Initial treatment strategy and clinical outcomes in Finnish MS patients : a propensity-matched study

Background The optimal treatment strategy with disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) remains uncertain. Objective To compare outcomes of initial treatment with infusion therapies and starting therapy with medium efficacy therapy in a propensity-matched cohort of Finnish RRMS patients. Methods A total of 154 RRMS patients initiating natalizumab, alemtuzumab, ocrelizumab or rituximab as first DMT (high efficacy DMT, heDMT group) and 1771 patients initially treated with injectable therapies, teriflunomide or dimethylfumarate and escalated based on disease activity (moderate efficacy DMT, meDMT group) were identified from the Finnish MS registry. Nearest neighbor propensity matching (1:1, caliper 0.1) was performed for age, sex, baseline Expanded Disability Status Scale (EDSS), annual relapse rate (ARR) one year prior DMT and time since MS symptom onset. Primary outcome was time to 6-month confirmed EDSS progression and the secondary outcome time to first relapse. Results In the propensity-matched group comparisons, the probability of 6-month confirmed disability progression (CDP) at 5 years after DMT start was 28.4% (95% CI 15.7-39.3) in the heDMT group (n = 66) and 47.0% (95% CI 33.1-58.1) in meDMT group (n = 66), p = 0.013. Probability of relapse at 5 years was 34.6% (95% CI 24.1-43.6) for heDMT (n = 105) and 47.2% (95% CI 36.6-56.1) for meDMT (n = 105), p = 0.019. Conclusions Initiating MS-therapy with heDMT significantly reduced the risk of 5-year disability progression and relapse compared to using meDMT as first DMT choice in propensity-matched groups of Finnish MS-patients.Peer reviewe

Enhanced Antibody Production in Clever-1/Stabilin-1-Deficient Mice

Clever-1, encoded by the Stab1 gene, is a scavenger and leukocyte trafficking receptor expressed by subsets of vascular and lymphatic endothelial cells and immunosuppressive macrophages. Monocyte Clever-1 also modulates T cell activation. However, nothing is known about the possible links between B cell function and Clever-1. Here, we found that Stab1 knockout mice (Stab1(-/-)) lacking the Clever-1 protein from all cells present with abnormally high antibody levels under resting conditions and show enhanced humoral immune responses after immunization with protein and carbohydrate antigens. Removal of the spleen does not abolish the augmented basal and post-immunization antibody levels in Clever-1-deficient mice. The increased IgG production is also present in mice in which Clever-1 is selectively ablated from macrophages. When compared to wildtype macrophages, Clever-1-deficient macrophages show increased TNF-alpha synthesis. In co-culture experiments, monocytes/macrophages deficient of Clever-1 support higher IgM production by B cells, which is blocked by TNF-alpha depletion. Collectively, our data show that the excessive inflammatory activity of monocytes/macrophages in the absence of Clever-1 results in augmented humoral immune responses in vivo

Multi-parametric surface plasmon resonance platform for studying liposome-serum interactions and protein corona formation

When nanocarriers are administered into the blood circulation, a complex biomolecular layer known as the “protein corona” associates with their surface. Although the drivers of corona formation are not known, it is widely accepted that this layer mediates biological interactions of the nanocarrier with its surroundings. Label-free optical methods can be used to study protein corona formation without interfering with its dynamics. We demonstrate the proof-of-concept for a multi-parametric surface plasmon resonance (MP-SPR) technique in monitoring the formation of a protein corona on surface-immobilized liposomes subjected to flowing 100 % human serum. We observed the formation of formulation-dependent “hard” and “soft” coronas with distinct refractive indices, layer thicknesses, and surface mass densities. MP-SPR was also employed to determine the affinity (KD) of a complement system molecule (C3b) with cationic liposomes with and without polyethylene glycol. Tendency to create a thick corona correlated with a higher affinity of opsonin C3b for the surface. The label-free platform provides a fast and robust preclinical tool for tuning nanocarrier surface architecture and composition to control protein corona formation.When nanocarriers are administered into the blood circulation, a complex biomolecular layer known as the "protein corona" associates with their surface. Although the drivers of corona formation are not known, it is widely accepted that this layer mediates biological interactions of the nanocarrier with its surroundings. Label-free optical methods can be used to study protein corona formation without interfering with its dynamics. We demonstrate the proof-ofconcept for a multi-parametric surface plasmon resonance (MP-SPR) technique in monitoring the formation of a protein corona on surface-immobilized liposomes subjected to flowing 100 % human serum. We observed the formation of formulation-dependent "hard" and "soft" coronas with distinct refractive indices, layer thicknesses, and surface mass densities. MP-SPR was also employed to determine the affinity (K-D) of a complement system molecule (C3b) with cationic liposomes with and without polyethylene glycol. Tendency to create a thick corona correlated with a higher affinity of opsonin C3b for the surface. The label-free platform provides a fast and robust preclinical tool for tuning nanocarrier surface architecture and composition to control protein corona formation.Peer reviewe

