Search Results (686)

Anti-PD-1 therapies have transformed cancer treatment by restoring antitumor T cell activity. Despite their broad clinical use, variability in treatment response and immune-related adverse events underscore the need for therapeutic optimization. This article provides an integrative overview of the pharmacokinetics (PKs) of anti-PD-1 antibodies—such as nivolumab, pembrolizumab, and cemiplimab—and examines pharmacokinetic–pharmacodynamic (PK-PD) relationships, highlighting the impact of clearance variability on drug exposure, efficacy, and safety. Baseline clearance and its reduction during therapy, together with interindividual variability, emerge as important dynamic biomarkers with potential applicability across different cancer types for guiding individualized dosing strategies. The review also discusses established biomarkers for anti-PD-1 therapies, including tumor PD-L1 expression and immune cell signatures, and their relevance for patient stratification. The evidence supports a shift from traditional weight-based dosing toward adaptive dosing and therapeutic drug monitoring (TDM), especially in long-term responders and cost-containment contexts. Notably, the inclusion of clearance-based biomarkers—such as baseline clearance and its reduction—into therapeutic models represents a key step toward individualized, dynamic immunotherapy. In conclusion, optimizing anti-PD-1 therapy through PK-PD insights and biomarker integration holds promise for improving outcomes and reducing toxicity. Future research should focus on validating PK-based approaches and developing robust algorithms (machine learning models incorporating clearance, tumor burden, and other validated biomarkers) for tailored cancer treatment. Full article

Next-generation cancer immunotherapy increasingly combines tumor-targeting antibodies or antibody–drug conjugates (ADCs) with immune effector cells to enhance therapeutic precision. However, many existing approaches rely on genetic modification or complex manufacturing, limiting their clinical scalability and rapid deployment. To address this issue, we developed an antibody capture protein (ACP)-based surface engineering platform that enables the rapid, reversible, and non-genetic functionalization of NK cells with therapeutic antibodies or ADCs. This approach uses a DMPE-PEG-lipid conjugate to anchor thiolated protein A (ACP) to the NK cell membrane via hydrophobic insertion, thereby stably and selectively binding to the Fc region of IgG molecules. Using this strategy, we developed ACP-modified NK cells (AC-NKs) that can selectively capture therapeutic antibodies (trastuzumab (TZ), trastuzumab-emtansine (T-DM1), and sacituzumab (SZ)) pre-bound to each target antigen on tumor cells and induce antigen-specific cytotoxic responses. The resulting AC-NKs exhibited enhanced tumor recognition and cytotoxicity against HER2-positive and Trop-2-positive cancer cells in vitro. Compared with conventional combination therapies, AC-NKs enhanced immune activation, as demonstrated by effective delivery of cytotoxic agents, enhanced cancer cell engagement, and upregulation of CD107a expression. Notably, the system supports multiple antigen targeting and tunable antibody loading, enabling adaptation to tumor heterogeneity and resistant phenotypes. This platform might also provide a simple, scalable, and safe method for rapidly developing programmable immune cell therapies without genetic modification. Its versatility supports multi-antigen targeting and broad applicability across NK and T cell therapies, offering a promising path toward personalized, off-the-shelf chemoimmunotherapy. Full article

Efficient water and nitrogen (N) management are essential for sustaining potato (Solanum tuberosum L.) production under limited resource conditions. This study investigated the effects of deficit irrigation and reduced N application on tuber quality parameters including specific gravity (SG), starch content (SC), and tuber dry matter (TDM) as well as agronomic water use efficiency (WUE) and nitrogen use efficiency (NUE) in four commercial potato cultivars (Canela Russet, Mesa Russet, Russet Norkotah 3, and Yukon Gold) over two seasons (2016 and 2017) at Colorado State University’s San Luis Valley Research Center. Three irrigation levels (100%, ~80%, and ~70% evapotranspiration replacement) and two N application rates (165 and 131 kg N ha⁻¹) were evaluated using four replications. Moderate deficit irrigation (up to ~18% ET reduction) improved or maintained SG, SC, and TDM in all four cultivars, while severe deficit irrigation (~30–40% reduction) reduced tuber quality. Reduced N application improved NUE in all cultivars without compromising tuber quality or yield. While WUE responded variably to deficit irrigation, NUE was highest under moderate to full irrigation and low N rate. Although effects on WUE were variable, integrating moderate deficit irrigation (18%) with reduced N application (20%) enhanced NUE while maintaining tuber quality. Full article

