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Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies

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Veröffentlicht/Copyright: 2. März 2023
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Open Medicine
Aus der Zeitschrift Open Medicine Band 18 Heft 1

Abstract

In recent years, off-label use of sirolimus (SIR) has been gaining attention in the clinical practice. However, since it is critical to achieve and maintain therapeutic blood levels of SIR during treatment, the regular monitoring of this drug in individual patients must be implemented, especially in off-label indications of this drug. In this article, a fast, simple, and reliable analytical method for determining SIR levels in whole blood samples is proposed. Sample preparation based on dispersive liquid–liquid microextraction (DLLME) followed by liquid chromatography-mass spectrometry (LC-MS/MS) was fully optimized toward the analysis of SIR and proposed as a fast, simple, and reliable analytical method for determining the pharmacokinetic profile of SIR in whole-blood samples. In addition, the practical applicability of the proposed DLLME-LC-MS/MS method was evaluated by analyzing the pharmacokinetic profile of SIR in whole blood samples obtained from two pediatric patients suffering from lymphatic anomalies, receiving this drug as off-label clinical indication. The proposed methodology can be successfully applied in routine clinical practice for the fast and precise assessment of SIR levels in biological samples, thus allowing SIR dosages to be adjusted in real time during pharmacotherapy. Moreover, the measured SIR levels in the patients indicate the need for monitoring between doses to ensure the optimal pharmacotherapy of patients.

Graphical abstract

Keywords: SIR; whole blood samples; DLLME; LC-MS/MS; therapeutic drug monitoring

1 Introduction

Sirolimus (SIR) (also known as rapamycin) is one of the most widely used immunosuppressive drugs. One reason for its widespread use is its ability to bind and form complexes with the FKBP12 protein, which allows it to suppress the PI3K-Akt-mammalian target of rapamycin (mTOR) signaling pathway, thus inhibiting cell growth, proliferation, and differentiation [1]. In addition, since SIR targets mTOR in mammals, it also affects the expression of the vascular endothelial growth factor responsible for angiogenesis and lymphangiogenesis [2]. Due to these inhibitory effects, the use of SIR in the prophylaxis of organ rejection in renal transplant patients aged 13 years or older has been approved by the Food and Drug Administration (FDA) since 1999 [3], and its use in the polytherapy of lymphangioleiomyomatosis in pediatric patients has been approved since 2003 [4]. Furthermore, SIR’s antiproliferative effects have led to its use for off-label applications, including the treatment of various types of cancers [5,6] and vascular anomalies [7,8,9]. For instance, a prospective screening of patients with generalized lymphatic anomaly (GLA) and Gorham–Stout disease revealed that incorporating SIR in therapeutic treatment can help to stabilize or reduce the symptoms of the disease [7]. Phase II trials have also confirmed the efficacy and safety of SIR in patients with lymphatic malformation (LM) and venous malformation resistant to standard therapy [10]. Nevertheless, it should be emphasized that such uses of SIR are new and that available dosing guidelines are based on the existing experimental protocols; thus, it is especially critical to monitor and adjust therapeutic regimens of this drug during off-label applications.

Pharmacokinetic studies of SIR, which are largely based on its administration in renal transplantation, have revealed that it has low oral bioavailability (∼15%), with even lower bioavailability among black patients [11,12]. Due to SIR’s narrow therapeutic index and high interindividual and intraindividual pharmacokinetic differences among patients, it is important to maintain its concentration within the recommended therapeutic range of 5–15 ng/mL (based on data from transplant patients), as concentrations outside of this range may result in acute transplant rejection (<5 ng/mL) or serious side effects, such as thrombocytopenia, leukopenia, or hypertriglyceridemia (>15 ng/L) [13,14]. In addition, SIR is also a substrate for cytochrome P450 3A4 enzymatic complexes in the liver; therefore, many drugs that act as inhibitors/inducers of CYP3A4 may interact with SIR and enhance its side effects [15]. Moreover, it may be even more difficult to predict the pharmacokinetics of SIR in off-label applications for treating disorders in children (e.g., lymphatic anomalies), as they possess different LADME processes related to the pharmacokinetics of drugs, including SIR, than adults [16].

