Development of a multivariable clinical prediction model for liposomal doxorubicin-induced cardiotoxicity in adult breast cancer patients: a retrospective multicenter study.

Background: The clinical use of anthracyclines is limited by the risk of cardiotoxicity. So, we aim to develop a clinical prediction model for liposomal doxorubicin-induced cardiotoxicity in adult breast cancer patients. Methods: We designed a multicenter retrospective cohort study. A total of 257 hospitalized breast cancer patients treated with doxorubicin liposomes were finally enrolled in the study, including 58 patients from Beijing Friendship Hospital and 199 from Beijing Cancer Hospital. In all, 32 cases developed cardiotoxicity, including 4 at the Beijing Friendship Hospital and 28 at the Beijing Cancer Hospital. The study involved breast cancer patients with no pre-existing heart disease, whose clinical data were collected from their medical records. All patients underwent electrocardiogram (ECG) and/or left ventricular ejection fraction (LVEF) measurements prior to treatment with doxorubicin liposomes. Patients were clinically assessed after each cycle of treatment, and ECG and/or LVEF measurements were performed at least once after treatment. Liposomal doxorubicin-induced cardiotoxicity was defined when one of the following three conditions was met: (I) a reduction in LVEF of at least 5% from the baseline and the absolute value was less than 55%, accompanied by congestive heart failure (CHF) symptoms or signs; (II) a reduction in LVEF of at least 10% to an absolute value of less than 55%, without CHF symptoms or signs; (III) the definite diagnosis of CHF. Variables associated with cardiotoxicity were identified by univariate and multivariate logistic regression, and the consistency and differentiation of the final model were evaluated. Results: In our final model, age [odds ratio (OR): 5.626, 95% confidence interval (CI): 2.321 to 13.639], cancer metastasis (OR: 3.873, 95% CI: 1.220 to 12.299), paclitaxel (OR: 3.601, 95% CI: 1.010 to 12.843), and hypertension (OR: 2.435, 95% CI: 1.046 to 5.671) were significantly associated with cardiotoxicity. The final model was tested for Hosmer-Lemeshow goodness-of-fit, the χ2 was 2.696 and the P value was 0.747, and the resultant predictive model had an area under the receiver operating characteristic (ROC; AUC) curve of 0.781. Conclusions: This study established a risk prediction model for liposomal doxorubicin-induced cardiotoxicity in breast cancer patients and performed a stratified risk scores.

Endorsement of the TRIPOD statement and the reporting of studies developing contrast-induced nephropathy prediction models for the coronary angiography/percutaneous coronary intervention population: a cross-sectional study.

OBJECTIVE: Clear and specific reporting of a research paper is essential for its validity and applicability. Some studies have revealed that the reporting of studies based on the clinical prediction models was generally insufficient based on the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) checklist. However, the reporting of studies on contrast-induced nephropathy (CIN) prediction models in the coronary angiography (CAG)/percutaneous coronary intervention (PCI) population has not been thoroughly assessed. Thus, the aim is to evaluate the reporting of the studies on CIN prediction models for the CAG/PCI population using the TRIPOD checklist. DESIGN: A cross-sectional study. METHODS: PubMed and Embase were systematically searched from inception to 30 September 2021. Only the studies on the development of CIN prediction models for the CAG/PCI population were included. The data were extracted into a standardised spreadsheet designed in accordance with the 'TRIPOD Adherence Assessment Form'. The overall completeness of reporting of each model and each TRIPOD item were evaluated, and the reporting before and after the publication of the TRIPOD statement was compared. The linear relationship between model performance and TRIPOD adherence was also assessed. RESULTS: We identified 36 studies that developed CIN prediction models for the CAG/PCI population. Median TRIPOD checklist adherence was 60% (34%-77%), and no significant improvement was found since the publication of the TRIPOD checklist (p=0.770). There was a significant difference in adherence to individual TRIPOD items, ranging from 0% to 100%. Moreover, most studies did not specify critical information within the Methods section. Only 5 studies (14%) explained how they arrived at the study size, and only 13 studies (36%) described how to handle missing data. In the Statistical analysis section, how the continuous predictors were modelled, the cut-points of categorical or categorised predictors, and the methods to choose the cut-points were only reported in 7 (19%), 6 (17%) and 1 (3%) of the studies, respectively. Nevertheless, no relationship was found between model performance and TRIPOD adherence in both the development and validation datasets (r=-0.260 and r=-0.069, respectively). CONCLUSIONS: The reporting of CIN prediction models for the CAG/PCI population still needs to be improved based on the TRIPOD checklist. In order to promote further external validation and clinical application of the prediction models, more information should be provided in future studies.

