First-line treatments for advanced non-squamous non-small cell lung cancer with immune checkpoint inhibitors plus chemotherapy: a systematic review, network meta-analysis, and cost-effectiveness analysis.

Introduction: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy is a promising first-line therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). The cost-effectiveness of combinations with different ICIs is yet to be compared. Methods: We utilized Bayesian network meta-analyses for the comparisons of overall survival, progression-free survival, and incidence of adverse events of the included treatments in the total population and subgroups with different programmed death-ligand 1 tumor proportional scores (TPS). The cost-effectiveness of the treatments from the perspectives of the US and Chinese healthcare systems was assessed using Markov models. Results: Three combinations, including pembrolizumab + chemotherapy (PembroC), nivolumab + ipilimumab + chemotherapy (NivoIpiC), and atezolizumab + chemotherapy (AteC), were included in our study. In terms of efficacy, PembroC was most likely to be ranked first for extending progression-free survival (PFS) (93.16%) and overall survival (OS) (90.73%). Nevertheless, from the US perspective, NivoIpiC and PembroC showed incremental cost-effectiveness ratios (ICERs) of $68,963.1/quality-adjusted life-years (QALY) and $179,355.6/QALY, respectively, compared with AteC. The one-way sensitivity analysis revealed that the results were primarily sensitive to the hazard ratios for OS or the cost of immunotherapy agents. At a willingness-to-pay (WTP) threshold of $150,000/QALY, NivoIpiC had the highest probability of being cost-effective (63%). As for the Chinese perspective, NivoIpiC and PembroC had ICERs of $145,983.4/QALY and $195,863.3/QALY versus AteC, respectively. The results were primarily sensitive to the HRs for OS. At a WTP threshold of $38,017/QALY, AteC had the highest probability of cost-effectiveness (94%). Conclusion: Although PembroC has the optimal efficacy, NivoIpiC and AteC were the most favorable treatments in terms of cost-effectiveness for patients with advanced non-squamous NSCLC from the US and Chinese perspectives, respectively.

MOF derivatization of multifunctional nanozyme: Peroxidase-like catalytic activity combined with magnetic solid phase extraction for colorimetric detection of Hg2.

Nanozyme-based colorimetric sensing has drawn immense attention due to the rapid development of nanozyme in recent years. However, the selectivity of nanozyme-based colorimetric sensing greatly limits its subsequent practical application. It is well known that sample pretreatment can not only improve selectivity by eliminating the sample matrix interference, but also improve sensitivity by enriching trace targets. Based on the easy facile surface modification properties of nanozyme, we rationally designed nanozyme combined with sample pretreatment for colorimetric biosensing, through separation and enrichment, thereby improving the selectivity and sensitivity of the nanozyme colorimetric biosensing. As a proof of concept, the detection of Hg2+ by nanozyme-based colorimetric sensing was used as an example. Magnetic peroxidase-like nanozyme Fe3S4 was designed and synthesized. The selectivity is improved by the specific adsorption of S-Hg bond and the interference elimination after magnetic separation. In addition, the sensitivity is improved by magnetic solid-phase extraction enrichment. Our established colorimetric sensing based on Fe3S4 nanozyme integrated sample pretreatment with an enrichment factor of 100 and the limit of detection (LOD) is 26 nM. In addition, this strategy was successfully applied to detect Hg2+ in environmental water samples. Overall, the strategy showed good selectivity and sensitivity, providing a new practical method for the application of nanozyme-based biosensing in sample pretreatment.

Rational design of nanozyme with integrated sample pretreatment for colorimetric biosensing.

Nanozymes have been widely used in the field of biosensing owing to their high stability, low cost, adjustable catalytic activity, and convenient modification. However, achieving high selectivity and sensitivity simultaneously in nanozyme-based colorimetric sensing remains a major challenge. Nanozymes are nanomaterials with enzyme-simulating activity that are often used as solid-phase adsorbents for sample pretreatment. Our design strategy integrated sample pretreatment function into the nanozyme through separation and enrichment, thereby improving the selectivity and sensitivity of nanozyme-based colorimetric biosensing. As a proof-of-concept, glucose was used as the model analyte in this study. A phenylboric acid-modified magnetic nanozyme (Cu/Fe3O4@BA) was rationally designed and synthesized. Selectivity was enhanced by boronate-affinity specific adsorption and the elimination of interference after magnetic separation. In addition, magnetic solid-phase extraction enrichment was used to improve the sensitivity. A recovery rate of more than 80% was reached when the enrichment factor was 50. The synthesized magnetic Cu/Fe3O4@BA was recyclable at least five times. The proposed method exhibited excellent selectivity and sensitivity, simple operation, and recyclability, providing a novel and practical strategy for designing multifunctional nanozymes for biosensing.

Rational design of cuprofullerene bipyridine nanozyme with high peroxidase-like activity for colorimetric sensing of bleomycin.

