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1.
World J Urol ; 42(1): 211, 2024 Apr 04.
Article En | MEDLINE | ID: mdl-38573354

PURPOSE: This study aimed to develop a nomogram prediction model to predict the exact probability of urinary infection stones before surgery in order to better deal with the clinical problems caused by infection stones and take effective treatment measures. METHODS: We retrospectively collected the clinical data of 390 patients who were diagnosed with urinary calculi by imaging examination and underwent postoperative stone analysis between August 2018 and August 2023. The patients were randomly divided into training group (n = 312) and validation group (n = 78) using the "caret" R package. The clinical data of the patients were evaluated. Univariate and multivariate logistic regression analysis were used to screen out the independent influencing factors and construct a nomogram prediction model. The receiver operating characteristic curve (ROC), calibration curves, and decision curve analysis (DCA) and clinical impact curves were used to evaluate the discrimination, accuracy, and clinical application efficacy of the prediction model. RESULTS: Gender, recurrence stones, blood uric acid value, urine pH, and urine bacterial culture (P < 0.05) were independent predictors of infection stones, and a nomogram prediction model ( https://zhaoyshenjh.shinyapps.io/DynNomInfectionStone/ ) was constructed using these five parameters. The area under the ROC curve of the training group was 0.901, 95% confidence interval (CI) (0.865-0.936), and the area under the ROC curve of the validation group was 0.960, 95% CI (0.921-0.998). The results of the calibration curve for the training group showed a mean absolute error of 0.015 and the Hosmer-Lemeshow test P > 0.05. DCA and clinical impact curves showed that when the threshold probability value of the model was between 0.01 and 0.85, it had the maximum net clinical benefit. CONCLUSIONS: The nomogram developed in this study has good clinical predictive value and clinical application efficiency can help with risk assessment and decision-making for infection stones in diagnosing and treating urolithiasis.


Urinary Calculi , Urinary Tract Infections , Urolithiasis , Humans , Models, Statistical , Nomograms , Prognosis , Retrospective Studies , Urinary Calculi/diagnosis , Urinary Tract Infections/diagnosis , Urinary Tract Infections/epidemiology
2.
J Integr Neurosci ; 23(4): 81, 2024 Apr 17.
Article En | MEDLINE | ID: mdl-38682217

BACKGROUND: Alzheimer's disease (AD) is an irreversible primary brain disease with insidious onset. The rise of imaging genetics research has led numerous researchers to examine the complex association between genes and brain phenotypes from the perspective of computational biology. METHODS: Given that most previous studies have assumed that imaging data and genetic data are linearly related and are therefore unable to explore their nonlinear relationship, our study applied a joint depth semi-supervised nonnegative matrix decomposition (JDSNMF) algorithm to solve this problem. The JDSNMF algorithm jointly decomposed multimodal imaging genetics data into both a standard basis matrix and multiple feature matrices. During the decomposition process, the coefficient matrix A multilayer nonlinear transformation was performed using a neural network to capture nonlinear features. RESULTS: The results using a real dataset demonstrated that the algorithm can fully exploit the association between strongly correlated image genetics data and effectively detect biomarkers of AD. Our results might provide a reference for identifying biologically significant imaging genetic correlations, and help to elucidate disease-related mechanisms. CONCLUSIONS: The diagnostic model constructed by the top features of the three modality data sets mined by the algorithm has high accuracy, and these features are expected to become new therapeutic targets for AD.


Alzheimer Disease , Machine Learning , Alzheimer Disease/genetics , Alzheimer Disease/diagnostic imaging , Humans , Neuroimaging/methods , Genetic Markers , Magnetic Resonance Imaging , Brain/diagnostic imaging , Brain/metabolism , Algorithms , Aged , Neural Networks, Computer
3.
PeerJ ; 12: e17131, 2024.
Article En | MEDLINE | ID: mdl-38563000

