Pazopanib attenuated bleomycin-induced pulmonary fibrosis via suppressing TGF-ß1 signaling pathway.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with a high mortality rate and limited treatment efficacy. Nintedanib, a tyrosine kinase inhibitor, is clinically used to treat pulmonary fibrosis. At present, only nintedanib is on the market for the treatment of pulmonary fibrosis. Pazopanib is a drug for the treatment of renal cell carcinoma and advanced soft tissue sarcoma. Methods: In this study, we explored whether pazopanib can attenuate bleomycin (BLM)-induced pulmonary fibrosis and explored its antifibrotic mechanism. In vivo and in vitro investigations were carried out to investigate the efficacy and mechanism of action of pazopanib in pulmonary fibrosis. Results: In vivo experiments showed that pazopanib can alleviate pulmonary fibrosis caused by BLM, reduce the degree of collagen deposition and improve lung function. In vitro experiments showed that pazopanib suppressed transforming growth factor-ß1 (TGF-ß1)-induced myofibroblast activation and promoted apoptosis and autophagy in myofibroblasts. Further mechanistic studies demonstrated that pazopanib inhibited the TGF-ß1/Smad and non-Smad signaling pathways during fibroblast activation. Conclusions: In conclusion, pazopanib attenuated BLM-induced pulmonary fibrosis by suppressing the TGF-ß1 signaling pathway. Pazopanib inhibits myofibroblast activation, migration, autophagy, apoptosis, and extracellular matrix (ECM) buildup by downregulating the TGF-ß1/Smad signal route and the TGF-ß1/non-Smad signal pathway. It has the same target as nintedanib and is a tyrosine kinase inhibitor.

Influence factors of metagenomic next-generation sequencing negative results in diagnosed patients with spinal infection.

The aim of this study was to evaluate the influence factors of metagenomic next-generation sequencing (mNGS) negative results in the diagnosed patients with spinal infection. mNGS test was applied in a cohort of 114 patients with suspected spinal infection, among which 56 patients had a final diagnosis of spinal infection. mNGS achieved a sensitivity of 75.0% (95% CI, 61.6% to 85.6%) and a specificity of 84.5% (95% CI, 72.6% to 92.7%), using histopathology and culture results as reference. Diagnosed patients with a negative culture result had lower white blood cell account, percentage of neutrophilic granulocyte, C-reactive protein (all P<0.05) and relatively higher rate of prior antimicrobial treatment history (P=0.059). However, diagnosed patients with a negative mNGS result did not have such difference with mNGS-positive patients, suggesting that mNGS was not strictly limited by the above indicators, which presented the advantages of this technique from another point of view.

Loss of RBM45 inhibits breast cancer progression by reducing the SUMOylation of IRF7 to promote IFNB1 transcription.

Type I interferons exhibit anti-proliferative and anti-cancer activities, but their detailed regulatory mechanisms in cancer have not been fully elucidated yet. RNA binding proteins are master orchestrators of gene regulation, which are closely related to tumor progression. Here we show that the upregulated RNA binding protein RBM45 correlates with poor prognosis in breast cancer. Depletion of RBM45 suppresses breast cancer progression both in cultured cells and xenograft mouse models. Mechanistically, RBM45 ablation inhibits breast cancer progression through regulating type I interferon signaling, particularly by elevating IFN-ß production. Importantly, RBM45 recruits TRIM28 to IRF7 and stimulates its SUMOylation, thereby repressing IFNB1 transcription. Loss of RBM45 reduced the SUMOylation of IRF7 by reducing the interaction between TRIM28 and IRF7 to promote IFNB1 transcription, leading to the inhibition of breast cancer progression. Taken together, our finding uncovers a vital role of RBM45 in modulating type I interferon signaling and cancer aggressive progression, implicating RBM45 as a potential therapeutic target in breast cancer.

Flexible light-stimulated artificial synapse based on detached (In,Ga)N thin film for neuromorphic computing.

Because of wide range of applications, the flexible artificial synapse is an indispensable part for next-generation neural morphology computing. In this work, we demonstrate a flexible synaptic device based on a lift-off (In,Ga)N thin film successfully. The synaptic device can mimic the learning, forgetting, and relearning functions of biological synapses at both flat and bent states. Furthermore, the synaptic device can simulate the transition from short-term memory to long-term memory successfully under different bending conditions. With the high flexibility, the excitatory post-synaptic current of the bent device only shows a slight decrease, leading to the high stability. Based on the experimental conductance for long-term potentiation and depression, the simulated three-layer neural network can achieve a high recognition rate up to 90.2%, indicating that the system comprising of flexible synaptic devices could have a strong learning-memory capability. Therefore, this work has a great potential for the development of wearable intelligence devices and flexible neuromorphic systems.

