Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents: a substudy of the SMILE trial.

Darunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and adolescents is evaluated. A joint population PK model that simultaneously used total DRV, unbound DRV, and total RTV concentrations was developed. Competitive and non-competitive models were examined to define RTV's influence on DRV pharmacokinetics. Linear and non-linear equations were tested to assess DRV protein binding. A total of 443 plasma samples from 152 adolescents were included in this analysis. Darunavir PK was best described by a one-compartment model first-order absorption and elimination. The influence of RTV on DRV pharmacokinetics was best characterized by ritonavir area under the curve on DRV clearance using a power function. The association of non-linear and linear equations was used to describe DRV protein binding to alpha-1 glycoprotein and albumin, respectively. In our population, simulations indicate that 86.8% of total and unbound DRV trough concentrations were above 0.55 mg/L [10 times protein binding-adjusted EC50 for wild-type (WT) HIV-1] and 0.0243 mg/L (10 times EC90 for WT HIV-1) targets, respectively. Predictions were also in agreement with observed outcomes from adults receiving 800/100 mg DRV/r once a day. Administration of 800/100 mg of DRV/r once daily provides satisfactory concentrations and exposures for adolescents aged 12 years and older.

Serum CA-125 as a predictor in the early diagnosis of ectopic pregnancy in Vietnam - A case-control study.

INTRODUCTION: This study aimed to determine the predictive value of cancer antigen-125 (CA-125) in combination with serum beta-human chorionic gonadotropin (ß-hCG) and progesterone in the early detection of ectopic pregnancy (EP). METHODS: Between May 2019 and May 2020, the cross-sectional study recruited 42 cases of EP and 42 cases of IUP at the same gestational age who visited the Department of Obstetrics and Gynecology, Hospital of Hue University of Medicine and Pharmacy. EP was diagnosed based on surgical (laparoscopy) and postoperative pathology examination. RESULTS: There were significant differences of mean level of ß-hCG (2570 mUI/mL vs. 18357.7 mUI/mL), progesterone (10.79 ± 8.16 ng/ml vs. 27.42 ± 4.17 ng/ml) and CA-125 (26.90 ± 10.26 U/mL vs. 70.61 ± 20.89 U/mL) between the EP and the IUP groups (p < 0.001). In the prediction of early diagnosis of EP, the cut-off value of CA-125 at 30.94 U/mL has a sensitivity of 89.3% and a specificity of 87,9%; the cut-off value of ß hCG at 2750mIU/ml has the sensitivity of 75%, specificity of 78,8%; the cut-off value of progesterone at 10.24 ng/mL has the sensitivity of 85.7%, specificity of 81.8%. A combination of CA-125, ß hCG, and progesterone had a sensitivity of 92.8% and a specificity of 90.9% in early diagnosis of EP. DISCUSSION: Serum CA-125 levels can be used independently or in combination with other markers in the early diagnosis of EP.

Extraction of curcumin from turmeric residue (Curcuma longa L.) using deep eutectic solvents and surfactant solvents.

Using waste materials to extract biologically active ingredients with green solvents is a new trend for sustainable development. Herein, different types of deep eutectic solvents (DESs) and surfactant solvents (SSs) were used to extract curcumin from turmeric residues (TRs), among which choline chloride-propylene glycol (ChCl-Pro) showed the highest yield. The optimized extraction conditions included a ChCl : Pro ratio of 1 : 2, water content in the DESs of 20%, solid : liquid ratio of 1 : 40 maintained for 60 min at 50 °C, and a TR particle size of 0.18 mm. The extraction yield was 54.2 mg g-1, which was 1.31 times higher than when methanol was used as a solvent. Distilled water was used to recover curcumin from the DES extract with a recovery yield of 99.7%. Furthermore, the antioxidant and acetylcholinesterase (AChE) inhibitory activities of the recovered curcumin were evaluated, with IC50 values of 25.58 ± 0.51 and 19.12 ± 0.83 µg mL-1, respectively. This study highlights the promising potential of using green solvents to extract bioactive compounds from waste materials.

Navigator channel adaptation to reconstruct three dimensional heart volumes from two dimensional radiotherapy planning data.