Global warming continues to exert unprecedented impacts on marine habitats. Species distribution models (SDMs) are proven powerful in predicting habitat distribution for marine demersal species under climate change impacts. The Antarctic toothfish, Dissostichus mawsoni (Norman 1937), an ecologically and commercially significant species, is endemic to the Southern Ocean. Utilizing occurrence records and environmental data, we developed an ensemble model that integrates various modelling techniques. This model characterizes species-environment relationships and predicts current and future fishable habitats of D. mawsoni under four climate change scenarios. Ice thickness, depth and mean water temperature were the top three important factors in affecting the distribution of D. mawsoni. The ensemble prediction suggests an overall expansion of fishable habitats, potentially due to the limited occurrence records from fishery-dependent surveys. Future projections indicate varying degrees of fishable habitat loss in large areas of the Amery Ice Shelf's eastern and western portions. Suitable fishable habitats, including the spawning grounds in the seamounts around the northern Ross Sea and the coastal waters of the Bellingshausen Sea and Amundsen Sea, were persistent under present and future environmental conditions, highlighting the importance to protect these climate refugia from anthropogenic disturbance. Though data deficiency existed in this study, our predictions can provide valuable information for designing climate-adaptive development and conservation strategies in maintaining the sustainability of this species.


Climate Change , Perciformes , Animals , Antarctic Regions , Ecosystem , Oceans and Seas
4.
Materials (Basel) ; 17(5)2024 Feb 20.
Article En | MEDLINE | ID: mdl-38473455

Heat treatment is an important process for optimizing the microstructures of superalloys, and the cooling rate after solid solution treatment is one of the most critical parameters. In this work, we treated solid solution MAR-M247 alloys with water quenching, air cooling, and furnace cooling. Microstructure characterization, hardness, and room temperature tensile tests were conducted to investigate the effect of cooling rate on the microstructure and mechanical properties of MAR-M247 alloys. The results showed that the cooling rate after solid solution treatment mainly affected the precipitation behavior of the secondary γ' phase, but it had few effects on other microstructure characterizations, including grain size, γ/γ' eutectic, and MC carbide. The water-quenched sample had the highest cooling rate (400 °C/s) and hardness (400 HV) but suffered from premature fracture because of quenching cracks. A further decrease in cooling rate from 1.5 °C/s to 0.1 °C/s deteriorated hardness (384 HV to 364 HV) and yield strength (960 MPa to 771 MPa) but increased elongation (8.5% to 13.5%). Moreover, the deformation mechanism was transformed from dislocation shearing to Orowan bypassing. The decreased yield strength was mainly due to the weakened precipitation strengthening resulting from γ'-phase coarsening. The improved elongation was attributed to not only the higher work-hardening index caused by interface dislocation networks but also the more uniform deformation, which delayed necking.

5.
Jpn J Radiol ; 2024 Feb 21.
Article En | MEDLINE | ID: mdl-38381250

PURPOSE: To evaluate the diagnostic accuracy of abdominal contrast-enhanced multi-slice spiral CT after oral diluted iodide in a time segment (post-ODI ACE-MSCT) for gastrointestinal fistula (GIF) in severe acute pancreatitis (SAP). MATERIALS AND METHODS: Patients with SAP who underwent both post-ODI ACE-MSCT and endoscopy/surgery from 2017 to 2023 were continuously retrospectively involved. Their demographic information and clinical features were recorded prospectively in an in-hospital database. Using endoscopy/surgery results as the reference standard, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of post-ODI ACE-MSCT for diagnosing GIF in SAP were calculated by a four-cell table. The consistency of the two diagnostic methods was evaluated by the Kappa test and McNemar's test. RESULTS: Using endoscopy/surgery as the reference standard, a total of 86 cases were divided into the GIF group (N = 52) and the non-GIF group (N = 34). Among the 52 cases of GIF, 88.5% (46/52) cases had a positive result and 11.5% (5/52) cases had a negative result of post-ODI ACE-MSCT for GIF. Among the 34 cases of non-GIF, 2.9% (1/34) case had a positive result and 97.1% (33/34) cases had a negative result of post-ODI ACE-MSCT for GIF. Post-ODI ACE-MSCT had a sensitivity of 88.5% (95% CI 75.9%-95.2%), a specificity of 97.1% (95% CI 82.9%-99.8%), a positive predictive value of 97.9% (95% CI 87.3%-99.9%), a negative predictive value of 84.6% (95% CI 68.8%-93.6%), and an accuracy of 91.9% (83.4%-96.4%). The kappa value was 0.834, and P < 0.001 by McNemar's test. There were no significant differences in diagnostic test characteristics between the two modalities. CONCLUSION: Post-ODI ACE-MSCT can diagnose GIF in SAP in a simple, noninvasive, and accurate way, and can provide earlier imaging evidence for clinical diagnosis and treatment.

