Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis.

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

Exploring the effect of Wuzhi capsule on the pharmacokinetics of regorafenib and its main metabolites in rat plasma using liquid chromatography-tandem mass spectrometry.

Regorafenib is a small-molecule tyrosine kinase inhibitor with severe hepatotoxicity. It undergoes metabolism mainly by CYP3A4 to generate active metabolites regorafenib-N-oxide (M2) and N-desmethyl-regorafenib-N-oxide (M5). Wuzhi capsule (WZC) is an herbal preparation derived from Schisandra sphenanthera and is potentially used to prevent regorafenib-induced hepatotoxicity. This study aims to explore the effect of WZC on the pharmacokinetics of regorafenib in rats. An efficient and sensitive liquid chromatography-tandem mass spectrometry method was developed to quantitatively determine regorafenib and its main metabolites in rat plasma. The proposed method was applied to the pharmacokinetic study of regorafenib in rats, with or without WZC. Coadministration of regorafenib with WZC resulted in a prolonged mean residence time (MRT) of the parent drug but had no statistically significant difference in other pharmacokinetic parameters. While for the main metabolites of regorafenib, WZC decreased the area under the curve and maximum concentration (Cmax ), delayed the time to reach Cmax , and prolonged the MRT of M2 and M5. These results indicate that WZC delayed and inhibited the metabolism of regorafenib to M2 and M5 by suppressing CYP3A4. Our study provides implications for the rational use of the WZC-regorafenib combination in clinical practice.

Construction and validation of a mitochondria-associated genes prognostic signature and immune microenvironment characteristic of sepsis.

BACKGROUND: Sepsis is a common critical condition seen in clinical settings, with mitochondrial dysfunction playing an important role in the progression of sepsis. However, a mitochondrial prognosis model related to sepsis has not been established yet, and the relationship between the sepsis immune microenvironment and mitochondria remains unclear. METHODS: Sepsis prognostic mitochondria-associated genes (MiAGs) were screened by univariate Cox, multivariate Cox, and LASSO analysis from the GEO dataset. Consensus Cluster was used to analyze MiAGs-based molecular subtypes for sepsis. The ESTIMATE and ssGSEA algorithms were used to analyze the situation of sepsis immune cell infiltration and its relation to MiAGs. Further, MiAGs score was calculated to construct a sepsis prognosis risk model to predict the prognosis of sepsis patients. Clinical blood samples were used to investigate the expression level of selected MiAGs in sepsis. Single-cell sequencing analysis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and ATP detection were used to verify the influence of MiAGs on mitochondrial dysfunction in sepsis. RESULTS: A total of 5 MiAGs of sepsis were screened. Based on MiAGs, sepsis MiAGs subtypes were analyzed, where Cluster A had a better prognosis than Cluster B, and there were significant differences in immune infiltration between the two clusters. The sepsis mitochondrial prognosis model suggested that the high MiAG score group had a shorter survival time compared to the low MiAG score group. Significant differences were also observed in the immune microenvironment between the high and low MiAG score groups. Prognostic analysis and the Nomogram indicated that the MiAG score is an independent prognostic factor in sepsis. Single-cell sequencing analysis exhibited the possible influence of MiAGs on the mitochondrial function of monocytes. Finally, the downregulation of the COX7B could effectively improve mitochondrial function in the LPS-stimulated sepsis model. CONCLUSION: Our findings suggest that MiAGs can be used to predict the prognosis of sepsis and that regulating the mitochondrial prognostic gene COX7B can effectively improve the mitochondrial function of immune cells in sepsis.

Molecular Subtypes Based on PANoptosis Genes and Characteristics of Immune Infiltration in Cutaneous Melanoma.

Cutaneous melanoma (CM) remains the most life-threatening form of skin cancer. Further risk stratification and search for new prognostic targets for CM are of positive clinical significance. PANoptosis is defined as an inflammatory programmed cell death mediated by the PANoptosome complex and cannot be characterized by pyroptosis, apoptosis or necroptosis alone. Although PANoptosis is closely associated with many diseases including cancer, it has not been reported in CM. Combined with GTEx and TCGA database, we extracted 14 PANoptosis-related genes (PAGs). The molecular subtypes of CM were then analyzed by PAGs and their associations with the immune microenvironment and immunotherapy reactivity were analyzed. LASSO and univariate Cox analysis was performed on PAGs-related differentially expressed genes to establish PAGs characteristics that could effectively predict the prognosis of CM patients. Immune infiltration, tumor mutation burden analysis, immunotherapy response and drug sensitivity analysis were used to further analyze the causes of prognostic differences. Our study provides a new perspective on the role of PANoptosis in CM.

