Self-assembling paclitaxel-mediated stimulation of tumor-associated macrophages for postoperative treatment of glioblastoma.

The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic "don't eat me" signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers an antitumor T cell response. As adjuvant therapy after surgery, this aCD47/PF supramolecular hydrogel effectively suppresses primary brain tumor recurrence and prolongs overall survivals with minimal off-target side effects.

Effect of Antilogous Platelet-Rich Plasma on the Revascularization of Rabbit Prefabricated Flap.

BACKGROUND We aimed to investigate the effect of the local application of autologous platelet-rich plasma (PRP) on the angiogenesis of the rabbit prefabricated flap. MATERIAL AND METHODS Femoral arteriovenous bundle prefabricated flaps were constructed on both sides of the abdomen of 20 New Zealand white rabbits and were randomly divided into experimental sides and control sides, with 40 sides in total. Autologous PRP was injected around the prefabricated femoral vascular bundle on the experimental side, and the same amount of saline was injected on the control side. After 14 days, stage II surgery was performed to lift the island flap with the implanted femoral vascular bundle at the tip of the preconfigured flap marker line and suture it in situ. Twenty rabbits were divided equally into 4 groups: group A, 7 days after stage I surgery; group B, 14 days after stage I surgery; group C, 7 days after stage II surgery; and group D, 14 days after stage II surgery. The survival of neovascularization and the flaps in the 4 groups were compared by microscopic observation, histology, and immunohistochemistry. RESULTS The density of neovascularization was much higher on the experimental side than on the control side in the 4 groups, and statistically significantly increased with time (P<0.05). Seven days after stage II surgery, flap survival was better on the experimental side than on the control side. CONCLUSIONS PRP effectively promoted the revascularization of a prefabricated flap, and vascular density increased with time.

Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity.

Background: Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph+) leukemia. Objectives: We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). Methods: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. Results: Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Conclusions: Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.