6.
Materials (Basel) ; 16(19)2023 Sep 25.
Article En | MEDLINE | ID: mdl-37834538

Strain-induced precipitation (SIP) behaviors of 7Mo super-austenitic stainless steel (SASS) under various deformation conditions were studied by stress relaxation tests. The research demonstrates that sigma phases are the primary SIP phases of 7Mo SASS. Generally, SIP is mainly distributed in granular shape at the boundaries of deformed grains or recrystallized grains, as well as around the deformed microstructure, such as deformation twin layers/matrix interfaces. The variation of deformation parameters can lead to changes in microstructure, therefore influencing the distribution of SIP. For instance, with the temperature increases, the SIP distribution gradually evolves from deformed grain boundaries to recrystallized grain boundaries. The average size of SIP increases with increasing temperature and strain, as well as decreasing strain rate. The SIP content also increases with increasing strain and decreasing strain rate, while exhibiting an initial rise followed by a decline with increasing temperature, reaching its maximum value at 850 °C. The presence of SIP can promote recrystallization by particle-induced nucleation (PSN) mechanism during the hot deformation process. Moreover, the boundaries of these recrystallized grains can also serve as nucleation sites for SIP, therefore promoting SIP. This process can be simplified as SIP→PSNRecrystallization→Nucleation sitesSIP. With the increase in holding time and the consumption of stored energy, the process gradually slows down, leading to the formation of a multi-layer structure, namely SIPs/Recrystallized grains/SIPs structure. Moreover, SIP at recrystallized grain boundaries can hinder the growth of recrystallized grains. Through this study, a comprehensive understanding of the SIP behaviors in 7Mo SASS under different deformation conditions has been achieved, as well as the interaction between SIP and recrystallization. This finding provides valuable insights for effective control or regulation of SIP and optimizing the hot working processes of 7Mo SASS.

7.
Materials (Basel) ; 16(17)2023 Aug 31.
Article En | MEDLINE | ID: mdl-37687678

Research on rare-earth fluorides is of urgent and critical importance for the preparation and emerging applications of high-purity alloys. The fluorination of Sc2O3 by NH4HF2 to fabricate ScF3 is investigated. The effects of the fluorination temperature, time and mass ratio of reactant on the fluorination rate and fluoride are discussed in this work. The fluorination reaction was first confirmed using thermodynamic calculation. The thermal and mass stability of the fluorination process were analyzed by thermogravimetric and differential scanning calorimetric (TG-DSC). The as-obtained products at different fluorination temperatures were characterized by Powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM). The results indicated that the fluorination began at room temperature (RT) with the formation of (NH4)3ScF6. With the increase of temperature, the reaction proceeded sequentially through the formation of NH4ScF4, (NH4)2Sc3F11, and finally ScF3. The fluorination rate increased with the increase of fluorination temperature and holding time. ScF3 with a purity of 99.997 wt.% could be obtained by fluorination at 400 °C for 2 h.