Development of anoikis-related long non-coding RNA signature associated with prognosis and immune landscape in cutaneous melanoma patients.

BACKGROUND: Anoikis is involved in many critical biological processes in tumors; however, function in CM is still unknown. In this study, the relevance between Anoikis-related lncRNAs (ARLs) and the clinicopathological characteristics of patients with CM was comprehensively assessed. METHODS: Through analysis of TCGA dataset, ARLs were identified by using TCGA dataset. Based on the ARLs, a risk model was established to anticipate the prognosis of patients with CM, besides, the prediction accuracy of the model was evaluated. The immune infiltration landscape of patients with CM was assessed comprehensively, and the correlation between ARLs and immunity was elucidated. Immunotherapy and drug sensitivity analyses were applied to analyze the treatment response in patients with CM with diverse risk scores. Different subgroups were distinguished among the patients using consensus cluster analysis. RESULTS: A risk model based on six ARLs was set up to obtain an accurate prediction of the prognosis of patients with CM. There were distinctions in the immune landscape among CM patients with diverse risk scores and subgroups. Six prognosis-related ARLs were highly correlated with the number of immune cells. Patients with CM with different risk scores have various sensitivities to immunotherapy and antitumor drug treatments. CONCLUSION: Our newly risk model associated with ARLs has considerable prognostic value for patients with CM. Not only has the risk model high prediction accuracy but it also indicates the immune status of CM patients, which will provide a new direction for the individualized therapy of patients with CM.

Reply to "A better interpretation of data regarding the opioid switching to methadone".

In our article ?Methadone switching for refractory cancer pain' (BMC palliative care, 2022) we explore the efficacy, safety and economics of methadone in treatment of patients with refractory cancer pain in China. Professor Mercadante provided a better interpretation of data regarding the opioid switching to methadone in the Matters Arising. In this article, we answered the questions in Mercadante et al.'s comments one by one.

Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer.

PURPOSE: The objective of this study was to investigate the pharmacokinetic characteristics of pegylated liposomal doxorubicin (PLD) in Chinese female patients with advanced breast cancer by constructing population pharmacokinetic (popPK) models of liposome-encapsulated and free doxorubicin. Additionally, the relationship between pharmacokinetic parameters and drug-related adverse events (AEs) was explored through toxicity correlation analysis. METHODS: A total of 20 patients with advanced breast cancer were selected from a PLD bioequivalence study. All patients received a single intravenous dose of 50 mg/m2 PLD. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A popPK model was simultaneously built to characterize the pharmacokinetic profiles of liposome-encapsulated and free doxorubicin by non-linear mixed effects model (NONMEM). PLD-related toxicities were graded according to the common terminology criteria for adverse events (CTCAE) v5.0. The Spearman correlation analysis was conducted to explore the relationship between pharmacokinetic parameters and drug-related AEs of both liposome-encapsulated doxorubicin and free doxorubicin. RESULTS: The concentration-time profiles of both liposome-encapsulated doxorubicin and free doxorubicin were well described by a one-compartment model. The most common AEs to PLD were nausea, vomiting, neutropenia, leukopenia, and stomatitis, most of which were grade I-II. The toxicity correlation analysis results indicated that stomatitis was related to the Cmax of liposome-encapsulated doxorubicin (P < 0.05). No other AEs were found to be correlated with the pharmacokinetic parameters of either free or liposome-encapsulated doxorubicin. CONCLUSION: A one-compartment model adequately described the popPK characteristics of both liposome-encapsulated and free doxorubicin in Chinese female patients with advanced breast cancer. Most AEs to PLD were mild. Additionally, the occurrence of mucositis may be positively correlated with the Cmax of liposome-encapsulated doxorubicin.