The literature contains only a few studies related to the therapeutic monitoring of SIR concentrations in real blood samples [12,17,18,19,20]. These studies utilize both enzyme immunoassays and chromatographic methods [12,17,18,19] and capillary electrophoresis (CE) [20] to measure the levels of SIR in biofluids. While the quickness and simplicity of enzyme immunoassays are distinct advantages, many researchers have observed cross-reactions between antibodies and SIR metabolites when using this method, which creates the risk of overestimating the SIR concentration. In addition, studies comparing enzyme-linked immunoassays and chromatographic/mass spectrometry have found that SIR levels measured with immunoassay tests were higher when both methods were used to analyze the same samples. Zhao et al. reported over 60% overestimation of the results obtained from the enzyme multiplied immunoassay technique (EMIT) in comparison to the liquid chromatography-mass spectrometry (LC-MS/MS) method during SIR determinations [21]. The issues related to the correlation of results between chromatographic methods and immunoassay tests in the determination of immunosuppressants were also revealed by Polledri et al. In the described study, the results from LC-MS/MS analysis were compared with the results from immunoassay tests, and the overestimation of the results in the case of the latter one was confirmed [22]. On the other hand, while chromatographic techniques allow for much greater sensitivity and selectivity for target compounds, it remains a challenge to develop fast and low-cost procedures using this technology. Moreover, the isolation and the analysis of SIR in therapeutic drug monitoring (TDM) is challenging and complicated, as SIR binds strongly to red blood cells (RBCs) (∼95%), which creates the need for a hemolysis step in whole blood testing. Thus, although significant advances in mass spectrometry have enabled sensitive and reproducible results, there is still a need to develop new sample preparation approaches that will allow the efficient hemolysis of RBCs and the isolation of SIR from whole blood samples, in addition to simple and reproducible performance between laboratories. Such novel approaches would help to overcome the problem of false-positive results frequently reported for immunological tests, as well as providing researchers and clinicians with a simple and precise methodology for monitoring real concentrations of SIR in biological matrices. With the exception of one study that utilized CE with an ultraviolet (UV) detector [20], the previous work in this analytical area has exclusively employed LC/MS, which confirms the universality of this technique in current laboratory practice [23,24,25,26,27]. Obviously, the use of LC-MS/MS may be more challenging than immunoassay tests in typical laboratories, in terms of both operation and maintenance costs. However, the use of TDM is recommended for a wide range of pharmaceuticals, which makes LC-MS/MS an appealing option, as it is able to monitor a range of drugs in patients simultaneously, including SIR [28].

The aim of this study is to develop a simple, fast, and sensitive analytical method based on LC-MS/MS that can be applied for the TDM of SIR in whole blood samples. The developed method was validated, and its usefulness for SIR monitoring was confirmed by applying it to analyze the pharmacokinetic profile of SIR in real whole-blood samples acquired from two pediatric patients with rare diseases (lymphatic anomalies) treated with SIR in off-label applications. The resultant SIR concentration profiles were then determined and compared with those of other pharmacokinetic studies of SIR. To the best of our knowledge, the proposed method is the first to combine dispersive liquid–liquid microextraction (DLLME) sample preparation and LC-MS/MS analysis for the profiling of SIR levels in the whole blood. Furthermore, this study is also the first to monitor the SIR pharmacokinetic profiles of pediatric patients with lymphatic anomalies at hourly intervals.

2 Materials and methods

2.1 Chemicals and reagents

EVE, which was used as an internal standard (IS), and SIR were obtained from Sigma-Aldrich (St. Louis, MO, USA), while LC-MS-grade methanol (MeOH), acetonitrile (ACN), and formic acid (FA) were supplied by Merck (Darmstadt, Germany). Ethanol (EtOH) and chloroform (Chl) were purchased from POCH (Gliwice, Poland) and Chempur (Poland), respectively. The ammonium acetate (AA) used to prepare the 200 mM ammonium formate stock solution was obtained from Sigma-Aldrich (St. Louis, MO, USA), and all water used in the experiments was purified with a milli-Q system (Molsheim, France). The 1,000 and 250 μL syringes (Hamilton) were supplied by Sigma-Aldrich (St. Louis, MO, USA), and the control whole blood samples were obtained from healthy volunteers.

2.2 Standard solutions

A stock solution of SIR and IS was prepared in EtOH at a concentration of 1 mg/mL, and working standard solutions of SIR at concentration levels of 0.1, 0.5, 1, 5, and 10 µg/mL were prepared by dissolving an appropriate volume of the stock solution in the working solutions. A working standard solution of IS at a concentration of 10 µg/mL was prepared by dissolving an appropriate volume of IS stock solution in EtOH. Both the stock and working SIR and IS solutions were stored at −80°C until use.

2.3 Preparation of calibration and quality control (QC) samples

Whole blood calibration samples with SIR concentrations in the range of 1–50 ng/mL and IS at 50 ng/mL were prepared via hemolysis, followed by DLLME to ensure the recovery of any erythrocyte-bound immunosuppressant. The optimization of the DLLME procedure has been described in detail in our previous article [29]. Briefly, 250 µL of whole blood was spiked with appropriate volumes of SIR calibration standards at concentrations of 0.1, 0.5, 1, 5, and 10 µg/mL and IS calibration standards at 10 µg/mL to obtain final concentrations of 1, 2.5, 5, 10, 25, and 50 ng/mL for SIR and 50 ng/mL for IS, respectively. Next, 750 µL of water was added to the enriched samples, with the resultant mixture being subjected to sonication for 20 s. The samples were then centrifuged (10 min, 4,000 rpm), and the obtained supernatant was transferred to Eppendorf tubes. After the hemolysis step, the DLLME procedure was performed. In this process, 1 mL of the extraction mixture, which consisted of 800 µL of EtOH and 200 µL of Chl, was rapidly injected into 1 mL of supernatant using a microsyringe (1,000 µL Hamilton) to create a cloudy solution. The samples were then stored at −80°C for 3 min to enhance the formation of droplets, followed by centrifugation at 3,000 rpm for 5 min. The droplets at the bottom of the tube (150 ± 20 µL) were collected and transferred to a different Eppendorf tube using a microsyringe (250 µL Hamilton), where they were evaporated to dryness at 45°C under vacuum conditions using a CentriVap (Labconco, Kansas City, Missouri, USA). The dry residue was reconstituted in 50 µL of a water/MeOH mixture (50:50, v/v) containing 5 mM AA, and the resultant solution was transferred to the inserts and analyzed via LC-MS/MS.