8.
Environ Sci Pollut Res Int ; 30(39): 90675-90688, 2023 Aug.
Article En | MEDLINE | ID: mdl-37462866

Researchers neglected the relevance of combining tourism with stakeholders' engagement and financial stability for unlocking the economic constraints. For this, current research intended to study the interplay of tourism recovery options under economic constraints with the role of stakeholders' engagement and financial stability. According to our data, China outperforms the other OECD members. The results shown that Russia comes in second with a consistent in tourism recovery, financial stability, and stakeholders' engagement; Indonesia and Turkey, which finished fourth and fifth in the rankings, have good tourism recovery prospects. Mexico and Brazil come in second and third, respectively, with the worst performance and the lowest scores recorded in the survey findings. The overall interplay among the variables was empirically produced based on the findings of this study and is a new inclusive assessment of financial stability and tourism recovery parameters. It is a useful tool for policy development and evaluation. This study also addresses the criticism of load selection at random and accurately depicts the entire scope of fiscal intervention in the economy to prudently enhance tourism recovery at large.


Stakeholder Participation , Tourism , Turkey , China , Indonesia , Economic Development
10.
Sci Adv ; 9(21): eade7280, 2023 05 26.
Article En | MEDLINE | ID: mdl-37235659

Mechanisms underlying arteriovenous malformations (AVMs) are poorly understood. Using mice with endothelial cell (EC) expression of constitutively active Notch4 (Notch4*EC), we show decreased arteriolar tone in vivo during brain AVM initiation. Reduced vascular tone is a primary effect of Notch4*EC, as isolated pial arteries from asymptomatic mice exhibited reduced pressure-induced arterial tone ex vivo. The nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-l-arginine (L-NNA) corrected vascular tone defects in both assays. L-NNA treatment or endothelial NOS (eNOS) gene deletion, either globally or specifically in ECs, attenuated AVM initiation, assessed by decreased AVM diameter and delayed time to moribund. Administering nitroxide antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl also attenuated AVM initiation. Increased NOS-dependent production of hydrogen peroxide, but not NO, superoxide, or peroxynitrite was detected in isolated Notch4*EC brain vessels during AVM initiation. Our data suggest that eNOS is involved in Notch4*EC-mediated AVM formation by up-regulating hydrogen peroxide and reducing vascular tone, thereby permitting AVM initiation and progression.


Arteriovenous Malformations , Hydrogen Peroxide , Nitric Oxide Synthase Type III , Animals , Mice , Arteries/metabolism , Hydrogen Peroxide/metabolism , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/metabolism , Nitroarginine/pharmacology
11.
Materials (Basel) ; 16(9)2023 Apr 28.
Article En | MEDLINE | ID: mdl-37176320

Super austenitic stainless steels are expected to replace expensive alloys in harsh environments due to their superior corrosion resistance and mechanical properties. However, the ultra-high alloy contents drive serious segregation in cast steels, where the σ phase is difficult to eliminate. In this study, the microstructural evolution of 7Mo super austenitic stainless steels under different homogenization methods was investigated. The results showed that after isothermal treatment for 30 h at 1250 °C, the σ phase in steels dissolved, while the remelting morphologies appeared at the phase boundaries. Therefore, the stepped solution heat treatment was further conducted to optimize the homogenized microstructure. The samples were heated up to 1220 °C, 1235 °C and 1250 °C with a slow heating rate, and held at these temperatures for 2 h, respectively. The elemental segregation was greatly reduced without incipient remelting and the σ phase was eventually reduced to less than 0.6%. A prolonged incubation below the dissolution temperature will lead to a spontaneous compositional adjustment of the eutectic σ phase, resulting in uphill diffusion of Cr and Mn, and reducing the homogenization efficiency of ISHT, which is avoided by SSHT. The hardness reduced from 228~236 Hv to 220~232 Hv by adopting the cooling process of "furnace cooling + water quench". In addition, the study noticed that increasing the Ce content or decreasing the Mn content can both refine the homogenized grain size and accelerate diffusion processes. This study provides a theoretical and experimental basis for the process and composition optimization of super austenitic stainless steels.

