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关键词： Cost per patient treated to target   glycemic control   hypoglycemia   semaglutide   tirzepatide   type 2 diabetes   weight loss  

摘要： Introduction Tirzepatide is a treatment for type 2 diabetes associated with improvements in glycemic control and weight loss, and a low risk of hypoglycemia when not used in combination with insulin or insulin secretagogues. A cost to target analysis of tirzepatide 5, 10 and 15 mg versus subcutaneous semaglutide 1 mg in the UK setting was performed, calculating the annual pharmacy cost per patient treated to six composite endpoints combining glycemic control (glycated hemoglobin [HbA1c] <= 6.5% [48 mmol/mol] and <7.0% [53 mmol/mol with weight loss (>= 5%, >= 10%, >= 15%) and avoidance of hypoglycemia. The costing analysis was based on the tirzepatide costs appraised by NICE as part of TA924. Methods The proportions of patients achieving composite treatment targets with tirzepatide and semaglutide (both in combination with metformin) were taken from a post-hoc analysis of the SURPASS-2 clinical trial (N = 1,845). Costs per patient treated to target were calculated by dividing the annual treatment costs associated with each intervention by the proportion of patients achieving the treatment target with each intervention. Results Tirzepatide 5, 10 and 15 mg were associated with a lower pharmacy cost per patient achieving treatment target than semaglutide 1 mg for the majority of endpoints evaluated. Differences became greater at more strict treatment targets. For example, the cost per patient achieving HbA1c <= 6.5%, weight loss >= 15%, and no hypoglycemia was GBP 5,650, GBP 8,665 and GBP 9,462 lower with tirzepatide 5, 10 and 15 mg, respectively, compared with semaglutide 1 mg over a 1-year time horizon. The only endpoint where semaglutide 1 mg was associated with a lower cost per patient achieving target was HbA1c <7.0%, weight loss >= 5%, and no hypoglycemia. Conclusions Compared to semaglutide, tirzepatide was associated with a lower annual pharmacy cost per patient with diabetes achieving treatment target in the UK for the majority of endpoints, with greater differ

关键词： Pruritus   mu-opioid receptor   opioid antagonists   naltrexone   nalbuphine   naloxone   refractory pruritus   systematic review  

摘要： BackgroundPruritus is a debilitating symptom and conventional therapies often provide incomplete relief. The mu-opioid receptor (MOR) pathway is a key regulator of itch, and mu-pathway-modulating agents are increasingly used off-label for refractory pruritus.AimThis systematic review evaluates the efficacy, safety, and real-world use of mu-opioid pathway modulators for pruritus of dermatologic and systemic origin.MethodsFollowing PRISMA guidelines (PROSPERO CRD420251207101 a comprehensive search of four databases identified 3,274 records, of which 69 studies met inclusion criteria, comprising 14 randomized controlled trials (RCTs;n = 795) and 55 non-randomized studies (n = 351). Owing to substantial clinical and methodological heterogeneity, findings were narratively synthesized.ResultsFive RCTs evaluated dermatologic conditions, including atopic dermatitis, prurigo nodularis, chronic urticaria, and lichen planopilaris, while nine RCTs assessed systemic pruritus, predominantly cholestatic and uremic pruritus. RCTs investigated oral or topical naltrexone, intravenous naloxone, nalmefene, and extended-release nalbuphine, with most demonstrating clinically meaningful reductions in pruritus intensity using validated itch scales. Non-randomized studies reported improvement across a wide range of dermatologic and systemic conditions, with adverse events generally mild and well tolerated.ConclusionsOverall, mu-opioid pathway modulators show promising efficacy with acceptable short-term safety across diverse pruritic conditions, although larger high-quality RCTs are required to define optimal dosing and support clinical translation.

关键词： Chebulinic acid (CA)   diabetic podocytopathy   LRH-1   PLIN5   lipotoxicity  

摘要： Diabetic kidney disease (DKD) is characterized by podocyte injury driven by intracellular lipid accumulation. Liver receptor homolog-1 (LRH-1) is a key nuclear receptor regulating lipid metabolism, yet its role in podocyte lipotoxicity remains unclear. This study identifies the LRH-1/perilipin 5 (PLIN5) axis as a critical pathway for maintaining lipid homeostasis in podocytes and a promising pharmacological target for DKD. We demonstrated that hyperglycemia suppressed the LRH-1/PLIN5 axis, leading to lipid droplet accumulation, oxidative stress, and podocyte injury in db/db mice and cultured podocytes. Activation of LRH-1 with agonist 1,2-dilauroyl-sn-glycerol-3-phosphocholine (DLPC) or its overexpression restored mitochondrial lipid utilization, reduced lysosomal lipotoxicity, and protected against renal injury by upregulating PLIN5. Furthermore, virtual screening of a natural product library identified chebulinic acid (CA) as a novel PLIN5-targeting agonist. CA treatment significantly upregulated PLIN5 expression, ameliorated lipid accumulation, and improved renal function in db/db mice. Our findings unveil the therapeutic potential of targeting the LRH-1/PLIN5 axis and present CA as a promising candidate for the treatment of diabetic podocytopathy. Highlights Liver receptor homolog-1 (LRH-1)/perilipin 5 (PLIN5) axis is identified as a key regulator of podocyte lipid metabolism in diabetic kidney disease. Activation of LRH-1 mitigates lipotoxicity by shifting lipid turnover toward mitochondrial oxidation and away from lysosomal degradation. Chebulinic acid (CA) is discovered as a novel natural-product agonist targeting PLIN5 through virtual screening. CA treatment ameliorates renal lipid accumulation and injury in a diabetic mouse model. Targeting the LRH-1/PLIN5 axis represents a promising therapeutic strategy for diabetic podocytopathy.

