"Three-in-One" Multifunctional Hollow Nanocages with Colorimetric Photothermal Catalytic Activity for Enhancing Sensitivity in Biosensing.

Immunochromatographic assays (ICAs) have been widely used in the field detection of mycotoxin contaminants. Nevertheless, the lack of multisignal readout capability and the ability of signaling tags to maintain their biological activity while efficiently loading antibodies remain a great challenge in satisfying diverse testing demands. Herein, we proposed a novel three-in-one multifunctional hollow vanadium nanomicrosphere (high brightness-catalytic-photothermal properties)-mediated triple-readout ICA (VHMS-ICA) for sensitive detection of T-2. As the key to this biosensing strategy, vanadium was used as the catalytic-photothermal characterization center, and natural polyphenols were utilized as the bridging ligands for coupling with the antibody while self-assembling with formaldehyde cross-linking into a hollow nanocage-like structure, which offers the possibility of realizing a three-signal readout strategy and improving the coupling efficiency to the antibody while preserving its biological activity. The constructed sensors showed a detection limit (LOD) of 2 pg/mL for T-2, which was about 345-fold higher than that of conventional gold nanoparticle-based ICA (0.596 ng/mL). As anticipated, the detection range of VHMS-ICA was extended about 8-fold compared with the colorimetric signal alone. Ultimately, the proposed immunosensor performed well in maize and oat samples, with satisfactory recoveries. Owing to the synergistic and complementary interactions between distinct signaling modes, the establishment of multimodal immunosensors with multifunctional tags is an efficient strategy to satisfy diversified detection demands.

Trifunctional Nanocomposites with Colorimetric Magnetic Catalytic Activities Labels in Sandwich Immunochromatographic Detection of Escherichia coli O157:H7.

The emergence of nanoenzymes has catalyzed the robust advancement of the lateral flow immunoassay (LFIA) in recent years. Among them, multifunctional nanocomposite enzymes with core-shell architectures are considered preferable for promoting the sensing ability due to their good biocompatibility, precise control over size, and surface properties etc. Herein, we developed a dual-channel ensured lateral flow immunoassay (DFLIA) platform utilizing a magnetic, colorimetric, and catalytic multifunctional nanocomposite enzyme (Fe3O4@TCPP@Pd) [TCPP, Tetrakis (4-carboxyphenyl) porphyrin] for the ultrasensitive and highly accurate rapid detection of Escherichia coli O157:H7 (E. coli O157:H7). Fe3O4@TCPP@Pd-mAb exhibits superior performance compared to traditional AuNPs, including enhanced sensitivity and an extended linear detection range, benefiting from its high brightness signal, strong magnetic separation ability, and high peroxidase activity (Vmax = 2.32 µM S1-). Moreover, the Fe3O4@TCPP@Pd-labeled mAb probe exhibited exceptional stability and high affinity toward E. coli O157:H7 (with an affinity constant of approximately 1.723 × 109 M-1), indicating its potential for the efficient capture of the pathogen. Impressively, the developed Fe3O4@TCPP@Pd-DFLIA achieved ultrasensitive detection for E. coli O157:H7 with pre- and postcatalytic naked-eye detection sensitivities of 255 cfu/mL and 77 cfu/mL, respectively, representing an approximately 41-fold improvement over the conventional AuNP-based LFIA and also possessed good specificity and reproducibility [relative standard deviation (RSD) < 10%]. Additionally, the established DFLIA exhibited satisfactory recoveries in detecting pork and milk samples, further validating the reliability of this platform for immunoassays and demonstrating its potential for utilization in bioassays and clinical diagnostics.

Zinc Coordination Lipid Nanoparticles Co-Delivering Calcium Peroxide and Chelating STING agonist for Enhanced Cancer Metalloimmunotherapy.