The provenance of the Middle-Upper Permian in the Lintan and Jiangligou areas, remnants of rift basin sedimentation within the West Qinling, remains controversial, hindering understanding of the basin-range coupling evolution of the Qinling Orogenic Belt and its periphery. Heavy minerals, major and trace elements, rare earth elements, detrital zircon U-Pb dating, and in situ Lu-Hf isotopes were analyzed to determine the provenance of the Middle-Upper Permian sandstones. Results were integrated with previous studies to investigate basin-range coupling processes. The results reveal the following: (1) The Upper Member of the Shilidun Formation in the Lintan area was deposited during the Late Permian. Heavy minerals are dominated by moderately to highly stable species. Source rocks were derived from intermediate-acidic magmatic rocks and low- to medium-grade metamorphic terrains. The provenance was primarily situated in a continental island arc tectonic setting. Diverse source rock types were identified, including materials from felsic igneous, quartzose recycled, and mafic igneous provenances. Detrital zircon U–Pb age spectra display two major peak ages at 285 Ma and 442 Ma, along with five subordinate peaks at 818 Ma, 970 Ma, 1734 Ma, 1956 Ma, and 2500 Ma. The ε_Hf(t) values range from –44.95 to 42.67, and T_DM2 ages vary from 367 Ma to 4106 Ma. It is concluded that the sedimentary materials were mainly derived from the North Qinling Orogenic Belt, with minor contributions from the basement of the North China Craton. (2) In the Jiangligou area, the Shiguan Formation is characterized by highly and stable heavy minerals. The provenance is dominated by intermediate-acidic magmatic rocks, within an oceanic island arc tectonic setting. Detrital zircon U–Pb age spectrum displays a prominent peak at 442 Ma. The ε_Hf(t) values range from –0.5 to 10.55, with T_DM2 ages ranging from 744 Ma to 897 Ma. These results indicate that the sedimentary materials were derived from the North Qilian Orogenic Belt. (3) The Permian in the Western Qinling exhibit multi-provenance supply, dominated by the North Qinling Orogenic Belt and the North China Craton basement, with local contributions from the North Qilian Orogenic Belt. Significant regional variations in provenance contributions were identified. This study further constrains the closure of the Shangdan Ocean to pre-Late Permian. It reveals that the Western Qinling was situated in a back-arc rift basin setting during the Late Paleozoic. Key sedimentary evidence is provided for understanding the tectonic evolution of the Paleo-Tethys Ocean and the collision between the North China and Yangtze cratons. Full article

Employing commercial off-the-shelf coherent optical transmission components and methods to design a continuous variable quantum key distribution (CVQKD) system is a promising trend of achieving QKD with high security key rate (SKR) and cost-effectiveness. In this paper, we explore a CVQKD system based on the widely used polarization division multiplexed (PDM) coherent optical transmission structure and pilot-aided digital signal processing methods. A simplified pilot-aided phase noise compensation scheme based on frequency division multiplexing (FDM) is proposed, which introduces less total excess noise than classical pilot-aided schemes based on time division multiplexing (TDM). In addition, the two schemes of training symbol (TS)-aided equalization are compared to find the optimal strategy for TS insertion, where the scheme based on block insertion strategy can provide the SKR gain of around 29%, 22%, and 15% compared with the scheme based on fine-grained insertion strategy at the transmission distance of 5 km, 25 km, and 50 km, respectively. The joint optimization of pilot-aided and TS-aided methods in this work can provide a reference for achieving a CVQKD system with a high SKR and low complexity in metropolitan-scale applications. Full article