Identification and experimental validation of mitochondria-related genes biomarkers associated with immune infiltration for sepsis.

Background: Sepsis remains a complex condition with incomplete understanding of its pathogenesis. Further research is needed to identify prognostic factors, risk stratification tools, and effective diagnostic and therapeutic targets. Methods: Three GEO datasets (GSE54514, GSE65682, and GSE95233) were used to explore the potential role of mitochondria-related genes (MiRGs) in sepsis. WGCNA and two machine learning algorithms (RF and LASSO) were used to identify the feature of MiRGs. Consensus clustering was subsequently carried out to determine the molecular subtypes for sepsis. CIBERSORT algorithm was conducted to assess the immune cell infiltration of samples. A nomogram was also established to evaluate the diagnostic ability of feature biomarkers via "rms" package. Results: Three different expressed MiRGs (DE-MiRGs) were identified as sepsis biomarkers. A significant difference in the immune microenvironment landscape was observed between healthy controls and sepsis patients. Among the DE-MiRGs, NDUFB3 was selected to be a potential therapeutic target and its significant elevated expression level was confirmed in sepsis using in vitro experiments and confocal microscopy, indicating its significant contribution to the mitochondrial quality imbalance in the LPS-simulated sepsis model. Conclusion: By digging the role of these pivotal genes in immune cell infiltration, we gained a better understanding of the molecular immune mechanism in sepsis and identified potential intervention and treatment strategies.

Population Pharmacokinetics of Anlotinib, a Multiple Receptor Tyrosine Kinase Inhibitor, in Chinese Patients With Malignant Tumors.

The objective of this study was to investigate the pharmacokinetic behavior of anlotinib in Chinese patients with malignant tumors using the population approach. A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single-dose phase and 12 mg once daily in the multiple-dose phase. A population pharmacokinetic model was established using nonlinear mixed-effects model method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetics was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. The pharmacokinetic profile of anlotinib was best described by a 1-compartment model with first-order absorption and first-order elimination. The population estimates of the apparent total clearance, apparent volume of distribution, and absorption rate constant were 8.91 L/h, 1950 L, and 0.745/h, respectively. Body weight was identified as a significant covariate on apparent volume of distribution. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant based on the simulations of the individual body weight effects. Taken together, this population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors and supports the same starting dose among them.

A Prognostic Cuproptosis-Related LncRNA Signature for Colon Adenocarcinoma.

Background: Cuproptosis, a recently discovered form of cell death, is caused by copper levels exceeding homeostasis thresholds. Although Cu has a potential role in colon adenocarcinoma (COAD), its role in the development of COAD remains unclear. Methods: In this study, 426 patients with COAD were extracted from the Cancer Genome Atlas (TCGA) database. The Pearson correlation algorithm was used to identify cuproptosis-related lncRNAs. Using the univariate Cox regression analysis, the least absolute shrinkage and selection operator (LASSO) was used to select cuproptosis-related lncRNAs associated with COAD overall survival (OS). A risk model was established based on the multivariate Cox regression analysis. A nomogram model was used to evaluate the prognostic signature based on the risk model. Finally, mutational burden and sensitivity analyses of chemotherapy drugs were performed for COAD patients in the low- and high-risk groups. Result: Ten cuproptosis-related lncRNAs were identified and a novel risk model was constructed. A signature based on ten cuproptosis-related lncRNAs was an independent prognostic predictor for COAD. Mutational burden analysis suggested that patients with high-risk scores had higher mutation frequency and shorter survival. Conclusion: Constructing a risk model based on the ten cuproptosis-related lncRNAs could accurately predict the prognosis of COAD patients, providing a fresh perspective for future research on COAD.

Methadone switching for refractory cancer pain.

