Renewable lignin-derived heteroatom-doped porous carbon nanosheets as an efficient oxygen reduction catalyst for rechargeable zinc-air batteries.

Lignin upgrading to various functional products is promising to realize high-value utilization of low-cost and renewable biomass waste, but is still in its infancy. Herein, using industry waste lignosulfonate as the biomass-based carbon source and urea as the dopant, we constructed a heteroatom-doped porous carbon nanosheet structure by a simple NaCl template-assisted pyrolytic strategy. Through the synergistic effect of the NaCl template and urea, the optimized lignin-derived porous carbon catalyst with high content of active nitrogen species and large specific surface area can be obtained. As a result, the fabricated catalysts exhibited excellent electrocatalytic oxygen reduction activity, as well as good methanol tolerance and stability, comparable to that of commercial Pt/C. Moreover, rechargeable Zn-air batteries assembled with this electrocatalyst have a peak power density of up to 150 mW cm-2 and prominent long-term cycling stability. This study offers an inexpensive and efficient way for the massive production of highly active metal-free catalysts from the plentiful, inexpensive and environmentally friendly lignin, offering a good direction for biomass waste recycling and utilization.

The correlation between the costs and clinical benefits of PD-1/PD-L1 inhibitors in malignant tumors: An evaluation based on ASCO and ESMO frameworks.

Background: Life expectancy for patients with malignant tumors has been significantly improved since the presence of the programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors in 2014, but they impose heavy financial burdens for patients, the healthcare system and the nations. The objective of this study was to determine the survival benefits, toxicities, and monetary of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors and quantify their values. Methods: Randomized controlled trials (RCTs) of PD-1/PD-L1 inhibitors for malignant tumors were identified and clinical benefits were quantified by American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). The drug price in Micromedex REDBOOK was used to estimate monthly incremental drug costs (IDCs) and the correlation between clinical benefits and incremental drug costs of experimental and control groups in each randomized controlled trial, and the agreement between two frameworks were calculated. Results: Up to December 2022, 52 randomized controlled trials were included in the quantitative synthesis. All the randomized controlled trials were evaluated by American society of clinical oncology value framework, and 26 (50%) met the American society of clinical oncology value framework "clinical meaningful value." 49 of 52 randomized controlled trials were graded by European society for medical oncology magnitude of clinical benefit scale, and 30 (61.2%) randomized controlled trials achieved European Society for Medical Oncology criteria of meaningful value. p-values of Spearman correlation analyses between monthly incremental drug costs and American society of clinical oncology value framework/European society for medical oncology magnitude of clinical benefit scale scores were 0.9695 and 0.3013, respectively. In addition, agreement between two framework thresholds was fair (κ = 0.417, p = 0.00354). Conclusion: This study suggests that there might be no correlation between the cost and clinical benefit of programmed cell death protein-1/programmed cell death protein ligand-1 inhibitors in malignancy, and the same results were observed in subgroups stratified by drug or indication. The results should be a wake-up call for oncologists, pharmaceutical enterprises and policymakers, and meanwhile advocate the refining of American Society of Clinical Oncology and European Society for Medical Oncology frameworks.

Detecting the Deformation Behavior of Bimodal Ti-6Al-4V Using a Digital Image Correlation Technique.

The evolution of a local strain of the Ti-6Al-4V alloy subjected to tensile loading was investigated in situ by using the digital image correlation technique. The results show that some local strain concentration areas have already appeared in the elastic deformation stage, which then connected and became concentrated in the gauge region when the specimen yielded. The strain compatibility of grains in the macroscopic region is kept constant. The deformation process is further divided into six parts based on the development of the maximum strain gradient, and the strain compatibility of each stage of the alloy is summarized and analyzed. The quasi-in situ experiment reveals that the primary α(αp) grains undertake the main deformation at the micro-scale.

First-Line Durvalumab in Addition to Etoposide and Platinum for Extensive-Stage Small Cell Lung Cancer: A U.S.-Based Cost-Effectiveness Analysis.

