Nanoparticle elasticity regulates the formation of cell membrane-coated nanoparticles and their nano-bio interactions.

Cell membrane-coated nanoparticles are emerging as a new type of promising nanomaterials for immune evasion and targeted delivery. An underlying premise is that the unique biological functions of natural cell membranes can be conferred on the inherent physiochemical properties of nanoparticles by coating them with a cell membrane. However, the extent to which the membrane protein properties are preserved on these nanoparticles and the consequent bio-nano interactions are largely unexplored. Here, we synthesized two mesenchymal stem cell (MSC) membrane-coated silica nanoparticles (MCSNs), which have similar sizes but distinctly different stiffness values (MPa and GPa). Unexpectedly, a much lower macrophage uptake, but much higher cancer cell uptake, was found with the soft MCSNs compared with the stiff MCSNs. Intriguingly, we discovered that the soft MCSNs enabled the forming of a more protein-rich membrane coating and that coating had a high content of the MSC chemokine CXCR4 and MSC surface marker CD90. This led to the soft MCSNs enhancing cancer cell uptake mediated by the CD90/integrin receptor-mediated pathway and CXCR4/SDF-1 pathways. These findings provide a major step forward in our fundamental understanding of how the combination of nanoparticle elasticity and membrane coating may be used to facilitate bio-nano interactions and pave the way forward in the development of more effective cancer nanomedicines.

Liver organoid as a 3D in vitro model for drug validation and toxicity assessment.

The past decade has seen many advancements in the development of three-dimensional (3D) in vitro models in pharmaceutical sciences and industry. Specifically, organoids present a self-organising, self-renewing and more physiologically relevant model than conventional two-dimensional (2D) cell cultures. Liver organoids have been developed from a variety of cell sources, including stem cells, cell lines and primary cells. They have potential for modelling patient-specific disease and establishing personalised therapeutic approaches. Additionally, liver organoids have been used to test drug efficacy and toxicity. Herein we summarise cell sources for generating liver organoids, the advantages and limitations of each cell type, as well as the application of the organoids in modelling liver diseases. We focus on the use of liver organoids as tools for drug validation and toxicity assessment.

Cancer Metastasis-on-a-Chip for Modeling Metastatic Cascade and Drug Screening.

Microfluidic chips are valuable tools for studying intricate cellular and cell-microenvironment interactions. Traditional in vitro cancer models lack accuracy in mimicking the complexities of in vivo tumor microenvironment. However, cancer-metastasis-on-a-chip (CMoC) models combine the advantages of 3D cultures and microfluidic technology, serving as powerful platforms for exploring cancer mechanisms and facilitating drug screening. These chips are able to compartmentalize the metastatic cascade, deepening the understanding of its underlying mechanisms. This article provides an overview of current CMoC models, focusing on distinctive models that simulate invasion, intravasation, circulation, extravasation, and colonization, and their applications in drug screening. Furthermore, challenges faced by CMoC and microfluidic technologies are discussed, while exploring promising future directions in cancer research. The ongoing development and integration of these models into cancer studies are expected to drive transformative advancements in the field.

Effect of metabolic syndrome components on the risk of malignancy in patients with gallbladder lesions.

Background: Gallbladder lesions have become more common nowadays. But there is limited evidence-based guidance on surveillance of these patients for malignancy. Predicting malignancy could help clinicians better manage this condition and improve the prognosis. We evaluated the independent and joint effects of metabolic syndrome components on the risk of malignancy among patients with gallbladder lesions. Methods: Using a multicenter database, consecutive patients with pathologically confirmed gallbladder lesions between 2012 and 2019 were identified. Univariate and multivariate logistic regression analyses were used to evaluate the effects of metabolic syndrome components (diabetes, hypertension, dyslipidemia and obesity) as additive or combined indicators for the risk of malignancy. Unadjusted and adjusted odds ratios were calculated. Results: Of the 625 patients, 567 patients were identified with benign gallbladder lesions and 58 patients with gallbladder cancer (GBC). GBC group had less obesity but more dyslipidemia. Among all metabolic syndrome components, only dyslipidemia was significantly associated with GBC (odds ratio 2.674, 95% confidence interval 1.173-6.094). Dyslipidemia was an independent risk factor for malignancy (adjusted odds ratio 2.164, 95% confidence interval 1.165-4.021), regardless of whether the other risk factors and metabolic syndrome components were combined. Patients with decreased high-density lipoprotein had 3.035-fold higher risk of malignancy (adjusted odds ratio 3.035, 95% confidence interval 1.645-5.600). Conclusions: Dyslipidemia is associated with a 2.674-fold increase in the risk of malignancy in patients with gallbladder lesions. Dyslipidemia is an independent risk factor for malignancy, regardless of the presence of the other risk factors and metabolic syndrome components.

