Innovent

Spin-torque and spin-Hall oscillators (SHOs) have emerged as promising candidates for building blocks in neuromorphic computing due to their ability to synchronize mutually, a process that can be mediated by propagating spin waves. We demonstrate a SHO that takes advantage of a low-damping magnetic garnet with dominant perpendicular magnetic anisotropy (PMA), namely gallium-substituted yttrium-iron-garnet (Ga:YIG). In-plane magnetized Ga:YIG allows for the operation at a high efficiency level while also enabling resonant spin-wave emission. A nonlinear self-localization of the excitation is avoided by exploiting the positive nonlinear frequency shift, which facilitates a current-controlled frequency of the emitted spin waves. Using micro-focused Brillouin light scattering spectroscopy, we investigate the properties of the local auto-oscillation and its spin-wave emission. Multiple modes are excited and compete internally, with two propagating modes detected up to distances larger than 10 μm. Their frequencies combine to an extended frequency bandwidth of ∼1.6 GHz. The experimentally observed two-mode system and its transition to a single mode at higher currents are reproduced via micromagnetic simulations, which account for the spatial variation of the PMA arising due to the microstructures on Ga:YIG. Our results propose a promising platform for hosting SHOs, interconnected via propagating spin waves, with particular relevance to neuromorphic computing.

BackgroundThis study evaluated the efficacy and safety of tafolecimab in patients with type 2 diabetes (T2D) and hypercholesterolemia by a post-hoc analysis of pooled data from three phase 3 trials.MethodsData from up to 12 weeks were analyzed to assess the effects of tafolecimab 450 mg every four weeks (Q4W) in patients with T2D and hypercholesterolemia. The primary endpoint was the percentage change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 12. Secondary endpoints included the proportion of participants achieving LDL-C levels below 1.8 mmol/L at weeks 12, the proportion of patients achieving LDL-C ≥ 50% reduction and LDL-C < 1.4 mmol/L, as well as percentage changes from baseline to week 12 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], and triglyceride (TG) levels.ResultsThe reduction in LDL-C from baseline was significantly greater in patients receiving tafolecimab than in those receiving placebo (estimated treatment difference: − 64.02%, 95% confidence interval: [− 68.08%, − 59.96%], P < 0.0001). The proportion of patients achieving a reduction of over 50% and an absolute LDL-C value below 1.4 mmol/L was significantly higher in the tafolecimab group than that in the placebo group (P < 0.0001). Furthermore, a significantly greater proportion of patients in the tafolecimab group achieved LDL-C levels below 1.8 mmol/L at week 12 compared to the placebo group (P < 0.0001). The tafolecimab group also showed significant reductions in TG, non-HDL-C, apo B, and Lp(a) from baseline to week 12 compared to the placebo group (all P < 0.001). The incidence of adverse events was generally similar between the two groups.ConclusionTafolecimab 450 mg Q4W demonstrated a superior lipid-lowering efficacy and favorable safety profile compared to placebo. This suggests it could be a promising new treatment option for Chinese patients with T2D and hypercholesterolemia.Graphical abstract

Hyaluronan (HA) levels are dynamically regulated homeostatically through biosynthesis and degradation. HA homeostasis is often perturbed under disease conditions. HA degradation products are thought to contribute to disease pathology. The hyaluronidase CEMIP requires the presence of living cells for its HA depolymerizing activity. CEMIP is overexpressed in a variety of pathological conditions, and the inhibition of its hyaluronidase activity therefore has therapeutic potential. To identify novel inhibitors of the CEMIP hyaluronidase activity, we established here a cell-compatible, medium-throughput assay for CEMIP-dependent HA depolymerization. The assay employs ultrafiltration plates to separate low- from high-molecular-weight HA, followed by quantification of HA fragments using an HA ELISA-like assay. Using this assay, we tested a range of compounds that have been reported to inhibit other hyaluronidases. Thereby, we identified several sulfated hydrocarbon polymers that inhibit CEMIP more potently than other hyaluronidases. One of these is heparin, a sulfated glycosaminoglycan produced by mast cells that constitutes the first described physiological CEMIP inhibitor. The most potent inhibitor (IC50 of 1.8 nM) is dextran sulfate, a synthetic sulfated polysaccharide. Heparin and dextran sulfate are used in numerous established and experimental biomedical applications. Their ability to inhibit CEMIP needs to be taken into account in these contexts.