The high catalytic activity of Cu-based nanozymes mainly depends on the efficient Fenton-like reaction of Cu+/ H2O2, but Cu+ cannot exist stably. Trying to find a material that can stably support Cu+ while promoting the electron cycle of Cu2+/Cu+ still faces serious challenges. C60 is expected to be an ideal candidate to solve this problem due to its unique structure and rich physicochemical properties. Here, we designed and synthesized a C60-doped Cu+-based nanozyme (termed as C60-Cu-Bpy) by loading high catalytic active site Cu+ onto C60 and coordinating with 2,2'-bipyridine (Bpy). The single crystal diffraction analysis and a series of auxiliary characterization technologies were used to demonstrate the successful preparation of C60-Cu-Bpy. Significantly, the C60-Cu-Bpy exhibited superior peroxidase-like activity during the catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). Then, the catalytic mechanism of C60-Cu-Bpy as peroxidase was elucidated in detail, mainly benefiting from the dual function of C60. On the one hand, C60 acted as a carrier to directly support Cu+, which has the ability to efficiently decompose H2O2 to produce reactive oxygen species. The other was that C60 acted as an electron buffer, contributing to promoting the Cu2+/Cu+ cycle to facilitate the reaction. Furthermore, a colorimetric sensor for the quantitative analysis of bleomycin was established based on the principle of bleomycin specific inhibition of C60-Cu-Bpy peroxidase-like activity, with satisfactory results in practical samples. This study provides a new strategy for the direct synthesis of Cu+-based nanozymes with high catalytic performance.

Cost-effectiveness of maintenance niraparib with an individualized starting dosage in patients with platinum-sensitive recurrent ovarian cancer in China.

Objective: Niraparib improved survival in platinum-sensitive recurrent ovarian cancer (PSROC) patients versus routine surveillance, accompanied by increased costs. Based on the NORA trial, we evaluated for the first time the cost-effectiveness of maintenance niraparib with individualized starting dosage (ISD) in China. Methods: A Markov model was developed to simulate the costs and health outcomes of each strategy. The total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were measured. One-way and probabilistic sensitivity analysis were performed to estimate model robustness. Scenario analyses were also conducted. Results: Compared to routine surveillance, niraparib additionally increased QALYs by 0.59 and 0.30 in populations with and without germline BRCA (gBRCA) mutations, with incremental costs of $10,860.79 and $12,098.54, respectively. The ICERs of niraparib over routine surveillance were $18,653.67/QALY and $39,212.99/QALY. At a willingness-to-pay (WTP) threshold of $37,488/QALY, the ISD enhanced the likelihood of cost-effectiveness from 9.35% to 30.73% in the gBRCA-mutated group and from 0.77% to 11.74% in the non-gBRCA mutated population. The probability of niraparib being cost-effective in the region with the highest per capita Gross Domestic Product (GDP) in China was 74.23% and 76.10% in the gBRCA-mutated and non-gBRCA mutated population, respectively. Niraparib was 100% cost-effective for National Basic Medical Insurance beneficiaries under the above WTP thresholds. Conclusion: Compared to routine surveillance, the ISD of niraparib for maintenance treatment of PSROC is cost-effective in the gBRCA-mutated population and more effective but costly in the non-gBRCA mutated patients. The optimized niraparib price, economic status, and health insurance coverage may benefit the economic outcome.

Three-in-one covalent organic framework nanozyme: Self-reporting, self-correcting and light-responsive for fluorescence sensing 3-nitrotyrosine.

Most current redox-type nanozyme-based colorimetric sensing platforms are susceptible to interference from the reductant when using chromogenic probe, and the unstable H2O2 used in the peroxidase-like nanozyme-based systems is prone to difficulty in sensing signal reproducibility, while peroxidase-like nanozyme with oxidase-mimicking activity is easy to bring background interference by O2. Since the strong structural designability of covalent organic frameworks (COFs) endows them great application value in the sensing fields, therefore, we envision the construction a COF oxidase-like nanozyme-based controllable sensing system that integrates self-reporting, self-correcting and light-responsive functions to avoid these affects. Herein, 3-nitrotyrosine (3-NT) biomarker was selected as model analyte. 1,3,5-triformylphloroglucinol (Tp) and 3,6-diaminoacridine (DA) were acted as building monomers of the multifunctional COF nanozyme (termed as TpDA). Owing to the excellent light-responsive oxidase-mimicking property of TpDA, 3-NT can be efficiently oxidized, the inner filter effect (IFE) between TpDA and the 3-NT oxidation product greatly quenches the intrinsic fluorescence of TpDA, making it a controllable self-reporting system for fluorescence turn-off sensing 3-NT. Additionally, the excessive reactive oxygen species (ROS) that generated continuously during photocatalysis can resist the interference of endogenous reductants. This study not only provides new insights to avoid the interference of H2O2, background and reductants from conventional redox-type nanozyme-based colorimetric systems but also opens avenues to rational construct versatile COF nanozyme-based sensor.