BACKGROUND: Methadone is commonly considered an alternative opioid treatment for refractory cancer pain. This study aims to investigate the efficacy, safety, and cost of methadone in the treatment of refractory cancer pain. METHODS: A retrospective study was conducted in patients who used methadone for refractory cancer pain from April 2016 to December 2020 at a cancer specialized hospital. Pain control, evaluated via pain score and breakthrough pain frequency, and adverse events of methadone were compared with analgesic regimens prior to methadone administration. The factors potentially affecting the switching outcome were analyzed via multivariate analysis. Moreover, the cost of pain control was estimated. RESULTS: Ninety patients received methadone for poor pain control (74.4%), intolerable adverse events (10.0%), or both (15.6%) after prior opioid treatments. Sixty-four patients (71.1%) were successfully switched to methadone with median pain score significantly decreased from 4.0 to 2.0 (p < 0.001) and median daily frequency of breakthrough pain from 3.0 to 0.0 (p < 0.001) at a maintained median conversion ratio of 6.3 [interquartile range (IQR): 4.0-10.0] to prior opioid treatment. Similar adverse event profiles of constipation, nausea, vomiting, and dizziness were observed between methadone and prior opioid regimens. The median daily cost of analgesic regimens was significantly reduced from $19.5 (IQR: 12.3-46.2) to $10.8 (IQR: 7.1-18.7) (p < 0.01) after switching to methadone. The 3-day switch method significantly improved the rate of successful switching compared with the stop and go method (odds ratio = 3.37, 95% CI: 1.30-8.76, p = 0.013). CONCLUSION: Methadone is an effective, safe, and cost-saving treatment for patients with refractory cancer pain.

Spectrum-Effect Relationship-Based Strategy Combined with Molecular Docking to Explore Bioactive Flavonoids from Sceptridium ternatum.

Sceptridium ternatum is a herbaceous plant with significant potential for pharmaceutical and cosmetic applications. In this study, we established a spectrum-effect relationship-based strategy to investigate the bioactive basis and tissue distribution in S. ternatum. First, a phytochemical analysis on the ethanol extracts from roots, stems, and leaves of S. ternatum was performed using the colorimetric method, high-performance liquid chromatography-ultraviolet (HPLC-UV), and high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOF-MS/MS). Then, radical scavenging assays and the lipopolysaccharide-stimulated RAW 264.7 cell model were used to estimate the antioxidant and anti-inflammatory activities, respectively. Spectrum-effect relationship analysis and molecular docking were further employed to evaluate the correlation between the phytochemical profile and anti-inflammatory activity. Our results demonstrate that S. ternatum leaves contained the most abundant flavonoids and exerted the best biological activities. Their IC50 values for scavenging 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) and 1,1-diphenyl-2-picrylhydrazyl radicals were 2.43 ± 0.13 and 5.36 ± 0.54 mg/mL, respectively. In lipopolysaccharide-stimulated RAW 264.7 cells, the leaf extract caused the greatest reduction in nitric oxide production (38.15%) and interleukin-6 release (110.86%). Spectrum-effect relationship analysis and molecular docking indicated that quercetin 3-O-rhamnoside-7-O-glucoside possessed high anti-inflammatory activity by binding with interleukin-6. In conclusion, S. ternatum is a rich source of bioactive flavonoids with potential for exploitation in the prevention and treatment of oxidative stress and inflammation-related pathologies.

A Novel Risk Model Based on Autophagy-Related LncRNAs Predicts Prognosis and Indicates Immune Infiltration Landscape of Patients With Cutaneous Melanoma.

Cutaneous melanoma (CM) is a malignant tumor with a high incidence rate and poor prognosis. Autophagy plays an essential role in the development of CM; however, the role of autophagy-related long noncoding RNAs (lncRNAs) in this process remains unknown. Human autophagy-related genes were extracted from the Human Autophagy Gene Database and screened for autophagy-related lncRNAs using Pearson correlation. Multivariate Cox regression analysis was implemented to identify ten autophagy-related lncRNAs associated with prognosis, and a risk model was constructed. The Kaplan-Meier survival curve showed that the survival probability of the high-risk group was lower than that of the low-risk group. A novel predictive model was constructed to investigate the independent prognostic value of the risk model. The nomogram results showed that the risk score was an independent prognostic signature that distinguished it from other clinical characteristics. The immune infiltration landscape of the low-risk and high-risk groups was further investigated. The low-risk groups displayed higher immune, stromal, and ESTIMATE scores and lower tumor purity. The CIBERSORT and single sample gene set enrichment analysis (ssGSEA) algorithms indicated a notable gap in immune cells between the low- and high-risk groups. Ten autophagy-related lncRNAs were significantly correlated with immune cells. Finally, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) results demonstrated that autophagy-related lncRNA-mediated and immune-related signaling pathways are crucial factors in regulating CM. Altogether, these data suggest that constructing a risk model based on ten autophagy-related lncRNAs can accurately predict prognosis and indicate the tumor microenvironment of patients with CM. Thus, our study provides a new perspective for the future clinical treatment of CM.