Initial treatment strategy and clinical outcomes in Finnish MS patients: a propensity-matched study

BackgroundThe optimal treatment strategy with disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS) remains uncertain.ObjectiveTo compare outcomes of initial treatment with infusion therapies and starting therapy with medium efficacy therapy in a propensity-matched cohort of Finnish RRMS patients.MethodsA total of 154 RRMS patients initiating natalizumab, alemtuzumab, ocrelizumab or rituximab as first DMT (high efficacy DMT, heDMT group) and 1771 patients initially treated with injectable therapies, teriflunomide or dimethylfumarate and escalated based on disease activity (moderate efficacy DMT, meDMT group) were identified from the Finnish MS registry. Nearest neighbor propensity matching (1:1, caliper 0.1) was performed for age, sex, baseline Expanded Disability Status Scale (EDSS), annual relapse rate (ARR) one year prior DMT and time since MS symptom onset. Primary outcome was time to 6-month confirmed EDSS progression and the secondary outcome time to first relapse.ResultsIn the propensity-matched group comparisons, the probability of 6-month confirmed disability progression (CDP) at 5 years after DMT start was 28.4% (95% CI 15.7–39.3) in the heDMT group (n = 66) and 47.0% (95% CI 33.1–58.1) in meDMT group (n = 66), p = 0.013. Probability of relapse at 5 years was 34.6% (95% CI 24.1–43.6) for heDMT (n = 105) and 47.2% (95% CI 36.6–56.1) for meDMT (n = 105), p = 0.019.ConclusionsInitiating MS-therapy with heDMT significantly reduced the risk of 5-year disability progression and relapse compared to using meDMT as first DMT choice in propensity-matched groups of Finnish MS-patients.</p

Light-Activated Liposomes Coated with Hyaluronic Acid as a Potential Drug Delivery System

Light-activated liposomes permit site and time-specific drug delivery to ocular and systemic targets. We combined a light activation technology based on indocyanine green with a hyaluronic acid (HA) coating by synthesizing HA–lipid conjugates. HA is an endogenous vitreal polysaccharide and a potential targeting moiety to cluster of differentiation 44 (CD44)-expressing cells. Light-activated drug release from 100 nm HA-coated liposomes was functional in buffer, plasma, and vitreous samples. The HA-coating improved stability in plasma compared to polyethylene glycol (PEG)-coated liposomes. Liposomal protein coronas on HA- and PEG-coated liposomes after dynamic exposure to undiluted human plasma and porcine vitreous samples were hydrophilic and negatively charged, thicker in plasma (~5 nm hard, ~10 nm soft coronas) than in vitreous (~2 nm hard, ~3 nm soft coronas) samples. Their compositions were dependent on liposome formulation and surface charge in plasma but not in vitreous samples. Compared to the PEG coating, the HA-coated liposomes bound more proteins in vitreous samples and enriched proteins related to collagen interactions, possibly explaining their slightly reduced vitreal mobility. The properties of the most abundant proteins did not correlate with liposome size or charge, but included proteins with surfactant and immune system functions in plasma and vitreous samples. The HA-coated light-activated liposomes are a functional and promising alternative for intravenous and ocular drug delivery

Changing the structural and mechanical anisotropy of foam-formed cellulose materials by affecting bubble-fiber interaction with surfactant

Cellulose fiber materials suitable for filtering, insulation, protective, and hygiene applications can be formed using aqueous foam as a carrier phase. The subtle fiber–bubble interaction provides a tool which can be utilized to alter both structural and mechanical material properties. Earlier model surface studies have only indicated clear surface-bubble adhesion when both the surface hydrophobicity and surface tension of the solution are high enough. In this work, we first show that for silica model surfaces these basic mechanisms are similar for both nonionic polyethylene glycol sorbitan monolaurate (Tween 20) and anionic sodium dodecyl sulfate (SDS) surfactants. In the second step, thick nonwoven materials were foam formed from hydrophilic or hydrophobic viscose fibers using small amounts of cellulose microfibers (CMFs) to form a bonding agent. There was a clear variation in structure and strength properties between the samples made using different fibers and surfactants. The partial alignment and layering of fibers in the wet foam led to anisotropy in the mechanical properties of the formed samples. Using SDS, the fiber alignment was very strong for hydrophilic fibers but was reduced for hydrophobic fibers because of stronger coupling to bubbles during structure forming, impacting the microscale fiber network. For nonionic Tween 20, in addition to surfactant adsorption on the fibers, the ethoxylated surfactant headgroups are suggested to form bridges between CMFs and other fibers, restricting fiber movements during formation. For hydrophilic fibers, this showed up as a lower in-plane compression modulus but higher transverse strength for Tween 20 compared with SDS surfactant. For hydrophobic fibers, the sensitivity of the mechanical properties on surfactant type was even stronger