BACKGROUND: The latest published CASPIAN trial demonstrated that adding durvalumab to etoposide and platinum (EP) improved survival dramatically for patients with extensive-stage small cell lung cancer (ES-SCLC). Considering the high cost of durvalumab, this study evaluated the cost-effectiveness of durvalumab plus EP (DEP) in the first-line setting for treatment-naïve patients with ES-SCLC from the U.S. payer perspective. MATERIALS AND METHODS: We developed a three-state Markov model to simulate the disease course and source consumption of ES-SCLC over a lifetime horizon. Pseudo-individual patient-level data were generated from digitized Kaplan-Meier curves. Direct medical costs, including drug and administration costs, disease management and adverse events treatment fees, best supportive care and terminal care costs were obtained from sources including the Centers for Medicare and Medicaid Services, Healthcare Cost and Utilization Project, and relevant literature. Health state utility values were derived from published literature. Main outcomes considered were total costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). All costs were adjusted for inflation to reflect 2019 U.S. dollars. The willingness-to-pay threshold was set as $150,000/QALY. One-way and probabilistic sensitivity analyses were used to explore the uncertainty of model assumptions. RESULTS: Compared with EP, DEP was projected to increase life expectancy by 0.86 LYs (1.73 vs. 0.87) and 0.44 QALYs (0.93 vs. 0.49). The incremental treatment cost was $95,907, and the corresponding ICER was $216,953/QALY. The result was most sensitive to the variation of durvalumab acquisition cost. Probabilistic sensitivity analysis revealed that the probability of DEP over EP regimen to be cost-effective was 9.4% at a willingness-to-pay threshold of $150,000/QALY. In the case of reducing the price of durvalumab by 30.7%, DEP was more cost-effective than EP. CONCLUSION: From the perspective of the U.S. payer, adding durvalumab to EP is estimated to be not cost-effective compared with EP alone for patients with untreated ES-SCLC. IMPLICATIONS FOR PRACTICE: The information provided by this analysis serves as a reference for decision makers. Lowering the price of durvalumab would be a potential measure to improve the economics of durvalumab plus etoposide and platinum (DEP), and the inclusion of durvalumab in the Medicare pharmacopeia could make DEP more economically available. These results may also guide physicians and patients to choose the most economically feasible treatment.

Cost-Effectiveness Analysis of Hepatic Arterial Infusion of FOLFOX Combined Sorafenib for Advanced Hepatocellular Carcinoma With Portal Vein Invasion.

BACKGROUND: Hepatic arterial infusion (HAI) of oxaliplatin, leucovorin, and fluorouracil (FOLFOX) plus sorafenib has a more desirable effect versus sorafenib for hepatocellular carcinoma (HCC) patients with portal vein invasion. However, considering the high cost of hepatic arterial infusion of chemotherapy (HAIC), this study evaluated the cost-effectiveness of HAIC plus sorafenib (SoraHAIC) versus standard care for HCC patients from the Chinese health system perspective. METHODS: A Markov multi-state model was constructed to simulate the disease course and source consumption of SoraHAIC. Costs of primary therapeutic drugs were calculated based on the national bid price, and hepatic artery catheterization fee was collected from the Fujian Provincial Price Bureau. Clinical data, other costs, and utility values were extracted from references. Primary outcomes included life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). The robustness of model was verified by uncertainty sensitivity analyses. RESULTS: SoraHAIC gained 1.18 QALYs (1.68 LYs) at a cost of $65,254, while the effectiveness and cost of sorafenib were 0.52 QALYs (0.79 LYs) and $14,280, respectively. The ICER of SoraHAIC vs sorafenib was $77,132/QALY ($57,153/LY). Parameter that most influenced the ICER was utility of PFS state. The probabilistic sensitivity analysis (PSA) showed that SoraHAIC was not cost-effective in the WTP threshold of 3*Gross Domestic Product (GDP) per capita of China ($30,492/QALY). But about 38.8% of the simulations were favorable to SoraHAIC at the WTP threshold of 3*GDP per capita of Beijing ($72,000/QALY). When 3*GDP per capita of Fujian ($47,285/QALY) and Gansu Province ($14,595/QALY) were used as WTP threshold, the acceptability of SoraHAIC was 0.3% and 0%, respectively. CONCLUSIONS: The study results indicated that SoraHAIC was not cost-effective in medium-, and low-income regions of China. In developed areas of China (Beijing), there was a 38.8% probability that the SoraHAIC regimen would be cost-effective.

Economic and health impacts of infectious diseases in China: A protocol for systematic review and meta analysis.