Metalloimmunotherapy has achieved great preclinical success against malignant tumors. Nonetheless, the limited immune cell infiltration and impaired immunogenicity within the tumor microenvironment (TME) significantly hinder its translation to clinical applications. In this study, a zinc coordination lipid nanoparticle is developed loaded with calcium peroxide hydrate (CaO2) nanoparticles and the STING agonist diABZI-2, which is termed A-CaO2-Zn-LNP. The release of Zn2+ from the A-CaO2-Zn-LNP and the calcium overload synergistically induced immunogenic cell death (ICD). In addition, CaO2 nanoparticles can consume H+ and release oxygen (O2) under acidic conditions. This treatment increased the pH and alleviated the hypoxia of the TME. Along with cGAS-STING activation by diABZI-2, A-CaO2-Zn-LNP ultimately results in enhanced anti-tumor systemic immunity and long-term immune memory via alleviating the immunosuppressive microenvironment. Taken together, A-CaO2-Zn-LNP offers a new nanoplatform that expands its application for cancer treatment by metalloimmunotheray.

An Improved Synchrosqueezing S-Transform and Its Application in a GPR Detection Task.

The S-transform is a fundamental time-frequency (T-F) domain analysis method in ground penetrating radar (GPR) data processing and can be used for identifying targets, denoising, extracting thin layers, and high-resolution imaging. However, the S-transform spectrum experiences energy leakage near the instantaneous frequency. This phenomenon causes frequency components to erroneously spread over a wider range, impacting the accuracy and precision of GPR data processing. Synchrosqueezing is an effective method to prevent spectrum leakage. In this work, we introduce the synchrosqueezing generalized phase-shifting S-transform (SS-GPST). Initially, it resolves the compatibility issue between the S-transform and the synchrosqueezing strategy through phase-shifting. Subsequently, the SS-GPST accomplishes spectral energy focusing and resolution enhancement via a generalized parameter and synchrosqueezing. A synthetic signal test shows that the SS-GPST excels over other methods at focusing degree, spectral resolution, and signal reconstruction accuracy and speed. In actual GPR tunnel detection data processing, we assess the adaptability of the SS-GPST from three aspects: spectral energy distribution, thin layer identification, and data denoising. The results indicate: (1) compared to other methods, the SS-GPST accurately expresses spectral components with a strong focusing degree and fewer interference components; (2) high-frequency slices of the SS-GPST accurately detect the top and bottom interfaces of a 3.0-3.5 cm reinforcement protection layer; and (3) due to fewer interference components in the SS-GPST spectrum, reconstructing GPR profiles through the SS-GPST inverse transform is an efficient denoising technique. The SS-GPST demonstrates adaptability to different data processing purposes, offers high-resolution T-F spectra, and shows potential to supersede the S-transform.

Key periodontal pathogens may mediate potential pathogenic relationships between periodontitis and crohn's disease.

BACKGROUND: Crohn's disease (CD)-associated periodontitis is common. However, the role of periodontal pathogens in the Coexistence of CD and periodontal disease remains unclear. METHODS: To investigate the potential relationship mediated by periodontal pathogens between periodontitis and CD, we collected salivary samples from healthy participants (H group, n = 12), patients with CD (Ch group, n = 10), patients with periodontitis (Ps group, n = 12), and patients with Coexistence of CD and periodontal disease (Cp group, n = 12) and analyzed them by 16 S rRNA sequencing. RESULTS: Patients with Coexistence of CD and periodontal disease had increased levels of Fusobacterium, Actinomyces, Leptotrichia, and Prevotella, which correlated with the severity of periodontitis. Conversely, the levels of Streptococcus, Neisseria, Haemophilus, and Gemella, which decreased in Coexistence of CD and periodontal disease, were negatively correlated with the severity of periodontitis. To further investigate the role of periodontal pathogens in CD development, representative periodontal pathogens causing periodontitis, Porphyromonas gingivalis and Fusobacterium nucleatum, were administered to mice. These pathogens migrate to, and colonize, the gut, accelerating CD progression and aggravating colitis, and even systemic inflammation. In vitro experiments using a Caco-2/periodontal pathogen coculture revealed that P. gingivalis and F. nucleatum increased intestinal permeability by directly disrupting the tight junctions of intestinal epithelial cells. CONCLUSION: Our findings strongly suggest that periodontal pathogens play a role in the relationship between periodontitis and CD. These results provide a basis for understanding the pathogenesis of Coexistence of CD and periodontal disease and may lead to the development of novel therapeutic strategies.

