As a key tool in hydraulic fracturing, the packer plays a vital role in the process of unconventional oil and gas production. Its sealing performance has a significant impact on production. The ...packer is in high-temperature and high-pressure (HTHP) environment for a long time. It is easy to produce significant stress relaxation, which affects the sealing performance of the packer. In this paper, rubber foundation tests at 150 °C temperature were carried out. The hyperelastic–viscoelastic model of the rubber material was determined. The influence of the stress relaxation on its sealing performance was investigated. In addition, the effects of setting load, height, inner diameter, and outer diameter on the sealing performance were systematically investigated. The findings show that under HTHP, the stress relaxation phenomenon leads to a 6.9% decrease in peak shear stress, 10.3% decrease in peak von Mises stress, and 6.7% decrease in peak contact stress, reducing the risk of damage to the packing element and leading to a decrease in its sealing performance. In addition, it was found that increasing the setting load can significantly increase the contact stress, which also increases the risk of damage. When increasing the height, the peak shear stress and peak contact stress do not change much but can significantly reduce the peak von Mises stress. When increasing the inner diameter, the peak shear stress and peak contact stress show a trend of first increasing and then decreasing, and the peak von Mises stress has been decreasing. Increasing the outer diameter can better improve the force situation, increase the contact stress, and make the contact stress distribution more uniform. It is necessary to consider the influence of stress relaxation on the sealing performance of the packer under HTHP; meanwhile, this paper has guiding significance for the design of packer structures.
Purpose
Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small ...cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects.
Methods
Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization.
Results
The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUC
0–24h
pool), while other circulating metabolites were minor, accounting for less than 10%. Mean
C
max
, AUC
0–∞,
T
1/2
and
T
max
values for ensartinib in plasma were 185 ng/mL, 3827 h ng/mL, 18.3 h and 3.25 h, respectively. The total radioactivity in plasma was cleared with terminal half-life of 27.2 h. Treatment with ensartinib was well tolerated, and no serious adverse events were reported.
Conclusion
It was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces.
Clinical trial registration
ClinicalTrials.gov NCT03804541.
Epigenetic changes are heritable changes in gene expression without changes in the nucleotide sequence of genes. Epigenetic changes play an important role in the development of cancer and in the ...process of malignancy metastasis. Previous studies have shown that abnormal epigenetic changes can be used as biomarkers for disease status and disease prediction. The reversibility and controllability of epigenetic modification changes also provide new strategies for early disease prevention and treatment. In addition, corresponding drug development has also reached the clinical stage. In this paper, we will discuss the recent progress and application status of tumor epigenetic biomarkers from three perspectives: DNA methylation, non-coding RNA, and histone modification, in order to provide new opportunities for additional tumor research and applications.
Pancreatic cancer is a malignancy that affects the digestive tract and has a low 5-year survival rate of lower than 15%. Owing to its genetic mutation and metabolic complexity, pancreatic cancer is ...difficult to treat with surgical resection, radiotherapy, and chemotherapy. The predominant modality of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), primarily attributed to mutations in
gene. Ferroptosis, an iron-mediated reactive oxygen species (ROS)-elevated nonapoptotic cell death caused by lipid peroxidation, is distinct from any other known type of cell death. Ferroptosis is closely related to the occurrence and progression of different types of cancers, including PDAC. Previous research has demonstrated that ferroptosis not only triggers cell death in PDAC and hampers tumor growth but also enhances the effectiveness of antitumor medications. In our review, we mainly focus on the core mechanism of ferroptosis, reveal its interrelationship with PDAC, and illustrate the progress of ferroptosis in different treatment methods of PDAC.
Neoadjuvant chemotherapy is increasingly the treatment for patients with inoperable breast cancer. Considering the side-effects of chemotherapy, there is a need for early evaluating response to ...neoadjuvant chemotherapy.
To determinate the diagnostic performance of 18F-fluorodeoxyglucose position emission tomography/computed tomography (FDG PET/CT) and FDG PET for evaluating response to neoadjuvant chemotherapy in patients with breast cancer.
"PubMed" (MEDLINE included) database, EMBASE, and Cochrane Database of Systematic Reviews were searched for relevant articles. We assessed the methodological quality of included study with Quality Assessment of Diagnosis Accuracy Studies (QUADAS) score tool, and used "Meta-DiSc" statistic software to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver-operating characteristic (SROC) curve.