Thalamic Atrophy Without Whole Brain Atrophy Is Associated With Absence of 2-Year NEDA in Multiple Sclerosis

Purpose: To study which brain volume measures best differentiate early relapsing MS (RMS) and secondary progressive MS (SPMS) patients and correlate with disability and cognition. To test whether isolated thalamic atrophy at study baseline correlates with NEDA (no evidence of disease activity) at 2 years.Methods: Total and regional brain volumes were measured from 24 newly diagnosed RMS patients 6 months after initiation of therapy and 2 years thereafter, and in 36 SPMS patients. Volumes were measured by SIENAX and cNeuro. The patients were divided into subgroups based on whole brain parenchyma (BP) and thalamic atrophy at baseline. Standard scores (z-scores) were computed by comparing individual brain volumes against healthy controls. A z-score cut-off of - 1.96 was applied to separate atrophic from normal brain volumes. The Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT) were assessed at baseline and at 2 years. Differences in achieving NEDA-3, NEDA-4, EDSS progression, and SDMT change were analyzed between patients with no thalamic or BP atrophy and in patients with isolated thalamic atrophy at baseline.Results: At baseline, 7 SPMS and 12 RMS patients had no brain atrophy, 8 SPMS and 10 RMS patients had isolated thalamic atrophy and 2 RMS and 20 SPMS patients had both BP and thalamic atrophy. NEDA-3 was reached in 11/19 patients with no brain atrophy but only in 2/16 patients with isolated thalamic atrophy (p = 0.012). NEDA-4 was reached in 7/19 patients with no brain atrophy and in 1/16 of the patients with isolated thalamic atrophy (p = 0.047). At 2 years, EDSS was same or better in 16/19 patients with no brain atrophy but only in 5/17 patients with isolated thalamic atrophy (p = 0.002). There was no significant difference in the EDSS, relapses or SDMT between patients with isolated thalamic atrophy and no atrophy at baseline.Conclusion: Patients with isolated thalamic atrophy were at a higher risk for not reaching 2-year NEDA-3 and for EDSS increase than patients with no identified brain atrophy. The groups were clinically indistinguishable. A single measurement of thalamic and whole brain atrophy could help identify patients needing most effective therapies from early on

Finite-Size and surface effects in maghemite nanoparticles: Monte Carlo simulations

Finite-size and surface effects in fine particle systems are investigated by Monte Carlo simulation of a model of a $\gamma$-Fe$_2$O$_3$ (maghemite) single particle. Periodic boundary conditions have been used to simulate the bulk properties and the results compared with those for a spherical shaped particle with free boundaries to evidence the role played by the surface on the anomalous magnetic properties displayed by these systems at low temperatures. Several outcomes of the model are in qualitative agreement with the experimental findings. A reduction of the magnetic ordering temperature, spontaneous magnetization, and coercive field is observed as the particle size is decreased. Moreover, the hysteresis loops become elongated with high values of the differential susceptibility, resembling those from frustrated or disordered systems. These facts are consequence of the formation of a surface layer with higher degree of magnetic disorder than the core, which, for small sizes, dominates the magnetization processes of the particle. However, in contradiction with the assumptions of some authors, our model does not predict the freezing of the surface layer into a spin-glass-like state. The results indicate that magnetic disorder at the surface simply facilitates the thermal demagnetization of the particle at zero field, while the magnetization is increased at moderate fields, since surface disorder diminishes ferrimagnetic correlations within the particle. The change in shape of the hysteresis loops with the particle size demonstrates that the reversal mode is strongly influenced by the reduced atomic coordination and disorder at the surface.Comment: Twocolumn RevTex format. 19 pages, 15 Figures included. Submitted to Phys. Rev.

Noncollinear magnetic ordering in small Chromium Clusters

We investigate noncollinear effects in antiferromagnetically coupled clusters using the general, rotationally invariant form of local spin-density theory. The coupling to the electronic degrees of freedom is treated with relativistic non-local pseudopotentials and the ionic structure is optimized by Monte-Carlo techniques. We find that small chromium clusters (N \le 13) strongly favor noncollinear configurations of their local magnetic moments due to frustration. This effect is associated with a significantly lower total magnetization of the noncollinear ground states, ameliorating the disagreement between Stern-Gerlach measurements and previous collinear calculations for Cr_{12} and Cr_{13}. Our results further suggest that the trend to noncollinear configurations might be a feature common to most antiferromagnetic clusters.Comment: 9 pages, RevTeX plus .eps/.ps figure

Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors : Results from a Phase I/II Clinical Trial

Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment. Patients and Methods: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8(+)T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.Peer reviewe