BackgroundCo-inhibition of immune checkpoints lymphocyte-activation gene 3 (LAG-3) and PD-1 is believed to enhance cancer immunotherapy through synergistic effects. Herein, we evaluate the safety and efficacy of IBI110 (anti-LAG-3 antibody) with sintilimab (an anti-PD-1 antibody) in Chinese patients with advanced solid tumors.MethodsIn this open-label phase I study, phase Ia dose escalation of IBI110 monotherapy and phase Ib combination dose escalation of IBI110 plus sintilimab were conducted in patients with advanced solid tumors. Additionally, phase Ib combination dose expansion of IBI110 plus sintilimab and chemotherapy was conducted in previously untreated, advanced squamous non-small cell lung cancer (sqNSCLC) and HER-2 negative gastric cancer (GC). In phase Ia dose escalation, patients received IBI110 monotherapy at 0.01/0.1/0.3/1/3/10/20 mg/kg Q3W. In phase Ib dose escalation, patients received IBI110 at 0.3/0.7/1.5/3/5/8/10 mg/kg Q3W plus sintilimab 200 mg Q3W. In phase Ib combination dose expansion, patients received IBI110 at recommended phase 2 dose (RP2D) plus sintilimab 200 mg Q3W and chemotherapy. The primary endpoints were safety, tolerability and efficacy including objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) assessed by RECIST v1.1 and overall survival (OS). The secondary endpoints included pharmacokinetics, pharmacodynamics and immunogenicity.ResultsIn phase Ia dose escalation (n = 28), treatment-related adverse events (TRAEs) occurred in 67.9% patients and grade ≥ 3 TRAEs occurred in 21.4% patients. In phase Ib combination dose escalation (n = 45), TRAEs occurred in 75.6% patients and grade ≥ 3 TRAEs occurred in 22.2% patients. No dose-limiting toxicity (DLT) was observed. The most common TRAE was anemia (17.9%, including 3.6% ≥ G3) in phase Ia dose escalation of IBI110 monotherapy (n = 28), aspartate aminotransferase increased (28.9%, all G1-G2) in phase Ib dose escalation of IBI110 plus sintilimab (n = 45), anemia (70.0%, all G1-G2) in phase Ib dose expansion in sqNSCLC (n = 20), and neutrophil count decreased (64.7%, including 17.6%≥ G3) in phase Ib dose expansion in GC (n = 17). The RP2D of IBI110 was determined at 200 mg (3 mg/kg) Q3W. ORR in phase Ia/Ib dose escalation was 3.6% with IBI110 monotherapy and 14% with IBI110 plus sintilimab. In phase Ib combination dose expansion of IBI110 plus sintilimab and chemotherapy, unconfirmed and confirmed ORR in sqNSCLC (n = 20) was 80.0% (95% CI, 56.3–94.3) and 75.0% (95% CI, 50.9–91.3), respectively and in GC (n = 17) was 88.2% (95% CI, 63.6–98.5) and 70.6% (95% CI, 44.0-89.7), respectively.ConclusionsIBI110 monotherapy and in combination with sintilimab were well-tolerated in Chinese patients with advanced solid tumors. Encouraging efficacy of IBI110 in combination with sintilimab and chemotherapies was observed in sqNSCLC and GC.Trial registrationClinicalTrials.gov Identifier: NCT04085185.

