RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor.

The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.

Changes in posterior corneal elevation after small incision lenticule extraction for different myopic diopters.

AIM: To study the changes and effect factors of posterior corneal surface after small incision lenticule extraction (SMILE) with different myopic diopters. METHODS: Ninety eyes of 90 patients who underwent SMILE were included in this retrospective study. Patients were allocated into three groups based on the preoperative spherical equivalent (SE): low myopia (SE≥-3.00 D), moderate myopia (-3.00 D>SE>-6.00 D) and high myopia (SE≤-6.00 D). Posterior corneal surfaces were measured by a Scheimpflug camera preoperatively and different postoperative times (1wk, 1, 3, 6mo, and 1y). Posterior mean elevation (PME) at 25 predetermined points of 3 concentric circles (2-, 4-, and 6-mm diameter) above the best fit sphere was analyzed. RESULTS: All surgeries were completed uneventfully and no ectasia was found through the observation. The difference of myopia group was significant at the 2-mm ring at 1 and 3mo postoperatively (1mo: P=0.017; 3mo: P=0.018). The effect of time on ΔPME was statistically significant (2-mm ring: P=0.001; 4-mm ring: P<0.001; 6-mm ring: P<0.001). The effect of different corneal locations on ΔPME was significant except 1wk postoperatively (1mo: P=0.000; 3mo: P=0.000; 6mo: P=0.001; 1y: P=0.001). Posterior corneal stability was linearly correlated with SE, central corneal thickness, ablation depth, residual bed thickness, percent ablation depth and percent stromal bed thickness. CONCLUSION: The posterior corneal surface changes dynamically after SMILE. No protrusion is observed on the posterior corneal surface in patients with different degrees of myopia within one year after surgery. SMILE has good stability, accuracy, safety and predictability.

Survival benefit from adjuvant TACE combined with Lenvatinib for patients with hepatocellular carcinoma and microvascular invasion after curative hepatectomy.

BACKGROUND AND AIMS: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy is unsatisfactory, especially for those with microvascular invasion (MVI). This study aimed to determine the impact of adjuvant transcatheter arterial chemoembolization (TACE) and Lenvatinib on the prognosis of patients with HCC and MVI after hepatectomy. METHODS: Patients diagnosed with HCC and MVI were reviewed, and stratified into four groups according to adjuvant TACE and/or Lenvatinib. Multivariate Cox regression analyses are used to determine independent risk factors. RESULTS: 346 patients were included, and divided into four groups (Group I, TACE+ Lenvatinib; Group II, Lenvatinib; Group III, TACE; Group IV, without adjuvant therapy). Multivariable analysis showed that compared to Group IV, Group I had the best effect on improving the overall survival (OS, HR 0.321, 95%CI 0.099-0.406, P = 0.001) and recurrence-free survival (RFS, HR 0.319, 95%CI 0.129-0.372, P = 0.001). Additionally, compared with Group II or Group III, Group I also can significantly improve the OS and RFS. There is no significant difference between Group II and Group III in OS and RFS. CONCLUSION: The combination of TACE and Lenvatinib should be considered for anti-recurrence therapy for patients with HCC and MVI after hepatectomy.

Precise planning based on 3D-printed dry-laboratory models can reduce perioperative complications of laparoscopic surgery for complex hepatobiliary diseases: a preoperative cohort study.