Modified microvessel density based on perfusion distance: a preferable NSCLC prognostic factor.

Background: Despite the vital role of blood perfusion in tumor progression, the prognostic value of typical blood perfusion markers, such as microvessel density (MVD) or microvessel area (MVA), in patients with non-small cell lung cancer (NSCLC) is still unclear. This study established a modified MVD (mMVD) measurement based on perfusion distance and determined its prognostic value in patients with NSCLC. Methods: A total of 100 patients with NSCLC were enrolled in this retrospective study. The intratumor microvessels of NSCLC patients were visualized using immunohistochemical staining for CD31. The blood perfusion distance was evaluated as the distance from each vessel to its nearest cancer cell (Dmvcc), and the cutoff value for prognosis was determined. Apart from the total MVD (tMVD), microvessels near cancer cells within the cutoff-Dmvcc were counted as mMVD. Predictive values for mortality and recurrence were evaluated and compared. Results: The Dmvcc ranged from 1.6 to 269.8 µm (median, 13.1 µm). The mMVD (range: 2-70; median 23) was counted from tMVD according to the cutoff-Dmvcc (~20 µm). Compared with tMVD, a larger fraction of mMVD (80% vs. 2.9%) played a significant role in overall survival, with an improved area under the receiver operating characteristic (ROC) curve (AUC) (0.74 vs. 0.56). A high mMVD was an independent positive indicator of overall survival (OS) and progression-free survival (PFS). In contrast, tMVD was only related to PFS at the optimal cutoff. Conclusions: Perfusion-distance-based mMVD is a promising prognostic factor for NSCLC patients with superior sensitivity, specificity, and clinical applicability compared to tMVD. This study provides novel insights into the prognostic role of tumor vessel perfusion in patients with NSCLC.

Cost-effectiveness analysis of durvalumab plus etoposide: platinum in the first-line therapy of extensive stage small-cell lung cancer from the Chinese payers' perspective.

INTRODUCTION: Results from the CASPIAN trial (Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer) trial demonstrated the clinical benefit of durvalumab plus etoposide-platinum (EP) chemotherapy as first-line treatment for patients with extensive stage small-cell lung cancer (ES-SCLC). However, considering the high price of durvalumab, it is unclear whether addition of durvalumab to EP chemotherapy has economic value compared with EP alone. In this study, we aimed to evaluate the cost-effectiveness of durvalumab plus EP chemotherapy as a first-line treatment for patients with ES-SCLC. METHODS: A Markov model comprising three health states (stable, progressive, and dead) was developed to simulate the process of small-cell lung cancer. Utility and costs were obtained from published resources. Health outcomes were derived from the CASPIAN trial. Costs were calculated based on the standard medical fees in Zhejiang Province from Chinese patients' perspective. Utility values were obtained from published data. One-way and probabilistic sensitivity analyses were applied to verify model robustness. RESULTS: The addition of durvalumab to EP chemotherapy costs more than $32,220, with a gain of 0.14 quality-adjusted life years (QALYs) compared with EP alone. The incremental cost-effective ratio was $230,142.9 per QALY, which exceeds the willingness to pay threshold of $28,527 per QALY. In the sensitivity analysis, the utility values for the progressive state, costs of durvalumab and EP chemotherapy, and costs for the progressive state were considered to be the three most sensitive factors in the model. CONCLUSION: The addition of durvalumab to EP chemotherapy is not a cost-effective strategy in the first-line therapy of ES-SCLC from the Chinese payers' perspective.

Integrated Transcriptomics and Reverse Pharmacophore Mapping-based Network Pharmacology to Explore the Mechanisms of Natural Compounds against Doxorubicin-induced Cardiotoxicity.

