Vascular injury of immature epiphyses impair stem cell engraftment in cartilage defects.

The purpose of our study was to investigate if vascular injury in immature epiphyses affects cartilage repair outcomes of matrix-associated stem cell implants (MASI). Porcine bone marrow mesenchymal stromal stem cells (BMSCs) suspended in a fibrin glue scaffold were implanted into 24 full-thickness cartilage defects (5 mm ø) of the bilateral distal femur of six Göttingen minipigs (n = 12 defects in 6 knee joints of 3 immature pigs; age 3.5-4 months; n = 12 defects in 6 knee joints of 3 mature control pigs; age, 21-28 months). All pigs underwent magnetic resonance imaging (MRI) at 2, 4, 12 (n = 24 defects), and 24 weeks (n = 12 defects). After the last imaging study, pigs were sacrificed, joints explanted and evaluated with VEGF, H&E, van Gieson, Mallory, and Safranin O stains. Results of mature and immature cartilage groups were compared using the Wilcoxon signed-rank test. Quantitative scores for subchondral edema at 2 weeks were correlated with quantitative scores for cartilage repair (MOCART score and ICRS score) at 12 weeks as well as Pineda scores at end of the study, using linear regression analysis. On serial MRIs, mature joints demonstrated progressive healing of cartilage defects while immature joints demonstrated incomplete healing and damage of the subchondral bone. The MOCART score at 12 weeks was significantly higher for mature joints (79.583 ± 7.216) compared to immature joints (30.416 ± 10.543, p = 0.002). Immature cartilage demonstrated abundant microvessels while mature cartilage did not contain microvessels. Accordingly, cartilage defects in immature joints showed a significantly higher number of disrupted microvessels, subchondral edema, and angiogenesis compared to mature cartilage. Quantitative scores for subchondral edema at 2 weeks were negatively correlated with MOCART scores (r = - 0.861) and ICRS scores (r = - 0.901) at 12 weeks and positively correlated with Pineda scores at the end of the study (r = 0.782). Injury of epiphyseal blood vessels in immature joints leads to subchondral bone defects and limits cartilage repair after MASI.

Anti-invasive efficacy and survival benefit of the YAP-TEAD inhibitor verteporfin in preclinical glioblastoma models.

BACKGROUND: Glioblastoma (GBM) remains a largely incurable disease as current therapy fails to target the invasive nature of glioma growth in disease progression and recurrence. Here, we use the FDA-approved drug and small molecule Hippo inhibitor Verteporfin (VP) to target YAP-TEAD activity, known to mediate convergent aspects of tumor invasion/metastasis, and assess the drug's efficacy and survival benefit in GBM models. METHODS: Up to 8 low-passage patient-derived GBM cell lines with distinct genomic drivers, including 3 primary/recurrent pairs, were treated with VP or vehicle (VEH) to assess in vitro effects on proliferation, migration, invasion, YAP-TEAD activity, and transcriptomics. Patient-derived orthotopic xenograft (PDX) models were used to assess VP's brain penetrance and effects on tumor burden and survival. RESULTS: VP treatment disturbed YAP/TAZ-TEAD activity; disrupted transcriptome signatures related to invasion, epithelial-to-mesenchymal, and proneural-to-mesenchymal transition, phenocopying TEAD1-knockout effects; and impaired tumor migration/invasion dynamics across primary and recurrent GBM lines. In an aggressive orthotopic PDX GBM model, short-term VP treatment consistently diminished core and infiltrative tumor burden, which was associated with decreased tumor expression of Ki67, nuclear YAP, TEAD1, and TEAD-associated targets EGFR, CDH2, and ITGB1. Finally, long-term VP treatment appeared nontoxic and conferred survival benefit compared to VEH in 2 PDX models: as monotherapy in primary (de novo) GBM and in combination with Temozolomide chemoradiation in recurrent GBM, where VP treatment associated with increased MGMT methylation. CONCLUSIONS: We demonstrate combined anti-invasive and anti-proliferative efficacy for VP with survival benefit in preclinical GBM models, indicating potential therapeutic value of this already FDA-approved drug if repurposed for GBM patients.

Hyperthermia treatment advances for brain tumors.

Hyperthermia therapy (HT) of cancer is a well-known treatment approach. With the advent of new technologies, HT approaches are now important for the treatment of brain tumors. We review current clinical applications of HT in neuro-oncology and ongoing preclinical research aiming to advance HT approaches to clinical practice. Laser interstitial thermal therapy (LITT) is currently the most widely utilized thermal ablation approach in clinical practice mainly for the treatment of recurrent or deep-seated tumors in the brain. Magnetic hyperthermia therapy (MHT), which relies on the use of magnetic nanoparticles (MNPs) and alternating magnetic fields (AMFs), is a new quite promising HT treatment approach for brain tumors. Initial MHT clinical studies in combination with fractionated radiation therapy (RT) in patients have been completed in Europe with encouraging results. Another combination treatment with HT that warrants further investigation is immunotherapy. HT approaches for brain tumors will continue to a play an important role in neuro-oncology.

Near-infrared triggered generation of reactive oxygen species from upconverting nanoparticles decorated with an organoiridium complex.

Recently, research efforts have been focused on developing near-infrared perturbable nanoparticles to sensitize photostimulable molecules for the production of reactive oxygen species. Research in this direction is looking to broaden the use of photodynamic therapy, an indispensable clinical tool for cancer therapeutics, which relies on the photoexcitation of a suitable photosensitizer, to convert light into reactive oxygen species that are toxic to cells. To date most commercially available photosensitizers are excited with high energy light (UV or visible) presenting disadvantages that limit the clinical use of this technique to cancers that are on or near the surface of the skin. Here, we develop a hybrid platform capable of near-infrared triggered generation of reactive oxygen species. This hybrid nanostructure is based on LiYF4:Tm3+,Yb3+ nanoparticles, which are capable of producing strong UV emissions, following excitation at 980 nm, through a multiphoton process known as upconversion. When appropriately surface functionalized with an organoiridium complex, excitation at 980 nm produces a strong UV emission, which is absorbed by the organoiridium molecules on the surface, in turn generating reactive oxygen species. Moreover, the effect of the organoiridium concentration on the surface of the upconverting nanoparticles as well as the nature of the sensitization process is discussed.

Sensitive Detection of ssDNA Using an LRET-Based Upconverting Nanohybrid Material.

Water-dispersible, optical hybrid nanoparticles are preferred materials for DNA biosensing due to their biocompatibility. Upconverting nanoparticles are highly desirable optical probes in sensors and bioimaging owing to their sharp emission intensity in the visible region. We herein report a highly sensitive ss-DNA detection based on an energy transfer system that uses a nanohybrid material synthesized by doping NaYF4:Tm(3+)/Yb(3+) upconverting nanoparticles (UCNPs) on silica coated polystyrene-co-acrylic acid (PSA) nanoparticles (PSA/SiO2) as the donor, and gold nanoparticles (AuNPs) decorated with Ir(III) complex as the acceptor. UCNPs tagged on PSA/SiO2 and the cyclometalated Ir(III)/AuNP conjugates were then linked through the ss-DNA sequence. Sequential addition of the target DNA to the probe molecular beacon complex resulted in the separation of the optical nanohybrid material and the quencher, leading to a measurable increase in the blue fluorescence emission intensity. Our results have shown a linear relationship between the fluorescence intensity and target DNA concentration down to the picomolar.