Formic Acid-Regulated Defect Engineering in Zr-Based Metal-Organic Frameworks toward Fluorescence Sensor for Sensitive Detection of Chlortetracycline.

The elaborate defect-engineering of luminescent metal-organic frameworks (MOFs) allows them with enhanced sensing performance. A modulator-induced defect formation strategy is adopted in this paper, and the impact of the open-metal sites on sensing process is rationalized. It is demonstrated that the defect level can be tuned to a remarkable extent by controlling the amount of modulator. When a particular defect concentration is reached, the UiO-66-xFA can be acted as highly sensitive ratiometric fluorescence probes for chlortetracycline (CTE) determination with an ultralow detection limit of 9.9 nm. Furthermore, by virtue of the obvious variation in fluorescence chromaticity of probes from blue to yellow, a sensory hydrogels-based smartphone platform is proposed for visible quantitation of CTE by identifying the RGB values. A delicate device integrated with UV lamp and dark cavity has been developed for avoiding inconsistencies of ambient light and visual errors. Finally, the sensor obtains satisfactory results in the detection of actual seafood samples, with no significant differences from those of liquid chromatography-mass spectrometry. This approach anticipates a novel route to sensitize optical sensors through the design and synthesis of moderate defects in luminescent MOFs.

Analysis of the spatiotemporal patterns and decoupling effects of China's water resource spatial equilibrium.

The significance of water resource spatial equilibrium (WRSE) research is to maximally remove the spatial restrictions of water on regional development, including social development, economic development and eco-environmental maintenance. Although great achievements have been made, national-scale WRSE research is rare; besides, the spatiotemporal patterns and decoupling effects of WRSE have been poorly studied in current research. Thus, the aim of this research is to measure the WRSE in China for the period 2008-2019 by using an improved coupling coordination model and to empirically analyse its distribution dynamics and decoupling effects. The results show that the WRSE status of China's 31 provincial administrative regions from 2008 to 2019 is at a moderate level. Based on the spatiotemporal patterns and decoupling effects analysis, areas in urgent need of improving WRSE status are identified, and tailored countermeasures are provided for each area. To our knowledge, this paper is the first nationwide study of the spatiotemporal patterns and decoupling effects of WRSE.

Prediction of human thermal comfort preference based on supervised learning.

Human thermal comfort is relevant to human life comfort and plays a pivotal role in occupational health and thermal safety. To ensure that intelligent temperature-controlled equipment can deliver a sense of cosiness to people while improving its energy efficiency, we designed a smart decision-making system that sets the thermal comfort adjustment preference as a label, reflecting both the human body's thermal feeling and its acceptance of the thermal environment. By training a series of supervised learning models underpinned by environmental and human features, the most appropriate adjustment mode in the current environment was predicted. To bring this design into reality, we tried six supervised learning models, and then, by comparison and evaluation, we identified that the Deep Forest's performance was the best. The model takes into account objective environmental factors and human body parameters. In this way, it can achieve high accuracy in application and good simulation and prediction results. The results can provide feasible references for feature selection and model selection in further research with the aim of testing thermal comfort adjustment preference. The model can provide recommendations for the thermal comfort preference in a specific place at a particular time, as well as guidance on human thermal comfort preference and thermal safety precautions in specific occupational groups.

Effects of different extreme cold exposure on heart rate variability.