Whole blood QC samples at concentrations of 1.00 (lower limit of quantification [LLOQ]), 2.50 (low limit of quantification [LQC]), 10.00 (middle limit of quantification [MQC]), or 25 ng/mL (high limit of quantification [HQC]) also were prepared using the described procedure earlier.

2.4 Instrumentation and chromatographic conditions

All analyses were conducted on a Nexera HPLC system equipped with a CT-20AC column oven, an LC-30AD solvent delivery unit, and an SIL-30AC thermostatic autosampler. Chromatographic separation was achieved on a YMC-Triart C8 column (50 × 2.1 mm, 5 µm) (YMC, Kyoto, Japan) maintained at a temperature of 45°C. The mobile phases consisted of MeOH (phase A) and water (phase B) with the addition of 0.1% FA and 10 mM AA solution. The gradient elution had a flow rate of 0.55 mL/min and utilized the following program: 0–0.20 min 80% A; 0.20–1.20 min 100% A; 1.20–1.31 min 80% A; and 1.31–2.50 min 80% A (re-equilibration). The injection volume was set at 1 µL, and the autosampler temperature was held at 4°C.

The chromatographic instrument was coupled to a mass spectrometer Sciex QTrap 6500 (AB Sciex, Concorde, Ontario, Canada) equipped with an electrospray ionization interface operated in a positive ionization mode, with all analyses being performed in a multiple reaction monitoring mode. The ion spray voltage was set at 5,500 V, and the temperature was set at 300°C. The curtain gas, ion source gas 1, and gas 2 were set at 20, 50, and 40 psi, respectively, and dwell time was set at 150 ms for each transition. The settings for SIR and the IS are presented in Table 1. Finally, the integrated data system used in this work was the MultiQuant 3.0.1. software package.

Table 1

The mass spectrometry conditions for the analysis of SIR and IS

Parameters SIR IS
Precursor ion (Da) 931.527 975.537
Product ion (Da) 864.300 908.400
DP (V) 26.000 36.000
CE (V) 25.000 25.000
CXP (V) 20.000 52.000

DP – declustering potential; CE – collision energy; CXP – collision exit potential.

2.5 Assay validation

The proposed analytical method for determining SIR in whole blood was validated according to the guidelines for bioanalytical methods [30,31]. To this end, the following parameters were evaluated: linearity, limits of detection (LOD), limits of quantification (LOQ), selectivity, accuracy, precision, stability, carry-over effects, and recovery. The validation parameters were determined using calibration and QC samples of whole blood.

2.5.1 Linearity

Linearity was determined by analyzing six calibration series of whole blood samples (each in triplicate) within a concentration range of 1–50 ng/mL. All series were made and measured within 1 day. The obtained results were used to calculate a calibration curve based on a linear regression model (y = bx + a), where y is the ratio of the SIR to IS areas versus SIR concentration of SIR (x) in ng/mL, b is the slope of the line, and a is the y intercept.

2.5.2 LOD and LOQ

The LOD and the LOQ were calculated according to the following equations:

(1) LOD = 3 . 3 Sa b ,

(2) LOQ = 10 Sa b ,

where Sa is the standard deviation (SD) of the intercept and b is the slope of the calibration curve.

2.5.3 Selectivity

Selectivity was estimated by analyzing a blank whole blood sample (i.e., unspiked) and samples that had been spiked with SIR at 25 ng/mL and IS at 50 ng/mL. In accordance with FDA and International Conference on Harmonization (ICH) guidelines, we assessed whether there was any interference in the analyte and IS retention times based on the matrix peaks.

2.5.4 Accuracy and precision

Accuracy and precision were measured by analyzing QC samples enriched with SIR at four concentration levels – namely, 1 (LLOQ), 2.5 (LQC), 10 (MQC), and 25 ng/mL (HQC) – and IS at a constant concentration of 50 ng/mL. All analyses were performed in triplicate. Measurements of the QC samples were performed on the same and different days of the experiments to estimate intra- and inter-day accuracy and precision. Accuracy was defined as the percentage recovery of the analyte in relation to the nominal concentration of the analyte spiked into the sample, while precision was expressed by the relative standard deviation (RSD (%)). The obtained data were then compared with FDA and ICH criteria.

2.5.5 Stability

The stability of SIR in whole blood was tested by analyzing low, middle, and high QCs containing the same SIR concentrations used to determine the precision and accuracy of the method (i.e., 2.5, 10, and 25 ng/mL). Before analysis, the spiked samples were stored under various thermal conditions – namely, 4 h at room temperature (∼25°C), 2 months at −80°C, and 24 h at 4°C – to test their short-term, long-term, and postpreparative stability (autosampler conditions). In addition, the QC samples were stored at −80°C and allowed to thaw to room temperature in a triple cycle to determine the effect of freezing and thawing on SIR stability. The results obtained for these samples were compared with the results for fresh QC samples, and the back-calculated SIR concentration levels were then estimated. Based on the criteria for bioanalytical methods, the samples were determined to be stable, as the SIR concentration at each level was within 100 ± 15% of the nominal concentration, while precision expressed by the RSD (%) value was ≤15%.

