Active Biotech (Sweden)

7555 Background: S100A9, a protein produced by myeloid-derived suppressor cells in the bone marrow microenvironment, promotes multiple myeloma (MM) progression and confers therapeutic resistance. Tasquinimod (tasq), an oral S100A9 inhibitor, has pre-clinical anti-myeloma effects alone and combined with proteasome inhibitor (PI) and immunomodulator (Imid) therapy (Cancer Res Commun 2023;3(3):420) and improved progression-free survival in prostate cancer patients (pts) (JCO 2016;34(22):2636-43). We previously reported preliminary results of a phase 1 trial of tasq alone and in combination with ixazomib (ixa), lenalidomide (len), and dexamethasone (dex) (IRd) in pts with RRMM (JCO 2023;41(16)suppl:8042; NCT04405167). For single-agent tasq, the recommended phase 2 dose (RP2D) was 1 mg daily (qd) after a 1 week (wk) run-in at 0.5 mg qd. We now report updated results of tasq in combination with IRd. Methods: In dose escalation, pts were refractory, intolerant, or contraindicated to len, pomalidomide, bortezomib, carfilzomib, and an anti-CD38 monoclonal antibody. In dose expansion, pts were refractory to the most recent Imid/PI combination or triple-class refractory. Tasq was given in 28-day cycles at 1 mg daily with either a 2 wk run-in (dose level 1: 0.25 mg qd x1 wk then 0.5 mg qd x1 wk) or a 1 wk run-in (dose level 2: 0.5 mg qd x1 wk). In dose escalation, pts received full doses of ixa (4 mg days 1/8/15), len (25 mg days 1-21, adjusted for renal dysfunction), and dex (40 mg qwk), but in dose expansion, doses of ixa, len, and dex were reduced per investigator discretion. Results: 16 pts received tasq with IRd at dose levels 1 (3 pts) and 2 (13 pts: 3 in escalation, 10 in expansion). Median age was 67 y (range 52-81); 75% were male; 19% were African American and 81% Caucasian. Pts had received median 7 prior lines of therapy (range 3-19), and all were triple-class refractory, with 81% (13 pts) refractory to their most recent Imid/PI combination. In dose escalation, no dose limiting toxicities were observed, and dose level 2 was the RP2D of tasq with IRd. The most common treatment-emergent adverse events were fatigue (10 pts: grade [gr] 3 in 1 pt), pain (9 pts: 0 gr ≥3), respiratory infection (9 pts: 4 gr 3, 2 gr 5), nausea/vomiting (8 pts: 0 gr ≥3), dyspepsia/gastritis (5 pts: 1 gr 3), and thrombocytopenia (5 pts: 1 gr 3, 3 gr 4). Among all 16 pts, there was 1 partial response (PR) and 7 minimal responses (MR). Among the 13 pts who were previously refractory to their most recent Imid/PI combination and would therefore not be expected to respond to the IRd backbone, there was 1 PR (lasting 20 months) and 5 MRs (lasting 1, 1, 2, 2, and 7 months). Conclusions: Tasquinimod, an S100A9 inhibitor, is well tolerated in combination with IRd and has anti-myeloma activity, as evidenced by responses in patients previously refractory to Imid/PI combination therapy. Further study is warranted of tasquinimod in combination with standard myeloma therapies. Clinical trial information: NCT04405167 .

<bold>Background:</bold> IL-33 is highlighted as a potential drug target in COPD. Despite this, critical knowledge about which cell types are involved in IL-33 mediated immunity in the distal lung remains elusive. <bold>Aim:</bold> To reveal the cellular distribution and expression of IL-33 and membrane and soluble splice variants of its receptor, ST2 (mST2 and sST2 respectively), in the distal lung of COPD patients. <bold>Methods:</bold> Lungs from 15 COPD patients and 8 controls were subjected to cutting-edge combined multiplex in situ hybridization and immunohistochemistry (mISH-IHC) to yield spatially resolved single-cell expression data. <bold>Results:</bold> Single-cell data identified endothelial cells as a major source of IL-33 and ST2 in the distal lung. The mISH-IHC analysis revealed a patchy upregulation of IL-33 and ST2 across CD31+, PECAM1+ alveolar capillary populations in COPD lungs (IL33 p<0.0001; sST2 p=0.0003; mST2 p<0.0001). Using markers to resolve endothelial sub-populations, data showed that general alveolar capillaries (gCap) had high baseline expression of IL-33, which was upregulated in COPD (p=0.02). Aerocytes (aCap) showed an increase in IL-33 and mST2 expression respectively (p=0.009, p=0.01) in COPD compared to healthy aerocytes. Mast cells were the primary immune cells expressing both sST2 and mST2, with an upregulation in COPD lungs (p=0.03, p=0.02). <bold>Conclusions:</bold> The identified subtypes of alveolar endothelial cells seem to play distinct and significant roles in IL-33 mediated immunity, with apparent activation in COPD. By exposing the structural basis for IL-33 mediated inflammation in human lungs, our findings offer crucial insights for developing treatment strategies that target this pathway in COPD.