Abstract Background: The prognosis of biliary tract cancer (BTC) is poor, with limited efficacy of first-line chemotherapy. SAGC is a randomized, controlled, phase 2 trial evaluating the efficacy of sintilimab (an anti-PD-1 inhibitor) and anlotinib (an anti-angiogenic VEGF-targeted agent) combined with standard chemotherapy as a first-line treatment in advanced BTC. Methods: Eighty eligible patients with unresectable, locally advanced, or metastatic BTC were randomized 1:1 to SAGC group (n = 40) to receive sintilimab (200 mg) and anlotinib (initial 10 mg, then adjusted for 8 mg on days 1-14) plus GC (gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8) every 3 weeks for up to 8 cycles, followed by sintilimab and anlotinib until disease progression or unacceptable toxicity or to GC group (n = 40), respectively. The primary endpoint was progression-free survival (PFS). The secondary endpoints included the objective response rate (ORR), overall survival (OS), and safety. The AKT/YAP-induced tumor-bearing mice model was established to study effect of anlotinib on the tumor immune microenvironment at varying doses (low-dose: 3 mg/kg, high-dose: 6 mg/kg). Results: The median follow-up was 13.4 months, and 77 of the 80 patients (96.3%) discontinued treatment. The median PFS was 8.5 months (SAGC group) and 6.2 months (GC group) (hazard ratio: 0.47 [95% CI, 0.22–0.64], P = 0.003). The ORR for the SAGC and GC groups were 51.4% and 29.4%, respectively. Overall, grade 3/4 treatment-related adverse events occurred in 75.0% (30/40) and 43.6% (17/39) of cases in the SAGC and GC groups, respectively. A post hoc analysis shown that patients in SAGC group who received 8mg (22 patients) of anlotinib daily had a higher ORR (54.5% vs. 38.8%) compared to those received 10mg (18 patients), and there was a trend towards an OS benefit (HR: 0.49 [95% CI, 0.14–1.18], P = 0.055). In vivo, the combination of low-dose anlotinib with anti-PD-1 resulted in heightened vascular pericyte coverage, improved vascular perfusion, enhanced cytotoxicity of activated T cells, and increased secretion of effector cytokines when compared to high-dose anlotinib. Conclusion: Sintilimab and anlotinib in addition to gemcitabine plus cisplatin treatment in patients with advanced BTC significantly improved PFS and had a manageable safety profile, and the survival benefit of anlotinib 8mg group is more superior. Low‐dose anlotinib plus anti–PD-1 immune therapy may synergistically improve the antitumor response with reducing adverse effects in vivo. Trial registration number ClinicalTrials.gov Identifier: NCT04300959.

Mg-based biodegradable metallic implants are gainingincreasedattraction for applications in orthopedics and dentistry. However,their current applications are hampered by their high rate of corrosion,degradation, and rapid release of ions and gas bubbles into the physiologicalmedium. The aim of the present study is to investigate the osteogenicand angiogenic potential of coated Mg-based implants in a sheep cranialdefect model. Although their osteogenic potential was studied to someextent, their potential to regenerate vascularized bone formationwas not studied in detail. We have studied the potential of magnesium–calcium(MgCa)-based alloys modified with zinc (Zn)- or gallium (Ga)-dopedcalcium phosphate (CaP) coatings as a strategy to control their degradationrate while enhancing bone regeneration capacity. MgCa and its implantswith CaP coatings (MgCa/CaP) as undoped or as doped with Zn or Ga(MgCa/CaP + Zn and MgCa/CaP + Ga, respectively) were implanted inbone defects created in the sheep cranium. MgCa implants degradedfaster than the others at 4 weeks postop and the weight loss was ca.50%, while it was ca. 15% for MgCa/CaP and <10% in the presenceof Zn and Ga with CaP coating. Scanning electron microscopy (SEM)analysis of the implant surfaces also revealed that the MgCa implantshad the largest degree of structural breakdown of all the groups.Radiological evaluation revealed that surface modification with CaPto the MgCa implants induced better bone regeneration within the defectsas well as the enhancement of bone–implant surface integration.Bone volume (%) within the defect was ca. 25% in the case of MgCa/CaP+ Ga, while it was around 15% for undoped MgCa group upon micro-CTevaluation. This >1.5-fold increase in bone regeneration for MgCa/CaP+ Ga implant was also observed in the histopathological examinationof the H&E- and Masson’s trichrome-stained sections. Immunohistochemicalanalysis of the bone regeneration (antiosteopontin) and neovascularization(anti-CD31) at the defect sites revealed >2-fold increase in theexpressionof the markers in both Ga- and Zn-doped, CaP-coated implants. Zn-dopedimplants further presented low inflammatory reaction, notable boneregeneration, and neovascularization among all the implant groups.These findings indicated that Ga- and Zn-doped CaP coating is an importantstrategy to control the degradation rate as well as to achieve enhancedbone regeneration capacity of the implants made of Mg-based alloys.