Orbital Shear Stress Regulates Differentiation and Barrier Function of Primary Renal Tubular Epithelial Cells.

Primary cells cultured in vitro gradually lose features characteristic of the in vivo phenotype. Culture techniques that help maintain cell-specific phenotype are advantageous for development of tissue engineered and bioartificial organs. Here we evaluated the phenotype of primary human renal tubular epithelial cells subjected to fluid shear stress by culturing the cells on an orbital shaker. Transepithelial electrical resistance (TEER), cell density, and gene and protein expression of proximal tubule-specific functional markers were measured in cells subjected to orbital shear stress. Cells cultured on an orbital shaker had increased TEER, higher cell density, and enhanced tubular epithelial specific gene and protein expression. This is likely due at least in part to the mechanical stress applied to the apical surface of the cells although other factors including increased nutrient and oxygen delivery and improved mixing could also play a role. These results suggest that orbital shaker culture may be a simple approach to augmenting the differentiated phenotype of cultured renal epithelial cells.

A modular microfluidic bioreactor with improved throughput for evaluation of polarized renal epithelial cells.

Most current microfluidic cell culture systems are integrated single use devices. This can limit throughput and experimental design options, particularly for epithelial cells, which require significant time in culture to obtain a fully differentiated phenotype. In addition, epithelial cells require a porous growth substrate in order to fully polarize their distinct apical and basolateral membranes. We have developed a modular microfluidic system using commercially available porous culture inserts to evaluate polarized epithelial cells under physiologically relevant fluid flow conditions. The cell-support for the bioreactor is a commercially available microporous membrane that is ready to use in a 6-well format, allowing for cells to be seeded in advance in replicates and evaluated for polarization and barrier function prior to experimentation. The reusable modular system can be easily assembled and disassembled using these mature cells, thus improving experimental throughput and minimizing fabrication requirements. The bioreactor consists of an apical microfluidic flow path and a static basolateral chamber that is easily accessible from the outside of the device. The basolateral chamber acts as a reservoir for transport across the cell layer. We evaluated the effect of initiation of apical shear flow on short-term intracellular signaling and mRNA expression using primary human renal epithelial cells (HRECs). Ten min and 5 h after initiation of apical fluid flow over a stable monolayer of HRECs, cells demonstrated increased phosphorylation of extracellular signal-related kinase and increased expression of interleukin 6 (IL-6) mRNA, respectively. This bioreactor design provides a modular platform with rapid experimental turn-around time to study various epithelial cell functions under physiologically meaningful flow conditions.

Electrospun acetalated dextran scaffolds for temporal release of therapeutics.

Electrospun acetalated dextran (Ac-DEX) scaffolds were fabricated to encapsulate resiquimod, an immunomodulatory toll-like-receptor (TLR) agonist. Ac-DEX has been used to fabricate scaffolds for sustained and temporal delivery of therapeutics because it has tunable degradation rates that are dependent on its synthesis reaction time or the molecular weight of dextran. Additionally, as opposed to commonly electrospun polyesters that shift the local pH upon degradation, the degradation products of Ac-DEX are pH-neutral: dextran, an alcohol, and the metabolic byproduct acetone. Formulations of Ac-DEX with two different degradation rates were used in this study. The effects of electrospinning conditions on the scaffold size and morphology were examined as well as fibroblast adhesion as imaged with fluorescence microcopy and scanning electron microscopy. Macrophage (MΦ) viability further indicates that the scaffolds are cytocompatible. Also, the controlled release profiles of resiquimod from loaded scaffolds and nitric oxide (NO) production by MΦ incubated with these scaffolds show the potential for Ac-DEX scaffolds to be used to temporally and efficiently deliver therapeutics. Overall, we present a novel scaffold that can have tunable and unique drug release rates for tissue engineering, drug delivery, immunomodulation, and wound healing applications.