Enhanced peroxidase-like activity of MOF nanozymes by co-catalysis for colorimetric detection of cholesterol.

Metal-organic frameworks (MOFs) have been widely used as nanozymes with a great development prospect due to their unique advantages. It is known that the current Fe-based or Cu-based MOF, etc., exhibits the catalytic activity of nanozymes through the Fenton catalytic reaction. And the conversion efficiency of the Fe3+/Fe2+ or Cu2+/Cu+ cycle is key to the catalytic activity. Therefore, we proposed a novel co-catalytic method to promote the reaction rate of the rate-limiting step of Cu2+/Cu+ conversion in the Fenton reaction of Cu2+/H2O2 to enhance the catalytic activity of the nanozymes. As a proof of concept, the MoCu-2MI nanozyme with high catalytic activity was successfully synthesized using Mo-doped Cu-2MI (2-methylimidazole). By using 3,3',5,5'-tetramethylbenzidine (TMB) as the chromogenic substrate, MoCu-2MI exhibited higher peroxidase-like activity than pure Cu-2MI. Then, it was confirmed that the newly introduced Mo played a crucial co-catalytic role by characterizing the possible catalytic mechanism. Specifically, Mo acted as a co-catalyst to accelerate the electron transfer in the system, and then promote the Cu2+/Cu+ cycle in the Cu-Fenton reaction, which was conducive to accelerating the production of a large number of reactive oxygen species (ROS) from H2O2, and finally improve the activity. Ultimately, a biosensor platform combined with MoCu-2MI and cholesterol oxidase realized the one-step colorimetric detection of cholesterol in the range of 2-140 µM with the detection limit as low as 1.2 µM. This study provides a new strategy for regulating the activity of MOF nanozymes.

Rational synthesis of FeNiCo-LDH nanozyme for colorimetric detection of deferoxamine mesylate.

The accurate surveillance and sensitive detection of deferoxamine mesylate (DFO) is of great significance to ensure the safety of thalassemia major patients. Herein, we report a new nanozyme-based colorimetric sensor platform for DFO detection. First, a metal-organic framework (ZIF-67) was used as a precursor for the synthesis of FeNiCo-LDH (Layered Double Hydroxide, LDH) via an ion exchange reaction stirring at room temperature. The results of electron microscopy and nitrogen adsorption-desorption showed that FeNiCo-LDH exhibited a 3D hollow and mesopores structure, which supplied more exposed active sites and faster transfer of mass. The as-prepared FeNiCo-LDH showed superior peroxidase-like activity with a low Km and high υmax. It can catalyze the decomposition of H2O2 to generate reactive oxygen species (ROS) and further react with 3,3',5,5'-tetramethylbenzidine (TMB) to form blue oxidized TMB (oxTMB), which has a characteristic absorption at 652 nm. Once DFO was introduced, it can complex with FeNiCo-LDH and inhibit the peroxidase-like activity of FeNiCo-LDH, making the color of oxTMB lighter. The quantitative range of DFO was 0.8-28 µM with a detection limit of 0.71 µM. This established method was applied to the detection of DFO content in urine samples of thalassemia patients, and the spiked recoveries were falling between 97.7% and 109.6%, with a relative standard deviation was less than 5%, providing a promising tool for the clinical medication of thalassemia patients.

Design, synthesis, and bioassay of 4-thiazolinone derivatives as influenza neuraminidase inhibitors.

A series of 4-thiazolinone derivatives (D1-D58) were designed and synthesized. All of the derivatives were evaluated in vitro for neuraminidase (NA) inhibitory activities against influenza virus A (H1N1), and the inhibitory activities of the five most potent compounds were further evaluated on NA from two different influenza viral subtypes (H3N2 and B), and then their in vitro anti-viral activities were evaluated using the cytopathic effect (CPE) reduction assay. The results showed that the majority of the target compounds exhibited moderate to good NA inhibitory activity. Compound D18 presented the most potent inhibitory activity with IC50 values of 13.06 µM against influenza H1N1 subtype. Among the selected compounds, D18 and D41 turned out to be the most potent inhibitors against influenza virus H3N2 subtype (IC50 = 15.00 µM and IC50 = 14.97 µM, respectively). D25 was the most potent compound against influenza B subtype (IC50 = 16.09 µM). In addition, D41 showed low toxicity and greater potency than reference compounds Oseltamivir and Amantadine against N1-H275Y variant in cellular assays. The structure-activity relationship (SAR) analysis showed that introducing 4-CO2H, 4-OH, 3-OCH3-4-OH substituted benzyl methylene can greatly improve the activity of 4-thiazolinones. Further SAR analysis indicated that 4-thiazolinone and ferulic acid fragments are necessary fragments of target compounds for inhibiting NA. Molecular docking was performed to study the interaction between compound D41 and the active site of NA. This study may providing important information for new drug development for anti-influenza virus including mutant influenza virus.