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Abstract Background Circulating tumor cells (CTCs), an indispensable liquid biopsy classifier, can provide extra information for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Methods We systematically analyzed the peripheral blood of preoperative HCC patients (n = 270) for CTC number, Ki67 index reflecting the proliferative CTC percentage (PCP), and CTC clusters correlated with the characteristics of malignant HCC tumors. Results Driver gene mutations were found with high levels of consistency between CTCs and primary tumors (n = 73). CTC number and PCP were associated with tumor size, microvascular invasion (MVI), presence or absence of multiple tumors, and thrombosis significantly. CTC number and PCP robustly separated patients with and without relapse, with a sensitivity of 88.89%/81.48% and a specificity of 72.73%/94.81% in the training set (n = 104) and corresponding values of 80.00%/86.67% and 78.38%/89.19% in the validation set (n = 52), showing a better performance than that associated with the alpha‐fetoprotein (AFP) level. CTC number, PCP, CTC clusters, and MVI were independent significant risk factors for HCC recurrence (P = 0.0375, P

Objectives: Teicoplanin has been extensively used in the treatment for infections caused by gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). However, current teicoplanin treatment is challenging due to relatively low and variable concentrations under standard dosage regimens. This study aimed to investigate the population pharmacokinetics (PPK) characteristics of teicoplanin in adult sepsis patients and provide recommendations for optimal teicoplanin dosing regimens.Methods: A total of 249 serum concentration samples from 59 septic patients were prospectively collected in the intensive care unit (ICU). Teicoplanin concentrations were detected, and patients’ clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modeling approach. Monte Carlo simulations were performed to evaluate currently recommended dosing and other dosage regimens. The optimal dosing regimens were defined and compared by different pharmacokinetic/pharmacodynamic parameters, including trough concentration (Cmin), the ratio of 24-h area under the concentration-time curve to the minimum inhibitory concentration (AUC0-24/MIC), as well as the probability of target attainment (PTA) and the cumulative fraction of response (CFR) against MRSA.Results: A two-compartment model adequately described the data. The final model parameter estimates for clearance, central compartment volume of distribution, intercompartmental clearance and peripheral compartment volume were 1.03 L/h, 20.1 L, 3.12 L/h and 101 L, respectively. Glomerular filtration rate (GFR) was the only covariate that significantly affected teicoplanin clearance. Model-based simulations revealed that 3 or 5 loading doses of 12/15 mg/kg every 12 h followed by a maintenance dose of 12/15 mg/kg every 24 h–72 h for patients with different renal functions were required to achieve a target Cmin of 15 mg/L and a target AUC0-24/MIC of 610. For MRSA infections, PTAs and CFRs were not satisfactory for simulated regimens. Prolonging the dosing interval may be easier to achieve the target AUC0-24/MIC than reducing the unit dose for renal insufficient patients.Conclusion: A PPK model for teicoplanin in adult septic patients was successfully developed. Model-based simulations revealed that current standard doses may result in undertherapeutic Cmin and AUC, and a single dose of at least 12 mg/kg may be needed. AUC0-24/MIC should be preferred as the PK/PD indicator of teicoplanin, if AUC estimation is unavailable, in addition to routine detection of teicoplanin Cmin on Day 4, follow-up therapeutic drug monitoring at steady-state is recommended.

Background Radix Ardisia (Jab Bik Lik Jib) is a common Miao medicine and is widely distributed in the Guizhou region of southern China. The botanical origin of Radix Ardisia includes the dry root and rhizome of Ardisia Crenata Sims (ACS) or Ardisia Crispa (Thunb.) A.DC. (AC), which are closely related species morphologically. However, the secondary metabolites in their roots are different from one another, especially the flavonoids, and these differences have not been thoroughly explored at the molecular level. This project preliminarily identified regulatory molecular mechanisms in the biosynthetic pathways of the flavonoids between ACS and AC using a multi-omics association analysis. Methods In this study, we determined the total levels of saponin, flavonoid, and phenolic in Radix Ardisia from different origins. Integrated transcriptome and metabolome analyses were used to identify the differentially expressed genes (DEGs) and differentially expressed metabolites (DEM). We also performed conjoint analyses on DEGs and DEMs to ascertain the degree pathways, and explore the regulation of flavonoid biosynthesis. Results The total flavonoid and phenolic levels in ACS were significantly higher than in AC (P

