Effects of Drugs Reabsorption Time Delays for a Pharmacokinetics Model in Humans

A three-compartmental delay model is formulated to describe the pharmacokinetics of drugs subjected to both intravenous and oral doses with reabsorptions by the central compartment. Model dynamics are analyzed rigorously, and two equilibrium points are obtained to be locally asymptotically stable under certain conditions. Time delays used as lags in reabsorption of drugs by central compartment from other two compartments caused rebounds or peaks and fluctuations in the time profiles for amounts of drug in all the compartments. Sensitivity analysis revealed that elimination rates decrease the amounts in all compartments. Furthermore, reabsorption rates cause superimposition at the initial phases of the drug amount profiles; subsequently, the quantities decrease in compartment one and increase in compartments two and three, respectively.

A Preoperative Nomogram for the Prediction of High-Volume Central Lymph Node Metastasis in Papillary Thyroid Carcinoma

BackgroundHigh-volume lymph node metastasis (HVLNM, equal to or more than 5 lymph nodes) is one of the adverse features indicating high recurrence risk in papillary thyroid carcinoma (PTC) and is recommended as one of the indications of completion thyroidectomy for patients undergoing thyroid lobectomy at first. In this study, we aim to develop a preoperative nomogram for the prediction of HVLNMs in the central compartment in PTC (cT1-2N0M0), where preoperative imaging techniques perform poor.MethodsFrom October 2016 to April 2021, 423 patients were included, who were diagnosed as PTC (cT1-2N0M0) and underwent total thyroidectomy and prophylactic central compartment neck dissection in our center. Demographic and clinicopathological features were recorded and analyzed using univariate and multivariate logistic regression analysis. A nomogram was developed based on multivariate logistic regression analysis.ResultsAmong the included patients, 13.4% (57 cases) were found to have HVLNMs in the central compartment. Univariate and multivariate logistic regression analysis showed that age (</=35 years vs. >35 years), BRAF with V600E mutated, nodule diameter, and calcification independently predicted HVLNMs in the central compartment. The nomogram showed good discrimination with an AUC of 0.821 (95% CI, 0.768–0.875).ConclusionThe preoperative nomogram can be used to quantify the probability of HVLNMs in the central compartment and may reduce the reoperation rate after thyroid lobectomy.

Prevalence of Central Compartment Lymph Node Metastases in Papillary Thyroid Micro-Carcinoma: A Retrospective Evaluation of Predictive Preoperative Features

Papillary thyroid micro-carcinomas are considered relatively indolent carcinomas, often occult and incidental, with good prognosis and favorable outcomes. Despite these findings, central lymph node metastases are common, and are related to a poor prognosis for the patient. We performed a retrospective analysis on patients treated with surgery for stage pT1a papillary thyroid micro-carcinomas. One hundred ninety-five patients were included in the analyses. The presence of central lymph node metastases was identified and studied. A multivariate analysis employing binary logistic regression was used to calculate adjusted odds ratios with 95% confidence intervals of possible central lymph node metastases risk factors. In the performed multivariate analysis, male gender, younger age, and histopathological characteristics, such as a tumor sub-capsular localization, were significantly associated with central lymph node metastases in pT1a patients. Central compartment lymph node metastases are present in a non-negligible number of cases in patients with papillary thyroid micro-carcinoma undergoing surgical resection. Studying these factors could be an effective tool for predicting patients’ central lymph node metastases in papillary thyroid micro-carcinomas, defining a tailored surgical treatment in the future.

Prediction of central compartment nodal metastases in papillary thyroid cancer using TI-RADS score, blood flow, and multifocality

Background The relationship between the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) and the risk of lymph node metastases in papillary thyroid cancer (PTC) could improve the detection rate of lymph node metastases in thyroid cancer and provide a scientific basis for clinical diagnosis. Purpose To evaluate the risk of lymph node metastases of PTC associated with the score from ACR TI-RADS adjusted for other correlative factors. Material and Methods A total of 560 patients with pathologically confirmed PTC were included in the study and classified into a metastases group and a non-metastases group. Clinical and pathological manifestations of the patients were collected. Results The median TI-RADS score was 13 (p25–p75 = 11–14) among the patients with lymph node metastases, higher than those without metastases 9 (8–10) ( P < 0.001). Multiple logistic regression indicated that TI-RADS score (odds ratio [OR] = 2.204), male sex (OR = 2.376), multifocality (OR = 4.170), and rich blood flow (OR = 3.656) were risk factors for lymph node metastases in patients with thyroid carcinoma. Some related factors such as TI-RADS score, age(<45years old), male, multifocality and rich blood flow were related to lymph node metastases in the central area of the neck which could provide therapeutic strategy for further treatment. Conclusion it is not just the TI-RADS score but also multifocality, blood flow, and sex that influence the prediction of the risk of PTC central lymph node metastases.

Population pharmacokinetic and exposure–response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma

Purpose Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure–response relationships for efficacy and safety in patients with RRMM. Methods A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily Cavg) for multi-variable time-to-event exposure–response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM. Results Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis–Menten elimination from the central compartment (Vmax) and non-renewable target-mediated elimination from the peripheral compartment (Kint). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and Kint, respectively, versus Ld; steady-state exposures were similar. Vmax increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily Cavg were 0.9983 (0.9969–0.9997) and 0.9981 (0.9964–0.9998) for PFS and grade 3 + AEs, respectively. Conclusions The PPK model adequately described the data and was appropriate for determining exposures for exposure–response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily Cavg prolonged PFS without increasing grade 3 + AEs.

Both Clathrin-Mediated and Membrane Microdomain-Associated Endocytosis Contribute to the Cellular Adaptation to Hyperosmotic Stress in Arabidopsis

As sessile organisms, plants must directly deal with an often complex and adverse environment in which hyperosmotic stress is one of the most serious abiotic factors, challenging cellular physiology and integrity. The plasma membrane (PM) is the hydrophobic barrier between the inside and outside environments of cells and is considered a central compartment in cellular adaptation to diverse stress conditions through dynamic PM remodeling. Endocytosis is a powerful method for rapid remodeling of the PM. In animal cells, different endocytic pathways are activated in response to osmotic stress, while only a few reports are related to the endocytosis response pathway and involve a mechanism in plant cells upon hyperosmotic stress. In this study, using different endocytosis inhibitors, the microdomain-specific dye di-4-ANEPPDHQ, variable-angle total internal reflection fluorescence microscopy (VA-TIRFM), and confocal microscopy, we discovered that internalized Clathrin Light Chain-Green Fluorescent Protein (CLC-GFP) increased under hyperosmotic conditions, accompanied by decreased fluorescence intensity of CLC-GFP at the PM. CLC-GFP tended to have higher diffusion coefficients and a fraction of CLC-GFP molecules underwent slower diffusion upon hyperosmotic stress. Meanwhile, an increased motion range of CLC-GFP was found under hyperosmotic treatment compared with the control. In addition, the order of the PM decreased, but the order of the endosome increased when cells were in hyperosmotic conditions. Hence, our results demonstrated that clathrin-mediated endocytosis and membrane microdomain-associated endocytosis both participate in the adaptation to hyperosmotic stress. These findings will help to further understand the role and the regulatory mechanism involved in plant endocytosis in helping plants adapt to osmotic stress.