Seventeen studies (a total of 781 subjects) met the inclusion criteria. The pooled sensitivity was 0.840 (95% confidence interval CI 0.796-0.878). The pooled specificity was 0.713 (95% CI 0.667-0.756). For FDG PET/CT (10 studies included), the pooled sensitivity was 0.847 (95% CI 0.793-0.892), the pooled specificity was 0.661 (95% CI 0.598-0.720). The pooled likelihood ratio (LR+), negative likelihood ratio (LR-), and diagnostic odds ratio (DOR) were 2.835 (95% CI 1.640-4.900), 0.221 (95% CI 0.160-0.305), and 17.628 (95% CI 7.431-41.818). The area under the SROC curve (AUC) was 0.8934. For FDG PET (7 studies included), the pooled sensitivity and specificity were 0.826 (95% CI 0.741-0.892) and 0.789 (95% CI 0.719-0.849). The pooled LR + , LR-, and DOR were 3.601 (95% CI 2.601-4.986), 0.242 (95% CI 0.157-0.374), and 13.641 (95% CI 7.433-25.030). The AUC was 0.8764.
Our results indicate that FDG PET/CT and PET have reasonable sensitivity in evaluating response to neoadjuvant chemotherapy in breast cancer; however, the specificity is relative low. The combination of other imaging methods with FDG PET/CT or PET is recommended.
Predicting the energy consumption of oil pipelines is an important part of pipeline companies’ energy-saving and consumption-reduction plans and the realization of refined management. In order to ...predict the energy consumption of the long-distance product oil pipeline faster and better, this manuscript innovatively uses the normal distribution function to improve the search mode of the fruit fly optimization algorithm (FOA). It establishes the normal distribution fruit fly optimization algorithm (NFOA). It enhances search accuracy in the central area and effectively expands the search scope. Experimental results show that the accuracy and stability of the algorithm are improved by 100% and 900%. Then, NFOA combined with support vector regression (NFOA-SVR) is used to predict the three long-distance product pipeline data sets in China. The results show that the optimization speed and prediction accuracy of NFOA-SVR in LCY-Others set and LW-total set are significantly better than the other two algorithms. In the LCY-Pump set, NFOA-SVR has the same accuracy as the other two algorithms. Finally, experiments on random data sets show that the accuracy and stability of NFOA-SVR gradually decrease with the increase of the standard deviation of the data set.
•A Normal Distribution Fruit Fly Optimization Algorithm (NFOA) is proposed.•Improving fruit fly distribution patterns using normal distribution theory.•Validating NFOA using benchmark functions.•Predicting oil pipeline energy consumption using NFOA-SVR.
Bone marrow stem cells are able to repair infarcted human myocardium following intracoronary transplantation via the infarct‐relative artery. However, traditional reperfusion strategies fail to open ...the artery in some patients, making effective delivery impossible. Our previous study demonstrated a safe and efficient approach to delivering bone marrow stem cells via a noninfarcted artery in an animal myocardial infarction model. The objective of the present study was to evaluate the safety and feasibility of autologous bone marrow mesenchymal stem cell transplantation via such an approach in patients with acute myocardial infarction (AMI). Sixteen patients with anterior AMI who had successfully undergone percutaneous coronary intervention (PCI) were enrolled in this pilot, randomized study. Three weeks after PCI, cultured bone marrow mesenchymal stem cells were injected into the myocardium via either the infarct‐relative artery (left anterior descending branch artery, LAD) or a noninfarct‐relative artery (right coronary artery, RCA). The safety and feasibility of the cell infusion were evaluated during the procedure and during 6 months of follow‐up. In addition, 2D echocardiography, technetium‐99m methoxyisobutylisonitrile (99mTc‐MIBI) and 18F‐deoxyglucose single photon emission computed tomography were employed to examine cardiac function, myocardial perfusion, and viable cardiomyocytes, respectively, at day 4 after PCI and 6 months after the cell infusion. There were no arrhythmia and any other side‐effects, including infections, allergic reactions or adverse clinical events, during, immediately after, or 6 months after cell transplantation. Cardiac function and myocardial perfusion had improved 6 months after PCI/bone marrow stem cells transplantation. Viable cardiomyocytes metabolism was detected in the infarcted areas in both groups after the cell infusion, as demonstrated by 18F‐deoxyglucose. Intracoronary infusion of autologous bone marrow mesenchymal stem cells via a noninfarct‐relative artery appears safe and feasible in the treatment of patients with AMI.
The skeleton is one of the favorable sites for the metastasis of almost all human malignant neoplasms. An accurate diagnosis of bone metastasis is crucial for the patient's staging and management.
