Prediction of drug-drug interactions between roflumilast and CYP3A4/1A2 perpetrators using a physiologically-based pharmacokinetic (PBPK) approach.

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.

A reproducibility study of knee cartilage volume and thickness values derived by fully automatic segmentation based on three-dimensional dual-echo in steady state data from 1.5 T and 3 T magnetic resonance imaging.

OBJECTIVE: To evaluate the repeatability of cartilage volume and thickness values at 1.5 T MRI using a fully automatic cartilage segmentation method and reproducibility of the method between 1.5 T and 3 T data. METHODS: The study included 20 knee joints from 10 healthy subjects with each subject having undergone double-knee MRI. All knees were scanned at 1.5 T and 3 T MR scanners using a three-dimensional (3D) high-resolution dual-echo in steady state (DESS) sequence. Cartilage volume and thickness of 21 subregions were quantified using a fully automatic cartilage segmentation research application (MR Chondral Health, version 3.0, Siemens Healthcare, Erlangen, Germany). The volume and thickness values derived from fully automatically computed segmentation masks were analyzed for the scan-rescan data from the same volunteers. The accuracy of the automatic segmentation of the cartilage in 1.5 T images was evaluated by the dice similarity coefficient (DSC) and Hausdorff distance (HD) using the manually corrected segmentation as a reference. The volume and thickness values calculated from 1.5 T and 3 T were also compared. RESULTS: No statistically significant differences were found for cartilage thickness or volume across all subregions between the scan-rescanned data at 1.5 T (P > 0.05). The mean DSC between the fully automatic and manually corrected knee cartilage segmentation contours at 1.5 T was 0.9946. The average value of HD was 2.41 mm. Overall, there was no statistically significant difference in the cartilage volume or thickness in most-subregions between the two field strengths (P > 0.05) except for the medial region of femur and tibia. Bland-Altman plot and intraclass correlation coefficient (ICC) showed high consistency between results obtained based on same and different scanning sequences. CONCLUSION: The cartilage segmentation software had high repeatability for DESS images obtained from the same device. In addition, the overall reproducibility of the images obtained from equipment of two different field strengths was satisfactory.

Corrosion Resistance Enhancement of CoCrFeMnNi High-Entropy Alloy with WC Particle Reinforcements via Laser Melting Deposition.

In the present work, a WC particle-reinforced CoCrFeMnNi high-entropy alloy (HEA) was fabricated by laser melting deposition (LMDed). The LMDed CoCrFeMnNi high-entropy alloy (CoCrFeMnNi) composite is primarily comprised of a face-centered cubic (FCC) crystal structure. However, in the case of CoCrFeMnNi with 2.5 wt.% WC, it exhibits a combination of an FCC matrix and a ceramic phase known as M23C6. The corrosion behavior of CoCrFeMnNi and CoCrFeMnNi with 2.5 wt.% WC particle in 0.5 M H2SO4 was comparatively investigated. Compared with CoCrFeMnNi, the passive film formed on the CoCrFeMnNi with 2.5 wt.% WC had a more stable and stronger protective property. The corrosion current density of the CoCrFeMnNi with 2.5 wt.% WC dropped by 149.1% compared to that of the CoCrFeMnNi, indicating that the CoCrFeMnNi with 2.5 wt.% WC had better corrosion resistance than that of the CoCrFeMnNi.

Prediction of pharmacokinetics and pharmacodynamics of trelagliptin and omarigliptin in healthy humans and in patients with renal impairment using physiologically based pharmacokinetic combined DPP-4 occupancy modeling.

BACKGROUND: This study aimed to build a mathematical model of physiologically based pharmacokinetic combined DPP-4 occupancy (PBPK-DO) in humans to provide some recommendations for dosing adjustment in patients with renal impairment. METHODS: The PBPK-DO model was built using physicochemical and biochemical properties and binding kinetics data of TRE and OMA, and then validated by the clinically observed pharmacokinetics (PK) and pharmacodynamics (PD). Finally, the model was applied to determine dose adjustment in patients with renal impairment. RESULTS: The predicted PK and DPP-4 occupancy matched well with the clinically observed data, and all absolute average-folding errors (AAFEs) were within 2. The simulations showed that TRE and OMA were both suggested to only support dose reduction by half in patients with severe renal impairment based on this PBPK-DO model, which is different from the commendations only in terms of their AUC0-336 changes. These simulation results were in good agreement with clinical recommendations about dosage adjustment in patients. CONCLUSION: The present PBPK-DO model can simultaneously predict PK and PD of TRE and OMA in humans and also provide valuable recommendations for dosing adjustment in renal impairment patients, which cannot be achieved by alone depending on PK change.