Frequent extreme cold events in recent years have brought serious threats to outdoor workers and rescuers. Changes in ambient temperature are associated with altered cardiac autonomic function. The study aims to investigate heart rate variability (HRV) and its relationship to other physiological parameters under extreme cold exposures. Twelve males underwent a 30-min preconditioning phase in a neutral environment followed by a 30-min cold exposure (-5, -10, -15, and -20 °C). Time-domain indexes(meanRR, SDNN, RMSSD, and pNN50), frequency domain indexes [Log(HF), Log(LF), and low frequency/high frequency (LF/HF)], parasympathetic nervous system (PNS), and sympathetic nervous system (SNS) were analysed. Results showed all HRV indexes of four cold exposures were significant. The decrease in temperature was accompanied by progressive PNS activation with SNS retraction. SDNN was the most sensitive HRV index and had good linear relationships with blood pressure, pulse, and hand temperature. The results are significant for formulating safety protection strategies for workers in extremely cold environments.Practitioner Summary: This study investigated heart rate variability (HRV) in 12 males during a 30-min cold exposure (-5, -10, -15, and -20 °C). Results showed all HRV indexes of four cold exposures were significant. The decrease in temperature was accompanied by progressive PNS activation with SNS retraction. SDNN was the most sensitive HRV index and had good linear relationships with blood pressure, pulse, and hand temperature.

Choice of Mandarin Spatial Demonstratives in Distant Interaction.

Scholars are divided on whether the Speaker's (S') choice of spatial demonstratives in verbal interaction is ego-centric or not. We studied the choice of "zhe (here)/ na (there)" by a Mandarin S instructing Hearer (H) from a few to dozens of meters. Using within-group and between-group experiments in a picture-description paradigm, we found that both S- and H- distance (Ds and Dh) to the Referent constantly influence S' demonstrative choice, and the social relation as a variable (Relation) between S and H also exerts some influence. Our findings support the idea that spatial reference in verbal interaction is somewhat non-egocentric.

Colistin Crosslinked Gemcitabine Micelles to Eliminate Tumor Drug Resistance Caused by Intratumoral Microorganisms.

In the tumor microenvironment, there exist microorganisms that metabolize anticancer drugs, leading to chemotherapy failure. To solve this problem, herein, we develop antibiotic and anticancer drug co-delivery micelles, termed colistin crosslinked gemcitabine micelle (CCGM). A self-immolative linker enables colistin and gemcitabine to be released on demand without affecting their antibacterial and anticancer effects. Once CCGM is delivered to the tumor microenvironment, intracellular glutathione triggers the release of colistin and gemcitabine, inhibiting the growth of microbes in the tumor, thus eliminating the microbe-induced drug resistance of tumor.

Integrin ß3 Deficiency Results in Hypertriglyceridemia via Disrupting LPL (Lipoprotein Lipase) Secretion.

OBJECTIVE: Integrin ß3 is implicated in numerous biological processes such as its relevance to blood triglyceride, yet whether ß3 deficiency affects this metabolic process remains unknown. Approach and Results: We showed that the Chinese patients with ß3-deficient Glanzmann thrombasthenia had a 2-fold higher serum triglyceride level together with a lower serum LPL (lipoprotein lipase) level than those with an αIIb deficiency or healthy subjects. The ß3 knockout mice recapitulated these phenotypic features. The elevated plasma triglyceride level was due to impaired LPL-mediated triglyceride clearance caused by a disrupted LPL secretion. Further analysis revealed that ß3 directly bound LPL via a juxtamembrane TIH (threonine isoleucine histidine)720-722 motif in its cytoplasmic domain and functioned as an adaptor protein by interacting with LPL and PKD (protein kinase D) to form the PKD/ß3/LPL complex that is required for ß3-mediated LPL secretion. Furthermore, the impaired triglyceride clearance in ß3 knockout mice could be corrected by adeno-associated virus serotype 9 (AAV9)-mediated delivery of wild-type but not TIH720-722-mutated ß3 genes. CONCLUSIONS: This study reveals a hypertriglyceridemia in both ß3-deficient Chinese patients and mice and provides novel insights into the molecular mechanisms of the significant roles of ß3 in LPL secretion and triglyceride metabolism, drawing attention to the metabolic consequences in patients with ß3-deficient Glanzmann thrombasthenia.

