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1.
Adv Sci (Weinh) ; 9(10): e2104510, 2022 04.
Article in English | MEDLINE | ID: mdl-35118834

ABSTRACT

Oxygen levels in vivo are autonomously regulated by a supply-demand balance, which can be altered in disease states. However, the oxygen levels of in vitro cell culture systems, particularly microscale cell culture, are typically dominated by either supply or demand. Further, the oxygen microenvironment in these systems is rarely monitored or reported. Here, a method to establish and dynamically monitor autonomously regulated oxygen microenvironments (AROM) using an oil overlay in an open microscale cell culture system is presented. Using this method, the oxygen microenvironment is dynamically regulated via the supply-demand balance of the system. Numerical simulation and experimental validation of oxygen transport within multi-liquid-phase, microscale culture systems involving a variety of cell types, including mammalian, fungal, and bacterial cells are presented. Finally, AROM is applied to establish a coculture between cells with disparate oxygen demands-primary intestinal epithelial cells (oxygen consuming) and Bacteroides uniformis (an anaerobic species prevalent in the human gut).


Subject(s)
Cell Culture Techniques , Oxygen , Animals , Coculture Techniques , Epithelial Cells/metabolism , Humans , Mammals/metabolism
2.
Integr Biol (Camb) ; 13(11): 259-268, 2021 12 30.
Article in English | MEDLINE | ID: mdl-34931665

ABSTRACT

Renal cell carcinoma (RCC) is the third most common genitourinary cancer in the USA. Despite recent advances in the treatment for advanced and metastatic clear cell RCC (ccRCC), the 5-year relative survival rate for the distant disease remains at 12%. Cabozantinib, a tyrosine kinase inhibitor (TKI), which is one of the first-line therapies approved to treat advanced ccRCC as a single agent, is now being investigated as a combination therapy with newer immunotherapeutic agents. However, not much is known about how cabozantinib modulates the immune system. Here, we present a high throughput tri-culture model that incorporates cancer cells, endothelial cells, and patient-derived immune cells to study the effect of immune cells from patients with ccRCC on angiogenesis and cabozantinib resistance. We show that circulating immune cells from patients with ccRCC induce cabozantinib resistance via increased secretion of a set of pro-angiogenic factors. Using multivariate partial least square regression modeling, we identified CD4+ T cell subsets that are correlated with cabozantinib resistance and report the changes in the frequency of these populations in ccRCC patients who are undergoing cabozantinib therapy. These findings provide a potential set of biomarkers that should be further investigated in the current TKI-immunotherapy combination clinical trials to improve personalized treatments for patients with ccRCC.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Anilides/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/secondary , Endothelial Cells , Female , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Male , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyridines
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