2.5.6 Carry-over

A carry-over test was performed to detect the presence of any residual analyte in the apparatus after the sample had been analyzed. For this purpose, the analysis of samples enriched in SIR and IS at a concentration of 50 ng/mL was performed before the analysis of the blank sample (i.e., without the presence of SIR and IS).

2.5.7 Recovery

The absolute recovery of the analytes from whole blood samples for the developed DLLME-based analytical method was calculated after the analysis of spiked samples to which calibration standards were added before and after extraction (2.5 and 25 ng/mL for SIR and 50 ng/mL for the IS). Once again, each sample was measured in triplicate. Thus, the obtained ratio of peak area responses in the samples spiked pre-extraction to those spiked postextraction enabled the evaluation of the absolute recovery results for the target analytes.

2.6 Collection of patient whole blood samples

Whole blood samples were collected from two pediatric patients in the Department of Pediatrics, Hematology and Oncology, at the University Clinical Center in Gdansk. The study was approved by the Ethics Committee of the Medical University of Gdansk, and the donors’ parents signed a consent form, agreeing to their child’s participation in the study. The conditions of the patients were established through medical history, as well as clinical and laboratory examinations.

Patient 1 was a 3-year-old boy with a severe form of a GLA with left chylothorax. Off-label SIR therapy was initiated bi-daily with an oral dose of 0.8 mg/m2 and gradually increased until a therapeutic blood concentration of 10–15 ng/mL had been reached. This required more than 2 months of treatment. The whole blood samples used to establish the SIR concentration profile in this study were collected from this patient once they had progressed to taking an SIR oral suspension at a dose of 1.9 mg every 12 h, which was approximately 3 months after the initiation of treatment. The whole blood samples were collected over 2 days at the following time intervals: (1) before the morning dose; (2) 2 h after the morning dose; (3) 3 h after the morning dose; (4) 6 h after the morning dose; (5) 12 h after the morning dose and immediately before the evening dose; (6) 24 h after the first and immediately before the second morning dose; (7) 26 h after the first and 2 h after the second morning dose; and (8) 27 h after the first dose and 3 h after the second morning dose. In addition to SIR, the patient’s therapy included the intake of zoledronic acid at a dose of 0.05 mg/kg every 4 weeks along with a nonsteroidal anti-inflammatory drug (metamizole sodium) and a calcium supplement, as well as 4,000 IU of cholecalciferol orally once per day. The SIR level for this patient before the administered drug dose was determined to be 14.2 ng/mL using an immunochemical test.

Patient 2 was an 11-year-old girl with generalized lymphadenopathy, immune thrombocytopenia, and autoimmune anemia (genetic tests indicated a very rare type 3 dyserythropoietic anemia). SIR was included in the patient’s treatment in the same manner as it would be used for an autoimmune lymphoproliferative syndrome. To achieve the recommended therapeutic concentration of 5–10 ng/mL, the initial SIR dose was set at 1 mg/m2 orally once per day and gradually increased to 2 mg/m2 once per day over a 2-month period. The samples that were used to establish the SIR concentration profile were collected when the patient was taking the target dose of the immunosuppressant. As with Patient 1, seven samples were collected from Patient 2 within 2 days: (1 A) before the first dose; (2 A) 2 h after the first dose; (3 A) 3 h after the first dose; (4 A) 6 h after the first dose; (5 A) 12 h after the first dose; (6 A) 24 h after the first dose and immediately before the second dose; and (7 A) 26 h after the first dose and 2 h after the second dose. Apart from SIR, Patient 2 was also receiving 2,000 IU of cholecalciferol orally once per day. The SIR concentration for this patient before the administered drug dose was determined to be 5.7 ng/mL using an immunochemical test.