Yttrium iron garnet (${\mathrm{Y}}_{3}{\mathrm{Fe}}_{5}{\mathrm{O}}_{12}$; YIG) has a unique combination of low magnetic damping, high spin-wave conductivity, and insulating properties that make it a highly attractive material for a variety of applications in the fields of magnetics and spintronics. While the room-temperature magnetization dynamics of YIG have been extensively studied, there are limited reports correlating the low-temperature magnetization dynamics to the material structure or growth method. Here we investigate liquid phase epitaxy grown YIG films and their magnetization dynamics at temperatures down to 10 K. We show there is a negligible increase in the ferromagnetic resonance linewidth down to 10 K, which is unique when compared with YIG films grown by other deposition methods. From the broadband ferromagnetic resonance measurements, polarized neutron reflectivity, and scanning transmission electron microscopy, we conclude that these liquid phase epitaxy grown films have negligible rare-earth impurities present, specifically the suppression of Gd diffusion from the ${\mathrm{Gd}}_{3}{\mathrm{Ga}}_{5}{\mathrm{O}}_{12}$ (GGG) substrate into the ${\mathrm{Y}}_{3}{\mathrm{Fe}}_{5}{\mathrm{O}}_{12}$ film, and therefore negligible magnetic losses attributed to the slow-relaxation mechanism. Overall, liquid phase epitaxy YIG films have a YIG/GGG interface that is five times sharper and have ten times lower ferromagnetic resonance linewidths below 50 K than comparable YIG films by other deposition methods. Thus, liquid phase epitaxy grown YIG films are ideal for low-temperature experiments/applications that require low magnetic losses, such as quantum transduction and manipulation via magnon coupling.

The implantation of endoprosthesis is a routine procedure in orthopaedics. Endoprosthesis are mainly manufactured from ceramics, polymers, metals or metal alloys. To ensure longevity of the implants they should be as biocompatible as possible and ideally have antibacterial properties, to avoid periprosthetic joint infections (PJI). Various antibacterial implant materials have been proposed, but have so far only been used sporadically in patients. PJI is one of the main risk factors for revision surgeries. The aim of the study was to identify novel implant coatings that both exhibit antibacterial properties whilst having optimal biocompatibility.Six different novel implant coatings and surface modifications (EBM TiAl6V4, strontium, TiCuN, TiNbN, gentamicin phosphate (GP), gentamicin phosphate+cationic polymer (GP+CP)) were compared to standard CoCrMo-alloy. The coatings were further characterized with regard to the surface roughness. E. coli and S. capitis were cultured on the modified surfaces to investigate the antibacterial properties. To quantify bacterial proliferation the optical density (OD) was measured and viability was determined using colony forming units (CFU). Murine bone marrow derived macrophages (BMMs) were cultured on the surfaces and differentiated into osteoblasts to quantify the mineralisation using the alizarin red assay.All novel coatings showed reduced bacterial proliferation and viability compared to standard CoCrMo-alloy. A significant reduction was observed for GP and GP+CP coated samples compared to CoCrMo (ODGP,E.coli = 0.18±0.4; ODGP+CP,E.coli = 0.13±0.3; p≤0.0002; N≥7-8). An increase in osteoblast-mediated mineralisation was observed on all surfaces tested compared to CoCrMo. Furthermore, GP and GP+CP coated samples showed a statistically significant increase (MGP = 0.21±0.1; MGP+CP = 0.25±0.2; p&lt;0.0001; N≥3-6).The preliminary data indicates that the gentamicin containing surfaces have the most effective antibacterial property and the highest osseointegrative capacity. The use of antibiotic coatings on prostheses could reduce the risk of PJI while being applied on osseointegrative implant surfaces.