BackgroundThe management of kidney injuries remains a big challenge and there is an urgent need to explore novel and alternative therapeutic strategies. MethodsThe current study focused on the evaluation for the first time of the possible nephroprotective activity of the hydro-alcoholic extract (HE) and supernatant fraction (SUP) of Anogeissus leiocarpus roots against potassium dichromate (K2Cr2O7) induced nephrotoxicity in rats. The renal function parameters, the oxidative stress biomarkers in the nephrotoxic rats induced by the injection of a single dose (15 mg/kg, sc.) of K2Cr2O7, meanwhile treated orally with the HE (500 mg/kg/day) or SUP (100 mg/kg/day) were evaluated. The antioxidant activity was also evaluated in ex vivo and the in vitro anti-inflammatory activity was carried out. ResultsThe K2Cr2O7-induced nephrotoxicity was evident by the disturbance in the levels of the renal parameters such as urea, creatinine, proteins, electrolytes and the induction of oxidative stress. The majority of the renal parameters were significantly restored when the HE and SUP were administered to the nephrotoxic rats. Remarkably, in vivo the extracts significantly alleviated the oxidative stress by enhancing the antioxidant levels (GSH and CAT), and by lowering the MDA level as well as in ex vivo. Furthermore in vitro, the extracts exhibited a strong anti-inflammatory effect. ConclusionThe promising capacity of the HE and SUP to alleviate the K2Cr2O7-induced nephrotoxicity is mainly due to their antioxidant and anti-inflammatory activities.

Prepacked chromatography columns and cassette filtration units offer many advantages in bioprocessing. These include reduced labor costs and processing times, ease of storage, and enhanced process flexibility. Rectangular formats are particularly attractive as they can be easily stacked and multiplexed together for continuous processing. Cylindrical chromatography beds have dominated bioprocessing even though their bed support and pressure-flow performance vary with bed dimensions. This work presents the performance of novel, rhombohedral chromatography devices with internally supported beds. They are compatible with existing chromatography workstations and can be packed with any standard commercial resin. The devices offer pressure-flow characteristics independent of container-volume, simple multiplexing, and separation performance comparable to cylindrical columns. Their bi-planar, internal bed support allows mechanically less-rigid resins to be used at up to four times higher maximal linear velocities, and productivities approaching 200 g/L/h for affinity resins, compared to the 20 g/L/h typical of many column-based devices. Three 5 L devices should allow processing of up to 3 kg of monoclonal antibody per hour.

HypothesisThe anomeric configuration (α or β) of n-hexadecyl-d-maltopyranoside (C16G2) has been shown to affect the morphology of the micelle, from elongated for α-C16G2 to worm-like micelles for β-C16G2. The entanglement of worm-like micelles often leads to strong modifications of the rheological behavior of the system and, as such, the anomeric configuration of C16G2 could also provide the possibility of controlling this. Furthermore, mixing these surfactants are hypothesized to result in mixed micelles allowing to finely tune the rheology of a system containing these sustainable surfactants. ExperimentsThe rheology of α- and β-C16G2, and mixtures of those, was determined by rotational and oscillatory rheology at different temperatures and surfactant concentrations. Micelle structure and composition for these systems were characterized using contrast variation small-angle neutron scattering and small-angle X-ray scattering. The results from these were connected in order to elaborate a molecular understanding of the rheological response of the system. FindingsThe self-assembly of these surfactants have been found to result in different rheological properties. β-C16G2 show a high viscosity with a non-Newtonian viscoelastic behavior, which was linked to the formation of worm-like micelles. In contrast, α-C16G2 self-assembled into short cylindrical micelles, resulting in a Newtonian fluid with low viscosity. Furthermore, mixtures of these two surfactants lead to systems with intermediate rheological properties as a result of the formation of micelles with intermediate morphology to those of the pure anomers. These results also show that the rheological properties of the system can be tuned to change the micelle morphology, which in turn depends on the anomeric configuration of the surfactant. Also, surfactant concentration, temperature of the system, and micelle composition for surfactant mixtures provide control over the rheological properties of the system in a wide temperature range. Therefore, these results open new possibilities in the development of sustainable excipients for formulation technology, where the characteristics of the system can be easily tailored through geometric variations in the monomer structure whilst maintaining the chemical composition of the system.

The chemical composition, total antioxidant capacity (TAC) and total flavonoids were assessed in fifty-two Andean potato cultivars, with local indigenous names, from Bolivia, comprising five species and one subspecies. Moisture content ranged from 63 to 81%, and on a fresh-weight basis, ash content from 1 to 2%, protein content from 3 to 11%, carbohydrate content from 9 to 35% and total lipids ≤ 0.01%. Solanum stenotomum cultivars showed the highest protein content. The TAC ranged from 1 to 10-μmol Trolox equivalents/g dry matter using Ferric reduction antioxidant power (FRAP) method and from 0.2 to 5 according to the 2,2′-azino-bis (3-ethylbenzithiazoline-6-sulphonic acid) (ABTS) method. The total flavonoids (TF) ranged from 2 to 19, expressed in μmol of catechin equivalents/g dry matter. The Andean potatoes studied appeared to be an important source of antioxidants and polyphenols, as well as proteins. They are therefore important for the diet of the economically depressed indigenous people of the Bolivian Andes. Furthermore, many of these potato cultivars, which still remain unknown outside the Andean region, can be considered superfoods because of their nutritional properties.

SummaryTicagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso‐occlusion crisis (VOC) in sickle cell disease (SCD). The HESTIA2 study (NCT02482298) randomised 87 adults with SCD (aged 18–30 years) 1:1:1 to twice‐daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient‐reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non‐major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary‐reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study.