Cortex or cancellous-which is early for the decrease of bone content for vertebral body in health?

OBJECTIVE: To obtain the cortex and cancellous parameter of the vertebral bone of healthy subjects using QCT. To explore which is earlier or faster for bone loss with age. MATERIALS AND METHODS: 733 physical examiners underwent chest low-dose CT examination were recruited, from April 1, 2021 to October 1, 2021. QCT sequence was used to obtain the bone mineral density of T12-L2 vertebral body without additional radiation. The mass and area of vertebral cortex and cancellous at the central level of L2 vertebral body were measured. The age -related characteristics of vertebral cortex and cancellous between male and female was analyzed and compared. RESULTS: The vBMD of T12-L2 vertebral body decreased with age. Significant differences were found in volumetric bone mineral density (vBMD) of T12-L2 vertebral body. For female, significant differences were found in bone content involving cortical mass, cancellous mass, cortical area, cancellous area, cortical mass/cancellous mass and cortical area/cancellous area in different age groups, respectively. The cortical mass decreased with age in female. The cancellous mass of female increased and then decreased with peak at 31-40 y. The cortical area of female decreased gradually before 71 y. The cancellous area of female increased and then decreased with peak at 51-60 y. The values of mass ratio and area ratio in female showed a slowly downward trend with age. Significant differences of bone content between non-menopausal and menopausal women were found except the cancellous mass. For male, no significant differences were found in all parameters of bone content. CONCLUSION: The changes of vertebral BMD, bone content of cortex and cancellous have different characteristics in different age. The change of cortex in female maybe earlier and faster than that of cancellous, especially in menopausal women.

Periodical assessment of four horns of knee meniscus using MR T2 mapping imaging in volunteers before and after amateur marathons.

To observe the changes and recovery of T2 values of menisci in amateur marathon participants at different times, and to examine the effect of marathon exercise on meniscal microstructure. Twelve healthy marathon volunteers were recruited continuously, including 5 males and 7 females, with mean (± SD) age of 27.5 ± 5.2 years. The body mass indices (BMIs) ranged from 17.6 to 27.2 kg/m2, with a mean of 21.9 ± 2.5 kg/m2. The 24 knee joints were scanned using a 3 T MR scanner at 1 week before the event, and at 12 h and 2 months after the event. T2 values of the anterior horn of the medial meniscus (MMAH), posterior horn of the medial meniscus (MMPH), anterior horn of the lateral meniscus (LMAH), and posterior horn of the lateral meniscus (LMPH) were measured by drawing the regions of interest (ROIs) on the T2 map images. Wilcoxon sign rank test was used to compare the T2 values between 1 week before and 12 h after the event, and between 1 week before and 2 months after the event in each anatomical region, respectively. The T2 values of the menisci at 12 h after the event were significantly higher (P < 0.05) than those at 1 week before the event. No statistically significant differences in the T2 values of the menisci were found between 2 months after and 1 week before the event (P > 0.05). The T2 values of MMAH, MMPH, LMAH, and LMPH showed a trend of "increasing first and then decreasing" over time, suggesting that the T2 values may reflect meniscal microstructure in amateur marathon runner.

Transabdominal laparoscopy and ureteroscopy one-stage surgery in the treatment of bilateral ureteropelvic junction obstruction combined with bilateral renal stones: A case report.

Ureteropelvic junction obstruction (UPJO) is a common congenital malformation of the urinary system, which is mostly unilateral and frequently combined with hydronephrosis and kidney stones. The incidence of kidney stones is ~20%, which markedly increases the difficulty and risk of surgery. The present report describes a rare case of bilateral UPJO combined with bilateral renal stones. Laparoscopy and ureteroscopy one-stage surgery was performed creatively. CT urography demonstrated that the hydronephrosis was markedly reduced after the surgery, the ureteropelvic junction was patent without stone residue and the surgical outcome was ideal.