Pan-cancer and multi-omics analyses revealed the diagnostic and prognostic value of BAZ2A in liver cancer.

BAZ2A, an epigenetic regulatory factor that affects ribosomal RNA transcription, has been shown to be highly expressed in several cancers and promotes tumor cell migration. This study explored the expression and mechanism of BAZ2A in tumorigenesis at the pan-cancer level. The Cancer Genome Atlas, Gene Expression Omnibus databases and TIMER2.0, cBioPortal and other tools were used to analyze the level of expression of BAZ2A in various tumor tissues and to examine the relationship between BAZ2A and survival, prognosis, mutation and immune invasion. In vitro experiments were performed to assess the function of BAZ2A in cancer cells. Using combined transcriptome and proteome analysis, we examined the possible mechanism of BAZ2A in tumors. BAZ2A exhibited high expression levels in multiple tumor tissues and displayed a significant association with cancer patient prognosis. The main type of BAZ2A genetic variation in cancer is gene mutation. Downregulation of BAZ2A inhibited proliferation, migration, and invasion and promoted apoptosis in LM6 liver cancer cell. The mechanism of BAZ2A in cancer development may involve lipid metabolism. These results help expand our understanding of BAZ2A in tumorigenesis and development and suggest BAZ2A may serve as a prognostic and diagnostic factor in several cancers.

SARS-CoV-2 Omicron XBB lineage spike structures, conformations, antigenicity, and receptor recognition.

A recombinant lineage of the SARS-CoV-2 Omicron variant, named XBB, appeared in late 2022 and evolved descendants that successively swept local and global populations. XBB lineage members were noted for their improved immune evasion and transmissibility. Here, we determine cryo-EM structures of XBB.1.5, XBB.1.16, EG.5 and EG.5.1 spike (S) ectodomains to reveal reinforced 3-RBD-down receptor inaccessible closed states mediated by interprotomer receptor binding domain (RBD) interactions previously observed in BA.1 and BA.2. Improved XBB.1.5 and XBB.1.16 RBD stability compensated for stability loss caused by early Omicron mutations, while the F456L substitution reduced EG.5 RBD stability. S1 subunit mutations had long-range impacts on conformation and epitope presentation in the S2 subunit. Our results reveal continued S protein evolution via simultaneous optimization of multiple parameters including stability, receptor binding and immune evasion, and the dramatic effects of relatively few residue substitutions in altering the S protein conformational landscape.

Flexible Monolithic Bifunctional Device Based on a Lift-off (In,Ga)N Film for Both Lighting and Self-Driven Detection.

Although flexible monolithic bifunctional devices are significant for next-generation optoelectronic devices, it is quite challenging to realize them. In this work, a flexible monolithic device with both functions of emission and self-driven detection has been proposed and demonstrated successfully. By a quick electrochemical etching method, the device is created using a lift-off (In,Ga)N film detaching from the epitaxial silicon substrate. The Si removal is beneficial for releasing stress and reducing the internal polarization effects under bending conditions, keeping the electroluminescence peak wavelength quite stable. With good flexibility, the monolithic bifunctional device can maintain both stable detection and emission performance under bending conditions. Furthermore, two functions of detection and lighting of the flexible monolithic device can not only be realized separately but also simultaneously. This means that the flexible monolithic device can detect and emit light at the same time. With the advantages of miniaturization and multifunctionality, this work paves an effective way to develop new monolithic multifunctional devices for both self-driven detection and wearable intelligent display.

Metal Nanoparticles Assisted Ultrafast Laser Plasmonic Microwelding of Oxide-Semiconductor Interconnects.