Background/Objectives: Adalimumab and Infliximab are biologics used to treat autoimmune diseases. Monitoring drug and anti-drug antibody (ADA) levels in patients helps optimize treatment. However, current quantitation methodologies for drug and total (free and drug-bound) ADAs often involve multi-step workflows. Automated systems can streamline the process. The i-Tracker chemiluminescent immunoassays (CLIA) are cartridge-based kits for quantifying serum levels of drugs such as Adalimumab, Infliximab, and associated ADAs. Herein, we aimed to establish performance characteristics of the i-Tracker Adalimumab, Infliximab, and total ADAs in serum on the random-access analyzer IDS-iSYS and to compare patient results with an electrochemiluminescent immunoassay (ECLIA)-based reference method. Methods: Remnant serum specimens, calibration material, or spiked serum were used to evaluate assay linearity, precision, functional sensitivity, and accuracy on the IDS-iSYS analyzer and to perform the method comparison. Results: The assays displayed linearity, accuracy, and up to 8% imprecision across clinically relevant analyte ranges. Compared to the reference method, the drug assays exhibited a strong linear fit (correlation coefficient > 0.95) with <±1.0 µg/mL mean bias. The total anti-Adalimumab assay demonstrated over 85% qualitative agreement. The total anti-Infliximab assay, however, showed higher detection rate of ADAs in Infliximab-treated patient specimens, yielding < 60% negative agreement with the reference method. Although i-Tracker total ADA assays exhibited drug sensitivity, they still detected ADAs in supratherapeutic drug concentrations. Conclusions: The i-Tracker assays demonstrated robust analytical performance, suggesting potential for clinical application. The method comparison underscored functional differences with the reference method, an important consideration when transitioning assay formats for monitoring Adalimumab- and Infliximab-treated patients. Full article

The Jiapigou mining district, a world-famous gold-producing district with a capacity that greatly exceeds 180 t Au, has a mining history longer than 200 years. The large amount of Jurassic Au mineralization in this district significantly differs from that in other districts of the North China Craton (130–115 Ma). However, the deep-seated dynamic processes and mechanisms that triggered the unique Jurassic mineralization in the Jiapigou district are poorly understood. Here, we present new data on the geology, petrography, and zircon U–Pb and Lu–Hf isotopes of the typical Huangnihe pluton in the Jiapigou district to address the above issues. The results revealed the following: (1) The Huangnihe pluton comprises mainly fine-grained granite and porphyritic granite, which were emplaced at 187 ± 2 Ma (n = 13) and 166 ± 2 Ma (n = 15), respectively. (2) The Hf isotope data indicate that the two episodes of granites exhibit distinct origins: the former (εHf(t) = −1.4 to +5.3; T_DM2 = 1784–1181 Ma) originated from juvenile lower crust, whereas the latter (εHf(t) = −14.9 to −9.7; T_DM2 = 2987–2518 Ma) was derived from Archean crust. (3) On the basis of published geochemical data, the estimated crustal thicknesses of the Jiapigou district ca. 187 Ma, ca. 175 Ma, and ca. 166 Ma ranged from 45 to 52 km, 43 km, and 58 to 63 km, respectively. Combined with regional observations, the results of this study further reveal the following: (1) The Jurassic magmatism in the Jiapigou district can be subdivided into three episodes: 187–186 Ma, ca. 175 Ma, and 166–165 Ma. (2) The crust in the Jiapigou district gradually thickened during the Jurassic and underwent partial melting during multiple episodes of Paleo-Pacific Plate subduction, thereby generating arc-like calc-alkaline (ca. 187 Ma), adakite-like (ca. 175 Ma), and adakite magmas (ca. 166 Ma) that were emplaced to form corresponding granitoids. Moreover, syn-ore magma mixing between the ca. 175 Ma adakite-like felsic magma and mantle-derived mafic magmas was considered a crucial process in magma evolution. This process in turn promoted the enrichment of ore-forming elements within the magma system, which significantly contributed to the formation of the large Au mineralization in the Jiapigou district. Full article

