Cost-utility analysis and drug pricing for tirzepatide for type 2 diabetes in the Chinese market compared with semaglutide.

AIM: To investigate the most matchable price of tirzepatide (TIRZ) compared with semaglutide (SEMA) in the treatment of type 2 diabetes in China. METHODS: The patient cohort and clinical efficacy data were derived from the SURPASS-2 trial. Cost-utility analysis and a binary search were performed to identify the most matchable price of TIRZ from a Chinese healthcare provider's perspective. RESULTS: After lifetime simulation, the quality-adjusted life years of TIRZ 5, 10, 15 mg and SEMA 1 mg were 11.17, 11.21, 11.27 and 11.12 years, respectively. Despite an initial assumption that the annual cost of TIRZ equals that of SEMA, our analysis revealed that TIRZ is probably more cost-effective than SEMA. A thorough evaluation of pricing showed that the cost ranges for TIRZ at doses of 5, 10 and 15 mg were $1628.61-$1846.23, $1738.40-$2140.95 and $1800.30-$2430.81, respectively. After adjustment in the univariate sensitivity analysis, the cost ranges for TIRZ 5, 10 and 15 mg were $1542.68-$1757.57, $1573.00-$1967.16 and $1576.54-$2133.96, respectively. These cost intervals were validated through robust probabilistic sensitivity analysis and scenario analysis, except for the cost range for TIRZ 5 mg. CONCLUSIONS: This study shows that, using SEMA as a reference, the annual costs for TIRZ 10 and 15 mg are $1573.00-$1967.16 and $1576.54-$2133.96, respectively, for patients with type 2 diabetes in China.

Can weight-adjusted waist circumference index become a single anthropometric predictor of prostate-specific antigen concentration? A National Health and Nutrition Examination Survey analysis (2003-2010).

Recent studies have introduced the weight-adjusted waist circumference index (WWI) as a viable obesity indicator that may better reflect centripetal obesity and its associated risks. In examining the connection between WWI and prostate-specific antigen (PSA), this study leveraged data from the National Health and Nutrition Examination Survey 2003-2010, including 5732 participants. Our initial analysis indicated a significant positive association between WWI and PSA levels. However, subsequent models that adjusted for covariates such as age, race, and a range of metabolic and cardiovascular health-related factors revealed that the strength and significance of this relationship were attenuated. Model 1 showed a highly significant correlation (p < 0.0001). Yet, in Model 2, which accounted for age and race, the association softened (p = 0.0520). Moreover, when a full spectrum of health covariates was included in Model 3, the association was no longer significant (p = 0.9775). These findings suggest that while an unadjusted correlation exists, its potential use as a diagnostic predictor is limited without considering the broader health context. Therefore, it is crucial to review such data with multiple considerations in mind, and extensive attention should be paid to the evaluation of covariates.

Cost-effectiveness of sacituzumab govitecan versus single-agent chemotherapy for metastatic triple-negative breast cancer: a trial-based analysis.

BACKGROUND: Sacituzumab govitecan (SG) has recently been approved in China for the post-line treatment of metastatic triple-negative breast cancer (mTNBC). SG substantially improves progression-free survival and overall survival compared with single-agent chemotherapy for pretreated mTNBC. However, in view of the high price of SG, it is necessary to consider its value in terms of costs and outcomes. This study aimed to estimate the cost-effectiveness of SG versus single-agent treatment of physician's choice (TPC) in the post-line setting for patients with mTNBC from a Chinese healthcare system perspective. METHODS: The cohort characteristics were sourced from the ASCENT randomized clinical trial, which enrolled 468 heavily pretreated patients with mTNBC between November 2017 and September 2019. A partitioned survival model was constructed to assess the long-term costs and effectiveness of SG versus TPC in the post-line treatment of mTNBC. Quality-adjusted life-months (QALMs) and total costs in 2022 US dollars were used to derive incremental cost effectiveness ratio (ICER). QALMs and costs were discounted at 5% annually. The willingness-to-pay (WTP) threshold was defined as $3188 per QALM, three times China's average monthly per capita gross domestic product in 2022. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses were performed to estimate the robustness of the results. RESULTS: Treatment with SG yielded an incremental 5.17 QALMs at a cost of $44,792 per QALM, much above the WTP threshold of $3188/QALM in China. One-way sensitivity analysis showed that SG price was a crucial factor in the ICER. Probabilistic sensitivity analysis revealed that the cost-effective acceptability of SG was 0% in the current setting. Scenario analyses indicated that the result was robust in all subgroups in ASCENT or under different time horizons. Furthermore, SG must reduce the price to enter the Chinese mainland market. When the monthly cost of SG reduce to $2298, SG has about 50% probability to be a preferred choice than TPC. CONCLUSIONS: SG was estimated to be not cost-effective compared with TPC for post-line treatment for mTNBC in China by the current price in HK under a WTP threshold of $3188 per QALM. A drastic price reduction is necessary to improve its cost-effectiveness.

