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关键词： HIV-1   ARV   cabotegravir   rilpivirine   zidovudine   intestinal failure   parenteral antiretroviral therapy  

摘要： Introduction: In patients with severe surgical and gastrointestinal complications, standard oral combination antiretroviral therapy (ARV) may be temporarily impossible. Long-acting cabotegravir/rilpivirine (CAB/RPV LA) is approved for virologically suppressed individuals pretreated with oral therapy, but data on its use in treatment-na & iuml;ve, critically ill patients with absent enteral absorption are extremely limited. Clinical presentation: We report a 26-year-old male admitted with fulminant hypertriglyceridaemic necrotizing pancreatitis complicated by abdominal compartment syndrome, multiple laparotomies, open abdomen with enteric fistulae, short bowel syndrome type I, chronic intestinal failure requiring parenteral nutrition, portal vein thrombosis, and prolonged intensive care. HIV-1 infection was diagnosed early (HIV RNA 5,000 copies/mL;CD4+ 780 cells/& micro;L). Within three months, HIV RNA rose to 320,000 copies/mL and CD4+ declined to 570 cells/& micro;L. Given absent gastrointestinal passage, standard ARV was initially deferred, but rapid virological rebound necessitated urgent treatment. An off-label fully parenteral regimen was initiated: intravenous zidovudine (AZT) with intramuscular CAB/RPV LA. Therapy was well tolerated alongside surgery, parenteral nutrition, antimicrobials, and anticoagulation. HIV RNA decreased to <20 copies/mL within 65 days and remained suppressed, with CD4+ recovery. Intravenous AZT was discontinued after 35 days, and CAB/RPV LA continued as maintenance during recovery and home parenteral nutrition. Discussion: Fully parenteral ARV, including CAB/RPV LA, may provide a safe and effective bridge to durable viral suppression in patients with absolute contraindications to oral therapy, warranting further evaluation.

关键词： Type 1 diabetes   diet   microbiome   probiotics   gluten   breastmilk   fecal microbiome transplant  

摘要： The incidence of type 1 diabetes (T1D) has risen sharply in recent decades, implicating the role of environmental factors in disease pathogenesis. Diet, a primary driver of gut microbiome development and composition, along with other environmental exposures, has emerged as a potential modulator of T1D risk and progression. While nutrients, such as certain vitamins, may exert protective effects, the roles of other dietary factors (e.g., early exposure to dietary antigens) remain unclear. Importantly, diet shapes the gut microbiome, which produces immunomodulatory metabolites, including secondary bile acids, short-chain fatty acids (SCFAs), and others that directly influence immune responses. This review presents evidence on how specific dietary factors, including macronutrients (fats, carbohydrates, proteins, such as gluten and milk proteins), fibers, and breastfeeding, affect the gut microbiome and T1D. We also discuss the effects of microbiome-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, on T1D and their potential as future therapeutic strategies. Although animal studies provide compelling mechanistic insights, the results from human trials remain inconsistent, underscoring the urgent need for longitudinal and interventional studies to establish causality. Understanding the complex interplay between diet, the gut microbiome, and immune homeostasis is essential for developing personalized strategies to prevent and treat T1D and delay-related complications.

关键词： Moringa oleifera seeds   cyanoglycosides   structure elucidation   diabetic nephropathy   metabolic reprogramming  

摘要： ContextDiabetic nephropathy (DN) is a major complication of diabetes. Moringa oleifera seeds are recognized as a source of bioactive compounds with potential health benefits, prompting investigation into their specific components and effects on *** study aimed to isolate bioactive compounds from M. oleifera seeds and evaluate their renoprotective effects and underlying mechanisms of action against high-glucose-induced diabetic *** and methodsFour cyanoglycosides and one cyanoaglycone were isolated from M. oleifera seeds using chromatographic techniques. The renoprotective effects of these compounds were then evaluated using an in vitro model of high-glucose-induced diabetic nephropathy in HBZY-1 mesangial cells. Mechanistic studies further investigated the compounds' effects on oxidative stress, inflammation, mitochondrial function, expression of the glycolysis-related protein PFKFB3, and the TGF-beta 1/Smad signaling *** previously undescribed cyanoglycosides were isolated alongside three known compounds. All five compounds demonstrated significant renoprotective effects in the high-glucose-induced HBZY-1 cell model. Mechanistically, these effects were achieved by suppressing oxidative stress and inflammation, protecting mitochondrial function, modulating the expression of the glycolysis-related protein PFKFB3, and inhibiting the TGF-beta 1/Smad signaling pathway, collectively contributing to beneficial metabolic *** study isolated two novel cyanoglycosides from M. oleifera seeds. These compounds, alongside known ones, protect against high-glucose-induced renal injury. Their renoprotection involves metabolic reprogramming via suppressing oxidative stress/inflammation, preserving mitochondrial function, modulating PFKFB3, and inhibiting TGF-beta 1/Smad signaling. These findings offer insights for utilizing M. oleifera seeds and suggest these cyanoglycosides as potential diabetic nephropathy ther

