB, the major transcription factor involved in tissue factor upregulation by inflammatory stimuli, is not activated by VEGF. These data show that VEGF induces a response in endothelial cells largely distinct from inflammatory stimuli, and suggest that EGR-1 is a major mediator of the activation of the tissue factor and possibly other VEGF-responsive genes.

Abstract: Axl inhibition by BGB324 is active in FLT3-mutated and FLT3 wild-type AML, and presence of Axl and Gas6 are required for therapeutic efficacy. AML cells educate BMDSCs to secrete Gas6, which mediates leukemia cell proliferation and therapy resistance.

Abstract: Introduction Disparities in age, socioeconomic status, insurance status and race/ethnicity have all been shown to impact the treatment and survival outcomes in patients with acute myeloid leukemia (AML). Database studies have highlighted that elderly patients with AML have worse survival outcomes. There is also evidence that Black and Hispanic patients with AML have an increased risk of death compared with Caucasian patients despite a higher prevalence of favorable cytogenetics and a younger age at diagnosis in those minority groups. We sought to assess the impact of age, race/ethnicity, socioeconomic and insurance status on treatment and survival outcomes in AML patients treated at our institution. Methods We performed a retrospective analysis of adult patients with newly diagnosed AML treated between April 2017 and August 2019 at Thomas Jefferson University Hospital. Patient specific variables included demographics, diagnosis, insurance coverage, treatment characteristics and survival outcomes. Socioeconomic status was assessed by matching the patient's residential address to the United States Area-Deprivation Index (ADI). Treatment characteristics included initial treatment type and time to treatment initiation (TTI). Initial treatment type included standard chemoimmunotherapy, clinical trial or novel therapy as defined by the Center for Medicare and Medicaid Services. The primary outcome of initial treatment type and secondary outcomes of TTI, progression free survival (PFS) and overall survival (OS) were analyzed using multivariable bias-reduced logistic regression and multivariable Cox proportional hazards models. Results Ninety-six patients were included in the analysis (median age 62; male, n = 48, female, n=48). 46% of patients were in the lower socioeconomic group (ADI = 6-10). 74% of patients were Caucasian, 17% were Black, 9% were Hispanic, and 9% were Asian or other. 44% of patients had private insurance, 44% had Medicare, 7% had Medicaid and 5% were uninsured. 58% of patients received standard chemoimmunotherapy, 35% received novel therapy, and 7% went on clinical trial. Patients who received novel therapy and clinical trial were older (p & lt;0.005). There were no significant differences found between the initial treatment type based on ADI, race/ethnicity or insurance type. There was a longer TTI as ADI increased (p & lt;0.016), in patients who were Black (p & lt; 0.002), Hispanic (p & lt;0.001), those with Medicaid (p & lt;0.007) and those who were older ( & lt;0.001). There were no significant differences in PFS and OS between the socioeconomic groups, race/ethnicity or insurance type. Older patients had a worse OS (p & lt;0.001). Conclusions In this cohort of newly diagnosed AML patients, age was the only significant predictor of initial treatment type with older patients more likely to receive novel therapy and clinical trial. This is likely due to the poor tolerability of intensive chemotherapy in older patients and multiple recent drug approvals to allow for alternative treatment strategies in this population. ADI, race/ethnicity and insurance type did not affect the choice of initial treatment type. Although there was a treatment delay in patients from lower socioeconomic areas, in patients who were Black or Hispanic, and in patients with Medicaid, this delay did not impact PFS or OS. Our cohort had a small percentage of minority patients which may have been too low to detect a difference in outcomes between race/ethnicity. Further studies assessing a larger cohort are warranted. Disclosures Palmisiano: Genentech: Research Funding; AbbVie: Research Funding. Binder:Sanofi: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees.

Abstract: Vascular endothelial cell growth factor (VEGF) is a major regulator of angiogenesis. We report here that treatment of endothelial cells with VEGF leads to upregulation of tissue factor mRNA and protein expression on the cell surface. Reporter gene studies show that transcriptional activation of the tissue factor gene by VEGF is mediated by a GC-rich promoter element containing overlapping binding sites for Sp1 and EGR-1. As shown by immunofluorescence and electrophoretic mobility shift assays, upon VEGF treatment EGR-1 rapidly accumulates in the nucleus and binds to its respective recognition site in the tissue factor promoter. Sp1 occupies this element in unstimulated cells and seems to be partially displaced by increasing amounts of EGR-1. Transfection of endothelial cells with an EGR-1 expression plasmid mimics the upregulation of tissue factor transcription observed after VEGF treatment. In contrast, NFκB, the major transcription factor involved in tissue factor upregulation by inflammatory stimuli, is not activated by VEGF. These data show that VEGF induces a response in endothelial cells largely distinct from inflammatory stimuli, and suggest that EGR-1 is a major mediator of the activation of the tissue factor and possibly other VEGF-responsive genes.

Abstract: The hematopoietic microenvironment regulates the behavior of hematopoietic stem and progenitor cells (HSPC) throughout vertebrate development. We sought to identify secreted factors that may play a role in HSPC engraftment in the caudal hematopoietic territory (CHT), an endothelial cell-rich vascular plexus that serves as the primary site of hematopoiesis in the developing zebrafish from 3-6 days post fertilization (dpf). We hypothesized that such factors would be highly expressed in endothelial cells relative to hematopoietic stem cells (HSCs). To identify these factors, endothelial cells and HSCs were purified from 3 dpf Flk1:mcherry; Runx1:GFP double transgenic zebrafish embryos and gene expression profiling was performed by microarray analysis. Gene set enrichment analysis of these data showed that zebrafish chemokines, cytokines, TGF-β, TNF, Notch and non-canonical WNT family members were enriched in the endothelial cell fraction with a nominal P ≤ 0.2. Genes from the leading edge of these gene sets were then used as candidates for gain-of-function testing. Coding sequences from candidate genes were cloned downstream of the zebrafish HSP70l promoter and microinjected into wildtype zebrafish embryos at the single-cell stage. Gene expression was induced in F0 transgenic animals by heat shock at 36 and 48 hours post fertilization. HSPC numbers were assayed by performing whole-mount in situ hybridization to identify runx1- and cmyb-expressing cells at 3 dpf. WNT5A was found to enhance HSPC numbers in this assay (P = 0.00046). We conclude non-canonical WNT family members, in particular WNT5A, regulate HSPC engraftment in the developing zebrafish. Disclosures Tamplin: Boston Children's Hospital: Patents & Royalties. Zon:FATE Therapeutics, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other; Scholar Rock: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other; Stemgent: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.