Albumin-to-D-dimer ratios: A novel prognostic factor for evaluating first-line chemotherapy efficacy in advanced lung adenocarcinoma patients.

The prognosis of advanced lung adenocarcinoma (LUAD) remains unfavorable, with chemotherapy constituting a primary treatment modality. Discerning the efficacy of chemotherapy for advanced LUAD is imperative. Prior investigations have demonstrated the prognostic value of albumin and D-dimer individually for malignancies; however, the predictive capacity of albumin-to-D-dimer ratios (ADR) for advanced LUAD subjected to first-line platinum-based chemotherapy remains unexplored. A cohort of 313 patients with advanced LUAD was retrospectively examined in this study, spanning from January 2017 to January 2021. ADR threshold values were ascertained via receiver operating characteristic analysis, followed by the evaluation of the association between pretreatment ADR and clinicopathological characteristics, disease control rate (DCR), and overall response rate (ORR) pertinent to first-line chemotherapy. Prognostic factors for progression-free survival (PFS) were determined employing Cox univariate and multivariate analyses. Subsequently, survival data were illustrated utilizing the Kaplan-Meier method and scrutinized through the log-rank test across the entire and subgroup populations. ADR demonstrated a superior area under the curve (AUC) value relative to albumin and D-dimer individually and exhibited enhanced prognostic predictive capability compared to albumin-to-fibrinogen ratios (AFR) for advanced LUAD (AUC: 0.805 vs. 0.640, DeLong test: p<0.001). ADR yielded a cut-off value of 16.608. A greater proportion of non-smokers was observed within the high-ADR group (ADR>16.608) compared to the low-ADR group (ADR≤16.608). Patients in the high-ADR group displayed elevated BMI and Na+ levels and reduced neutrophil count, monocyte count, globulin, and alkaline phosphatase (all p<0.05). Notably, the high-ADR group exhibited heightened DCR (96.7% vs. 89.2%, p=0.008) and ORR rates (70.1% vs. 51.0%, p=0.001) relative to the low-ADR group. Multivariate analysis outcomes indicated that high ADR constituted an independent risk factor for PFS (hazard ratio: 0.24, p<0.001). Furthermore, patients in the high-ADR cohort displayed a significantly prolonged median PFS (254 vs. 142 days, p<0.0001) compared to their low-ADR counterparts. In subpopulations exhibiting favorable implications for PFS, as determined by multivariate analysis, high-ADR patients consistently demonstrated extended PFS durations relative to the low-ADR group (all p<0.0001). Collectively, our findings suggest that ADR constitutes a novel and promising prognostic indicator for advanced LUAD patients, surpassing the accuracy of albumin and D-dimer individually and AFR. ADR thus serves as a potent instrument for assessing treatment effects and PFS in advanced LUAD patients undergoing first-line chemotherapy.