3 Results

3.1 Method validation

The analysis of the calibration samples confirmed the developed method’s linearity over the entire concentration range of 1–50 ng/mL (six series of measurements performed in triplicate). The calibration curve equation was y = 0.019 (±0.0010)x + 0.0064 (±0.00004), where y and x were the peak area ratio of SIR/IS and the SIR concentration, respectively. In addition, the prepared calibration curve had a correlation coefficient (R 2 ) of ≥0.999. The LOD and LOQ were calculated using the calibration curve equation and were found to be 0.2 and 0.6 ng/mL, respectively. Chromatograms were obtained after the analysis of blank whole blood samples and after the analysis of blood samples spiked with SIR and enriched with ISs at concentrations of 25 ng/mL (SIR) and 50 ng/mL (IS); these chromatograms showed no interference from SIR vs IS and SIR/IS vs background signals (Figure 1), which confirmed the proposed method’s selectivity. The analysis of the LLOQ and three QC samples (LQC, MQC, and HQC) showed that the intraday and interday precision for the LLOQ were 5.48 and 8.80, respectively, while the intraday and interday accuracy were 95.67 and 93.02%, respectively (Table 2). In the case of the QC samples, the intraday and interday precision values ranged from 3.11 to 5.73% and 0.23 to 5.28%, respectively. The intraday and interday accuracy were less than 99.52 and 99.32%, respectively. These results confirm that the precision and accuracy of the developed analytical method are consistent with the applicable standards of bioanalytical methods. The validation also included a stability test of the low, middle, and high QCs (2.5, 10, 25 ng/mL). The obtained results for the storage of SIR and the IS at various thermal conditions (as detailed in Section 2.5.5) clearly show that SIR in whole blood remains stable under all temperature conditions, including after freezing and thawing cycles (Table S2). The obtained RSD (%) was ≤9.21%, while the accuracy was from 94.48 to 108.40%, which indicates that the results of the SIR and IS concentration determinations do not depend on the conditions under which the samples are stored before analysis. These results are consistent with previous reports [32,33]. In addition, the carry-over effect was examined to determine whether there was analyte transfer between analyses due to the presence of residues in the elements of the apparatus. The analytical signals obtained for a blank sample analyzed after the sample with the highest SIR concentration (50 ng/mL) were evaluated at 1.95 ± 0.02% of the peak area obtained after the analysis of the sample with the lowest analyte concentration (1 ng/mL); thus, carry-over effects did not affect the accuracy of the measurements or the measured SIR concentrations. The mean absolute recoveries for SIR and the IS from whole blood samples were 65.57 ± 5.24% and 67.27 ± 4.66%, respectively.

Figure 1 LC-MS/MS selected ion chromatogram with [M + NH4]+-signals of (a) blank whole blood; (b) whole blood sample spiked with SIR at a concentration of 1 ng/mL; (c) whole blood sample spiked with SIR at a level of 50 ng/mL; and (d) whole blood spiked with IS at a level of 50 ng/mL.
Figure 1

LC-MS/MS selected ion chromatogram with [M + NH4]+-signals of (a) blank whole blood; (b) whole blood sample spiked with SIR at a concentration of 1 ng/mL; (c) whole blood sample spiked with SIR at a level of 50 ng/mL; and (d) whole blood spiked with IS at a level of 50 ng/mL.

Table 2

Intraday and interday precision and accuracy for the quantification of SIR in whole blood samples by the LC-MS/MS method (n = 6)

Intraday (n = 6) Interday (n = 6)
QCs Concentration (ng/mL) Precision RSD (%) Accuracy (%) Concentration (ng/mL) Precision RSD (%) Accuracy (%)
Spiked (ng/mL) Found (mean ± SD) Spiked (ng/mL) Found (mean ± SD)
LLOQ 1 0.96 ± 0.05 5.48 95.67 1 0.93 ± 0.08 8.80 93.02
LQC 2.5 2.59 ± 0.15 5.73 103.64 2.5 2.55 ± 0.13 5.28 101.93
MQC 10 10.08 ± 0.47 4.65 100.84 10 9.93 ± 0.15 1.56 99.32
HQC 25 24.88 ± 0.77 3.11 99.52 25 25.01 ± 0.06 0.23 100.04

3.1.1 Real sample monitoring

The developed and validated DLLME-LC-MS/MS method was used to determine the SIR concentration profile in samples from two oncologic pediatric patients (Section 2.6). In the case of Patient 1, who was taking 1.9 mg dose of SIR orally every 12 h, the peak concentrations found in the samples collected 2 h after drug intake were as follows: 19.63 ± 0.48 ng/mL after the morning dose on the first day and 21.54 ± 0.41 ng/mL after the morning dose on the second day (Figure 2a). In the hours following the collection of the first sample on the morning of Day 1, the SIR concentration in the whole blood samples decreased consistently (3 h—18.15 ± 0.54 ng/mL; 6 h—14.34 ± 0.37 ng/mL), reaching the trough concentration (8.98 ± 0.29 ng/mL) 12 h after administration. The trough concentration of SIR 12 h after the evening dose (i.e., the next dose) was equal to 9.94 ± 0.32 ng/mL.

Figure 2 Sirolimus concentration in whole blood versus time profile for (a) Patient 1 taking 1.9 mg of SIR once every 12 h and (b) Patient 2 taking 2.0 mg of SIR once every 24 h. The dashed line indicates the time period during which no samples were taken.
Figure 2

Sirolimus concentration in whole blood versus time profile for (a) Patient 1 taking 1.9 mg of SIR once every 12 h and (b) Patient 2 taking 2.0 mg of SIR once every 24 h. The dashed line indicates the time period during which no samples were taken.

For Patient 2, who was taking a 2.0 mg dose of SIR orally once every 24 h, the overall concentration profile of the drug was slightly different. Similar to Patient 1, the highest measured SIR concentration in whole blood samples from Patient 2 was observed 2 h after intake. However, due to the different dose levels and regimens, Patient 2’s SIR levels were 28.49 ± 0.66 ng/mL 2 h after intake on the first day, and 32.39 ± 0.86 ng/mL on the second day of sampling (Figure 2b). Further differences in the SIR pharmacokinetic profiles of the two patients were attributable to the different dosing regimens (i.e., Patient 1 took SIR twice per day, while Patient 2 only received SIR once per day). For Patient 1, the lowest SIR concentration was found in the samples collected 12 h after intake, while the SIR concentration in Patient 2 was found to decrease during the 24 h after intake. The rate of decrease in Patient 2 was as follows: 22.92 ± 0.54 ng/mL at 3 h; 13.59 ± 0.49 ng/mL at 6 h; 8.55 ± 0.41 ng/mL at 12 h; and 3.23 ± 0.23 ng/mL at 24 h after administration.