Exploring the relationship of brown adipose tissue to bone microarchitecture using 7T MRI and micro-CT.

BACKGROUND: Brown adipose tissue (BAT) is involved both in energy production and bone metabolism. The purpose of this study was to analyze the relationship between BAT and microarchitecture at cancellous and cortical bone using Kunming mice and the methods of 7T magnetic resonance imaging (MRI) combined with micro-CT. METHODS: Twenty-four female Kunming mice were examined by 7T MRI and measured T2* relaxation time on the deep and superficial interscapular BAT (iBAT) and subcutaneous white adipose tissue (sWAT). Cancellous bone microarchitecture of the distal femur and cortical bone of the middle femur were examined by micro-CT. A paired t-test was used to analyze the differences in T2* values between iBAT and sWAT. The correlation between BAT T2* values and bone microstructure parameters were analyzed using Pearson's correlation. RESULTS: T2* values of the deep and superficial iBAT (6.36±3.31 ms and 6.23±2.61 ms) were significantly shorter than those of sWAT (16.30±3.05 ms, t(deep) iBAT=-10.816), t(superficial) iBAT =-12.276, p<0.01). Deep iBAT T2* values were significantly and negatively correlated with bone volume, cancellous thickness, and bone thickness (Th) and trabecular thickness (Tb.Th) of the cancellous bone of femur. Deep iBAT T2* values were significantly and positively correlated with the structural model index of cancellous bone of femur. Deep iBAT T2* values were significantly and negatively correlated with bone mineral density of the cortical bone of femur. CONCLUSIONS: MRI can distinguish the two adipose tissues from each other. T2* values of BAT were lower than WAT on MRI. BAT related bone remodeling was more correlated with the microstructure of cancellous bone than that of cortical bone.

Effect of Radiofrequency Plasma Spheroidization Treatment on the Laser Directed Energy Deposited Properties of Low-Cost Hydrogenated-Dehydrogenated Titanium Powder.

Titanium for additive manufacturing presents a challenge in the control of costs in the fabrication of products with expanding applications compared with cast titanium. In this study, hydrogenated-dehydrogenated (HDH) titanium powder with a low cost was employed to produce spherical Ti powder using the radiofrequency plasma (RF) technique. The spherical Ti powder was used as the raw material for laser directed energy deposition (LDED) to produce commercially pure titanium (CP-Ti). Microstructural analyses of the powder revealed that RF treatment, not only optimized the shape of the titanium powder, but also benefited in the removal of the residual hydride phase of the powder. Furthermore, the LDED-HDH-RF-produced samples showed an excellent combination of tensile strength and tensile ductility compared to the cast and the LDED-HDH-produced samples. Such an enhancement in the mechanical properties was attributed to the refinement of the α grain size and the dense microstructure. The present work provides an approach for LDED-produced CP-Ti to address the economic and mechanical properties of the materials, while also providing insights into the expanding application of HDH titanium powder.

Deciphering the roles of miR-16-5p in malignant solid tumors.

MiR-16-5p, a member of the miR-16 family, has been reported to be abnormal expression in tumor tissues and blood of tumor patients, and also downregulated in most cancer cell lines. Aberrant expression of miR-16-5p promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and can also affect the treatment sensitivity, such as radiotherapy and chemotherapy. Generally, miR-16-5p plays an anti-tumor role and these diverse functions of miR-16-5p in tumors collectively indicate that miR-16-5p may become an attractive target for novel anticancer therapies and a powerful diagnostic and prognostic biomarker for early tumor detection and population risk screening. Herein we review the role and utilization of miR-16-5p in malignant tumor in detail.

Successful treatment of radiotherapy and apatinib in patient with mediastinal mixed non-seminomatous germ cell tumor: A case report.