Multi-technology integrated network pharmacology-based study on phytochemicals, active metabolites, and molecular mechanism of Psoraleae Fructus to promote melanogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: According to the Compendium of Materia Medica (Shizhen Li, Ming dynasty) and Welfare Pharmacy (Song dynasty), Psoraleae Fructus (PF), a traditional Chinese medicine (TCM) has a bitter taste and warm nature, which has the effect of treating spleen and kidney deficiency and skin disease. Although PF has been widely used since ancient times and has shown satisfactory efficacy in treating vitiligo, the active substances and the mechanism of PF in promoting melanogenesis remain unclear. AIM OF THE STUDY: To explore the active substances and action mechanisms of PF in promoting melanogenesis. MATERIALS AND METHODS: Firstly, UPLC-UV-Q-TOF/MS was used to characterize the components in PF extract and identify the absorption components and metabolites of PF after oral administration at usual doses in rats. Secondly, the active substances and related targets and pathways were predicted by network pharmacology and molecular docking. Finally, pharmacodynamic and molecular biology experiments were used to verify the prediction results. RESULTS: The experimental results showed that 15 compounds were identified in PF extract, and 44 compounds, consisting of 8 prototype components and 36 metabolites (including isomers) were identified in rats' plasma. Promising action targets (MAPK1, MAPK8, MAPK14) and signaling pathways (MAPK signaling pathway) were screened and refined to elucidate the mechanism of PF against vitiligo based on network pharmacology. Bergaptol and xanthotol (the main metabolites of PF), psoralen (prototype drug), and PF extract significantly increased melanin production in zebrafish embryos. Furthermore, bergaptol could promote the pigmentation of zebrafish embryos more than psoralen and PF extract. Bergaptol significantly increased the protein expression levels of p-P38 and decreased ERK phosphorylation in B16F10 cells, which was also supported by the corresponding inhibitor/activator combination study. Moreover, bergaptol increased the mRNA expression levels of the downstream microphthalmia-associated transcription factor (MITF) and tyrosinase in B16F10 cells. Our data elucidate that bergaptol may promote melanogenesis by regulating the p-P38 and p-ERK signaling pathway. CONCLUSIONS: This study will lay a foundation for discovering potential new drugs for treating vitiligo and provide feasible ideas for exploring the mechanism of traditional Chinese medicine.

UGT1A1 genotype-guided irinotecan dosing during neoadjuvant chemoradiotherapy for locally advanced rectal cancer: A prospective analysis of SN-38 concentration.

Irinotecan plays a crucial role in the neoadjuvant chemoradiotherapy (nCRT) of rectal cancer, but its optimal dosing is still unclear. In this study, we included 101 eligible patients with the UGT1A1*28 genotype of UGT1A1*1*1 (74.3%) and UGT1A1*1*28 (25.7%) and UGT1A1*6 genotypes of GG (63.4%), GA (32.7%), and AA (3.9%). All patients received preoperative radiotherapy (50 Gy/25 fractions) with concurrent irinotecan (UGT1A1*1*1: 80 mg/m2 ; UGT1A1*1*28: 65 mg/m2 ) and capecitabine (CapIri). SN-38 concentrations were measured at 1.5, 24, and 49 h post-administration. Patients were divided into four groups (Q1-Q4) based on the SN-38 concentration. The complete-response (CR) rate was the primary endpoint. The analysis demonstrated that the 49 h SN-38 concentration was relatively optimal for predicting efficacy and toxicity. The Q4 group had a significantly higher CR rate than the Q1 group (p = .019), but also higher rates of adverse events (p = .009). We screened the recommended 49 h SN-38, with a 0.5-1.0 ng/mL concentration range. We also validated the correlation between UGT1A1*6 polymorphism and SN-38 concentration, along with the clinical efficacy of irinotecan. In conclusion, our study identified the relatively optimal timepoint and concentration range for monitoring SN38 concentrations and revealed the clinical significance of UGT1A1*6 and UGT1A1*28 polymorphisms in guiding irinotecan administration, offering meaningful insights for personalised irinotecan dosing.

Cost-utility analysis of trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer in Chinese setting.