Integration of wafer-scale oxide and semiconductor materials meets the difficulties of residual stress and materials incompatibility. In this work, Ag NPs thin film is contributed as an energy confinement layer between oxide (Sapphire) and semiconductor (Si) wafers to localize the materials interaction during ultrafast laser irradiation. Due to the plasmonic effects generated within constructed dielectric-metal-dielectric structures (i.e., Sapphire-Ag-Si), thermal diffusion and chemical reaction between Ag and its neighboring materials facilitate the microwelding of Sapphire and Si wafers. Ag NPs can be totally sintered within the junction area to bridge oxide and semiconductor, while Al─O─Ag bond and Ag─Si bond are formed at Ag-Sapphire and Ag─Si interfaces, respectively. As-received heterogeneous joint exhibits a high shear strength up to 5.4 MPa, with the fracture occurring inside Si wafer. Meanwhile, insertion of metal nanolayer can greatly relieve the residual stress-induced microcracking inside the brittle materials. Such wafer-scale Sapphire and Si interconnects thus show robust strength and excellent impermeability even after thermal shocking (-40 °C to 120 °C) for 200 cycles. This metal NPs layer-assisted plasmonic microwelding technology can extend to broad materials integration, which is promising for high-performance microdevices development in MEMS, MOEMS, or microfluidics.

Enhance the responsivity of self-driven ultraviolet photodetector by (Al,Ga)N nanowire/graphene/PVDF heterojunction with high stability.

Due to the low-power consumption, self-driven ultraviolet (UV) photodetectors have great potentials in a broad range of applications, such as optical communication, ozone monitoring, bio-medicine, and flame detection. In this Letter, it is pretty novel to enhance the photocurrent and responsivity of self-driven UV photodetectors by (Al,Ga)N nanowire/graphene/polyvinylidene fluoride (PVDF) heterojunction successfully. Compared to those of the photodetector with only nanowire/graphene heterojunction, it is found that both the photocurrent and responsivity of the photodetector with nanowire/graphene/PVDF heterojunction can be enhanced more than 100%. It is proposed that PVDF could maintain the internal gain by increasing the number of carrier cycles. Furthermore, this photodetector can also have a high detectivity of 5.3×1011 Jones and fast response speed under 310 nm illumination. After preserving for one month without any special protection, both photocurrent and responsivity of the photodetector with nanowire/graphene/PVDF heterojunction are demonstrated to be quite stable. Therefore, this work paves an effective way to improve the performance of photodetectors for their applications in the fields of next-generation optoelectronic devices.

High-Rate Nonaqueous Mg-CO2 Batteries Enabled by Mo2 C-Nanodot-Embedded Carbon Nanofibers.

The widespread acceptance of nonaqueous rechargeable metal-gas batteries, known for their remarkably high theoretical energy density, faces obstacles such as poor reversibility and low energy efficiency under high charge-discharge current densities. To tackle these challenges, a novel catalytic cathode architecture for Mg-CO2 batteries, fabricated using a one-pot electrospinning method followed by heat treatment, is presented. The resulting structure features well-dispersed molybdenum carbide nanodots embedded within interconnected carbon nanofibers, forming a 3D macroporous conducting network. This cathode design enhances the volumetric efficiency, enabling effective discharge product deposition, while also improving electrical properties and boosting catalytic activity. This enhancement results in high discharge capacities and excellent rate capabilities, while simultaneously minimizing voltage hysteresis and maximizing energy efficiency. The battery exhibits a stable cycle life of over 250 h at a current density of 200 mA g-1 with a low initial charge-discharge voltage gap of 0.72 V. Even at incredibly high current densities, reaching 1600 mA g-1 , the battery maintains exceptional performance. These findings highlight the crucial role of cathode architecture design in enhancing the performance of Mg-CO2 batteries and hold promise for improving other metal-gas batteries that involve deposition-decomposition reactions.

IRF4 Participates in Pulmonary Fibrosis Induced by Silica Particles through Regulating Macrophage Polarization and Fibroblast Activation.

Long-term exposure to silica dust can cause silicosis, which is characterized by chronic progressive inflammatory injury, fibroblast activation, and the deposition of extracellular matrix. IRF4 is involved in immune response. However, the potential regulation of IRF4 in silicosis and pulmonary fibrosis remains largely unexplored. In this study, RNA-seq analysis identified the upregulated expression of IRF4 in fibrotic lung tissues of mice exposed to silica particles. And we verified the increased expression of IRF4 in SiO2-treated macrophages and TGF-ß1-treated fibroblasts. We further found that the down-regulation of IRF4 impeded the macrophage polarization and the release of pro-fibrotic factors. Moreover, the down-regulation of IRF4 alleviated the migration, invasion, and the expression of fibrotic molecules in fibroblasts. Using ChIP-qPCR assay, we confirmed that IRF4 regulated the transcriptional activity of the IL-17A promoter, thus stimulated fibroblast activation, migration and invasion. In vivo experiment, the AAV-siIRF4 was designed to interfere with the expression of IRF4 in lung tissues of mice exposed to silica particles. Whole blood, bronchoalveolar lavage fluid and lung tissues were obtained from mice at 7, 14, 28 and 56 days after silica exposure. The results showed that the leukocyte content and inflammatory factors reached a peak at day 14 and remained peak for a long time after IRF4 knockdown. Furthermore, the fibrotic responses of mouse lung tissues were alleviated after IRF4 knockdown. Our study explored the important roles of IRF4 in inflammatory and fibrotic responses, which provided a new target for the treatment of silicosis and pulmonary fibrosis.