BACKGROUND & AIMS: Complications after laparoscopic liver resection (LLR) are important factors affecting the prognosis of patients, especially for complex hepatobiliary diseases. The present study aimed to evaluate the value of a three-dimensional (3D) printed dry-laboratory model in the precise planning of LLR for complex hepatobiliary diseases. METHODS: Patients with complex hepatobiliary diseases who underwent LLR were preoperatively enrolled, and divided into two groups according to whether using a 3D-printed dry-laboratory model (3D vs. control group). Clinical variables were assessed and complications were graded by the Clavien-Dindo classification. The Comprehensive Complication Index (CCI) scores were calculated and compared for each patient. Multivariable analysis was performed to determine the risk factors of postoperative complications. RESULTS: Sixty-two patients with complex hepatobiliary diseases underwent the precise planning of LLR. Among them, thirty-one patients acquired the guidance of a 3D-printed dry-laboratory model, and others were only guided by traditional enhanced CT or MRI. The results showed no significant differences between the two groups in baseline characters. However, compared to the control group, the 3D group had a lower incidence of intraoperative blood loss, as well as postoperative 30-day and major complications, especially bile leakage (all P < 0.05). The median score on the CCI was 20.9 (range 8.7-51.8) in the control group and 8.7 (range 8.7-43.4) in the 3D group (mean difference, -12.2, P = 0.004). Multivariable analysis showed the 3D model was an independent protective factor in decreasing postoperative complications. Subgroup analysis also showed that a 3D model could decrease postoperative complications, especially for bile leakage in patients with intrahepatic cholelithiasis. CONCLUSION: The 3D-printed models can help reduce postoperative complications. The 3D-printed models should be recommended for patients with complex hepatobiliary diseases undergoing precise planning LLR.

Association between the triglyceride-glucose index and all-cause and CVD mortality in the young population with diabetes.

BACKGROUND: Although studies have demonstrated the value of the triglyceride-glucose (TyG) index for cardiovascular disease (CVD) and cardiovascular mortality, however, few studies have shown that the TyG index is associated with all-cause or CVD mortality in young patients with diabetes. This study aimed to investigate the association between the TyG index and all-cause and CVD mortality in young patients with diabetes in the United States. METHODS: Our study recruited 2440 young patients with diabetes from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Mortality outcomes were determined by linking to National Death Index (NDI) records up to December 31, 2019. Cox regression modeling was used to investigate the association between TyG index and mortality in young patients with diabetes. The nonlinear association between TyG index and mortality was analyzed using restricted cubic splines (RCS), and a two-segment Cox proportional risk model was constructed for both sides of the inflection point. RESULTS: During a median follow-up period of 8.2 years, 332 deaths from all causes and 82 deaths from cardiovascular disease were observed. Based on the RCS, the TyG index was found to have a U-shaped association with all-cause and CVD mortality in young patients with diabetes, with threshold values of 9.18 and 9.16, respectively. When the TyG index was below the threshold value (TyG index < 9.18 in all-cause mortality and < 9.16 in CVD mortality), its association with all-cause and CVD mortality was not significant. When the TyG index was above the threshold (TyG index ≥ 9.18 in all-cause mortality and ≥ 9.16 in CVD mortality), it showed a significant positive association with all-cause mortality and CVD mortality (HR 1.77, 95% CI 1.05-2.96 for all-cause mortality and HR 2.38, 95% CI 1.05-5.38 for CVD mortality). CONCLUSION: Our results suggest a U-shaped association between TyG index and all-cause and CVD mortality among young patients with diabetes in the United States, with threshold values of 9.18 and 9.16 for CVD and all-cause mortality, respectively.

Optimization system for training efficiency and load balance based on the fusion of heart rate and inertial sensors.

Objectives: To enhance the daily training quality of athletes without inducing significant physiological fatigue, aiming to achieve a balance between training efficiency and load. Design methods: Firstly, we developed an activity classification training model using the random forest algorithm and introduced the "effective training rate" (the ratio of effective activity time to total time) as a metric for assessing athlete training efficiency. Secondly, a method for rating athlete training load was established, involving qualitative and quantitative analyses of physiological fatigue through subjective fatigue scores and heart rate data. Lastly, an optimization system for training efficiency and load balance, utilizing multiple inertial sensors, was created. Athlete states were categorized into nine types based on the training load and efficiency ratings, with corresponding management recommendations provided. Results: Overall, this study, combining a sports activity recognition model with a physiological fatigue assessment model, has developed a training efficiency and load balance optimization system with excellent performance. The results indicate that the prediction accuracy of the sports activity recognition model is as high as 94.70%. Additionally, the physiological fatigue assessment model, utilizing average relative heart rate and average RPE score as evaluation metrics, demonstrates a good overall fit, validating the feasibility of this model. Conclusions: This study, based on relative heart rate and wearable devices to monitor athlete physiological fatigue, has developed a balanced optimization system for training efficiency and load. It provides a reference for athletes' physical health and fatigue levels, offering corresponding management recommendations for coaches and relevant professionals.

Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40 weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40 weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Polydopamine-Modified Copper Coordination Mesoporous Silica Nanoparticles Loaded with Disulfiram for Synergistic Chemo-Photothermal Therapy.

Disulfiram (DSF) degrades to diethyldithiocarbamate (DTC) in vivo and coordinates with copper ions to form CuET, which has higher antitumor activity. In this study, DSF@CuMSN-PDA nanoparticles were prepared using mesoporous silica with copper ions, DSF as a carrier, and polydopamine (PDA) as a gate system. The nanoparticles selectively released CuET into tumor tissue by taking advantage of the tumor microenvironment, where PDA could be degraded. The release ratio reached 79.17% at pH 5.0, indicating pH-responsive drug release from the nanoparticles. The PDA-gated system provided the nanoparticles with unique photothermal conversion performance and significantly improved antitumor efficiency. In vivo, antitumor experiments showed that the designed DSF@CuMSN-PDA nanoparticles combined with near-infrared light (808 nm, 1 W/cm2) irradiation effectively inhibited tumor growth in HCT116 cells by harnessing the combined potential of chemotherapy and photothermal therapy; a synergistic effect was achieved. Taken together, these results suggest that the designed DSF@CuMSN-PDA construct can be employed as a promising candidate for combined chemo-photothermal therapy.

Detection of lard adulteration in 3 kinds of vegetable oils by liquid chromatography-mass spectrometry with porous graphite carbon column.

Liquid chromatography‒mass spectrometry employing porous graphite carbon columns and an n-octane-isopropanol mobile phase was utilized for the separation of triacylglycerols (TAGs) in various edible oils, aiming to identify lard adulteration in soybean, corn, and sunflower seed oils. Experiments were conducted using a Hypercarb column (2.1 mm × 100 mm, 5 µm) and an n-octane-isopropanol (70:30, V/V) mobile phase at a flow rate of 0.25 mL· min-1 and a column temperature of 60 °C. Detection was achieved through atmospheric pressure chemical ionization-mass spectrometry. Analysis of diverse edible oil samples revealed that oils of the same type shared similar TAG compositions, while different types exhibited distinct TAG profiles. Distinct variations in triglyceride composition were observed across different edible oils. Based on liquid chromatography‒mass spectrometry analysis, the characteristic component 1-stearic acid-2-palmitic acid-3-oleic acid glyceride (SPO), which may also include PSO, was identified in lard through principal component analysis and orthogonal partial least squares discriminant analysis. This component served as a marker for detecting as low as 0.1% lard adulteration in soybean, corn, and sunflower seed oils. The technique offers a precise and effective approach for the identification of lard adulteration in these edible oils.

Complexation of Hexavalent Neptunium(VI) with Oxydiacetic Acid and Its Amide Derivatives in Aqueous Solution: Spectrophotometry and DFT Calculations.