PURPOSE: Trastuzumab deruxtecan (T-DXd) expressed substantial improvement in the progression-free survival and overall survival contrasted with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC), becoming the second-line standard of care, promisingly. We aim to estimate the cost-utility of T-DXd versus T-DM1 in HER2-positive mBC from the Chinese healthcare perspective. METHODS: A partitioned survival model was applied to examine the cost-utility of T-DXd versus T-DM1. Clinical patients and outcome data were sourced from the DESTINY-Breast 03 trial. Costs and utilities were sourced in Chinese setting. Total costs, quality-adjusted life months (QALMs), and an incremental cost-utility ratios (ICUR) were calculated for cost-utility analysis. The willingness-to-pay threshold was set at $3188/QALM. Univariate, scenario, and probabilistic sensitivity analyses were performed. RESULTS: T-DXd group gained ∆QALM of 7.09 months and ∆Cost of $304,503 compared with T-DM1 therapy, which caused an ICUR of $42,936/QALM. The results of sensitivity analyses confirmed the base-case findings. Furthermore, T-DXd must reduce the price to enter the Chinese mainland market. At least when the cycle cost of T-DXd is reduced to $2975, T-DXd has an 83.3% chance of becoming a better choice. CONCLUSIONS: T-DXd appears to be not cost effective compared with T-DM1 for HER2-positive mBC patients previously treated with trastuzumab and a taxane.

Prospective multicenter online testing of the carotid endarterectomy risk stratification calculator carotidscore.ru.

Aim: To evaluate the incidence of complications, including fatal outcomes, ischemic strokes, and transient ischemic attacks, associated with carotid endarterectomy (CEA) in patients categorized as low-, medium-, and high-risk based on their CarotidSCORE (carotidscore.ru). Material and Methods: This prospective, multicenter study was conducted from January 1, 2022, to December 20, 2022, and enrolled 5,496 patients with stenosis of the internal carotid artery (ICA), who were categorized into four groups according to their risk level. Group 1 (n=1,759) included patients at low risk; Group 2 (n=2,483) included those at medium risk; Group 3 (n=429) included those at high risk, who underwent carotid angioplasty with stenting (CAS) due to the high risk of complications associated with carotid endarterectomy (CEA); and Group 4 (n=825) did not use CarotidSCORE (carotidscore.ru). Patients in Groups 1, 2, and 4 underwent CEA. Results: During the postoperative hospital stay, the highest number of complications, including fatal outcomes (p=0.0007), ischemic strokes (p<0.0001), and the combined endpoints (p<0.0001) were observed in Group 4. No complications were reported in Group 1. Conclusion: The use of CarotidSCORE (carotidscore.ru) allows for the identification of high-risk patients, enabling clinicians to opt for CAS instead of CEA and reduce the incidence of complications.

Iodide-Dependent Selective Dehydroaromatization Affording Maleimide-Fused 9,10-Phenanthrenes and Their Analogues.

A novel and selective synthesis of polycyclic fused maleimides from easily available raw materials under metal-free conditions is presented. This cascade protocol involves self-condensation of cyclohexanones, followed by Diels-Alder reaction with maleimides, intramolecular dehydration, and selective dehydroaromatization in a one-pot fashion, affording maleimide-fused 9,10-phenanthrenes and their analogues in satisfactory yields. Notably, iodide reagents play a critical role in switching the selectivity toward full or partial dehydrogenation compounds.

Research progress on deep learning in magnetic resonance imaging-based diagnosis and treatment of prostate cancer: a review on the current status and perspectives.

Multiparametric magnetic resonance imaging (mpMRI) has emerged as a first-line screening and diagnostic tool for prostate cancer, aiding in treatment selection and noninvasive radiotherapy guidance. However, the manual interpretation of MRI data is challenging and time-consuming, which may impact sensitivity and specificity. With recent technological advances, artificial intelligence (AI) in the form of computer-aided diagnosis (CAD) based on MRI data has been applied to prostate cancer diagnosis and treatment. Among AI techniques, deep learning involving convolutional neural networks contributes to detection, segmentation, scoring, grading, and prognostic evaluation of prostate cancer. CAD systems have automatic operation, rapid processing, and accuracy, incorporating multiple sequences of multiparametric MRI data of the prostate gland into the deep learning model. Thus, they have become a research direction of great interest, especially in smart healthcare. This review highlights the current progress of deep learning technology in MRI-based diagnosis and treatment of prostate cancer. The key elements of deep learning-based MRI image processing in CAD systems and radiotherapy of prostate cancer are briefly described, making it understandable not only for radiologists but also for general physicians without specialized imaging interpretation training. Deep learning technology enables lesion identification, detection, and segmentation, grading and scoring of prostate cancer, and prediction of postoperative recurrence and prognostic outcomes. The diagnostic accuracy of deep learning can be improved by optimizing models and algorithms, expanding medical database resources, and combining multi-omics data and comprehensive analysis of various morphological data. Deep learning has the potential to become the key diagnostic method in prostate cancer diagnosis and treatment in the future.