4 Discussion

In current clinical practice, enzyme-linked immunoassays are preferred over mass spectrometry-based methods for the fast analysis of SIR levels in biological samples; however, enzyme-linked immunoassays suffer from many limitations, particularly by the cross reactions with SIR metabolites and other potential matrix components. Such cross reactions may affect the obtained results, for example, by overestimating data concerning SIR concentrations in real biological samples. Therefore, more precise alternative methods, such as mass spectrometry techniques, should be considered as promising options for overcoming the limitations of typical protocols for analyzing the pharmacokinetics of SIR.

In this study, an analytical method comprising sample preparation via DLLME followed by LC-MS/MS analysis was presented as a novel approach for the isolation and the quantification of SIR in complex matrices. This microextraction procedure for the isolation of SIR from whole blood samples was applied for the first time as previous reports concerning the sample preparation step were mostly based on conventional approaches, which suffers from several drawbacks (Table S1). On the contrary, DLLME is widely recognized as an eco-friendly modification of traditional LLE that is characterized by its simplicity and significantly reduced consumption of organic solvents. In the case of the developed DLLME procedure, the consumption of organic solvent was low when the time required for sample preparation per 1 sample including both hemolysis step and DLLME was only about 3 min. The literature contains only one study in which DLLME is applied for the isolation of SIR from biological fluids [34]. However, instead of using whole blood samples to determine SIR levels, the authors of this study used serum samples in developing an analytical method for the TDM of this strongly erythrocyte-bound drug. Conversely, in the current study, SIR extraction was performed using whole blood samples according to a previously developed procedure that combines DLLME with erythrocyte lysis; detailed information about the optimization steps for this procedure can be found in our previous work [29]. The method development process also included the selection of optimal chromatographic conditions to obtain the best results. To this end, we tested three different chromatographic columns: a YMC-Triart C8 column (50 mm × 2.1 mm, 5 µm) from YMC (Kyoto, Japan); a Discovery HS C18 (50 mm × 4.6 mm, 3 µm) column from Supelco (Bellefonte, USA); and a Kinetex® C18 reverse-phase column (50 mm × 2.1 mm, 1.7 μm) from Phenomenex (CA, USA). The results clearly indicated that the best resolution, time retention, and signal intensity for SIR were obtained on the C8 stationary phase; thus, this column was selected for use in subsequent analyses. Moreover, to ensure the best possible conditions for the quantification of SIR, different mobile phase compositions were tested. The analysis was performed using ACN or MeOH as the organic phase in a gradient elution with different gradient settings. Ultimately, the use of MeOH as an organic phase component in the gradient mode (described in detail in Section 2.4) enabled the best chromatographic conditions such as peak shape and symmetry, short analysis times, and improved signal intensity for both SIR and the IS. In this study, EVE was used as IS, which was in line with therapeutic regimens in which both EVE and SIR are used in combination with cyclosporin A or tacrolimus, but never used simultaneously. The application of the selected conditions facilitated the determination of SIR in whole blood samples in a total analysis time of 2.5 min, which is advantage over most of the reported LC(UPLC)-MS [17,18,21,23,24,25,26,27,33] and CE-based studies [20] on SIR quantification (Table S1). In addition, the chromatographic parameters enabled low LOD and LOQ values, which were equal to 0.2 and 0.6 ng/mL, respectively. Thus, the LOQ was lower [17,20,24,25,32] or comparable [18,21,26,27,33] with previously reported protocols for the analysis of SIR in biological matrices (Table S1). What’s more, to the best of our knowledge, this is the first study to document a validation protocol for a DLLME-LC-MS/MS method for SIR analysis that was performed and calculated according to ICH and FDA requirements. Furthermore, the results of the sensitivity, selectivity, precision, accuracy, stability, recovery, and carry-over tests (detailed in Section 3) proved that the proposed method complies with the current ICH and FDA criteria for bioanalytical methods, and is therefore suitable for routine use in controlling SIR concentrations in biological samples.