BACKGROUND: Doxorubicin-Induced Cardiotoxicity (DIC) has greatly limited the clinical benefits of this frontline drug in oncotherapy. Drug combination with Natural Compounds (NCs) that possess potency against DIC is considered as a promising intervention strategy. However, the Mechanisms of Action (MoAs) underlying such drug interactions remain poorly understood. The aim of this study was to systematically pursuit of the molecular mechanisms of NCs against DIC. METHODS: First, the gene expression signatures of DIC were characterized from transcriptomics datasets with doxorubicin-treated and untreated cardiomyocytes using differentially expressed gene identification, functional enrichment analysis, and protein-protein interaction network analysis. Secondly, reverse pharmacophore mapping-based network pharmacology was employed to illustrate the MoAs of 82 publicly reported NCs with anti-DIC potency. Cluster analysis based on their enriched pathways was performed to gain systematic insights into the anti-DIC mechanisms of the NCs. Finally, the typical compounds were validated using Gene Set Enrichment Analysis (GSEA) of the relevant gene expression profiles from a public gene expression database. RESULTS: Based on their anti-DIC MoAs, the 82 NCs could be divided into four groups, which corresponded to ten MoA clusters. GSEA and literature evidence on these compounds were provided to validate the MoAs identified through this bioinformatics analysis. The results suggested that NCs exerted potency against DIC through both common and different MoAs. CONCLUSION: This strategy integrating different types of bioinformatics approaches is expected to create new insights for elucidating the MoAs of NCs against DIC.

Long Distance From Microvessel to Cancer Cell Predicts Poor Prognosis in Non-Small Cell Lung Cancer Patients.

BACKGROUND: Blood supply, which is crucial for nutrition and drug delivery, was determined by microvessel density as well as the diffusion distance between vessels and cancer cells. Therefore, we evaluated the distance from microvessels to cancer cells (Dmvcc) and its role in the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: Patients with primary NSCLC were retrospectively analyzed. The tumor samples were immunochemically stained with CD31 to visualize the microvessels. The Dmvcc was defined as the mean distance from each microvessel to its nearest cancer cell in the "hot-spot" of an individual patient. The patients were stratified into short- and long-distance groups using five strategies, including dichotomy by the median value, optimal cutoff, trichotomy, quartation and per-10 µm increase. The correlation between the Dmvcc and survival was evaluated by using univariate and multivariate analyses with various Dmvcc strategies. RESULTS: In total, 100 patients were analyzed. The median value of Dmvcc was 13.1 µm (ranged, 1.6 to 269.7 µm; mean value, 24.4 ± 33.5 µm). The optimal cutoff value of Dmvcc for predicting survival outcome was 20 µm. Dmvcc was significantly related to overall survival (OS) with all the five categories (p = 0.001-0.000004) and progression-free survival (PFS) categorized by optimal cutoff value (p = 0.024), trichotomy (p = 0.041) and per-10 µm increase (p = 0.040) after adjusting for other factors. Patients with longer Dmvcc (≥20 µm) were observed to have poor survival outcomes (OS: HR = 13.5, 95CI: 4.42-41.18, p = 0.000005; PFS: 3.26, 95CI: 1.56-6.81, p = 0.002). A high Dmvcc per-10 µm was associated with a significantly increased risk of cancer-related death and progression by 98% (p = 0.0001) and 30% (p = 0.044), respectively. CONCLUSION: The NSCLC tissues had varying distances from microvessels to cancer cells, and long distances were strongly associated with poor survival.

Comparison of Proteomics Profiles Between Xenografts Derived from Cell Lines and Primary Tumors of Thyroid Carcinoma.