Unfolding the solution coordination chemistry of high-valent transuranium elements with the "CHON"-type ligands is important to understand the fundamental chemistry of actinides and to design more efficient extractants for partitioning of transuranium elements in advanced nuclear fuel cycles. Here, the complexation of a hexavalent neptunyl ion (NpO22+ or Np(VI)) with oxydiacetic acid (ODA) has been systematically investigated in comparison with its amide analogues N,N-dimethyl-3-oxa-glutaramic acid (DMOGA) and N,N,N',N'-tetramethyl-3-oxa-glutaramide (TMOGA) both experimentally and computationally. The formation of both 1:1 and 1:2 complexes between Np(VI) and the three ligands was identified by spectrophotometry, and their stability constants were obtained and compared with those of hexavalent U(VI) and Pu(VI). The corresponding bonding nature is elucidated by using energy decomposition analysis (EDA), electrostatic potential (ESP), ELF contours, and natural orbitals for chemical valence (NOCV) methods, which shows that the Np-O bonds are essentially ionic in character and the unoccupied 6d orbitals of Np play a key role in enhancing the covalent interactions between Np(VI) and the three ligands.

PDMS-embedded wearable FBG sensors for gesture recognition and communication assistance.

This study introduces fiber Bragg grating (FBG) sensors embedded in polydimethylsiloxane (PDMS) silicone elastomer specifically engineered for recognizing intricate gestures like wrist pitch, finger bending, and mouth movement. Sensors with different PDMS patch thicknesses underwent evaluation including thermal, tensile strain, and bending deformation characterization, demonstrating a stability of at least four months. Experiments revealed the FBG sensors' accurate wrist pitch recognition across participants after calibration, confirmed by statistical metrics and Bland-Altman plots. Utilizing finger and mouth movements, the developed system shows promise in assisting post-stroke patients and individuals with disabilities, enhancing their interaction capabilities with the external surroundings.

Portable optical fiber biosensors integrated with smartphone: technologies, applications, and challenges [Invited].

The increasing demand for individualized health monitoring and diagnostics has prompted considerable research into the integration of portable optical fiber biosensors integrated with smartphones. By capitalizing on the benefits offered by optical fibers, these biosensors enable qualitative and quantitative biosensing across a wide range of applications. The integration of these sensors with smartphones, which possess advanced computational power and versatile sensing capabilities, addresses the increasing need for portable and rapid sensing solutions. This extensive evaluation thoroughly examines the domain of optical fiber biosensors in conjunction with smartphones, including hardware complexities, sensing approaches, and integration methods. Additionally, it explores a wide range of applications, including physiological and chemical biosensing. Furthermore, the review provides an analysis of the challenges that have been identified in this rapidly evolving area of research and concludes with relevant suggestions for the progression of the field.

TyG-GGT is a Reliable Non-Invasive Predictor of Advanced Liver Fibrosis in Overweight or Obese Individuals.

BACKGROUND: Liver fibrosis is a predisposing factor for liver cancer. This study will investigate the predictive role of the Triglyceride-glucose and Gamma-glutamyl transferase index (TyG-GGT) as a non-invasive indicator of advanced liver fibrosis in individuals with obesity or overweight. METHOD: We enrolled patients who underwent metabolic and bariatric surgery as well as intraoperative liver biopsies at Zhejiang provincial people's hospital from August 2020 to March 2023. Clinical characteristics, comorbidities, laboratory data, and pathological variables of patients were collected and analysed. Then, we conducted logistics regression model to compare the performance of the TyG-GGT index with other 4 non-invasive models. RESULTS: A total of 65 patients were included in this study. 43(66.2%) of them were female, with the mean body mass index (BMI) of 39.0 ± 7.3 kg/m2. Meanwhile, 24(36.9%) patients were diagnosed with diabetes. Advanced liver fibrosis were observed in 16.9% of patients, while liver cirrhosis was found in 4.6% of patients. The multivariable logistics regression showed that TyG-GGT was an independent risk factor of advanced liver fibrosis (OR = 6.989, P = 0.049). Additionally, compared to another 4 non-invasive liver fibrosis models (NFS = 0.66, FIB4 = 0.65, METS-IR = 0.68, APRI = 0.65), TyG-GGT exhibits the highest AUC value of 0.75. CONCLUSIONS: More than one-third of patients undergoing metabolic and bariatric surgery are afflicted with nonalcoholic steatohepatitis (NASH), and a significant proportion exhibit advanced fibrosis. TyG-GGT was a potentially reliable predictor for screening individuals with overweight or obesity at high risk of advanced liver fibrosis, thus providing clinical guidance for early intervention in this targeted group.