Human physiological responses of exposure to extremely cold environments.

Extremely cold events have occurred more frequently in the past few years. People exposed to extremely cold exposure could suffer the threats of human health and safety like cold stress and injury. This study aims to investigate human physiological responses of exposure to extremely cold environments and the moment of temperature step. The experiments of 12 subjects exposed to three different cold exposure conditions (-5 °C, -10 °C, -15 °C) were carried out in a climate chamber. Most critical physiological parameters, including the core temperature, local skin temperature, blood pressure, heart rate, respiration rate and blood oxygen saturation, were measured to evaluate human physiological responses. In the particular short term study, the results show that the local skin temperature and blood pressure are the most significant indexes for evaluating the risk of cold strain in extremely cold environment. The finger temperature is a critical index of hand and finger flexibility, and it will lead to serious injuries and reduced manual performance when exposed to below -5 °C for more than 20 min. The high physiological strain at the very beginning moment of cold exposure can significantly affect the ability to make correct judgment and action, and it is suggested that the personnel adapt for 3 min after entering into the extremely cold environment to stabilize physiological parameters and thus enhancing the safety and occupational performance. The experimental data of this study is also of great significance for the development and validation of thermophysiological models.

Role of bone marrow-derived mesenchymal stem cell defects in CD8+ CD28- suppressor T-lymphocyte induction in patients with immune thrombocytopenia and associated mechanisms.

Many immune dysfunctions participate in immune thrombocytopenia (ITP) pathogenesis, including numeric and functional defects in suppressor T (Ts) cells and immune-regulation abnormalities in mesenchymal stem cells (MSCs). Recent studies showed that MSCs can promote Ts cell differentiation. Thus, we compared the Ts cell induction ability of bone marrow-derived MSCs (BM-MSCs) between patients with ITP and normal controls (NCs), and examined the mechanism of this difference. Co-culture of CD8+ T cells with BM-MSCs revealed that BM-MSCs elevated Ts cell percentage and function, but the efficiency was lower in patients with ITP than in NCs. Blockade experiments showed that blockade of interleukin 6 (IL-6) partially reversed Ts cell induction by BM-MSCs. Addition of exogenous IL-6 down-regulated Ts cell apoptosis. Moreover, BM-MSCs enhanced IL-10 secretion and inhibition ability of Ts cells. IL-6 secretion, regulatory abilities of IL-10 expression in Ts cells, and the enhanced efficiency of Ts cells inhibition function by BM-MSCs were all decreased in patients with ITP. All-trans retinoic acid preconditioning promoted BM-MSC induction of Ts cell percentages and umbilical cord-derived (UC) MSCs efficiently improved ITP Ts cell numbers and dysfunction. In conclusion, defects of BM-MSCs in Ts cell induction are involved in ITP pathogenesis, and exogenous UC-MSCs may be useful for ITP therapy.

A surfactant-stripped cabazitaxel micelle formulation optimized with accelerated storage stability.