RATIONALE: Mediastinal non-seminomatous germ cell tumors (MNSGCTs) are rare malignancies. Chemotherapy followed by surgical resection has been regarded as the standard management, but treatment options for chemotherapy-refractory patients or those with unresectable tumors are limited, resulting in a very poor prognosis. PATIENT CONCERNS: An 18-year-old female presented with symptoms of cough, chest tightness, and shortness of breath for 2 months, and the symptoms gradually worsened. DIAGNOSIS: Computed tomography (CT) revealed a large mediastinal mass invading the pericardium and great blood vessels. Serum human chorionic gonadotropin (HCG) and α-fetoprotein (AFP) levels were normal. Histopathological examination of biopsy specimens revealed mixed MNSGCT with embryonal carcinoma and immature teratoma components. INTERVENTIONS: The patient achieved complete remission (CR) and long-term survival after multimodal therapy comprising chemotherapy, positron emission tomography/CT (PET/CT)-guided volumetric-modulated arc therapy (VMAT), and anti-angiogenic targeted therapy. OUTCOMES: The patient was followed up for more than 4 years without recurrence, metastasis, or treatment-related adverse effects. LESSONS: The case presented here highlights the importance of multidisciplinary diagnosis and treatment, providing evidence that radiotherapy and anti-angiogenic therapy may play an important role in unresectable or residual tumors after failure of conventional treatments of MNSGCT. Percutaneous biopsy is necessary for diagnosis if the tumor is unresectable, and serum AFP and HCG levels are normal. Additionally, PET/CT is an effective method for evaluation of efficacy and radiotherapy guidance for patients with MNSGCTs.

Diagnostic value of diffusion-weighted imaging-derived apparent diffusion coefficient and its association with histological prognostic factors in breast cancer.

Diffusion-weighted imaging (DWI) has been proven to be effective in detecting breast malignancies and has been widely implemented for breast imaging. However, the exact association between certain DWI biomarkers and well-known prognostic factors remains to be fully elucidated. By studying the association between the apparent diffusion coefficient (ADC) and prognostic factors, the present study aimed to explore the diagnostic value and prognostic potential of the ADC in breast lesions. The study included 539 female subjects with histopathologically confirmed breast lesions who underwent DWI of the breast tissue. The diagnoses comprised 307 subjects with malignant breast tumors and 232 with benign breast tumors. The maximum ADC and mean ADC (ADCmean) values of the breast lesions were calculated. For malignant tumors, the association between ADC and major prognostic factors, including histological grade, nuclear grade and lymph node status, as well as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2) and proliferation marker protein Ki-67.(Ki-67) status, were evaluated. The ADCmean demonstrated the best diagnostic performance in distinguishing between malignant and benign lesions. With the optimum cut-off value at 1.30×10-3 mm2/sec, ADCmean had a sensitivity and specificity of 84.1 and 90.2%, respectively. In those patients with malignant breast lesions, a decreased ADC was associated with breast lesions with high nuclear and histological grades, and lymph node-positive, ER-negative, PR-negative and HER-2-negative status, and Ki-67 ≥14%. In conclusion, the ADC is a useful imaging biomarker for differentiating between benign and malignant breast tumors. The marked association between the ADC and prognostic factors also demonstrated its value in evaluating the malignancy of breast lesions.

Profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets using gastrointestinal simulation technology.

The aim of the present study was to correlate in vitro properties of drug formulation to its in vivo performance, and to elucidate the deciding properties of oral absorption. Gastrointestinal simulation technology (GST) was used to simulate the in vivo plasma concentration-time curve and was implemented by GastroPlus™ software. Lansoprazole, a typical BCS class II drug, was chosen as a model drug. Firstly, physicochemical and pharmacokinetic parameters of lansoprazole were determined or collected from literature to construct the model. Validation of the developed model was performed by comparison of the predicted and the experimental plasma concentration data. We found that the predicted curve was in a good agreement with the experimental data. Then, parameter sensitivity analysis (PSA) was performed to find the key parameters of oral absorption. The absorption was particularly sensitive to dose, solubility and particle size for lansoprazole enteric-coated tablets. With a single dose of 30 mg and the solubility of 0.04 mg/ml, the absorption was complete. A good absorption could be achieved with lansoprazole particle radius down to about 25 µm. In summary, GST is a useful tool for profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets and guiding the formulation optimization.