Endocytic activation and exosomal secretion of matriptase stimulate the second wave of EGF signaling to promote skin and breast cancer invasion.

The dysfunction of matriptase, a membrane-anchored protease, is highly related to the progression of skin and breast cancers. Epidermal growth factor (EGF)-induced matriptase activation and cancer invasion are known but with obscure mechanisms. Here, we demonstrate a vesicular-trafficking-mediated interplay between matriptase and EGF signaling in cancer promotion. We found that EGF induces matriptase to undergo endocytosis together with the EGF receptor, followed by acid-induced activation in endosomes. Activated matriptase is then secreted extracellularly on exosomes to catalyze hepatocyte growth factor precursor (pro-HGF) cleavage, resulting in autocrine HGF/c-Met signaling. Matriptase-induced HGF/c-Met signaling represents the second signal wave of EGF, which promotes cancer cell scattering, migration, and invasion. These findings demonstrate a role of vesicular trafficking in efficient activation and secretion of membrane matriptase and a reciprocal regulation of matriptase and EGF signaling in cancer promotion, providing insights into the physiological functions of vesicular trafficking and the molecular pathological mechanisms of skin and breast cancers.

Associations of nirmatrelvir-ritonavir treatment with death and clinical improvement in hospitalized patients with COVID-19 during the Omicron wave in Beijing, China: a multicentre, retrospective cohort study.

BACKGROUND: The effectiveness of nirmatrelvir-ritonavir has mainly been shown in non-hospitalized patients with mild-to-moderate coronavirus disease 2019 (COVID-19). The real-world effectiveness of nirmatrelvir-ritonavir urgently needs to be determined using representative in-hospital patients with COVID-19 during the Omicron wave of the pandemic. METHODS: We performed a multicentre, retrospective study in five Chinese PLA General Hospital medical centers in Beijing, China. Patients hospitalized with COVID-19 from 10 December 2022 to 20 February 2023 were eligible for inclusion. A 1:1 propensity score matching was performed between the nirmatrelvir-ritonavir group and the control group. RESULTS: 1010 recipients of nirmatrelvir-ritonavir and 1010 matched controls were finally analyzed after matching. Compared with matched controls, the nirmatrelvir-ritonavir group had a lower incidence rate of all-cause death (4.6/1000 vs. 6.3/1000 person-days, p = 0.013) and a higher incidence rate of clinical improvement (47.6/1000 vs. 45.8/1000 person-days, p = 0.012). Nirmatrelvir-ritonavir was associated with a 22% lower all-cause mortality and a 14% higher incidence of clinical improvement. Initiation of nirmatrelvir-ritonavir within 5 days after symptom onset was associated with a 50% lower mortality and a 26% higher clinical improvement rate. By contrast, no significant associations were identified among patients receiving nirmatrelvir-ritonavir treatment more than 5 days after symptom onset. Nirmatrelvir-ritonavir was also associated with a 50% increase in survival days and a 12% decrease in days to clinical improvement. CONCLUSION: Among hospitalized patients with COVID-19 during the Omicron wave in Beijing, China, the early initiation of nirmatrelvir-ritonavir was associated with clinical benefits of lowering mortality and improving clinical recovery.

A high concentrate diet inhibits forkhead box protein A2 expression, and induces oxidative stress, mitochondrial dysfunction and mitochondrial unfolded protein response in the liver of dairy cows.