The developed analytical protocol was subsequently applied for the determination of SIR levels in real blood samples obtained from two pediatric patients with lymphatic anomalies (Section 2.6). In both clinical cases, namely, GLA (Patient 1) and generalized lymphadenopathy (Patient 2), mutations in the PI3K/Akt/mTOR pathway were observed; hence, the administration of SIR (mTOR inhibitor) to treat such conditions is justified, which has led to increased interest in its use as a part of polytherapy for these disorders [7,35]. Most prior data for this orphan use of SIR have come from clinical trials focused on demonstrating its dose–response toxicity and efficacy [7,8,10]. However, high pharmacokinetic variability between patients makes it challenging to determine the correct dosage of SIR. Thus, methods enabling the precise analysis of SIR levels in blood samples from individual patients are an essential component of optimal therapeutic regimens. The monitoring of SIR concentrations is usually performed every week at the beginning of therapy, then every 2 weeks, and finally, every month once the target blood concentration of SIR has been achieved. In typical clinical protocol, a sample is taken for an immunoassay test once per day before the administration of the next dose of the drug [36,37]. Thus, in clinical practice, the dosage of SIR is adjusted to the target therapeutic range based on its levels in the blood at a single analytical time point. Unfortunately, such analysis does not provide precise information about the drug’s LADME (ADME) process, including its absorption and distribution, which may significantly affect the dosage size and frequency used in the selected dosing schedule. In the current study, the obtained results revealed that both patients reached the maximum SIR concentration 2 h after intake, with SIR absorption occurring at the same time, despite their difference in age (3 and 11 years) (Figure 2). It should also be emphasized that some differences are apparent when comparing the SIR concentrations in the samples collected for Patient 1 at the same time points on subsequent days (19.63 ± 0.48 vs 21.54 ± 0.41 ng/mL for peak concentration). During the second day of sampling, the maximum concentration (i.e., 2 h after drug intake) was higher than at the same time point on the first day; conversely, the concentration of SIR was lower 3 h after administration on the second day compared to the same time point on the first day (13.39 ± 0.36 ng/mL vs 18.15 ± 0.54 ng/mL) (Figure 2). These results may suggest that the interday profiles of SIR concentrations in the test patient may be different. In turn, significant differences were evident in the elimination stage of this drug. Specifically, while the SIR concentration profile for Patient 1 (intake every 12 h) was relatively stable, significant fluctuations in SIR levels were observed in Patient 2 (intake every 24 h). In addition, it is also interesting that, in the case of Patient 2, a similar dependence was observed in the SIR levels determined in samples taken at the same time points on different days. However, the maximum SIR concentration on the second day was higher than the maximum SIR concentration on the first day at 28.49 ± 0.66 ng/mL and 32.39 ± 0.86 ng/mL, respectively. The results obtained for both patients indicate that the concentration of SIR tends to increase on the days following administration, but decreased to very similar values after taking each dose (Figure 2). For instance, SIR levels of 2.94 ± 0.14 ng/mL and 3.23 ± 0.23 ng/mL were recorded in the second patient 24 h after administration. In addition, a t 1/2 of < 12 h was achieved with the bi-daily SIR dosage regimen, and a t 1/2 of < 6 h was attained with the daily dosage regimen. Thus, a bi-daily regimen appears to be the optimal dosage scheme for maintaining a steady SIR concentration during treatment. Nonetheless, it should be emphasized that several factors may have influenced the differences observed in the pharmacokinetic profiles of SIR in the two patients in this study. For instance, the ages of patients (i.e., 3 and 11 years old) and the co-administration of other drugs may have affected the obtained pharmacokinetic values and profile for SIR. As previously reported, the t 1/2 of SIR in pediatric patients is shorter than in adults [16]. Indeed, the t 1/2 for the 3-year-old patient taking SIR twice per day was longer than the t 1/2 for the older pediatric patient taking SIR once per day. In addition, the obtained results also indicated that the SIR levels determined for both patients were frequently outside the target therapeutic window established for this drug (Figure 2). In the case of Patient 1 (dose of 1.9 mg every 12 h), the concentration value, as clinically indicated, should be within 10–15 ng/mL. However, the peak (19.63 ± 0.48 ng/mL) and trough concentrations (8.98 ± 0.29 ng/mL) measured for this patient were outside the recommended values. The same results were observed for Patient 2 (dose of 2.0 mg every 24 h), for whom the therapeutic range was set at 5–10 ng/mL. For this patient, maximal and minimal concentrations of 28.49 ± 0.66 and 2.94 ± 0.14 ng/mL were observed, respectively. Thus, the obtained results strongly indicate the presence of large fluctuations in SIR concentration at a steady state in the individual patients, and that TDM should be personalized during SIR therapy. Given that SIR concentrations outside of the recommended range can result in adverse effects, the measured concentration levels in both patients indicate the need for monitoring between doses to ensure the optimal dosage size is being administered. In addition, it should also be noted that the predose SIR concentrations determined in this study via chromatography differed from those determined in the same patients via immunochemical techniques (Section 2.6). Based on the immunochemical test, the level of SIR measured before the administration of the next dose of this drug to the first and second patient was equal to 14.2 and 5.7 ng/mL, respectively. In our MS-based methodology, SIR concentration in the samples collected from each patient at the same time point was equal to 10.79 ± 0.57 and 2.94 ± 0.14 ng/mL, respectively. Those results are in line with previous reports, suggesting the overestimation of the results when using immunoassay tests [21,22]. Specifically, the predose concentrations of SIR detected via DLLME-LC-MS/MS analysis were lower than those indicated by the immunochemical tests. In this study, about 30–50% higher levels of SIR were detected when using immunoassay test in comparison to SIR concentration found using the DLLME-LC-MS/MS method. This discrepancy in the measured concentrations of SIR was observed especially in the samples with lower levels of this drug. Thus, the risk of overestimating the SIR concentration by immunoassay tests increased with a decrease in SIR concentration. These results align with previous observations regarding the cross-reactivity of immunochemical tests, which result in overestimated SIR levels. For example, in the case of immunoassay tests, as it was mentioned earlier, over 60% overestimation of the results obtained from the EMIT in comparison to the LC-MS/MS method during SIR determinations was reported [21]. In the study described by Polledri et al., when the results from a certified in vitro diagnostic kit coupled to a medical device and LC-MS/MS analysis were compared with the results from immunoassay tests, the overestimation of the results in the case of immunoassay test was calculated at the level of 30% [22]. However, more comparative studies of SIR analysis via both techniques are needed to confirm the aforementioned speculations. Furthermore, this study had a number of limitations, including a small sample size (i.e., two patients); a relatively short-time monitoring time for the SIR pharmacokinetic profile; and the presence of other, nonanalytical factors mainly related to the status of the patients and their response to drug therapy (e.g., vomiting), which could also affect measured SIR levels. Therefore, it will be necessary to conduct long-term studies wherein SIR levels are determined in larger groups of patients to determine whether the findings of the present study can be applied in routine clinical practice, specifically for monitoring SIR levels in patients with lymphatic anomalies. Nevertheless, the data from previous studies do not present the SIR profile between subsequent doses as the samples were collected every few days or even months [36,37,38]. Thus, in the aforementioned studies, the level of SIR was monitored in whole blood samples collected from patients solely before the administration of the next dose of this drug, and no further analyses of the SIR profile in subsequent hours after its administration were reported.