关键词： Mangroves   aboveground biomass density (AGBD)   spectral-temporal metrics (STM)   Sentinel-1/2 time-series   UAV-LiDAR  

摘要： Accurate estimation of mangrove aboveground biomass density (AGBD) is crucial for assessing ecosystem productivity and blue carbon sequestration. However, frequent cloud cover, complex canopy structures, and scarce ground samples pose critical challenges for coastal AGBD mapping. We developed an annual Mangrove AGBD estimation Model (MAGB-STM) by considering three methodological aspects i) integrating spectral-temporal metrics (STM) derived from Sentinel-1 radar polarization and Sentinel-2 spectral and vegetation index features to capture mangrove dynamics;(ii) leveraging a random observation selection (ROS) strategy to simulate varying clear sky observation (CSO) densities across the 2017-2024 time series for transferability assessment;and (iii) evaluating synergistic contributions by comparing the proposed single-year approach against single-source models (Sentinel-1 or Sentinel-2 alone) and multi-year models trained using combined 2017 to 2024 data. We validated the model in the Zhanjiang Mangrove National Nature Reserve (ZMNNR) using 2024 UAV-LiDAR and field samples, and further evaluated it in three other mangrove regions using multi-year UAV-LiDAR data, with reference AGBD derived from point cloud structural features. Results showed that 1) The MAGB-STM model, integrating optical and SAR data through STM, achieved superior performance (R2 = 0.76, RMSE = 14.81 Mg & centerdot;ha-1, MAE = 12.39 Mg & centerdot;ha-1). This improvement, corresponding to an R2 increase of 0.24-0.39 over single-source models, demonstrates the complementary characteristics of the SAR backscatter signal and optical STM in mangrove structural components and biomass growth. (2) The temporal density of per-pixel CSO and their STM statistics were identified as key variables for a single-year MAGB-STM model;the ROS strategy achieved an approximately 8% relative increase in mean R2 against the 0.76 baseline across years by mitigating the impact of CSO density fluctuations. (3) The ROS strateg

关键词： China's Yangtze River Economic Belt   Impervious surface area   super resolution   semantic segmentation   1-meter ISA maps  

摘要： High-resolution impervious surface area (ISA) mapping is critical for a wide range of applications, including sustainable urban planning, flood risk assessment, and land use monitoring. However, the production of meter ISA products has long relied on commercial very high-resolution (VHR) satellite imagery, which is cost-prohibitive and geographically limited. To this end, we propose a novel joint framework by integrating super-resolution and segmentation, called JointSeg, which enables the generation of 1-meter ISA maps directly from freely available Sentinel-2 imagery (10m resolution). JointSeg was trained on multimodal cross-resolution inputs, offering a scalable and affordable alternative to traditional approaches. This synergistic design enables gradual resolution enhancement from 10m to 1m while preserving fine-grained spatial textures and ensuring high classification fidelity through effective cross-scale feature fusion. This method has been successfully applied to the Yangtze River Economic Belt (YREB a region characterized by complex urban-rural patterns and diverse topography. As a result, a comprehensive ISA mapping product for 2021, referred to as ISA-1, was generated, covering an area of over 2.2 million square kilometers. Quantitative comparisons against the 10m ESA WorldCover and other benchmark products reveal that ISA-1 achieves an F1-score of 85.71%, outperforming bilinear-interpolation-based segmentation by 9.5%, and surpassing other ISA datasets by 21.43%-61.07%. In densely urbanized areas (e.g., Suzhou, Nanjing ISA-1 reduces ISA overestimation through improved discrimination of green spaces and water bodies. Conversely, in mountainous regions (e.g., Ganzi, Zhaotong it identifies significantly more ISA due to its enhanced ability to detect fragmented anthropogenic features such as rural roads and sparse settlements, demonstrating its robustness across diverse landscapes. Moreover, we present biennial ISA maps from 2017 to 2023, capturing spatiotem