关键词： Triggering receptor expressed on myeloid cell-1   myasthenia gravis   enzyme-linked immunosorbent assay   biomarker   T cell  

摘要： Triggering receptor expressed on myeloid cells-1 (TREM-1) and TREM-2, cell surface receptors involved in innate and adaptive immunity, exist in soluble (sTREM-1 and sTREM-2) and membrane-bound forms, with the soluble form serve as biomarkers in many immune diseases. However, the role of TREM-1 and TREM-2 in myasthenia gravis (MG) remains unclear. This study aims to investigate the expression of TREM-1 and TREM-2 in MG, as well as their potential role in the immunopathological mechanism of MG. We enrolled a total of 85 MG patients and 43 healthy controls (HC). Enzyme-linked immunosorbent assay and flow cytometry were used to quantify the expression of TREM-1 and TREM-2 in MG patients and HC. The levels of TREM-1 and TREM-2 mRNA of peripheral blood mononuclear cells were measured by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) in MG and HC. In vitro experiments were performed to explore the functional effects of intervening TREM-1 on CD4+T cells. We found that serum sTREM-1 levels were significantly elevated in MG patients Compared to HC, whereas sTREM-2 showed no difference. Additionally, sTREM-1 levels in MG patients positively correlated with disease severity and memory B-cell proportions. TREM-1 expression was reduced and most significantly on CD4+T and CD8+T cells in MG patients. Inhibition of TREM-1 inhibited Treg cell differentiation but had no significant effect on Th1, Th2, and Th17, indicating its pathogenic role in MG.

关键词： PD-1 blockade   gut microbiota   intestinal ischemia reperfusion injury   IL-10   gut barrier  

摘要： PD-1 blockade therapy is widely used in clinical practice. Intestinal ischemia reperfusion (IR) injury is a serious clinical complication that leads to remote organ damage through disruption of the gut barrier. However, the effects of PD-1 blockade on gut homeostasis and intestinal IR injury remain unclear. Here, we demonstrate that, in contrast to PD-1 deficiency, PD-1 blockade activates intestinal immunoglobulin A (IgA) responses in mice via a MyD88-dependent pathway. The increased production and bacteria-binding capacity of IgA induced by PD-1 blockade significantly reshape the gut microbial composition and metabolite profile. Furthermore, PD-1 blockade promotes intestinal mucosal CD4+ T cell IL-10 production. Notably, microbiota depletion by antibiotics attenuates intestinal IL-10 production, whereas transplantation of PD-1 blockade-altered microbiota facilitates IL-10 upregulation. These IL-10 enhancements appears to be driven by an increase in Lachnospiraceae_NK4A136_group, a recognized butyrate-producing bacterium, and elevated levels of microbiota-derived butyrate, which were increased after PD-1 blockade and significantly correlated with enhanced IL-10 production in the intestinal mucosa. The upregulation of intestinal IL-10 following PD-1 blockade suppresses inflammatory activation, thereby ameliorating the gut barrier impairment and remote organ injury induced by intestinal IR. In addition, we show that, in vivo and in vitro, butyrate supplementation enhances IL-10 expression in CD4+ T cells through PI3K gamma/phospho-mTOR signaling. Collectively, these findings indicate that PD-1 blockade promotes intestinal mucosal CD4+ T cell IL-10 production by modulating immune-microbiota interactions and subsequently mitigates intestinal IR-induced gut barrier dysfunction and organ damage.

关键词： Tumor immunity   tumor immunology   T cell exhaustion PD-1 LAG-3   tumor immunotherapy  

摘要： BackgroundPD-1 and LAG-3 are immune checkpoint molecules frequently co-expressed in the tumor microenvironment, where they synergistically drive T-cell exhaustion and immune escape. Dual blockade of these pathways represents a promising strategy to overcome immunotherapy *** review systematically synthesizes mechanistic studies on PD-1/LAG-3 synergy and summarizes preclinical and clinical advances in dual blockade therapies, with emphasis on bispecific antibodies and combination trial ***-1 and LAG-3 cooperatively suppress T-cell function via complementary signaling pathways. Combined inhibition substantially restores antitumor immunity. A PD-1/LAG-3 bispecific antibody has been approved for melanoma, with numerous trials ongoing across other *** demonstrated efficacy, challenges including variable response rates, resistance mechanisms, and immune-related adverse events remain. Future efforts should prioritize biomarker identification and regimen optimization to enable precision application of dual blockade.

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 diff

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 str

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 spa

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 *** 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 ***1 plays a critical role in tumour progression and represents a promising therapeutic target for cancer treatment