Abstract: Calcium pyrophosphate (CPP) crystals and monosodium urate (MSU) crystals are frequently found in the same synovial fluids of gouty patients suggesting an interaction in crystal formation and deposition. This association has never been reported in tophus. Objectives: we aimed to describe the prevalence of CPP crystal deposition in tophus and to determine the associated risk factors. Methods: 22 tophi consecutively harvested were fixed in 4% paraformaldehyde and embedded in paraffin. 5-µm thick sections were analyzed by compensated polarized microscopy (CPM) after hematoxylin and eosin staining. Characterization of CPP crystals were performed by scan electronic microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Clinical characteristics were compared between patients having tophus with CPP deposition and patients having tophus without CPP crystals. Results: All tophi appeared multi-lobulated depositions of MSU crystals separated by fibrous tissue and surrounded by a foreign giant cell reaction. CPP crystals were identified in few lobules of 5 tophi (22.7%) harvested from 3 great toes, 1 elbow bursa and 1 finger of 5 patients. CPP crystals formed aggregate deposition within the lobule of MSU crystals. Both monoclinic and triclinic CPP crystal phases were identified by CPM, SEM and FTIR. Tophi were harvested from 22 male gouty patients with a mean age of 50.8 (28-66) years and a mean BMI of 24.2 kg/m2 (18.9-29.4). Mean serum urate level (SUL) was 499 ± 107 µmol/L. 59% of patients had chronic renal disease stage 2 or 3, 40.9% dyslipidemia, 22.7% type 2 diabetes mellitus, 13.6% hypertension and 50% obesity. Patients with tophi containing CPP deposition were older (61.2 [56-66] vs 47.8 [28-64] years, p=0.009) and had a longer gout duration (19 [10-31] vs 9 [3-20] years, p= 0.007) and tophus duration (11.4 [8-16] vs 4.5 [1-9] years, p 〈 0.0001) than patients with tophi alone. Tophi did not display calcification on radiographies performed before surgery. However, the density of tophi containing CPP crystal deposition was higher than the density of tophi without CPP crystals (51 [25-100] vs 21.5% [0-40] , p=0.009). The proportion of bone erosion and gout arthropathy was similar between the two groups. Similarly, no difference was observed for SUL (467 ± 43 vs 509 ± 109 µmol/L), estimated glomerular filtration rate (76.6 ± 11.9 vs 74.9 ± 15.7 ml/min/1.73m2) and prevalence of comorbidities. Interestingly, no calcification was detected on knee and wrist radiographies of patients with tophi containing CPP deposition. Conclusion: These results reported for the first time, in a small sample size, that CPP crystal deposition occurred within tophus lobules. They suggested that long-time course tophi might act as a facilitating agent of CPP nucleation. This hypothesis needs specific confirmation studies Disclosure of Interests: : None declared

Abstract: Despite growing interest in right ventricular form and function in diseased states, there is a paucity of data regarding characteristics of right ventricular function – namely contractile and lusitropic reserve, as well as ventricular‐arterial coupling, in the healthy heart during rest, as well as submaximal and peak exercise. Pressure‐volume analysis of the right ventricle, during invasive cardiopulmonary exercise testing, demonstrates that that the right heart has enormous contractile reserve, with a three‐ or fourfold increase in all metrics of contractility, as well as myocardial energy production and utilization. The healthy right ventricle also demonstrates marked augmentation in lusitropy, indicating that diastolic filling of the right heart is not passive. Rather, the right ventricle actively contributes to venous return during exercise, along with the muscle pump. Ventricular‐arterial coupling is preserved during submaximal and peak exercise in the healthy heart.

