Focused ultrasound transiently opens the blood-brain barrier and provides the potential to modulate tumor immunostimulatory effect.

Glioma-associated microglia/macrophages (GAMs) comprise macrophages of peripheral origin and brain-intrinsic microglia, which support tumor progression. Chemokine C-C ligand 5 (CCL5) is an inflammatory mediator produced by immune cells and is involved in tumor growth and migration in several cancers, including glioma. However, the mechanisms detailing how CCL5 facilitates glioma invasion remain largely unresolved. Glioma migration and invasion were determined by wound healing, transwell assay, and 3D µ-slide chemotaxis assay. The expression levels of CCL5, CD68, matrix metalloproteinase 2 (MMP2), phosphorylated Ca²⁺/calmodulin-dependent protein kinase II (p-CaMKII), p-Akt, and phosphorylated proline-rich tyrosine kinase 2 were determined by cytokine array, quantitative PCR, western blot, or immunohistochemistry. Zymography and intracellular calcium assays were used to analyze MMP2 activity and intracellular calcium levels, respectively. CCL5 modulated the migratory and invasive activities of human glioma cells in association with MMP2 expression. In response to CCL5, glioma cells underwent a synchronized increase in intracellular calcium levels and p-CaMKII and p-Akt expression levels. CCL5-directed glioma invasion and increases in MMP2 were suppressed after inhibition of p-CaMKII. Glioma cells tended to migrate toward GAM-conditioned media activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) in which CCL5 was abundant. This homing effect was associated with MMP2 upregulation, and could be ameliorated either by controlling intracellular and extracellular calcium levels or by CCL5 antagonism. Clinical results also revealed the associations between CCL5 and GAM activation. Our results suggest that modulation of glioma CaMKII may restrict the effect of CCL5 on glioma invasion and could be a potential therapeutic target for alleviating glioma growth.

Interleukin-12 (IL-12) has long been considered to be effective in triggering an anticancer immune response, however, the dosage has been limited by potential systemic immunotoxicity. Since focused ultrasound (FUS) has been confirmed to temporally and locally open the blood–brain barrier (BBB), the purpose of this study was to elucidate the possibility of combining FUS-induced BBB opening with IL-12 delivery to enhance the anticancer immunological response for glioma treatment. FUS energy combined with microbubble administration was delivered transcranially to open BBB, and C-6 glioma rats were used in this study. The efficacy in inducing BBB opening and the corresponding immunological response were primarily evaluated in normal animals. The anticancer immune-triggering chemokine, IL-12, was intraperitoneally administered during the treatment phase to evaluate the effect of immunological response on tumor progression. Glioma animals were sub-grouped to evaluate the effect of the immune response in suppressing glioma when IL-12 was combined with FUS-induced BBB opening. We performed flow cytometry to verify consequent immune cell population changes of peripheral/tissue lymphocytes as well as macrophages from the animals. Brain sections of sacrificed animals were also used for histological and immunohistochemical analysis. IL-12 level among experimental groups were measured via ELISA analysis. We also analyzed survival and followed tumor progression in vivo via T2-weighted magnetic resonance imaging. FUS-induced BBB opening had no obvious effect on the T lymphocytes population in normal animals, either in the brain or systemically. Yet, it triggered mild changes in the tumor-infiltrating lymphocyte (TIL) population, particularly in numbers of CD3+CD8+ cytotoxic T lymphocytes (CTLs) in the tumor region. IL-12 administration triggered a profound increase in all TIL populations, including CD3+CD4+ T helper cells (Th), CTL, and CD4+CD25+ regulatory T cells (Treg), but combined FUS-BBB opening with IL-12 administration produced the most significant IL-12 increase, CTL increase and CTL/Treg ratio increase, thus contributing to the most significant suppression of tumor progression and increased animal survival. This study provides evidence that FUS-BBB opening can enhance immune-modulating agent delivery to the brain, which improve the anticancer immune response in brain tumor treatment.

Microfluidics is a rapidly growing discipline that involves studying and manipulating fluids at reduced length scale and volume, typically on the scale of micro- or nanoliters. Under the reduced length scale and larger surface-to-volume ratio, advantages of low reagent consumption, faster reaction kinetics, and more compact systems are evident in microfluidics. However, miniaturization of microfluidic chips and systems introduces challenges of stricter tolerances in designing and controlling them for interdisciplinary applications. Recent advances in artificial intelligence (AI) have brought innovation to microfluidics from design, simulation, automation, and optimization to bioanalysis and data analytics. In microfluidics, the Navier–Stokes equations, which are partial differential equations describing viscous fluid motion that in complete form are known to not have a general analytical solution, can be simplified and have fair performance through numerical approximation due to low inertia and laminar flow. Approximation using neural networks trained by rules of physical knowledge introduces a new possibility to predict the physicochemical nature. The combination of microfluidics and automation can produce large amounts of data, where features and patterns that are difficult to discern by a human can be extracted by machine learning. Therefore, integration with AI introduces the potential to revolutionize the microfluidic workflow by enabling the precision control and automation of data analysis. Deployment of smart microfluidics may be tremendously beneficial in various applications in the future, including high-throughput drug discovery, rapid point-of-care-testing (POCT), and personalized medicine. In this review, we summarize key microfluidic advances integrated with AI and discuss the outlook and possibilities of combining AI and microfluidics.

Atypical and malignant meningiomas are rare. Our aim was to examine the treatment outcomes following surgical resection, and analyze associations between clinical characteristics and overall survival (OS) or relapse free survival (RFS). 102 patients with atypical or malignant meningiomas underwent microsurgical resection between June 2001 and November 2009 were analyzed retrospectively. We compared demographics, clinical characteristics, treatment, and complications. The five-year and ten-year overall survival rates were 93.5% and 83.4%, respectively. Three factors significantly reduced OS: Malignant meningiomas (p < 0.001), which also decreased RFS (p < 0.001); female patients (p = 0.049), and patients with Karnofsky Performance Status (KPS) < 70 at diagnosis (p = 0.009). Fifty two patients (51%) experienced tumor relapse. Total resection of tumors significantly impacted RFS (p = 0.013). Tumors located at parasagittal and posterior fossa area lead to higher relapse rate (p = 0.004). Subtotal resection without adjuvant radiotherapy lead to the worst local control of tumor (p = 0.030). An MIB-1 index <8% improved OS and RFS (p = 0.003). Total resection of atypical and malignant meningiomas provided better outcome and local control. Adjuvant radiation therapy is indicated for patients with malignant meningiomas, with incompletely excised tumors; or with tumors in the parasagittal or posterior fossa area. The MIB-1 index of the tumor is an independent prognostic factor of clinical outcome.