Structure, Health Benefits, Mechanisms, and Gut Microbiota of Dendrobium officinale Polysaccharides: A Review.

Dendrobium officinale polysaccharides (DOPs) are important active polysaccharides found in Dendrobium officinale, which is commonly used as a conventional food or herbal medicine and is well known in China. DOPs can influence the composition of the gut microbiota and the degradation capacity of these symbiotic bacteria, which in turn may determine the efficacy of dietary interventions. However, the necessary analysis of the relationship between DOPs and the gut microbiota is lacking. In this review, we summarize the extraction, structure, health benefits, and related mechanisms of DOPs, construct the DOPs-host axis, and propose that DOPs are potential prebiotics, mainly composed of 1,4-ß-D-mannose, 1,4-ß-D-glucose, and O-acetate groups, which induce an increase in the abundance of gut microbiota such as Lactobacillus, Bifidobacterium, Akkermansia, Bacteroides, and Prevotella. In addition, we found that when exposed to DOPs with different structural properties, the gut microbiota may exhibit different diversity and composition and provide health benefits, such as metabolism regulations, inflammation modulation, immunity moderation, and cancer intervention. This may contribute to facilitating the development of functional foods and health products to improve human health.

Recent Northward Expansion of a Passerine Bird Species, Brownish-Flanked Bush Warbler (Horornis fortipes).

Northward expansions of bird distributions have been commonly observed in the Northern Hemisphere, likely as a result of climate change. The causes and ecological impacts of such range shifts have received extensive attention, but studies on the process of range shifts are still relatively scarce. The Brownish-flanked Bush Warbler (Horornis fortipes) has expanded northward from 35° N to 40° N during the past decade. In this study, we collated 77 records of the species beyond its traditional distribution during the past ten years from citizen science data. Most of the new records were from northeast of its traditional distribution, including the North China Plain, Taihang Mountains, and Taishan Mountain, and a few records from the northern margin of the Qinling Mountains and Qinghai-Tibet Plateau. We concluded that the Brownish-flanked Bush Warbler has bred in this new area in at least six sites. The newly established populations are assumed to belong to the subspecies H. f. davidianus, which can be divided into eastern and western dialect groups based on differences in songs. Song recordings from 10 males from Beijing and its adjacent areas were collected. Bayesian analysis based on the acoustic traits indicated that these males were most likely from the western dialect area, with a posterior probability of 99.975%. Combining topographical data with the habitat preference of the species, we inferred that these individuals spread northeastward from the Qinling Mountains to Taihang Mountains, and further along the Yanshan Mountains. This study is a case study of the distribution expansion of a bird species, which reflects the dynamics of a species in the early stage of its northward expansion.

Bioorthogonal Reaction-Mediated Enzymatic Elongation-Driven Dendritic Nanoassembly for Genome-Wide Analysis of 5-Hydroxymethyluracil in Breast Tissues.

5-Hydroxymethyluracil (5hmU) is an oxidation derivative of thymine in the genomes of various organisms and may serve as both an epigenetic mark and a cancer biomarker. However, the current 5hmU assays usually have drawbacks of laborious procedures, low specificity, and unsatisfactory sensitivity. Herein, we demonstrate the click chemistry-mediated hyperbranched amplification-driven dendritic nanoassembly for genome-wide analysis of 5hmU in breast cell lines and human breast tissues. The proposed strategy possesses good selectivity, ultralow background, and high sensitivity with a detection limit of 83.28 aM. This method can accurately detect even a 0.001% 5hmU level in the mixture. Moreover, it can determine 5hmU at single-cell level and distinguish the expressions of 5hmU in tissues of normal persons and breast cancer patients, holding great promise in 5hmU-related biological research and clinical diagnosis.