BACKGROUND: A worldwide concern has been raised that novel infectious diseases may outbreak rapidly with a limited response time due to globalization. Severe Acute Respiratory Syndrome, influenza A, Avian Influenza Virus, and Corona Virus Disease 2019 are acute respiratory diseases that have been affected by the movements of people, and globalization accelerates these movements. These infectious diseases not only have an overwhelming health impact but also impact the worldwide economy. METHODS: We will conduct a systematic review and meta-analysis in Chinese National Knowledge Infrastructure, WANFANG Database, and the VIP Database for Chinese Technical Periodicals, Web of Science, PubMed, EMBASE, the Cochrane Library, EBSCO host, ProQuest, ProQuest Dissertations & Theses A&I, SAGE Journals, ScienceDirect, JSTOR, and Scopus. We will evaluate the risk of bias of included RCTs according to the criteria and technique proposed in the Cochrane Handbook V.5.1.0 and use ROBINS-I to assess risk of bias in nonrandomized studies. We will use GRADE to evaluate the quality of evidence. RESULTS: Results of this review will be submitted to a peer-reviewed journal. CONCLUSION: To the best of our knowledge, this study will firstly evaluate both health and economic impact of infectious diseases in china and may provide strategy development ideas for future resistance.

miR­508­3p suppresses the development of ovarian carcinoma by targeting CCNA2 and MMP7.

Ovarian cancer is the most lethal gynecological tumor, and the 5­year survival rate is only ~40%. The poor survival rate is due to cancer diagnosis at an advanced stage, when the tumor has metastasized. A better understanding of the molecular pathogenesis of tumor growth and metastasis is needed to improve patient prognosis. MicroRNAs (miRs) regulate carcinogenesis and development of cancers. However, the role of miR­508­3p in ovarian cancer remains largely unknown. Thus, the present study aimed to investigate the possible functions of miR­508­3p in the modulation of development of ovarian cancer. The results of the present study demonstrated that miR­508­3p mimics inhibited ovarian cancer cell proliferation, migration and invasion. Reporter gene assay results demonstrated that miR­508­3p suppressed cancer cell proliferation by directly targeting the 3'­untranslated region (UTR) of cyclin A2 (CCNA2) and suppressed migration and invasion by directly targeting the 3'­UTR of matrix metalloproteinase 7 (MMP7). In addition, high CCNA2 and MMP7 expression levels were associated with low miR­508­3p expression in ovarian cancer tissues. Furthermore, miR­508­3p and CCNA2 were independent predictors for overall survival in patients with ovarian cancer. To the best of our knowledge, this is the first study to demonstrated that miR­508­3p suppressed ovarian cancer development by directly targeting CCNA2 and MMP7. The results of this study suggested the potential value of miR­508­3p and CCNA2 as prognostic indicators and therapeutics for ovarian cancer.

Cost-Utility Analysis of Pembrolizumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small Cell Lung Cancer With Different PD-L1 Expression Levels.

To evaluate the cost-utility of pembrolizumab versus chemotherapy as the first-line setting for metastatic non-small cell lung cancer (NSCLC) from the US health care system perspective, a Markov model was developed to compare the lifetime cost and effectiveness of pembrolizumab versus chemotherapy for untreated metastatic NSCLC, based on the clinical data derived from phase III randomized controlled trial (KEYNOTE-042; ClinicalTrials.gov; NCT02220894). Weibull distribution was fitted to simulate the parametric survival functions. Drug costs were collected from official websites, and utility values were obtained from published literature. Total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were computed as primary output indicators. The impact of different PD-L1 expression levels on ICER was also evaluated. One-way and probabilistic sensitivity analyses were performed to assess the model uncertainty. Compared with chemotherapy, patients treated with pembrolizumab provided an additional 1.13, 1.01, and 0.59 QALYs in patients with PD-L1 expression levels of ≥50%, ≥20%, and ≥1%, with corresponding incremental cost of 53,784, 47,479, and 39,827, respectively. The resultant ICERs of pembrolizumab versus chemotherapy were 47,596, 47,184, and 68,061/QALY, in three expression levels of PD-L1, respectively, all of which did not exceed the WTP threshold of 180,000/QALY. Probability sensitivity analysis outcome supported that pembrolizumab exhibited evident advantage over chemotherapy to be cost-effective. One-way sensitivity analysis found that ICERs were most sensitive to utility value of pembrolizumab in progression survival state. All the adjustment of parameters did not qualitatively change the result. For treatment-naive, metastatic NSCLC patients with PD-L1+, pembrolizumab was estimated to be cost-effective compared with chemotherapy for all PD-L1 expression levels at a WTP threshold of 180,000/QALY in the context of the US health care system.

Nitric oxide is involved in hemin-induced cucumber adventitious rooting process.