To ...investigate and compare diagnostic performance of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BS) for detection of bone metastasis in malignancies using meta-analysis.
PubMed (Medline included) was searched for relevant articles. We assessed the methodological quality with Quality Assessment of Diagnosis Accuracy Studies (QUADAS) score tool, and used statistical software to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver-operating characteristic (SROC) curve.
Six studies met inclusion criteria. For 18F-FDG PET/CT, the pooled sensitivity and specificity were 0.934 and 0.975, respectively. The pooled positive likelihood ratio (LR+), negative likelihood ratio (LR-) and diagnostic odds ratio (DOR) were 34.990, 0.068 and 559.02, respectively. The area under the SROC curve was 0.9854. For BS, the pooled sensitivity, specificity, LR + , LR- and DOR were 0.706 (0.642-0.764), 0.911 (0.896-0.926), 13.982 (2.419-80.817), 0.319 (0.143-0.712), and 60.420 (21.393-170.64), respectively. The area under the SROC curve was 0.9386.
The results indicate that 18F-FDG PET/CT do have both higher sensitivity and specificity than bone scintigraphy for detecting metastatic bone tumor. However, further research is needed to evaluate the diagnostic performance of 18F-FDG PET/CT and BS in each common malignancy.
Aims
To determine the absorption, distribution, metabolism and excretion of abivertinib, a third‐generation epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced ...non‐small cell lung cancer (NSCLC).
Methods
Seven patients with advanced NSCLC were given a single 200 mg/83 μCi oral suspension of 14C‐abivertinib. Blood, urine and faeces were collected. Mass balance of radioactivity, the pharmacokinetics of abivertinib, and the total radioactivity were determined. Metabolite profiling and characterisation were performed.
Results
The mean recovery was 82.16%, with 2.38 and 79.78% of the radioactive dose excreted in urine and faeces, respectively. The unchanged abivertinib was the major radioactive component detected in plasma within the first 24 hours after dosing, accounting for 59.17% of the total drug‐related radioactivity. Abivertinib in urine accounted for only 0.96% of the administered dose, whereas in faeces it accounted for 33.36%. Eight metabolites were detected and characterised in plasma, among which MII‐7, a product of cysteine glycine conjugate, was the only circulating metabolite, accounting for approximate 10.6% of the total drug‐related exposure. MII‐2 (an abivertinib cysteine–glycine adduct) and M7 (a reduced product of abivertinib) were the 2 major metabolites in the excreta, accounting for 20.0 and 12.4%, respectively, of the drug‐related radioactivity in faeces.
Conclusion
Following a single oral administration, the unchanged abivertinib was the predominant drug‐related material in plasma, urine and faeces. The drug‐related materials were primarily eliminated via the faecal route. Direct glutathione conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.
Purpose
Fruquintinib (HMPL-013) is a novel, potent, and highly selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors (1, 2 and 3). This study was conducted to ...investigate the metabolism, excretion, and pharmacokinetics of HMPL-013 after a single oral dose to healthy Chinese men.
Methods
Six subjects were administrated an oral suspension containing 5 mg of
14
C-labeled HMPL-013 (100 μCi) in a fasted state. Blood and excreta samples were collected at the designated time points or intervals for pharmacokinetics and radiometric analyses. Safety assessments were conducted throughout the study.
Results
Over a 336-h post-dose collection period, mean recovery was 90.11% of the radiolabeled dose, with 60.31% in urine and 29.80% in feces. Mean
C
max
, AUC
0−∞
, and
T
max
for HMPL-013 in plasma were 113 ng/mL, 4797 h ng/mL, and 2 h, respectively. Radioactivity and HMPL-013 were cleared from circulation with terminal half-lives of 41.1 and 33.4 h. HMPL-013 was the predominant circulating radioactive component, representing 72.48% of the total radioactivity. M11 was the major circulating metabolite, accounting for 17.31% of the total radioactivity. An additional seven circulating metabolites were identified, each accounting for less than 5% of the total radioactivity. In urine, HMPL-013 accounted for only 0.50% of the administered dose. Three major metabolites M285, M381, and M409-4 were identified in urine accounting for 10.48, 21.16, and 8.92% of the dose, respectively. In feces, HMPL-013 accounted for 5.34% of the dose. M205, M365-2, and M380 were the major metabolites, accounting for 2.29, 3.30, and 2.59% of the dose, respectively.
Conclusion
HMPL-013 was well tolerated and absorbed rapidly, with parent compound being the predominant circulating component. HMPL-013 was extensively metabolized prior to excretion, and urine was the major route of excretion.