BACKGROUND: Biologically-based models that utilize 3D radiation dosimetry data to estimate the risk of late cardiac effects could have significant utility for planning radiotherapy in young patients. A major challenge arises from having only 2D treatment planning data for patients with long-term follow-up. In this study, we evaluate the accuracy of an advanced deformable image registration (DIR) and navigator channels (NC) adaptation technique to reconstruct 3D heart volumes from 2D radiotherapy planning images for Hodgkin's Lymphoma (HL) patients. METHODS: Planning CT images were obtained for 50 HL patients who underwent mediastinal radiotherapy. Twelve image sets (6 male, 6 female) were used to construct a male and a female population heart model, which was registered to 23 HL "Reference" patients' CT images using a DIR algorithm, MORFEUS. This generated a series of population-to-Reference patient specific 3D deformation maps. The technique was independently tested on 15 additional "Test" patients by reconstructing their 3D heart volumes using 2D digitally reconstructed radiographs (DRR). The technique involved: 1) identifying a matching Reference patient for each Test patient using thorax measurements, 2) placement of six NCs on matching Reference and Test patients' DRRs to capture differences in significant heart curvatures, 3) adapting the population-to-Reference patient-specific deformation maps to generate population-to-Test patient-specific deformation maps using linear and bilinear interpolation methods, 4) applying population-to-Test patient specific deformation to the population model to reconstruct Test-patient specific 3D heart models. The percentage volume overlap between the NC-adapted reconstruction and actual Test patient's true heart volume was calculated using the Dice coefficient. RESULTS: The average Dice coefficient expressed as a percentage between the NC-adapted and actual Test model was 89.4 ± 2.8%. The modified NC adaptation technique made significant improvements to the population deformation heart models (p = 0.01). As standard evaluation, the residual Dice error after adaptation was comparable to the volumetric differences observed in free-breathing heart volumes (p = 0.62). CONCLUSIONS: The reconstruction technique described generates accurate 3D heart models from limited 2D planning data. This development could potentially be used to retrospectively calculate delivered dose to the heart for historically treated patients and thereby provide a better understanding of late radiation-related cardiac effects.

Reconstruction of 3D lung models from 2D planning data sets for Hodgkin's lymphoma patients using combined deformable image registration and navigator channels.

PURPOSE: Late complications (cardiac toxicities, secondary lung, and breast cancer) remain a significant concern in the radiation treatment of Hodgkin's lymphoma (HL). To address this issue, predictive dose-risk models could potentially be used to estimate radiotherapy-related late toxicities. This study investigates the use of deformable image registration (DIR) and navigator channels (NCs) to reconstruct 3D lung models from 2D radiographic planning images, in order to retrospectively calculate the treatment dose exposure to HL patients treated with 2D planning, which are now experiencing late effects. METHODS: Three-dimensional planning CT images of 52 current HL patients were acquired. 12 image sets were used to construct a male and a female population lung model. 23 "Reference" images were used to generate lung deformation adaptation templates, constructed by deforming the population model into each patient-specific lung geometry using a biomechanical-based DIR algorithm, MORFEUS. 17 "Test" patients were used to test the accuracy of the reconstruction technique by adapting existing templates using 2D digitally reconstructed radiographs. The adaptation process included three steps. First, a Reference patient was matched to a Test patient by thorax measurements. Second, four NCs (small regions of interest) were placed on the lung boundary to calculate 1D differences in lung edges. Third, the Reference lung model was adapted to the Test patient's lung using the 1D edge differences. The Reference-adapted Test model was then compared to the 3D lung contours of the actual Test patient by computing their percentage volume overlap (POL) and Dice coefficient. RESULTS: The average percentage overlapping volumes and Dice coefficient expressed as a percentage between the adapted and actual Test models were found to be 89.2 +/- 3.9% (Right lung = 88.8%; Left lung = 89.6%) and 89.3 +/- 2.7% (Right = 88.5%; Left = 90.2%), respectively. Paired T-tests demonstrated that the volumetric reconstruction method made a statistically significant improvement to the population lung model shape (p < 0.05). The error in the results were also comparable to the volume overlap difference observed between inhale and exhale lung volumes during free-breathing respiratory motion (POL: p = 0.43; Dice: p = 0.20), which implies that the accuracies of the reconstruction method are within breathing constraints and would not be the confining factor in estimating normal tissue dose exposure. CONCLUSIONS: The result findings show that the DIR-NC technique can achieve a high degree of reconstruction accuracy, and could be useful in approximating 3D dosimetric representations of historical 2D treatment. In turn, this could provide a better understanding of the biophysical relationship between dose-volume exposure and late term radiotherapy effects.

Adapting population liver motion models for individualized online image-guided therapy.

Respiratory motion varies on a daily basis in abdominal cancer patients, affecting the ability to successfully deliver local therapy and requiring increased treatment margins to account for this variation. Deformable registration techniques can accurately describe respiratory motion, however, online application can be limited by long computational times and user intervention. A technique has been developed to quickly quantify patient breathing motion from respiratory-sorted volumetric images by calculating 1D shifts in image intensities between spatially corresponding regions of interest (navigator channels) on patient's images. The 1D motion at the superior, inferior, anterior, and posterior liver edges was detected and applied to adapt a population liver respiratory motion model. For validation, deformable registration was performed for each patient using a validated technique, MORFEUS, for relative validation, and vessel bifurcations, identified on patient's inhale and exhale images, for absolute validation. The accuracy of the adapted-population model to describe the patient respiratory motion was (absolute mean +/- SD) 0.26 +/- 0.11 cm and 0.30 +/- 0.21 cm in the superior-inferior (SI) and anterior-posterior (AP) directions, respectively. The accuracy of predicting the tumor COM motion was 0.30 +/- 0.22 cm, and 0.34 +/- 0.31, while the absolute validation, based on bifurcations was 0.26 +/- 0.16 cm and 0.13 +/- 0.04 cm in the SI and AP directions, respectively. This technique was developed to complement and quickly adapt a full 3D biomechanical based deformable registration technique, MORFEUS, to be applied in the online setting.