Hemin, a heme oxygenase-1 (HO-1) inducer, was shown to exert numerous beneficial physiological functions in animals. Our previous study suggests that HO-1/carbon monoxide (CO) acts as a novel downstream signal system in the auxin-induced adventitious rooting. The objective of this study was to test whether nitric oxide (NO) is involved in hemin-induced cucumber adventitious rooting. Applications of hemin or CO aqueous solution to auxin-depleted cucumber explant induced up-regulation of cucumber HO-1 transcripts (CsHO1), NO production, and thereafter adventitious root formation, and some above responses were blocked by the combination treatment with two nitric oxide synthase (NOS)-like enzyme inhibitors N(G)-nitro-L-arginine methylester hydrochloride and N(G)-nitro-L-arginine, a HO-1 specific inhibitor zinc protoporphyrin IX, and a specific NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt. However, these blocking responses were not observed using tungstate, an inhibitor of nitrate reductase, another NO producing enzyme in plants. Furthermore, the guanylate cyclase inhibitors 1H-(1,2,4)-oxadiazole[4,3-a]quinoxalin-1-one and 6-anilino-5,8-quinolinedione reduced root development induced by hemin, whereas the cell-permeable cyclic guanosine monophosphate (cGMP) derivative 8-Br-cGMP reversed this effect. Together, our results indicated that at least in our experimental conditions, NO might operate downstream of hemin promoting adventitious root formation probably in a cGMP-dependent manner.

Involvement of heme oxygenase-1 in ß-cyclodextrin-hemin complex-induced cucumber adventitious rooting process.

UNLABELLED: Our previous results showed that ß-cyclodextrin-hemin complex (CDH) exhibited a vital protective role against cadmium-induced oxidative damage and toxicity in alfalfa seedling roots by the regulation of heme oxygenase-1 (HO-1) gene expression. In this report, we further test whether CDH exhibited the hormonal-like response. The application of CDH and an inducer of HO-1, hemin, were able to induce the up-regulation of cucumber HO-1 gene (CsHO1) expression and thereafter the promotion of adventitious rooting in cucumber explants. The effect is specific for HO-1 since the potent HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blocked the above responses triggered by CDH, and the inhibitory effects were reversed further when 30% saturation of CO aqueous solution was added together. Further, molecular evidence showed that CDH triggered the increases of the HO-1-mediated target genes responsible for adventitious rooting, including one DnaJ-like gene (CsDNAJ-1) and two calcium-dependent protein kinase (CDPK) genes (CsCDPK1 and CsCDPK5), and were inhibited by ZnPP and reversed by CO. The calcium (Ca2+) chelator ethylene glycol-bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) and the Ca2+ channel blocker lanthanum chloride (LaCl3) not only compromised the induction of adventitious rooting induced by CDH but also decreased the transcripts of above three target genes. However, the application of ascorbic acid (AsA), a well-known antioxidant in plants, failed to exhibit similar inducible effect on adventitious root formation. In short, above results illustrated that the response of CDH in the induction of cucumber adventitious rooting might be through HO-1-dependent mechanism and calcium signaling. KEY MESSAGE: Physiological, pharmacological and molecular evidence showed that ß-cyclodextrin-hemin complex (CDH) was able to induce cucumber adventitious rooting through heme oxygenase-1 (HO-1)-dependent mechanism and calcium signaling.

Molecular cloning and expression of a cucumber (Cucumis sativus L.) heme oxygenase-1 gene, CsHO1, which is involved in adventitious root formation.

Our previous work showed that in cucumber (Cucumis sativus), auxin rapidly induces heme oxygenase (HO) activity and the product of HO action, carbon monoxide (CO), then triggers the signal transduction events leading to adventitious root formation. In this study, the cucumber HO-1 gene (named as CsHO1) was isolated and sequenced. It contains four exons and three introns and encodes a polypeptide of 291 amino acids. Further results show that CsHO1 shares a high homology with plant HO-1 proteins and codes a 33.3 kDa protein with a 65-amino transit peptide, predicting a mature protein of 26.1 kDa. The mature CsHO1 was expressed in Escherichia coli to produce a fusion protein, which exhibits HO activity. The CsHO1:GFP fusion protein was localized in the chloroplast. Related biochemical analyses of mature CsHO1, including Vmax, Km, Topt and pHopt, were also investigated. CsHO1 mRNA was found in germinating seeds, roots, stem, and especially in leaf tissues. Several well-known adventitious root inducers, including auxin, ABA, hemin, nitric oxide donor sodium nitroprusside (SNP), CaCl(2), and sodium hydrosulfide (NaHS), differentially up-regulate CsHO1 transcripts and corresponding protein levels. These results suggest that CsHO1 may be involved in cucumber adventitious rooting.