The Xifanping Cu–(Au) deposit, a small-scale porphyry system in the central Jinshajiang–Red River tectonic belt (JSRR), formed in a Cenozoic collisional setting. This study integrates zircon U–Pb geochronology, Lu–Hf isotopes, whole-rock geochemistry, and zircon trace element analyses of ore-bearing and barren porphyries, combined with regional comparisons, to constrain magma sources, metallogenic controls, and genetic processes. Ore-bearing biotite quartz monzonite porphyries were emplaced at 32.15 ± 0.43 Ma and 32.49 ± 0.57 Ma, post-dating barren quartz monzonite porphyry (33.15 ± 0.51 Ma). These ages are consistent with molybdenite Re–Os ages (32.1 ± 1.6 Ma), indicating near-synchronous magmatism and mineralization. Both porphyry types belong to the shoshonitic, peraluminous series, enriched in LILE, depleted in HFSE, enriched in LREE, and lacking significant Eu anomalies. Their εHf (t) values (–2.94 to +3.68) and crustal model ages (TDM2 = 0.88–1.30 Ga) indicate derivation from Neoproterozoic subduction-modified lower crust. Ore-bearing porphyries, however, exhibit higher zircon Ce⁴⁺/Ce³⁺ ratios (average = 584 vs. 228 for barren porphyries) and elevated hydrous mineral contents (>10 vol.% amphibole + biotite), indicating more oxidized and water-rich parental magmas. Compared with large-scale porphyry systems (e.g., Dexing, northern Chile), the absence of adakitic signatures and only moderate oxidation limited the scale of mineralization. Overall, the Xifanping deposit formed through partial melting of Neoproterozoic subduction-modified lower crust in a post-collisional extensional regime: at ~33.2 Ma, melting of metasomatized ancient lower crust generated barren porphyries; at ~32 Ma, further evolution and differentiation of this lower crust magmas led to the extraction and enrichment of ore-forming materials from the thicken lower crust, producing hydrated, oxidized, ore-bearing magmas that intruded at shallow levels to form base and precious metal mineralizations. These results underscore the distinctive metallogenic characteristics of small-scale porphyry systems in collisional settings and provide new insights into how source composition and magma oxidation state constrain mineralization potential. Full article

Background: Pickleball has gained global popularity as a socially engaging and accessible sport, but little is known about its short-term psychological effects on younger populations, particularly university students. This pilot study examines whether participation in a pickleball class during a university course produces immediate mood improvements among Japanese first-year students. Methods: A total of 106 sports science students (75 men and 31 women; M = 18.44, SD = 0.55) participated in a 100 min pickleball tournament. Mood states were measured pre- and post-activity using a Two-Dimensional Mood Scale (TDMS) to assess vitality, stability, pleasure, and arousal. A mixed-design ANOVA (time × gender) was used for analysis. Results: A significant main effect of time was found for vitality (F(1,103) = 4.97, p = 0.028, η² = 0.046), indicating improved vitality after participation. Other mood indices showed positive but non-significant trends (pleasure: p = 0.127; arousal: p = 0.067; stability: p = 0.812). No significant main effects of gender or time × gender interactions were observed. Qualitative responses supported these findings, with 64% of participants describing the activity as “fun” or “good” and 24% referencing social themes such as “cooperation” and “exchange”. Conclusions: Short-term participation in pickleball during a university class improved vitality and fostered social enjoyment among first-year students, with broadly similar benefits for men and women. As a pilot study, the findings highlight pickleball’s potential as a low-barrier, socially interactive activity to support students’ mental health in educational settings, although future studies with diverse samples and controlled designs are needed. Full article

Integrating phase change materials (PCMs) into building envelopes offers a powerful method for enhancing thermal mass and reducing heating, ventilation, and air conditioning energy demand. This study provides a comprehensive analysis of combining PCMs with various roof designs (flat, gable, and domed) and shading strategies in a Mediterranean climate to optimize residential building performance. Through a 3E (energetic, environmental, and economic) assessment and computational fluid dynamics (CFD) modeling, we determined that the use of PCM23 significantly enhances occupant comfort, improving the predicted mean vote by 17% and enhancing overall thermal comfort by 14%. The most effective configuration, a gable roof with integrated PCMs, outperformed a flat roof by reducing annual energy consumption by 20% (1103 kWh). This optimal design also yielded substantial economic and environmental benefits, including a 16.2 TD/m² reduction in annual energy costs, a short investment payback period, and a 4% decrease in operational CO₂ emissions. These results highlight the significant potential of pairing PCMs with passive architectural features to create more energy-efficient, cost-effective, and comfortable living environments. Full article