12.
Materials (Basel) ; 16(5)2023 Feb 27.
Article En | MEDLINE | ID: mdl-36903077

The plate-like iron-rich intermetallic phases in recycled aluminum alloys significantly deteriorate the mechanical properties. In this paper, the effects of mechanical vibration on the microstructure and properties of the Al-7Si-3Fe alloy were systematically investigated. Simultaneously, the modification mechanism of the iron-rich phase was also discussed. The results indicated that the mechanical vibration was effective in refining the α-Al phase and modifying the iron-rich phase during solidification. The forcing convection and a high heat transfer inside the melt to the mold interface caused by mechanical vibration inhibited the quasi-peritectic reaction: L + α-Al8Fe2Si → (Al) + ß-Al5FeSi and eutectic reaction: L → (Al) + ß-Al5FeSi + Si. Thus, the plate-like ß-Al5FeSi phases in traditional gravity-casting were replaced by the polygonal bulk-like α-Al8Fe2Si. As a result, the ultimate tensile strength and elongation were increased to 220 MPa and 2.6%, respectively.

13.
Cancer Med ; 12(3): 2538-2550, 2023 02.
Article En | MEDLINE | ID: mdl-35912894

OBJECTIVE: Despite controversy over its origin and definition, the significance of tumour deposit (TD) has been underestimated in the tumour node metastasis (TNM) staging system for colon cancer, especially in stage III patients. We aimed to further confirm the prognostic value of TD in stage III colon cancer and to establish a more accurate 'coN' staging system combining TD and lymph node metastasis (LNM). METHODS: Information on stage III colon cancer patients with a definite TD status was retrospectively collected from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2017. The effect of TD on prognosis was estimated using Cox regression analysis. Maximally selected rank statistics were used to select the optimal cut-off value of TD counts. The predictive power of conventional N staging and the new coN staging was evaluated and compared by Akaike's information criterion (AIC), Harrell's concordance index (C-index) and time-dependent receiver operating characteristic (ROC) curves. Clinicopathological data of stage III colon cancer patients in the Xiangya database from 2014 to 2018 were collected to validate the coN staging system. RESULTS: A total of 39,185 patients with stage III colon cancer were included in our study: 38,446 in the SEER cohort and 739 in the Xiangya cohort. The incidence of TD in stage III colon cancer was approximately 30% (26% in SEER and 30% in the Xiangya database). TD was significantly associated with poorer overall survival (OS) (HR = 1.37, 95% CI 1.31-1.44, p < 0.001 in SEER). The optimal cut-off value of TD counts was 4, and the patients were classified into the TD0 (count = 0), TD1 (count = 1-3) and TD2 (count ≥ 4) groups accordingly. The estimated 5-year OS was significantly different among the three groups (69.4%, 95% CI 68.8%-70.0% in TD0; 60.5%, 95% CI 58.9%-62.2% in TD1 and 42.6%, 95% CI 39.2%-46.4% in TD2, respectively, p < 0.001). The coN system integrating LNM and TD was established, and patients with stage III colon cancer were reclassified into five subgroups (coN1a, coN1b, coN2a, coN2b and coN2c). Compared with conventional N staging, the coN staging Cox model had a smaller AIC (197097.581 vs. 197358.006) and a larger C-index (0.611 vs. 0.601). The AUCs of coN staging at 3, 5 and 7 years were also greater than those of conventional N staging (0.6305, 0.6326, 0.6314 vs. 0.6186, 0.6197, 0.6160). Concomitant with the SEER cohort results, the coN staging Cox model of the Xiangya cohort also had a smaller AIC (2883.856 vs. 2906.741) and a larger C-index (0.669 vs. 0.633). Greater AUCs at 3, 5 and 7 years for coN staging were also observed in the Xiangya cohort (0.6983, 0.6774, 0.6502 vs. 0.6512, 0.6368, 0.6199). CONCLUSIONS: Not only the presence but also the number of TDs is associated with poor prognosis in stage III colon cancer. A combined N staging system integrating LNM and TD provides more accurate prognostic prediction than the latest AJCC N staging in stage III colon cancer.