Metallic Powder Promotes Nitridation Kinetics for Facile Synthesis of (Oxy)Nitride Photocatalysts.

Nitrogen-containing semiconductors (including metal nitrides, metal oxynitrides, and nitrogen-doped metal oxides) have been widely researched for their application in energy conversion and environmental purification because of their unique characteristics; however, their synthesis generally encounters significant challenges owing to sluggish nitridation kinetics. Herein, a metallic-powder-assisted nitridation method is developed that effectively promotes the kinetics of nitrogen insertion into oxide precursors and exhibits good generality. By employing metallic powders with low work functions as electronic modulators, a series of oxynitrides (i.e., LnTaON2 (Ln = La, Pr, Nd, Sm, and Gd), Zr2 ON2 , and LaTiO2 N) can be prepared at lower nitridation temperatures and shorter nitridation periods to obtain comparable or even lower defect concentrations compared to those of the conventional thermal nitridation method, leading to superior photocatalytic performance. Moreover, some novel nitrogen-doped oxides (i.e., SrTiO3- x Ny and Y2 Zr2 O7- x Ny ) with visible-light responses can be exploited. As revealed by density functional theory (DFT) calculations, the nitridation kinetics are enhanced via the effective electron transfer from the metallic powder to the oxide precursors, reducing the activation energy of nitrogen insertion. The modified nitridation route developed in this work is an alternative method for preparing (oxy)nitride-based materials for energy/environment-related heterogeneous catalysis.

Simultaneous online SPE-HPLC-MS/MS quantification of gefitinib, osimertinib and icotinib in dried plasma spots: Application to therapeutic drug monitoring in patients with non-small cell lung cancer.

Gefitinib, osimertinib and icotinib are the most commonly used tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with EGFR mutation. Therapeutic drug monitoring (TDM) for these TKIs has become a standard and essential procedure. Dried plasma spots (DPS) was choosen for microsampling strategies for TDM, allowing easy and cost-effective logistics in many settings. This study developd and validated an assay for the simultaneous quantitative determination of gefitinib, osimertinib and icotinib in DPS by online solid-phase extraction-liquid chromatography-tandem mass spectrometry (online SPE-LC-MS) system. The TKIs were extracted from DPS with methanol and enriched on a Welch Polar-RP SPE column (30 × 4.6 mm, 5 µm), followed by separation on Waters X Bridge C18 analytical column(4.6 × 100 mm, 3.5 µm). The method achieved LLOQ of 2 ng mL-1 for gefitinib and osimertinib (4 ng mL-1 for icotinib), respectively (r2 > 0.99). Precision (within-run 1.54-7.41 % RSD; between-run 3.03-12.84 % RSD), accuracy (range from 81.47 % to 105.08 %; between-run bias 87.87-104.13 %). Osimertinib and icotinib were stable in DPS stored at - 40 °C for 30 days, 4 °C, 42 °C and 60 °C for 5 days and well-sealed 37 °C,75 % humidity (except gefitinib). Lastly, the assay was applied to TDM of TKIs in 46 patients and the results were compared to SALLE assisted LC-MS analysis, it could be confirmed that the developed method achieves similarly good results as the already established one and no bias could be detected. It implies that this method capable of supporting clinical follow-up TDM of TKIs in DPS from poor medical environment.

Bidirectional association between NAFLD and gallstone disease: a systematic review and meta-analysis of observational studies.