Gut microbiota and hypertension: a bibliometric analysis of recent research (2014-2023).

Background: Cardiovascular diseases persist as the primary cause of mortality in the global population. Hypertension (HTN) is widely recognized as one of the most crucial risk factors contributing to severe cardiovascular conditions. In recent years, a growing body of research has highlighted the therapeutic potential of gut microbiota (GM) in addressing cardiovascular diseases, particularly HTN. Consequently, unraveling and synthesizing the connections between GM and HTN, key research domains, and the underlying interaction mechanisms have grown increasingly vital. Methods: We retrieved articles related to GM and HTN from 2014 to 2023 using Web of Science. Bibliometric tools employed in this analysis include CiteSpace and VOSviewer. Result: From 2014 to 2023, we identified 1,730 related articles. These articles involved 88 countries (regions) and 9,573 authors. The articles were published in 593 journals, with 1000 references exhibiting co-occurrence more than 10 times. The number of studies in this field has been increasing, indicating that it remains a research hotspot. We expect this field to continue gaining attention in the future. China leads in the number of published articles, while the United States boasts the most extensive international collaborations, signifying its continued prominence as a research hub in this domain. Tain You-Lin, Hsu Chien-Ning, Raizada Mohan K, and Yang Tao are among the authors with the highest publication volume. Publications in this field are frequently found in nutrition, cardiovascular, and molecular biology journals. The most frequently occurring keywords include metabolic syndrome, cardiovascular disease, inflammation, short-chain fatty acids, trimethylamine N-oxide, chronic kidney disease, heart failure, and high-salt diet. Conclusion: The relationship between GM and HTN is presently one of the most active research areas. By employing bibliometric tools, we analyzed critical and innovative articles in this field to provide an objective summary of the primary research directions, such as the relationship between GM and HTN, GM metabolites, high-salt diet, the developmental origins of health and disease, obstructive sleep apnea-Induced hypertension and antihypertensive peptide. Our analysis aims to offer researchers insights into hotspots and emerging trends in the field of GM and HTN for future research reference.

Zanubrutinib Ameliorates Cardiac Fibrosis and Inflammation Induced by Chronic Sympathetic Activation.

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which have now become a severe public health problem worldwide. ß-Adrenergic receptor (ß-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous research has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-ß related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by ß-AR overactivation; (2) Methods: In vivo: Male C57BL/6J mice were treated with or without the ß-AR agonist isoproterenol (ISO) to establish a cardiac fibrosis animal model; (3) Results: In vivo: Results showed that the BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by ß-AR. In vitro: Results showed that ZB alleviated ß-AR-induced cardiac fibroblast activation and macrophage pro-inflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited ß-AR-induced cardiac fibrosis and inflammation by the BTK, STAT3, NF-κB, and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates ß-AR-induced cardiac fibrosis and inflammation.

Peptide-Appended Nanosonosensitizers Targeting Tumor Glycolysis for Synergistic Sonodynamic-Immunometabolic Therapy of Spinal-Metastasized Tumors.

Despite recent advancements in cancer immunotherapy, challenges have yet to be surmounted to achieve two major goals of magnifying antitumor immunity and remodeling the immunosuppressive tumor microenvironment. Here, a nanosystem (ODM-R) that integrates oxygen-deficient molybdenum oxide (ODM) nanosonosensitizers and R7 peptides with tumor metabolism regulation effects is designed and fabricated for synergistic sonodynamic-immunometabolic therapy of spinal-metastasized tumors. The ODM generates reactive oxygen species upon ultrasound irradiation to implement sonodynamic therapy (SDT), inducing cancer cell apoptosis and immunogenic cell death. The R7 attached on ODM markedly inhibits the uptake of glucose and excretion of lactic acid in cancer cells by perturbing the glycolysis process. The combination of SDT and tumor glycolysis obstruction by ODM-R guarantees satisfactory efficacy in synergizing with PD-L1 antibody to eradicate spinal-metastasized tumors, achieving concurrent sonodynamic-triggered immune activation and immunosuppressive tumor microenvironment remodeling. This work provides a proof-of-concept of nanosonosensitizers for boosting cancer immunotherapy by SDT and tumor metabolic regulation.

Protective effect of agar oligosaccharide on male Drosophila melanogaster suffering from oxidative stress via intestinal microflora activating the Keap1-Nrf2 signaling pathway.