Abstract: Context. Recent observations with the Atacama Large Millimeter Array (ALMA) have shown that the large dust aggregates observed at millimeter wavelengths settle to the midplane into a remarkably thin layer. This sets strong limits on the strength of the turbulence and other gas motions in these disks. Aims. We intend to find out if the geometric thinness of these layers is evidence against the vertical shear instability (VSI) operating in these disks. We aim to verify if a dust layer consisting of large enough dust aggregates could remain geometrically thin enough to be consistent with the latest observations of these dust layers, even if the disk is unstable to the VSI. If this is falsified, then the observed flatness of these dust layers proves that these disks are stable against the VSI, even out to the large radii at which these dust layers are observed. Methods. We performed hydrodynamic simulations of a protoplanetary disk with a locally isothermal equation of state, and let the VSI fully develop. We sprinkled dust particles with a given grain size at random positions near the midplane and followed their motion as they got stirred up by the VSI, assuming no feedback onto the gas. We repeated the experiment for different grain sizes and determined for which grain size the layer becomes thin enough to be consistent with ALMA observations. We then verified if, with these grain sizes, it is still possible (given the constraints of dust opacity and gravitational stability) to generate a moderately optically thick layer at millimeter wavelengths, as observations appear to indicate. Results. We found that even very large dust aggregates with Stokes numbers close to unity get stirred up to relatively large heights above the midplane by the VSI, which is in conflict with the observed geometric thinness. For grains so large that the Stokes number exceeds unity, the layer can be made to remain thin, but we show that it is hard to make dust layers optically thick at ALMA wavelengths (e.g., τ 1.3mm ≳ 1) with such large dust aggregates. Conclusions. We conclude that protoplanetary disks with geometrically thin midplane dust layers cannot be VSI unstable, at least not down to the disk midplane. Explanations for the inhibition of the VSI out to several hundreds of au include a high dust-to-gas ratio of the midplane layer, a modest background turbulence, and/or a reduced dust-to-gas ratio of the small dust grains that are responsible for the radiative cooling of the disk. A reduction of small grains by a factor of between 10 and 100 is sufficient to quench the VSI. Such a reduction is plausible in dust growth models, and still consistent with observations at optical and infrared wavelengths.

Abstract: P-BCMA-101 and P-BCMA-ALLO1, autologous and allogeneic BCMA targeting CAR-T cell therapies respectively, are manufactured using a novel transposon-based system called piggyBac (PB). They comprise a high percentage of desirable stem cell memory T-cells associated with efficacy and safety. Single agent P-BCMA-101 data was previously reported showing marked efficacy and minimal toxicity (PRIME study), and exploratory combination cohorts have also been evaluated. P-BCMA-ALLO1 is expected to be first assessed in patients by the time of this presentation. Here we report results for P-BCMA-101 exploratory cohorts and P-BCMA-ALLO1. PRIME is a Phase 1/2 clinical trial to assess the safety and efficacy of P-BCMA-101 in patients with RRMM (≥ 3 prior lines, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or double refractory) (NCT03288493). Patients undergo apheresis to harvest T cells and P-BCMA-101 is then manufactured. Patients then receive a 3-day cyclophosphamide (300 mg/m 2/day) / fludarabine (30 mg/m 2/day) lymphodepletion (LDC) regimen. Following 2 days of rest, patients received a single administration of P-BCMA-101 in escalating doses starting at 0.75 x 10 6 CAR-T cells/kg. Similar P-BCMA-101 dose escalation was performed in combination cohorts with rituximab (Rit) or lenalidomide (Len). During the study, use of a nanoplasmid (NP) vector in CAR-T manufacturing was implemented to improve transposition efficiency and cell quality. As of June 30 th, 2021, 90 unique patients have been treated with P-BCMA-101 in 5 dose levels of single agent P-BCMA-101, 3 dose levels of P-BCMA-101 with Rit and 2 dose levels of P-BCMA-101 with Len. The median age is 61 years and 66/37% were M/F. Patients were heavily pre-treated with a median of 6 prior regimens (range 3-18), 100% had received prior PI and IMiD, 74% daratumumab and 63% ASCT. 13 patients were treated in combination with Rit and 9 in combination with Len. Like prior reports of P-BCMA-101, the safety profile compares favorably to other CAR-T. No dose limiting toxicities (DLT) were observed in the single agent or the combination cohorts. The addition of Rit or Len did not increase toxicity. Grade 1-2 CRS was seen in 25% (no G3/4) of patients and ICANS in 7% (2% G3). Tocilizumab was used in 11% of patients. There were no treatment related deaths or unexpected/off-target toxicities. The most common treatment emergent adverse events were cytopenias, infections and constitutional symptoms (≥ G3 neutropenia 74%, thrombocytopenia 30%, anemia 35%), as expected with CAR-T and LDC. The overall response rate (ORR) with the Rit and Len combinations was 73% and 71% respectively. The favorable safety profile allowed outpatient treatment in 23 (25%) patients. Founded on the P-BCMA-101 data, an allogeneic CAR-T (P-BCMA-ALLO1) using a similar PB construct was created and demonstrated excellent preclinical safety and efficacy