Colonic Neoplasms , Extranodal Extension , Humans , Lymphatic Metastasis/pathology , Neoplasm Staging , Extranodal Extension/pathology , Retrospective Studies , Lymph Nodes/pathology , Prognosis , Colonic Neoplasms/pathology
14.
Front Immunol ; 13: 987394, 2022.
Article En | MEDLINE | ID: mdl-36330510

Objective: The poor prognosis and heterogeneity of stage III colon cancer (CC) suggest the need for more prognostic biomarkers. The tumor microenvironment (TME) plays a crucial role in tumor progression. We aimed to explore novel immune infiltration-associated molecules that serve as potential prognostic and therapeutic targets. Methods: TME immune scores were calculated using "TMEscore" algorithm. Differentially expressed genes between the high and low TME immune score groups were identified and further investigated through a protein-protein interaction network and the Molecular Complex Detection algorithm. Cox regression, meta-analysis and immunohistochemistry were applied to identify genes significantly correlated with relapse-free survival (RFS). We estimated immune infiltration using three different algorithms (TIMER 2.0, CIBERSORTx, and TIDE). Single-cell sequencing data were processed by Seurat software. Results: Poor RFS was observed in the low TME immune score groups (log-rank P < 0.05). EPSTI1 was demonstrated to be significantly correlated with RFS (P < 0.05) in stage III CC. Meta-analysis comprising 547 patients revealed that EPSTI1 was a protective factor (HR = 0.79, 95% CI, 0.65-0. 96; P < 0.05)). More immune infiltrates were observed in the high EPSTI1 group, especially M1 macrophage and myeloid dendritic cell infiltration (P < 0.05). Conclusion: The TME immune score is positively associated with better survival outcomes. EPSTI1 could serve as a novel immune prognostic biomarker for stage III CC.


Colonic Neoplasms , Neoplasm Recurrence, Local , Humans , Prognosis , Colonic Neoplasms/diagnosis , Tumor Microenvironment , Biomarkers , Neoplasm Proteins
15.
Materials (Basel) ; 15(19)2022 Sep 20.
Article En | MEDLINE | ID: mdl-36233865

Creep deformation is one of the main failure forms for superalloys during service and predicting their creep life and curves is important to evaluate their safety. In this paper, we proposed a back propagation neural networks (BPNN) model to predict the creep curves of MarM247LC superalloy under different conditions. It was found that the prediction errors for the creep curves were within ±20% after using six creep curves for training. Compared with the θ projection model, the maximum error was reduced by 30%. In addition, it is validated that this method is applicable to the prediction of creep curves for other superalloys such as DZ125 and CMSX-4, indicating that the model has a wide range of applicability.

16.
Materials (Basel) ; 15(19)2022 Sep 24.
Article En | MEDLINE | ID: mdl-36233982

The stability of the thermal properties of diamond/Al composites during thermal cycling is crucial to their thermal management applications. In this study, we realize a well-bonded interface in diamond/Al composites by interfacial in situ Al4C3 engineering. As a result, the excellent stability of thermal conductivity in the diamond/Al composites is presented after 200 thermal cycles from 218 to 423 K. The thermal conductivity is decreased by only 2-5%, mainly in the first 50-100 thermal cycles. The reduction of thermal conductivity is ascribed to the residual plastic strain in the Al matrix after thermal cycling. Significantly, the 272 µm-diamond/Al composite maintains a thermal conductivity over 700 W m-1 K-1 after 200 thermal cycles, much higher than the reported values. The discrete in situ Al4C3 phase strengthens the diamond/Al interface and reduces the thermal stress during thermal cycling, which is responsible for the high thermal conductivity stability in the composites. The diamond/Al composites show a promising prospect for electronic packaging applications.