Background: Mitochondrial disease is a term used to describe a set of heterogeneous genetic diseases caused by impaired structure or function of mitochondria. Pyruvate therapy for mitochondrial disease is promising from a clinical point of view. Methods: According to PRISMA guidelines, the following databases were searched to identify studies regarding pyruvate therapy for mitochondrial disease: PubMed, EMBASE, Cochrane Library, and Clinicaltrials . The search was up to April 2019. The endpoints were specific biomarkers (plasma level of lactate, plasma level of pyruvate, L/P ratio) and clinical rating scales [Japanese mitochondrial disease-rating scale (JMDRS), Newcastle Mitochondrial Disease Adult Scale (NMDAS), and others]. Two researchers independently screened articles, extracted data, and assessed the quality of the studies. Results: A total of six studies were included. Considerable differences were noted between studies in terms of study design, patient information, and outcome measures. The collected evidence may indicate an effective potential of pyruvate therapy on the improvement of mitochondrial disease. The majority of the common adverse events of pyruvate therapy were diarrhea and short irritation of the stomach. Conclusion: Pyruvate therapy with no serious adverse events may be a potential therapeutic candidate for patients with incurable mitochondrial diseases, such as Leigh syndrome. However, recent evidence taken from case series and case reports, and theoretical supports of basic research are not sufficient. The use of global registries to collect patient data and more adaptive trial designs with larger numbers of participants are necessary to clarify the efficacy of pyruvate therapy.

There is a growing interest to understand impacts of latent infection age and infection age on viral infection dynamics by using ordinary and partial differential equations. On one hand, activation of latently infected cells needs specificity antigen, and latently infected CD4+ T cells are often heterogeneous, which depends on how frequently they encountered antigens, how much time they need to be preferentially activated and quickly removed from the reservoir. On the other hand, infection age plays an important role in modeling the death rate and virus production rate of infected cells. By rigorous analysis for the model, this paper is devoted to the global dynamics of an HIV infection model subject to latency age and infection age from theoretical point of view, where the model formulation, basic reproduction number computation, and rigorous mathematical analysis, such as relative compactness and persistence of the solution semiflow, and existence of a global attractor are involved. By constructing Lyapunov functions, the global dynamics of a threshold type is established. The method developed here is applicable to broader contexts of investigating viral infection subject to age structure.

Abstract Stathmin‐1 is a microtubule depolymerization protein that regulates cell division, growth, migration, and invasion. Overexpression of stathmin‐1 has been observed to be associated with metastasis, poor prognosis, and chemoresistance in various human cancers. Our previous studies found that serum stathmin‐1 was significantly elevated in patients with esophageal squamous cell carcinoma (ESCC) by ELISAs. Here, we constructed high‐affinity monoclonal antibodies and then developed a competitive AlphaLISA for rapid, accurate quantitation of stathmin‐1 in serum. Compared to ELISA, our homogeneous AlphaLISA showed better sensitivity and accuracy, a lower limit of detection, and a wider linear range. The measurements of nearly 1000 clinical samples showed that serum stathmin‐1 level increased dramatically in patients with squamous cell carcinoma (SCC), especially in ESCC, with a sensitivity and a specificity of 81% and 94%, respectively. Even for early stage ESCC, stathmin‐1 achieved an area under the receiver operating characteristic curve (AUC) of 0.88. Meanwhile, raised concentrations of stathmin‐1 were associated with lymph node metastasis and advanced cancer stage. Notably, various types of SCC showed significantly higher AUCs in serum stathmin‐1 detection compared to adenocarcinoma. Furthermore, we confirmed that stathmin‐1 was enriched in the oncogenic exosomes, which can explain the reason why it enters into the blood to serve as a tumor surrogate. In conclusion, this large‐scale and systematic study of serum stathmin‐1 measured by our newly established AlphaLISA showed that stathmin‐1 is a very promising diagnostic and predictive marker for SCC in the clinic, especially for ESCC.

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In tetracoordinate chemistry, there is an attractive scientific problem of how to make the planar configuration more stable than the tetrahedral configuration. For tetracoordinate nitrogen, the abundant studies indicate that the planar tetracoordinate nitrogen (ptN) is far less stable than the tetrahedral tetracoordinate nitrogen (ttN). Herein, we introduced four S atoms to the unstable ptN-NGa4+ and stable ttN-NGa4+ by following an electron-compensation strategy. Surprisingly, ptN-NGa4S4+ is more stable than ttN-NGa4S4+. Thermodynamically, ptN-NGa4S4+ is the global energy minimum, which is 46.7 kcal mol−1 lower in energy than ttN-NGa4S4+. Dynamically, the BOMD simulations indicated that ptN-NGa4S4+ has excellent dynamic stability at 4, 298, 500 and 1000 K, but the ttN-NGa4S4+ is isomerized at 1000 K. Electronically, the HOMO–LUMO gap of ptN-NGa4S4+ (6.91 eV) is much wider than that of ttN-NGa4S4+ (5.25 eV). Moreover, AdNDP analyses showed that the eight 2c–2e Ga–S σ-bonds eliminated the 4s2 lone pair/4s2 lone pair repulsion between the four Ga atoms and provided a strong spatial protection for ptN-NGa4S4+; and that the four 3c–2e Ga-S-Ga π back-bonds could compensate electrons for Ga, weakening the electron-deficiency of Ga. Simultaneously, the double 6σ/2π aromaticity further enhanced the stability of ptN-NGa4S4+. Thus, as the dynamically stable global energy minimum displaying double aromaticity, ptN-NGa4S4+ will be more promising than ttN-NGa4S4+ in gas phase generation. [ABSTRACT FROM AUTHOR]