High-concentrate diet induce subacute ruminal acidosis (SARA) and cause liver damage in ruminants. It has been reported that forkhead box protein A2 (FOXA2) can enhance mitochondrial membrane potential but its function in mitochondrial dysfunction induced by high concentrate diets is still unknown. Therefore, the aim of this study was to elucidate the effect of high-concentrate (HC) diet on hepatic FOXA2 expression, mitochondrial unfolded protein response (UPRmt), mitochondrial dysfunction and oxidative stress. A total of 12 healthy mid-lactation Holstein cows were selected and randomized into 2 groups: the low concentrate (LC) diet group (concentrate:forage = 4:6) and HC diet group (concentrate:forage = 6:4). The trial lasted 21 d. The rumen fluid, blood and liver tissue were collected at the end of the experiment. The results showed that the rumen fluid pH level was reduced in the HC group and the pH was lower than 5.6 for more than 4 h/d, indicating that feeding HC diets successfully induced SARA in dairy cows. Both FOXA2 mRNA and protein abundance were significantly reduced in the liver of the HC group compared with the LC group. The activity of antioxidant enzymes (CAT, G6PDH, T-SOD, Cu/Zn SOD, Mn SOD) and mtDNA copy number in the liver tissue of the HC group decreased, while the level of H2O2 significantly increased, this increase was accompanied by a decrease in oxidative phosphorylation (OXPHOS). The balance of mitochondrial division and fusion was disrupted in the HC group, as evidenced by the decreased mRNA level of OPA1, MFN1, and MFN2 and increased mRNA level of Drp1, Fis1, and MFF. At the same time, HC diet downregulated the expression level of SIRT1, SIRT3, PGC-1α, TFAM, and Nrf 1 to inhibit mitochondrial biogenesis. The HC group induced UPRmt in liver tissue by upregulating the mRNA and protein levels of CLPP, LONP1, CHOP, Hsp10, and Hsp60. In addition, HC diet could increase the protein abundance of Bax, CytoC, Caspase 3 and Cleaved-Caspase 3, while decrease the protein abundance of Bcl-2 and the Bcl-2/Bax ratio. Overall, our study suggests that the decreased expression of FOXA2 may be related to UPRmt, mitochondrial dysfunction, oxidative stress, and apoptosis in the liver of dairy cows fed a high concentrate diet.

Digital economy structuring for sustainable development: the role of blockchain and artificial intelligence in improving supply chain and reducing negative environmental impacts.

In the current global context of environmental degradation and resource constraints, the pursuit of sustainable development has become an imperative. One avenue that holds promise for achieving this objective is the application of digital technologies, which have the potential to decouple economic growth from its carbon footprint. However, it is crucial to ensure that these technologies are designed and governed in a prudent manner, with a strong alignment to environmental priorities. This study focuses on exploring the potential roles of blockchain and artificial intelligence (AI) in supply chain coordination and impact mitigation. Furthermore, they have the capacity to incentivize recycling and circular business models, as well as facilitate carbon accounting and offsetting. To fully realize these benefits, it is essential to deploy these technologies within inclusive collaborative frameworks that take into consideration social and ecological considerations. The study also offers policy recommendations that highlight key leverage points for digital innovation, enabling countries to embark on smart and green industrial transformation pathways. By harnessing the potential of blockchain and AI in supply chains, governments can promote transparency, traceability, and accountability, thereby fostering sustainable practices and reducing environmental impacts. Incorporating blockchain and AI technologies into supply chain approaches leads to a substantial improvement in efficiency, as demonstrated by a numerical analysis. In conclusion, the integration of innovative digital technologies offers significant opportunities to optimize production systems and economic activity while prioritizing sustainability objectives for the betterment of society and the environment. These technologies have the potential to mitigate environmental externalities by addressing information imbalances within global supply chains. However, it is essential to prioritize inclusive governance that emphasizes democratic participation to mitigate any unintended negative consequences, especially for vulnerable communities. By ensuring inclusive decision-making processes, we can maximize the positive impact of these technologies while minimizing potential harm.

Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment.

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic lysosomal environment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibit pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer (TNBC) and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy. This article is protected by copyright. All rights reserved.