BACKGROUND: Growing evidence indicates an association between NAFLD and gallstone disease (GD), while some does not support this. The aim of this meta-analysis was to evaluate the bidirectional association between NAFLD and GD. RESEARCH DESIGN AND METHODS: Five electronic databases were searched from inception to May 2022. The association was analyzed based on the odds ratio (OR) and 95% confidence interval (CI) with Reviewer Manager 5.3. RESULTS: Ten studies involving 284,512 participants met the criteria for GD predicting the onset of NAFLD. GD patients had a higher incidence of NAFLD (OR:1.48, CI:1.32-1.65, p < 0.00001), especially the incidence of moderate-to-severe NAFLD (OR:1.63; CI:1.40-1.79), with females at a higher risk (OR: 1.84; CI: 1.48-2.29). The inverse association was explored in eight studies involving 326,922 participants. The GD incidence in NAFLD patients was higher (OR:1.71, CI:1.63-1.79, p < 0.00001) and may increase due to female sex (OR: 4.18; CI: 1.21-14.37) and high BMI (OR: 1.80; CI: 1.36-2.56), compared with the non-NAFLD group. Besides, this bidirectional association was also confirmed in the Chinese population. CONCLUSIONS: The findings supported positive concurrent and bidirectional relationships between NAFLD and GD. Therefore, clinicians may alert the possibility of NAFLD in patients with GD and vice versa.

Cost-utility analysis of semaglutide for type 2 diabetes after its addition to the National Medical Insurance System in China.

INTRODUCTION: The main research purpose is to compare the long-term cost-effectiveness of semaglutide (SEMA) with that of dulaglutide (DULA) for patients with inadequately controlled type 2 diabetes throughout their lifetime. If necessary, the second aim is to investigate a further price cut for SEMA to provide sound advice for government drug price adjustments. METHODS: Cost-utility analysis was performed by the United Kingdom Prospective Diabetes Study Outcomes Model 2 (UKPDS OM2) from the perspective of health care providers in China. Baseline characteristics and clinical efficacy of SEMA and DULA were sourced from the high-dose comparison in the SUSTAIN-7 trial. A binary search was used to identify the scope for further reduction in the price of SEMA. The impact of individual parameters was assessed with sensitivity analyses. RESULTS: Main analysis (SEMA vs. DULA) revealed a mean difference in quality-adjusted life years (QALYs) of 0.04 QALYs and costs of $1132.29. The incremental cost-utility ratio was $26 957.44/QALY, showing that SEMA was a better option compared with DULA. In sensitivity analyses, the discount rate made the greatest contribution to the incremental cost-utility ratio. In the binary search, there was still scope to reduce the SEMA cost further by approximately 6.83% to be cost-effective, taking DULA as a reference. CONCLUSION: After its addition to the National Medical Insurance System in China, SEMA is expected to be a cost-effective choice compared with DULA for patients with type 2 diabetes with inadequately controlled from the cost-utility analysis. However, there is still scope to reduce the annual cost of SEMA further.

Pyrochlore-structural Nd2Ta2O5N2 photocatalyst with an absorption edge of over 600 nm for Z-scheme overall water splitting.

A pyrochlore-structural oxynitride Nd2Ta2O5N2 with a visible light absorption edge of ca. 620 nm was explored for photocatalytic water splitting. Dual functions of Nd2Ta2O5N2 were confirmed by proton reduction and water oxidation half-reactions through separately loading Pt or CoOx as a cocatalyst in the presence of the corresponding sacrificial reagent. Finally, the platinum modified sample (Pt/Nd2Ta2O5N2) was prepared and employed as the H2-evolving photocatalyst to fabricate an effective photocatalytic Z-scheme overall water splitting together with PtOx/WO3 as the O2-evolving photocatalyst and IO3-/I- as shuttle ions under visible light irradiation.

Identification of bicyclol metabolites in rat plasma, urine and feces by UPLC-Q-TOF-MS/MS and evaluation of the efficacy and safety of these metabolites based on network pharmacology and molecular docking combined with toxicity prediction.