关键词： Piezo1   TME   mechanical signals   tumour progression   immunotherapy  

摘要： Background/objectivesAs a pivotal mechanosensitive ion channel, Piezo-type mechanosensitive ion channel component 1 (Piezo1) converts mechanical stimuli into biochemical signals that regulate key oncogenic processes, including tumour cell proliferation, migration and invasion. Emerging evidence demonstrates that Piezo1 is widely expressed across various cellular compartments of the tumour microenvironment (TME and its elevated expression strongly correlates with adverse clinical outcomes. A comprehensive understanding of the complex interactions between Piezo1 activation and cytokine networks in different TME cell populations is therefore essential for developing innovative and effective anti-tumour therapeutic strategies. In this review, we aimed to highlight the molecular mechanisms of Piezo1, systematically elucidating how the mechanical stimulation-Piezo1 signalling pathway within the TME contributes to tumour immune escape and malignant progression. Furthermore, we summarized current research advances in Piezo1-targeting drugs and clinical trials, and discuss strategies to improve tissue specificity while minimizing off-target effects.DiscussionA comprehensive literature review was conducted, focusing on the specific mechanisms through which Piezo1 regulates endothelial cells, immune cells, cancer-associated fibroblasts and the extracellular matrix within the TME. Activation of Piezo1 in endothelial and immune cells promotes tumour angiogenesis and immune evasion.ConclusionPiezo1 plays a critical role in tumour progression and represents a promising therapeutic target for cancer treatment

关键词： Degenerative musculoskeletal diseases   gut microbiota   GLP-1  

摘要： Degenerative musculoskeletal diseases are characterized by the progressive loss of structural integrity and functional capacity in muscles, bones, joints, and other related tissues. These conditions primarily include osteoarthritis, osteoporosis, sarcopenia, and intervertebral disc degeneration. These diseases progress gradually, leading to chronic pain, impaired mobility, and a significantly elevated risk of disability. Given their high prevalence and substantial health burden, degenerative musculoskeletal diseases pose a major challenge in the context of population aging. Although various types of degenerative musculoskeletal diseases affect different primary tissues, they share common pathological features including chronic inflammation, oxidative stress, and dysregulated cell death. These shared mechanisms imply the existence of a common molecular regulatory network. Glucagon-like peptide-1 (GLP-1 a peptide secreted under the regulation of the gut microbiota (GM has garnered increasing attention for its protective roles in bone, cartilage, muscle, and intervertebral disc tissues. GLP-1 reduces inflammation, mitigates oxidative stress, inhibits apoptosis, and supports microbial homeostasis. This review outlines the mechanisms through which the GM regulates GLP-1 secretion. It further summarizes the core functions and disease-specific pathways by which GLP-1 confers protection against degenerative musculoskeletal diseases. Finally, it explores potential therapeutic strategies targeting the "GM-GLP-1" axis, highlighting microbiota modulation and GLP-1 pathway enhancement as promising treatment approaches for degenerative musculoskeletal diseases.

关键词： Dendritic cell type 1   dendritic cell type 2   DC vaccine   progenitor cell   cancer therapy   immunotherapy  

摘要： While existing cancer therapies manage to reduce tumor burden, they often fail to produce durable or curative outcomes. Alternatively, cell-based approaches - particularly dendritic cell (DC) vaccines conceal the potential to elicit robust tumor-specific T-cell responses, equipping patients with T-cells capable of eradicating tumor cells and preventing future relapses. To date, most DC vaccines have been generated with monocyte-derived DCs (moDCs nowadays considered less potent at priming T-cells than blood-derived DC subsets, arguing for the usage of blood DCs for vaccine development. However, their scarcity in blood has hindered their clinical application, limiting their use in DC-based vaccination trials. To overcome this limitation, we developed a protocol to generate clinically relevant quantities of conventional DC type 1 (cDC1s) and DC2-like cells (cDC2s) from progenitor cells isolated from peripheral blood without the need for G-CSF mobilization, enabling their use for autologous vaccinations. The protocol is feeder layer free, yields clinically relevant amounts of cDC1s and cDC2s-like cells, and can be translated into a GMP-compliant setup. The ex vivo-generated DCs resemble their natural counterparts, acquire a robust pro-inflammatory phenotype (e.g., CD83, CCR7, and IL-12p70 and efficiently expand pro-inflammatory T-cells (e.g., IFN-gamma). Notably, in an in vitro immunization model, these DCs primed naive T-cells for the expansion of tumor-antigen-specific CD8 T-cells exhibiting strong immune-stimulating features (e.g., IFN-gamma, CD107a). In summary, this study demonstrates that blood progenitors differentiate into cDC1 and cDC2-like cells capable of eliciting potent antigen-specific T-cell subsets, offering a promising avenue for the development of more effective DC-based cancer therapies.

关键词： HIV   AIDS animal model   nonhuman primate   northern pig-tailed macaque   stHIV-1sv/G53D  

摘要： Simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infections in nonhuman primates closely approximate human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS but intrinsic viral differences limit translational relevance. A physiologically accurate HIV-1 model remains elusive. Here, we established a progressive HIV-1-like infection model using northern pig-tailed macaques (NPMs) infected with stHIV-1sv/G53D and monitored for 200 days. Results showed persistent viremia, progressive CD4+ T-cell depletion, and influenza-like symptoms, mirroring clinical features of HIV-1 infection. Infected macaques recapitulated T-cell exhaustion, innate immune activation, chronic immunosuppression, multi-organ biomarker alterations, and microbial dysbiosis. Transient and attenuated antiviral immunity may underlie this disease trajectory. In summary, this model serves as a complementary platform for validating direct antiviral strategies targeting HIV-1.