Agar oligosaccharide (AOS) is a new kind of marine functional oligosaccharide with generous biological activities. To investigate the antioxidative effects of AOS in vivo, 3 % aqueous hydrogen peroxide (H2O2) was used to induce oxidative stress in male Drosophila melanogaster (D. melanogaster) fed 5 % sucrose (SUC). AOS (0.125 %) in the medium extended the lifespan of D. melanogaster suffering from oxidative stress by improving antioxidant capacity and intestinal function. Electron microscopic observation of epithelial cells showed that AOS alleviated the damage caused by H2O2 challenge in the intestine of D. melanogaster, including a reduction of gut leakage and maintenance of intestinal length and cell ultrastructure. The Keap1-Nrf2 (analogues of CncC gene in D. melanogaster) signaling pathway was significantly activated based on gene expression levels and a reduction in ROS content in the intestine of D. melanogaster suffering from oxidative stress. The improvement of antioxidant capacity may be related to the regulation of intestinal microflora with AOS supplementation for D. melanogaster. Nrf2-RNAi, sterile and gnotobiotic D. melanogaster were used to validate the hypothesis that AOS activated the Keap1-Nrf2 signaling pathway to achieve antioxidant effects by regulating intestinal microflora. The above results contribute to our understanding of the antioxidative mechanism of AOS and promote its application in the food industry.

Advanced and Readily-Available Wireless-Powered Blue-Light-Implant for Non-Invasive Peri-Implant Disinfection.

Non-invasive light-based antibacterial therapy has a good prospect in non-surgical treatment of peri-implant infections. However, its applications are severely limited by poor penetration of light into human tissues, leading to unsatisfying outcomes. Moreover, as an essential prerequisite for traditional light therapy, lasers can no longer meet the patients' needs for convenient treatment at any time. To break through the spatial and temporal limitations of traditional light therapy, a wireless-powered blue-light zirconia implant for readily available treatment of peri-implant infection is proposed. In space, complete irradiation to complex peri-implant structure is realized by the built-in wireless-powered light source, thus improving the efficacy. In time, wireless-powering allows timely and controllable anti-infection treatment. Blue micro-light emitting diodes are used as therapeutic light sources, which effectively kill peri-implant infection-related bacteria without exogenous photosensitive agents. Porphyromonas gingivalis biofilm on implant surface can be completely killed after 20 min irradiation in vitro. The bactericidal rate of peri-implant methicillin-resistant Staphylococcus aureus infection reaches 99.96 ± 0.03% under 30 min per day blue light exposure in vivo. Within the scope of this study, the treatment of peri-implant infection with blue-light implant has preliminary feasibility, giving a new approach to non-invasive treatment of deep oral infections, including peri-implant infections.

Once-Weekly Basal Insulin Fc Demonstrated Similar Glycemic Control to Once-Daily Insulin Degludec in Insulin-Naive Patients With Type 2 Diabetes: A Phase 2 Randomized Control Trial.

OBJECTIVE: Basal insulin Fc (BIF) (insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed the safety and efficacy of BIF versus degludec in insulin-naive patients with type 2 diabetes (T2D) previously treated with oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS: During this randomized, parallel, open-label study, 278 insulin-naive patients with T2D were randomly assigned (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose of 80-100 mg/dL (4.4 to <5.6 mmol/L). The primary end point was HbA1c change from baseline to week 26 (noninferiority margin 0.4%). Secondary end points included fasting blood glucose (FBG), six-point glucose profiles, and rate of hypoglycemia. RESULTS: After 26 weeks of treatment, BIF demonstrated a noninferior HbA1c change from baseline versus degludec, with a treatment difference of 0.06% (90% CI -0.11, 0.24; P = 0.56). Both BIF and degludec treatment led to significant reductions in FBG from baseline. At week 26, the between-treatment difference for BIF versus degludec was 4.7 mg/dL (90% CI 0.1, 9.3; P = 0.09). The rate of level 2 hypoglycemia was low and not significantly different between treatment groups (BIF 0.22 events/patient/year, degludec 0.15 events/patient/year; P = 0.64); there was no severe hypoglycemia. The occurrence of treatment-emergent adverse events was also similar between BIF and degludec. CONCLUSIONS: Once-weekly BIF achieved excellent glycemic control similar to degludec, with no concerning hypoglycemia or other safety findings.