Bicyclol (BIC) has been widely used to treat drug-induced liver injury (DILI), however, it still has the problems of low solubility and bioavailability. Besides, the metabolic characteristics of BIC remain unclear. In the current study, we identified the metabolite of BIC in rat plasma, urine and feces, and evaluated the efficacy and safety of these metabolites. Based on the fragmentation behavior, we totally identified 11 metabolites and 7 metabolites in plasma, 8 metabolites in urine and 8 metabolites in feces. Notably, M1-M3, M6, M7, M10 and M11 were identified for the first time. M7 was the most abundant metabolite in the rat plasma. The metabolic pathways mainly involved demethylation, dealkylation, hydrolysis, methylation, oxidation and glucuronidation. In addition, the efficacy and safety of BIC's metabolites were evaluated by network pharmacology and molecular docking combined with toxicity prediction. The analysis of network pharmacology indicated that BIC's metabolites against DILI through the MAPK signaling pathway and Hepatitis B pathway. The molecular docking results showed that the binding energy of 5 compounds that docked with "7nuw" and 10 compounds that docked with "4tjz" was lower than BIC. 11 compounds possessed higher solubility and lower toxicity than BIC in prediction. Thus, the identification and evaluation of BIC's metabolites contributed to a better understanding of pharmacological mechanism of BIC and the high-value metabolites of high efficacy, safety and solubility provided a basis for drug development.

Novel Brain-Stiffness-Mimicking Matrix Gel Enables Comprehensive Invasion Analysis of 3D Cultured GBM Cells.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, which is fast growing and tends to invade surrounding normal brain tissues. Uncovering the molecular and cellular mechanisms of GBM high invasion potential is of great importance for the treatment and prognostic prediction. However, the commonly used two-dimensional (2D) cell culture and analysis system suffers from lack of the heterogeneity and in vivo property of brain tissues. Here, we established a three-dimensional (3D) cell culture-based analysis system that could better recapitulate the heterogeneity of GBM and mimic the in vivo conditions in the brain. The GBM cell lines, DBTRG and U251, were cultured by hanging drop culture into the GBM multicellular spheroids, which were embedded in the optimized 3D brain-stiffness-mimicking matrix gel (0.5 mg/ml Collagen Ⅰ + 3 mg/ml Matrigel+ 3.3 mg/ml Hyaluronic Acid (HA)). The biochemical composition of the optimized matrix gel is similar to that of the brain microenvironment, and the elastic modulus is close to that of the brain tissue. The dynamics of the GBM spheroids was examined using high-content imaging for 60 h, and four metrics including invasion distance, invasion area, single-cell invasion velocity, and directionality were employed to quantify the invasion capacity. The result showed that DBTRG cells possess higher invasion capacity than U251 cells, which was consistent with the results of the classic transwell test. Transcriptome analysis of both cell lines was performed to explore the underlying molecular mechanisms. Our novel brain-stiffness-mimicking matrix gel enables comprehensive invasion analysis of the 3D cultured GBM cells and provides a model basis for in-depth exploration of the mechanisms regulating GBM invasion including the interaction between GBM cells and brain stroma.

Robust Prediction of Prognosis and Immunotherapy Response for Bladder Cancer through Machine Learning Algorithm.

The important roles of machine learning and ferroptosis in bladder cancer (BCa) are still poorly understood. In this study, a comprehensive analysis of 19 ferroptosis-related genes (FRGs) was performed in 1322 patients with BCa from four independent patient cohorts and a pan-cancer cohort of 9824 patients. Twelve FRGs were selected through machine learning algorithm to construct the prognosis model. Significantly differential survival outcomes (hazard ratio (HR) = 2.09, 95% confidence interval (CI): 1.55−2.82, p < 0.0001) were observed between patients with high and low ferroptosis scores in the TCGA cohort, which was also verified in the E-MTAB-4321 cohort (HR = 4.71, 95% CI: 1.58−14.03, p < 0.0001), the GSE31684 cohort (HR = 1.76, 95% CI: 1.08−2.87, p = 0.02), and the pan-cancer cohort (HR = 1.15, 95% CI: 1.07−1.24, p < 0.0001). Tumor immunity-related pathways, including the IL-17 signaling pathway and JAK-STAT signaling pathway, were found to be associated with the ferroptosis score in BCa through a functional enrichment analysis. Further verification in the IMvigor210 cohort revealed the BCa patients with high ferroptosis scores tended to have worse survival outcome after receiving tumor immunotherapy. Significantly different ferroptosis scores could also be found between BCa patients with different reactions to treatment with immune checkpoint inhibitors.