Targeting of a novel fusion protein containing methioninase to the urokinase receptor to inhibit breast cancer cell migration and proliferation.

It has been shown that methionine depletion inhibits tumor cell growth and reduces tumor cell survival. A novel fusion protein targeted specifically to tumor cells was developed. The fusion protein contained two components: the amino terminal fragment of human urokinase (amino acids 1-49) that binds to the urokinase receptor protein expressed on the surface of invasive cancer cells, and the enzyme L-methioninase (containing 398 amino acids) which depletes methionine and arrests the growth of methionine-dependent tumors. The influence of the fusion protein on the growth and motility of human breast cancer cells was examined using a culture wounding assay. It was determined that MCF-7 breast cancer cells, used in this study, were methionine-dependent and that the fusion protein bound specifically to urokinase receptors of the surface of the cancer cells. Further treatment of the cancer cells with fusion protein over the concentration range 10(-8) to 10(-6) M produced a dose-dependent inhibition of both the migration and proliferation index of MCF-7 cells in the culture wounding assay over a period of 1 to 3 days. The results of this study suggest that this novel fusion protein may serve as a prototype for specific targeting of methioninase and perhaps other cytotoxic agents to cancer cells.

Keratinocyte growth factor stimulates the migration and proliferation of breast cancer cells in a culture wounding model.

Growth factors are known to influence the progression, motility and invasiveness of tumor cells. In a previous study, we reported that conditioned media from NIH 3T3 cells (mouse fibroblast), which contains KGF, increased the motile morphology of estrogen receptor (ER)-positive breast cancer cells and produced no effect on ER-negative cells. The present study examined the influence of human KGF on two estrogen receptor (ER)-positive human breast cancer cell lines (MCF-7 and T-47D) using a culture wounding model to evaluate cell proliferation and migration over a period of 48h. In the present study we observed that KGF enhanced the migration and proliferation of both MCF-7 and T-47D breast cancer cells. In both cell lines the response to KGF was found to be both dose- and time-dependent. However, the total migration and proliferation response of the MCF-7 cells to KGF was much greater than that observed in the T-47D cells. The results of this study demonstrate that human KGF enhances the migration and proliferation of human breast cancer cells. Further, these results support the concept that KGF may be an early signal in the progression of breast cancer to a more motile and metastatic phenotype.

Specific and non-specific KGF inhibition of KGF-induced breast cancer cell motility.

BACKGROUND: Keratinocyte growth factor (KGF), a member of the fibroblast growth factor family, is a mesenchymally derived mediator of epithelial cell proliferation and migration. In a previous study, we reported that KGF enhanced the motility of human breast cancer cells. The objective of the present study was to examine the influence of specific and non-specific KGF inhibitors on KGF-induced motility and proliferation in ER-positive MCF-7 cells. MATERIALS AND METHODS: In the present study three KGF inhibitors were employed [Heparin, Innohep, a low molecular weight heparin (LMWH) and KGFR2 beta (IIIb)/Fc, a chimeric KGFR fragment]. Heparin and LMWH bind to low affinity sites on KGF and produce non-specific inhibition, while KGFR2 beta (IIIb)/Fc, a soluble chimera of an extracellular KGFR fragment, is a more specific KGF inhibitor. Cellular motility was measured using two methods: culture wounding over a period of 48 hours; and secondly, time-lapse videomicroscopy (TLVM). RESULTS: In these experiments KGF was found to produce a dose-dependent enhancement of MCF-7 cell motility over a dosage range of 5 to 500 ng/ml. In the TLVM experiments, Heparin (30 ng/ml), LMWH (30 ng/ml) and KGFR2 beta (IIIb)/Fc (50 micrograms/ml) completely inhibited KGF-induced motility of MCF-7 cells during the initial 2-hour observation period. In the culture wounding assay, LMWH produced a greater reduction in KGF-induced motility than heparin at 48 hours post-treatment. CONCLUSION: The results of this study indicate that KGF-mediated enhancement of breast cancer cells motility and proliferation is inhibited by both specific and non-specific KGF inhibitors. LMWH appears to produce an inhibition of KGF with a much longer duration of action than Heparin. Our results suggest that KGF inhibition may be a potential new therapeutic approach for the treatment of metastatic breast cancer.