Pluronic (Poloxomer) micelles can solubilize cabazitaxel (CTX), a second-generation taxane, and then be subjected to low-temperature "surfactant-stripping" to selectively remove loose and free surfactant, thereby increasing the drug-to-surfactant ratio. We previously found that the addition of certain other co-loaded hydrophobic cargo to the micelles can result in stabilized, surfactant-stripped cabazitaxel (sss-CTX) micelles, which resist drug aggregation in aqueous storage, a common challenge for taxanes. Here, we show that elevated temperatures can accelerate the aggregation of sss-CTX micelles, thereby enabling rapid optimization of formulations with respect to the type and ratio of co-loader used for stabilization. A sss-CTX micelle formulation was developed using mifepristone as the co-loader, at a 60% mass ratio to the CTX. Drug release, hemolysis and complement activation were investigated in vitro. Microtubule stabilization and in vitro cytotoxicity were similar for sss-CTX and a conventional Tween-80 micelle formulation. In vivo pharmacokinetics also revealed similar blood circulation of the two formulations. In subcutaneous Lewis lung carcinoma tumors, as well as in an aggressive mouse model of malignant pleural effusion, sss-CTX showed a similar therapeutic effect as the Tween-80 based formulation. Altogether, these data show that sss-CTX can achieve similar efficacy as conventional Tween-80 formulations, albeit with substantially higher drug-to-surfactant ratio and with capability of extended aqueous storage.

Outcome of CARE: a 6-year national registry of acquired haemophilia A in China.

Acquired haemophilia A (AHA) is a rare haemorrhagic disorder caused by autoantibodies directed against the functional epitopes of coagulation factor VIII (FVIII). Its management relies on prompt diagnosis, control of bleeding and eradication of the inhibitor by immunosuppression. China Acquired Hemophilia Registry (CARE), a nationwide multicentre registry, was intended to survey the status of AHA and standardize its diagnosis and therapy in China. One hundred and eighty-seven registered patients had an average age of 52 years. Diagnosis was delayed in 46·5% patients. There was a significant delay from diagnosis to immunosuppressive therapy in 68·3% patients. Bleeding control was significantly higher in patients treated with prothrombin complex concentrate (PCC) versus FVIII replacement therapy (84·6% vs. 34·4%; P < 0·001). Inhibitor eradication with a combination of steroids and cyclophosphamide showed a higher partial remission (PR) rate (92·2% vs. 70·3%) and stable complete remission (CR) rate (82·8% vs. 48·6%) than with steroids alone. Logistic regression model showed age and malignancy were significantly related to survival at final follow-up. The mean age for the survivors [51 years (IQR, 35-65 years)] was significantly lower than that of the non-survivors [79 years (IQR, 67-86 years)] (P < 0·001). Overall survival was higher in non-malignancy group than malignancy group (94·9% vs. 70%) (OR = 1·313; 95% CI, 0·913-1·889, P = 0·015).

Increased plasma sCXCL16 levels may have a relationship with Th1/Th2 imbalance in primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is a disease of autoimmunity in which there are Th1/Th2 imbalance and disordered cytokine profiles. CXC chemokine ligand 16 (CXCL16) was proved to implicate in some autoimmune diseases. Our research aimed to determine plasma soluble CXCL16 (sCXCL16) levels and its effects in ITP. We used ELISA to measure plasma sCXCL16, IFN-γ and IL-4 and flow cytometry to determine expression of CXCR6 on lymphocyte subsets. We used real-time PCR to detect the CXCL16 and CXCR6 mRNA expression. Additionally, plasma sCXCL16, CXCL16 and CXCR6 mRNA levels of 8 patients were monitored before and after treatment. We found that patients with active ITP had higher circulating sCXCL16 in plasma than healthy controls and patients in remission. Meanwhile, negative relationships between sCXCL16 and platelet count, IL-4 and positive relationships between sCXCL16 and IFN-γ, IFN-γ/IL-4 ratio were observed. Besides, expression of CXCR6 on lymphocyte subsets and mRNA levels of CXCL16 and CXCR6 were all increased in active ITP. Additionally, plasma sCXCL16 and IFN-γ levels and CXCR6 mRNA expression were down-regulated after effective treatment compared with those before treatment. Thus, increased plasma sCXCL16 might be implicated in the pathogenesis of ITP and have a relationship with Th1/Th2 imbalance.

A new Mammutidae (Proboscidea, Mammalia) from the Late Miocene of Gansu Province, China.