5 Conclusion

This study has presented a DLLME-LC-MS/MS method for the precise determination of the pharmacokinetic profile of SIR in whole blood samples acquired from pediatric patients. The proposed DLLME protocol offers a simple and fast sample pretreatment method that can be applied in typical analytical laboratories. In addition, the use of a mass-spectrometry-based method (LC-MS/MS) to determine SIR is consistent with current practices in developing analytical methods for TDM studies. Furthermore, the development of a quick and simple analytical method that utilizes mass spectrometry also provides a promising alternative to enzyme-linked immunosorbent assays, which remain the most common method for measuring SIR levels despite their tendency to overestimate results. The validation of the proposed DLLME-LC-MS/MS protocol complies with the current requirements for bioanalytical methods; thus, the developed method can be directly applied for the therapeutic monitoring of even trace levels of SIR in clinical samples.

The practical applicability of the presented method was also demonstrated by using it to determine SIR concentration profiles in real blood samples collected at hourly intervals from two pediatric patients with lymphatic anomalies. While the determination of SIR was performed to demonstrate the proposed method’s usefulness in analyzing real biological samples, the obtained results may also be of clinical interest, as this is the first study to monitor SIR levels in an off-label clinical indication. To the best of our knowledge, previous studies of such orphan clinical indications of SIR in lymphatic anomalies have only monitored levels of this drug after a single dose; thus, these studies did not allow changes in the concentration of SIR between doses to be tracked during pharmacotherapy. Nevertheless, more in-depth studies of SIR’s ADME process are needed, as the present study only analyzed whole blood samples from two patients collected over a 27-hour period and did not consider other factors that might affect SIR metabolism. Therefore, more research should be conducted using the proposed DLLME-LC-MS/MS method – particularly using large samples – to gain a more robust understanding of SIR’s pharmacokinetics and to prove the developed method’s usefulness in routine clinical practice during the TDM of SIR in individual patients.

# These authors contributed equally to the manuscript.

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Acknowledgements

The authors would like to extend special thanks to Prof. Tomasz Smoleński, Head of the Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland, for providing access to the Sciex QTrap 6500 in the Bioanalytical Laboratory in the Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland. The authors would also like to thank Mrs. Katarzyna Smug, analytical specialist, the Bioanalytical Laboratory in the Department of Biochemistry, Medical University of Gdańsk, Gdańsk, Poland, for her help in conducting the LC-MS/MS analysis.

  1. Funding information: This study was not supported by grant or any other funding from external sources.

  2. Author contributions: Conceptualization, N.T., A.R. and A.P.; methodology, N.T. and A.R.; software, A.R.; validation, N.T. and A.R.; formal analysis, A.P.; investigation, N.T., N.K. and O.M.; resources, N.T.; data curation, A.R.; writing—original draft preparation, N.T., A.R., A.P.; writing—review and editing, I.O., A.R., P.K., E.B and M.A.K; visualization, N.T and A.R.; supervision, T.B., E.B and M.A.K; project administration, N.T. and A.R.; funding acquisition, T.B. All authors read and approved the final manuscript.

  3. Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article. Dr. Anna Roszkowska serves as an Editor in Open Medicine, but it did not affect the peer-review process.

  4. Data availability statement: The analyzed datasets generated in this study are available from the corresponding author on reasonable request.

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Received: 2022-08-29
Revised: 2022-12-30
Accepted: 2023-01-05
Published Online: 2023-03-02

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0652
Schlagwörter für diesen Artikel
SIR; whole blood samples; DLLME; LC-MS/MS; therapeutic drug monitoring
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
Heruntergeladen am 11.5.2026 von https://www.degruyterbrill.com/document/doi/10.1515/med-2023-0652/html?lang=de
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