Spatiotemporal mapping of gene expression landscapes and developmental trajectories during zebrafish embryogenesis.

A major challenge in understanding vertebrate embryogenesis is the lack of topographical transcriptomic information that can help correlate microenvironmental cues within the hierarchy of cell-fate decisions. Here, we employed Stereo-seq to profile 91 zebrafish embryo sections covering six critical time points during the first 24 h of development, obtaining a total of 152,977 spots at a resolution of 10 × 10 × 15 µm3 (close to cellular size) with spatial coordinates. Meanwhile, we identified spatial modules and co-varying genes for specific tissue organizations. By performing the integrated analysis of the Stereo-seq and scRNA-seq data from each time point, we reconstructed the spatially resolved developmental trajectories of cell-fate transitions and molecular changes during zebrafish embryogenesis. We further investigated the spatial distribution of ligand-receptor pairs and identified potentially important interactions during zebrafish embryo development. Our study constitutes a fundamental reference for further studies aiming to understand vertebrate development.

Cost-Utility Analysis of Once-Weekly Semaglutide, Dulaglutide, and Exenatide for Type 2 Diabetes Patients Receiving Metformin-Based Background Therapy in China.

Introduction: The substantial financial burden associated with type 2 diabetes (T2D) over a lifetime cannot be neglected. Therefore, the objective of this study was to evaluate the pharmacoeconomic value of three once-weekly GLP-1 RAs, namely subcutaneous semaglutide (sc. SEMA), dulaglutide (DULA), and extended-release exenatide (e-r EXEN), in treating patients with T2D that cannot be controlled with metformin-based background therapy, and to find a suitable price reduction for non-cost-effective medications, to provide reasonable recommendations to the administration for adjusting drug prices. Methods: The baseline characteristics of the simulation patient cohort were sourced from a comprehensive meta-analysis synthesizing 453 trials evaluating 21 hypoglycemic agents from nine categories of drugs. The UKPDS OM2 was applied to project the long-term effectiveness and costs from a Chinese health care provider's perspective. After cost-utility analysis, the reasonable price adjustment of non-cost-effective options was explored via binary search. Uncertainty was measured by means of sensitivity analysis. Results: After a 40-year simulation, the sc. SEMA, DULA, and e-r EXEN groups yielded 9.6315, 9.5968, and 9.5895 quality-adjusted life years (QALYs), respectively. In terms of expenditure, the total costs for the sc. SEMA, DULA, and e-r EXEN groups were $42012.47, $24931.27, and $40264.80, respectively. DULA was dominant over e-r EXEN due to the higher QALYs and lower total costs. The ICURs of sc. SEMA vs. DULA and sc. SEMA vs. e-r EXEN were $492994.72/QALY and $41622.69/QALY (ICUR > λ), respectively, indicating that sc. SEMA was not more cost-effective than DULA or e-r EXEN. The INMB and absolute NMB yielded the same conclusions which were robust to one-way, scenario, and probabilistic sensitivity analyses. After several assumptions in the binary search, sc. SEMA and e-r EXEN appear to become cost-effective when their annual costs are decreased by 57.67% and 70.34%, respectively, with DULA as a counterpart. Conclusion: From the cost-utility analysis, DULA appears to be the most cost-effective option among sc. SEMA, DULA, and e-r EXEN for the treatment of patients with T2D receiving metformin-based background therapy. With a 57.67% or 70.34% reduction in cost, sc. SEMA or e-r EXEN, respectively, would become as cost-effective as DULA in China.