The "Yanghecun specimen", a proboscidean specimen represented by a mandible from Miocene of China and previously described as Gomphotheriidae, is here reviewed and described as a new genus and species of Mammutidae: Sinomammut tobieni. This taxon is a longirostrine mastodon, lacking lower tusks, and bearing a wide last molar with oblique and non-inflated lophids, broad transverse interlophids, and yoke-like wear figures. Phylogenetic analysis of Mammutidae based on dental and mandibular features recovered S. tobieni as sister group of the mastodon Mammut. The longirostrine condition and the well-developed lower incisors seem to be primitive for Mammutidae, while the brevirostry is the derived condition, probably emerged during the middle Miocene (12-11 Mya). However, two derived conditions are recognized to the lower tusks: the absence of lower tusks (S. tobieni) and the occasional presence of vestigial lower tusks (Mammut).

The application effect of the optimized scheduling model of virtual power plant participation in the new electric power system.

To build a comprehensive framework for virtual power plant (VPP) development aligned with market dynamics and to devise effective strategies to foster its growth, this study undertakes several key steps. Firstly, it constructs a VPP development framework based on market conditions, to drive the evolution of new power systems and facilitating energy transformation. Secondly, through a blend of theoretical analysis and model construction, the fundamental principles of VPP are systematically elucidated, and a decision model for the VPP development framework, focusing on price demand response, is formulated. Lastly, an optimal scheduling model for the new power system is developed, with its efficacy validated across three distinct scenarios. The findings underscore the critical importance of integrating energy storage technologies, particularly pumped storage hydropower systems, for achieving balance and optimization within new power systems. Model verification reveals that the incorporation of energy storage power stations significantly enhances system stability and efficiency, particularly in addressing the volatility associated with renewable energy sources. Additionally, the analysis indicates that while the adoption of energy storage technologies may marginally increase overall power generation costs, the total power generation cost declines with the integration of battery storage and pumped storage hydropower stations. This suggests that leveraging energy storage technologies not only enhances system operational reliability but also contributes to reducing the overall cost of power production to a certain extent. In summary, this study presents an economic and environmentally sustainable scheduling model for new power systems within the context of market trading environments. By offering both theoretical insights and practical guidance, it aims to support sustainable development and energy transformation initiatives. Ultimately, the study is poised to foster the adoption of clean energy, facilitate the establishment of smart grids, and bolster the sustainable utilization of energy resources, thereby advancing environmental conservation efforts.

Evaluation of first-line and salvage therapies for unresectable malignant mesothelioma: A systematic review and network meta-analysis.

BACKGROUND: Randomized controlled trials (RCTs) of systemic therapies for unresectable malignant mesothelioma have reported conflicting results. It is crucial and urgent to find optimal treatment options for this malignancy, which currently has a poor prognosis. METHODS: Databases PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences were searched until February 29, 2024. The main outcomes of interest were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and grade ≥3 treatment-related adverse events (TRAEs). RESULTS: We analyzed 16 RCTs with a total of 5018 patients. Among first-line therapies, nivolumab and ipilimumab significantly increased OS and resulted in fewer grade ≥3 TRAEs. Bevacizumab plus chemotherapy significantly increased PFS. Among salvage therapies, ramucirumab and chemotherapy was associated with the best OS and PFS, but resulted in more grade ≥3 TRAEs. Subgroup analysis by histologic types suggested that in first-line settings, bevacizumab and chemotherapy increase OS the most for epithelioid type, while the nivolumab plus ipilimumab treatment increases OS the most for non-epithelioid type. In salvage therapies, ramucirumab and chemotherapy increase OS for both epithelioid and non-epithelioid types. CONCLUSION: Nivolumab plus ipilimumab was associated with the best OS among first-line treatments. Ramucirumab and chemotherapy was associated with the best clinical outcomes in salvage settings. Treatment for malignant mesothelioma should be tailored based on different clinicopathological characteristics.