leading to the initiation of a Phase 1 clinical trial (NCT04960579). P-BCMA-ALLO1 CAR-T cells are generated from healthy donor T-cells using Cas-CLOVER to knockout Beta-2 microglobulin to prevent host vs graft rejection, TCRβchain for graft vs host disease prevention. Proprietary booster molecules are utilized to increase manufacturing yield and cell quality. The CAR binding domain is a novel anti-BCMA VCAR that produced superior efficacy in tumor models. These constructs contain the same PB transposon transgene cassette, DHFR for gene selection and an iCasp9-based safety switch, successfully assessed in the PRIME study. The primary objective of the P-BCMA-ALLO1 phase 1 trial is to assess the safety and maximum tolerated dose (MTD) based on DLT in RRMM patients who have received a PI, IMid and CD38 mAb. Secondary objectives will assess the anti-myeloma effect of P-BCMA-ALLO1 and biomarkers. The protocol is designed to treat 40 RRMM patients in a standard 3+3 dose escalation with a P-BCMA-ALLO1 starting dose of 0.75 X 10 6 cells/kg. Patients will receive P-BCMA-ALLO1 following LDC with cyclophosphamide (300 mg/m 2/day) / fludarabine (30 mg/m 2/day X 3 days. In conclusion, transposon generated autologous CAR-T cells demonstrate excellent clinical activity with a favorable toxicity profile in RRMM, can be safely combined with Len and Rit, and administered in the outpatient setting. Allogeneic CAR-T cells generated from this platform represent a further advance. Current data from both clinical studies will be presented. Disclosures Derman: Sanofi: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy. Ali: BMS: Research Funding; Aduro: Research Funding; Poseida: Research Funding; Aduro: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy; BMS: Consultancy; Janssen: Consultancy. Dholaria: Pfizer: Research Funding; MEI: Research Funding; Poseida: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Angiocrine: Research Funding; Jazz: Speakers Bureau; Celgene: Speakers Bureau. Berdeja: Bioclinica: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Lilly: Research Funding; Abbvie: Research Funding; EMD Sorono: Research Funding; Takeda: Consultancy, Research Funding; Prothena: Consultancy; Servier: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Vivolux: Research Funding; Cellularity: Research Funding; Novartis: Research Funding; Poseida: Research Funding; CURIS: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Teva: Research Funding; Legend: Consultancy; Kite Pharma: Consultancy; Bluebird: Research Funding; Constellation: Research Funding; Glenmark: Research Funding; Genentech: Research Funding; Kesios: Research Funding. Cohen: GlaxoSmithKline: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy; BMS/Celgene: Consultancy; Novartis: Research Funding; Oncopeptides: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Patel: Oncopeptides: Consultancy; BMS Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy. Siegel: Karyopharm: Honoraria; Amgen Inc.: Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Celularity: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. McArthur: Poseida: Current Employment, Current equity holder in publicly-traded company. McCaigue: Poseida: Current Employment, Current equity holder in publicly-traded company. Martin: Poseida: Current Employment, Current equity holder in publicly-traded company. Ghoddusi: Poseida: Current Employment, Current equity holder in publicly-traded company. Namini: Poseida: Current Employment, Current equity holder in publicly-traded company. Ostertag: Poseida: Current Employment, Current equity holder in publicly-traded company. Spear: Poseida: Current Employment, Current equity holder in publicly-traded company. Belani: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company. Shah: Indapta Therapeutics: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Amgen: Consultancy; Janssen: Research Funding; Bluebird Bio: Research Funding; Precision Biosciences: Research Funding; Karyopharm: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Sanofi: Consultancy; CSL Behring: Consultancy; Kite: Consultancy; GSK: Consultancy; Sutro Biopharma: Research Funding; Teneobio: Research Funding.

Abstract: Poly( N ‐isopropylacrylamide) was polymerized with comonomers containing a biphenyl moiety to create a unique thermoresponsive physically crosslinked system due to the presence of π – π interactions between the biphenyl moieties. The biphenyl monomers used were 2‐phenylphenol monoacrylate (2PPMA) and 4‐phenylphenol monoacrylate (4PPMA). These monomers were utilized to synthesize a set of polymers with biphenyl monomer (2PPMA/4PPMA) content from 2.5 to 7.5 mol% and with initiator concentrations of 0.1 and 1.0 wt%. The resulting polymers were characterized using various techniques, such as gel permeation chromatography (GPC), swelling studies and mechanical testing. A decrease in the average molecular weight of the polymers due to the increase in the concentration of initiator was confirmed from GPC results. Swelling studies confirmed the expected temperature‐dependent swelling properties and explored the impact of the biphenyl comonomers. These studies indicated that with an increase in biphenyl comonomer content, the physical crosslinking increases which leads to a decrease in the swelling ratio. The results from the mechanical tests also indicate the effect of the concentration of biphenyl comonomers. These physically crosslinked polymeric systems with their unique properties have potential applications spanning environmental remediation/sensing, biomedicine, etc. © 2021 Society of Industrial Chemistry.