Surgical outcomes of colonic stents as a bridge to surgery versus emergency surgery for malignant colorectal obstruction: A systematic review and meta-analysis of high quality prospective and randomised controlled trials.

Self-expanding metallic stent placement as a bridge to surgery has been reported as an alternative to emergency surgery for acute malignant colorectal obstruction. However, results from clinical trials and previous meta-analyses are conflicting. We carried out a meta-analysis to compare the surgical and oncological outcomes between emergency surgery and self-expanding metallic stents for malignant large bowel obstruction. Pubmed, Embase, CINAHL, Web of Science and Cochrane were searched for prospective and randomised controlled trials. The outcomes of focus included 3- and 5-year overall and disease-free survival, overall tumour recurrence, overall complication and 30-day mortality rate, length of hospital and ICU stay, overall blood loss, number of patients requiring transfusion, total number of lymph nodes harvested, stoma and primary anastomosis rate. Twenty-seven studies were included with a total of 3894 patients. There was no significant difference in terms of 3-year and 5-year disease-free and overall survival. Stenting resulted in less blood loss (mean difference -234.72, P < 0.00001) and higher primary anastomosis rate (RR 1.25, P < 0.00001). For curative cases, bridge to surgery groups had lower 30-day mortality rate (RR 0.65, P = 0.01), lower overall complication rate (RR 0.65, P < 0.0001), more lymph nodes harvested (mean difference 2.51, P = 0.005), shorter ICU stay (mean difference -2.27, P = 0.02) and hospital stay (mean difference -7.24, 95% P < 0.0001). Compared to emergency surgery, self-expanding metallic stent interventions improve short-term surgical outcomes, especially in the curative setting, but have similar long-term oncological and survival outcomes.

Concise Review: Quantitative Detection and Modeling the In Vivo Kinetics of Therapeutic Mesenchymal Stem/Stromal Cells.

Mesenchymal stem/stromal cells (MSCs) present a promising tool in cell-based therapy for treatment of various diseases. Currently, optimization of treatment protocols in clinical studies is complicated by the variations in cell dosing, diverse methods used to deliver MSCs, and the variety of methods used for tracking MSCs in vivo. Most studies use a dose escalation approach, and attempt to correlate efficacy with total cell dose. Optimization could be accelerated through specific understanding of MSC distribution in vivo, long-term viability, as well as their biological fate. While it is not possible to quantitatively detect MSCs in most targeted organs over long time periods after systemic administration in clinical trials, it is increasingly possible to apply pharmacokinetic modeling to predict their distribution and persistence. This Review outlines current understanding of the in vivo kinetics of exogenously administered MSCs, provides a critical analysis of the methods used for quantitative MSC detection in these studies, and discusses the application of pharmacokinetic modeling to these data. Finally, we provide insights on and perspectives for future development of effective therapeutic strategies using pharmacokinetic modeling to maximize MSC therapy and minimize potential side effects. Stem Cells Translational Medicine 2018;7:78-86.

Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. METHODS: A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA using droplet digital PCR (ddPCR) allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. RESULTS: Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1 level in the I/R injured liver than that in the control. Correspondingly, the ddPCR results illustrate a higher MSC concentration in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ddPCR results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. DISCUSSION: The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveal the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.