Azoles are the primary agents for antifungal activity in clinical medicine due to their broad-spectrum efficacy and favorable safety profiles compared to older agents. Triazoles, including fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole, have varied pharmacokinetic and pharmacodynamic properties. This is due to various polymorphisms in hepatic enzymes, necessitating genotype-guided dosing and therapeutic drug monitoring (TDM) to optimize treatment outcomes. This review highlights the clinical relevance of pharmacogenomics in azole therapy, particularly the role of cytochrome P450 (CYP450) enzyme polymorphisms in influencing drug levels, efficacy, and toxicity. Understanding these genetic and metabolic factors is essential for personalized antifungal treatment strategies, improving patient safety and therapeutic outcomes. Full article

Background/Objectives: Vancomycin is a commonly used antibiotic in critically ill patients with severe methicillin-resistant Staphylococcus aureus infections. Due to its narrow therapeutic window, under- or overdosing is likely to result in adverse effects, especially in patients with conditions associated with altered pharmacokinetics such as obesity. The objective of this study was to investigate the impact of obesity on serum concentrations of vancomycin in critically ill patients receiving intravenous vancomycin by continuous infusion based on ideal body weight (IBW). Methods: This retrospective observational study performed at the University Hospital of Leipzig, Germany, included all patients admitted to the intensive care unit (ICU) between January 2009 and December 2015 who received guideline-based vancomycin therapy based on IBW. Serum concentrations were obtained through routinely performed therapeutic drug monitoring (TDM). Results: A total of 1066 patients with a median age of 62 years were included in this study. The median (25%; 75% quantile) vancomycin treatment duration was 4 (2; 7) days and the median time to reach target concentrations of 20–25 mg L⁻¹ was 3 (2; 4) days without a significant difference between BMI groups. Overall, only 25.9% of patients were in the therapeutic range of 20–25 mg L⁻¹ in the entire treatment interval. 47.8% of vancomycin concentrations obtained from TDM were below the desired target range with no differences between the BMI groups (p = 0.077). 26.3% of measurements exceeded the target range, with a significant increase in the morbidly obese group (p < 0.001). A higher BMI was associated with an increased ICU, in-hospital, 28- and 90-day mortality in morbidly obese patients (p < 0.05). Age, BMI and high SAPS-II and SOFA scores were significant predictors of an increased risk of death. Conclusions: Our preliminary findings suggest that IBW-based dosing may help reduce the risk of supratherapeutic concentrations in morbidly obese patients. The high rates of sub- and supratherapeutic vancomycin serum concentrations across all patients highlight the need for close TDM and dose adjustments, particularly in morbidly obese patients with the highest rates of supratherapeutic vancomycin serum concentrations and of RRT. Full article

The Chaluo granite is situated in the middle section of the Yidun magmatic arc in western Sichuan Province, China. It holds great significance for the study of the geological evolution of the Paleo-Neotethys tectonic belts. The Chaluo granite mainly consists of alkaline feldspar, quartz, and biotite, with a small amount of apatite. LA-ICP-MS zircon U-Pb dating yielded crystallization ages of (87 ± 3) Ma for the Chaluo granite, indicating its formation in the Late Cretaceous. Elemental geochemical testing results showed that the Chaluo granite exhibits I-type granite characteristics. It has undergone significant fractional crystallization processes, with high SiO₂ contents (72.83–76.63 wt%), K (K₂O/Na₂O = 1.33–1.53), Al₂O₃ (Al₂O₃ = 12.24–13.56 wt%, A/CNK = 0.91–1.08), and a high differentiation index (DI = 88.91–92.49). Notably, the MgO contents were low (0.10–0.26 wt%), and there were significant depletions of Nb, Sr, Ti, and Eu, while Rb, Pb, Th, U, Zr, and Hf were significantly enriched. The total rare earth element (REE) contents were relatively low (211–383 ppm), showing significant light REE (LREE) enrichment (LREE/HREE = 4.46–5.57) and a pronounced negative Eu anomaly (δEu = 0.09–0.17). In situ zircon Hf analyses, combined with ²⁰⁶Pb/²³⁸U ages, gave ε_Hf(t) values ranging from −3.8 to 1.72 and two-stage Hf ages (t_DM2) of 875–1160 Ma. Together with the S and Pb isotope compositions of the Chaluo granite, its magma likely originated from the partial melting of Middle–Neoproterozoic sedimentary rocks enriched in biogenic S. The tectonic-setting analysis indicates that the Chaluo granite formed in a post-orogenic intracontinental extensional environment. This environment was triggered by the northward subduction-collision of the Lhasa block, followed by slab break-off and the upwelling of the asthenosphere in the Neo-Tethys orogenic belt. We propose that the Paleo-Tethys tectonic belt was influenced by the Neo-Tethys tectonic activity, at least in the Yidun magmatic arc region during the Late Cretaceous. Full article