Patient-consistent xenograft model is a challenge for all cancers but particularly for thyroid cancer, which shows some of the greatest genetic divergence between human tumors and cell lines. In this study, proteomic profiles of tumor tissues from patients, included anaplastic thyroid carcinoma (ATC) and papillary thyroid carcinoma, and xenografts (8305C, 8505C, FRO, BAPAP and IHH4) were obtained using HPLC-tandem mass spectrometry and compared based on all proteins detected (3,961), cancer-related proteins and druggable proteins using pairwise Pearson's correlation analysis. The human tissue showed low proteomic similarity to the ATC cell lines (8305C, r = 0.344-0.416; 8505C, 0.47-0.579; FRO, 0.267-0.307) and to PTC cell lines (BCPAP, 0.303-0.468; IHH4, 0.262-0.509). Human tissue showed the following similarity to cell lines at the level of 135 cancer-related pathways. The ATC cell lines contained 47.4% of the cancer-related pathways (19.26%-33.33%), while the PTC cell lines contained 40% (BCPAP, 25.93%; IHH4, 28.89%). In patient tumor tissues, 44-60 of 76 and 52-53 of 93 druggable proteins were identified in ATC and PTC tumors, respectively. Ten and 29 druggable proteins were not identified in any of the ATC and PTC xenografts, respectively. We provide a reference for CDX selecting in in vivo studies of thyroid cancer.

Comprehensive evaluation of the antioxidant capacity of Sceptridium ternatum using multiple colorimetric methods and 1,1-diphenyl-2-picrylhydrazyl-high-performance liquid chromatography analysis.

Sceptridium ternatum is a medicinal herb with multiple health benefits. However, its antioxidant activity and active components have not been clarified. In this study, the antioxidant capacity of S. ternatum was comprehensively investigated using multiple colorimetric methods and 1,1-diphenyl-2-picrylhydrazyl-high-performance liquid chromatography analysis. First, the phenolic content, flavonoid content, and radical scavenging ability of S. ternatum were parallelly determined using colorimetric methods performed in 96-well microplates. The flavonoid content, rather than the phenolic content, was highly correlated with its antioxidant activity. Sceptridium ternatum was shown to be a rich source of flavonoids, with a highest flavonoid yield of 3.44 ± 0.11 mg/g. Subsequently, 1,1-diphenyl-2-picrylhydrazyl-high-performance liquid chromatography experiment and quadrupole time-of-flight mass spectrometry analyses were carried out for rapid screening of the individual antioxidants. A total of 14 O-glycosyl flavonoids with quercetin or kaempferol aglycone have been characterized. Particularly, quercetin 3-O-rhamnoside-7-O-glucoside exhibited the most potent antioxidant ability. Its half-maximal effective concentrations for scavenging 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) radicals were 70.55 ± 2.69 and 106.90 ± 1.76 µg/mL, respectively, which were comparable with those of l-ascorbic acid. Our results indicated that the combined colorimetric and chromatographic methods provided a practical strategy for the discovery of bioactive compounds from natural products.

Preventive Effect and Mechanism of Ethyl Acetate Extract of Sceptridium ternatum in Monocrotaline-Induced Pulmonary Arterial Hypertension.

OBJECTIVE: To observe the effect and molecular mechanism of ethyl acetate extract of Sceptridium ternatum (STE) on the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). METHODS: The main chemical components of Sceptridium ternatum were determined, and the effects in PAH rats were observed. A total of 140 Sprague Dawley rats were randomly and equally divided into the normal group, the model group, the Bosentan group, and the STE groups (2.5, 5, 10 g/kg) by the random number table method. The characteristic indicators of PAH were measured, and immunohistochemistry was used to observe the lung tissue of rats. Morphological changes of the lung tissue were observed under the light microscope. RESULTS: Compared with the normal group, rats in the model group showed a significant increase in right ventricular free wall thickness (RVFWT), mean pulmonary arterial pressure (mPAP), mean right ventricular pressure (mRVP), max right ventricular pressure (max RVP), weight of right ventricle (RV), and lung index (LI), while a significant decrease in pulmonary artery acceleration time (PAAT, P<0.01). Compared with the model group, rats treated with STE had a significant decrease of RVFWT, mPAP, mRVP, max RVP, and RV, while a significant increase of PAAT (P<0.01). After injection of MCT, nuclear factor- κB (NF- κB) p65 and α -smooth muscle actin (α -SMA) expression levels were up-regulated, and on the contrary, the treatment groups showed a significant down-regulation without dose-dependent trend. CONCLUSIONS: STE can relieve the PAH in rats. STE may relieve pulmonary vascular disease and pulmonary injury by down-regulating the expression of NF- κB p65 and α -SMA.