17.
Opt Express ; 30(21): 38060-38076, 2022 Oct 10.
Article En | MEDLINE | ID: mdl-36258379

In this study, a 1550 nm coherent high-spectral-resolution lidar (CHSRL) is developed to measure the optical properties of aerosols and atmospheric wind profiles in the atmospheric boundary layer. To determine the optical properties, a coherent frequency discriminator based on the fast Fourier transform is designed in the CHSRL to separate the Mie and the Rayleigh-Brillouin backscatter spectra to fulfill the needs of high-spectral measurements. The atmospheric wind velocity is retrieved using the simultaneously measured Doppler shift. This non-optical frequency discriminator is a feasible and low-cost solution compared to a narrow-bandwidth optical filter, such as a Fabry-Perot interferometer or an atomic filter. However, shot, amplifier spontaneous emission, and detector noise interfere with the Rayleigh-Brillouin spectrum. Therefore, a spectrum correction algorithm is proposed to recover the interfered Rayleigh-Brillouin spectrum, and the measurement results of the spectral line agree well with those modeled with Tenti S6 at different central frequencies. Finally, field observations for comparison are conducted with the co-located CHSRL, Raman lidar, and coherent Doppler wind lidar. The comparison results indicate that the correlation coefficient of the aerosol backscatter coefficient is 0.84. The correlation coefficient and standard deviation of wind velocity are 0.98 and 0.13 m · s-1, respectively.

18.
Cancer Immunol Res ; 10(10): 1175-1189, 2022 10 04.
Article En | MEDLINE | ID: mdl-35981087

Novel therapeutic approaches combining immune-checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3 (LAG-3) is an immune-checkpoint molecule that inhibits T-cell activity and antitumor immune responses, acting through an independent mechanism from that of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Here, we describe the development and preclinical characterization of relatlimab, a human antibody that binds to human LAG-3 with high affinity and specificity to block the interaction of LAG-3 with the ligands MHC II and fibrinogen-like protein-1, and to reverse LAG-3-mediated inhibition of T-cell function in vitro. Consistent with previous reports, in mouse models, the combined blockade of LAG-3 and PD-1 with surrogate antibodies resulted in enhanced antitumor activity greater than the individual blockade of either receptor. In toxicity studies in cynomolgus monkeys, relatlimab was generally well tolerated when combined with nivolumab. These results are consistent with findings from the RELATIVITY-047 phase II/III trial showing that relatlimab combined with nivolumab is a well-tolerated regimen that demonstrates superior progression-free survival compared with nivolumab monotherapy in patients with unresectable or metastatic melanoma.


Melanoma , Nivolumab , Animals , Antibodies, Blocking/therapeutic use , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , CTLA-4 Antigen , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Fibrinogen/therapeutic use , Humans , Immune Checkpoint Inhibitors , Macaca fascicularis , Melanoma/pathology , Mice , Nivolumab/therapeutic use , Programmed Cell Death 1 Receptor
19.
ACS Appl Mater Interfaces ; 14(30): 35215-35228, 2022 Aug 03.
Article En | MEDLINE | ID: mdl-35878880

Manipulating the interfacial structure is vital to enhancing the interfacial thermal conductance (G) in Cu/diamond composites for promising thermal management applications. An interconnected interlayer is frequently observed in Cu/diamond composites; however, the G between Cu and diamond with an interconnected interlayer has not been addressed so far and thus is attracting extensive attention in the field. In this study, we designed three kinds of interlayers between a Cu film and a diamond substrate by magnetron sputtering coupled with heat treatment, including a W interlayer, an interconnected W-W2C interlayer, and a W2C interlayer, to comparatively elucidate the relationship between the interfacial structure and the interfacial thermal conductance. For the first time, we experimentally measured the G between Cu and diamond with an interconnected interlayer by a time-domain thermoreflectance technique. The Cu/W-W2C/diamond structure exhibits an intermediate G value of 25.8 MW/m2 K, higher than the 19.9 MW/m2 K value for the Cu/W2C/diamond structure and lower than the 29.4 MW/m2 K value for the Cu/W/diamond structure. The molecular dynamics simulations show that the G of the individual W2C/diamond interface is much higher than those of the individual Cu/diamond and W/diamond interfaces and W2C could reduce the vibrational mismatch between Cu and diamond; however, the G of the Cu/W2C/diamond structure is reduced by the lower thermal conductivity of W2C. This study provides insights into the relationship between the interconnected interfacial structure and the G between Cu and diamond and offers guidance for interface design to improve the thermal conductivity in Cu/diamond composites.

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