Modern neuromorphic processors exhibit neuron densities that are orders of magnitude lower than those of the biological cortex, hindering the deployment of large-scale spiking neural networks (SNNs) on single chips. To bridge this gap, we propose HDNIP, a 40 nm high-density neuromorphic inference platform with a density-first architecture. By eliminating area-intensive on-chip SRAM and using 1280 compact cores with a time-division multiplexing factor of up to 8192, HDNIP integrates 10 million neurons and 80 billion synapses within a 44.39 ${\mathrm{mm}}^2$ synthesized area. This achieves an unprecedented neuron density of 225 k neurons/${\mathrm{mm}}^2$, over 100 times greater than prior art. The resulting bandwidth challenges are mitigated by a ReRAM-based near-memory computation strategy combined with input reuse, reducing off-chip data transfer by approximately 95%. Furthermore, adaptive TDM and dynamic core fusion ensure high hardware utilization across diverse network topologies. Emulator-based validation using large SNNs, demonstrates a throughput of 13 GSOP/s at a low power consumption of 146 mW. HDNIP establishes a scalable pathway towards single-chip, low-SWaP neuromorphic systems for complex edge intelligence applications. Full article

Background: Tacrolimus is a cornerstone of immunosuppressive therapy following heart transplantation. Despite routine therapeutic drug monitoring (TDM), substantial interindividual variability in tacrolimus pharmacokinetics presents a persistent challenge. Pharmacogenetic profiling—particularly of CYP3A5 and CYP3A4 polymorphisms—offers a promising approach to individualize tacrolimus dosing and improve clinical outcomes. Case Presentation: We describe a 54-year-old male heart transplant recipient with persistently subtherapeutic tacrolimus trough concentrations despite escalating standard doses. Tacrolimus dosing initially started at 3.5 mg twice daily, escalated to 7.0 mg twice daily, with final maintenance dosing at 6.5 mg twice daily. TDM values were persistently subtherapeutic at 3–5 ng/mL for over a month before achieving therapeutic targets >10 ng/mL. Pharmacogenetic testing revealed a CYP3A5 expresser genotype (*1/*3) and normal CYP3A4 activity (*1/*1), suggesting enhanced metabolic clearance. In accordance with CPIC guidelines, tacrolimus dosing was intensified and supported by co-administration of diltiazem (60 mg twice daily, later adjusted to 90 mg twice daily), a CYP3A4 inhibitor. Subsequent TDM confirmed achievement of therapeutic levels. At nine months post-transplant, the patient exhibited stable graft function and excellent clinical status. Discussion: This case underscores the value of genotype-informed tacrolimus dosing in clinical scenarios where standard TDM is insufficient. Pharmacogenetic variation—particularly involving CYP3A5 expression—has been consistently associated with altered tacrolimus exposure and dose requirements. The literature supports routine genotyping in solid organ transplant recipients, although implementation remains limited. Additional considerations include drug–drug interactions, notably with CYP3A-modulating agents such as diltiazem and antifungals, which may further influence tacrolimus pharmacokinetics. Current evidence suggests that the utility of CYP3A4 genotyping may be phase-dependent, being more impactful during early post-transplant periods. Conclusions: Incorporating pharmacogenetic data alongside TDM facilitates more precise and individualized tacrolimus therapy, optimizing immunosuppressive efficacy and minimizing risk. This case, supported by literature review, advocates for broader integration of genotype-guided strategies in transplant pharmacotherapy. Full article