Bone marrow-derived CD13+ cells sustain tumor progression: A potential non-malignant target for anticancer therapy

Non-malignant cells found within neoplastic lesions express alanyl (membrane) aminopeptidase (ANPEP, best known as CD13), and CD13-null mice exhibit limited tumor growth and angiogenesis. We have recently demonstrated that a subset of bone marrow-derived CD11b+CD13+ myeloid cells accumulate within neoplastic lesions in several murine models of transplantable cancer to promote angiogenesis. If these findings were confirmed in clinical settings, CD11b+CD13+ myeloid cells could become a non-malignant target for the development of novel anticancer regimens

Spontaneous Formation of L-Isoaspartate and Gain of Function in Fibronectin

Isoaspartate formation in extracellular matrix proteins, by aspartate isomerization or asparagine deamidation, is generally viewed as a degradation reaction occurring in vivo during tissue aging. For instance, non-enzymatic isoaspartate formation at RGD-integrin binding sites causes loss of cell adhesion sites, which in turn can be enzymatically "repaired" to RGD by protein-L-isoAsp-O- methyltransferase. We show here that isoaspartate formation is also a mechanism for extracellular matrix activation. In particular, we show that deamidation of Asn(263) at the Asn-Gly-Arg (NGR) site in fibronectin N-terminal region generates an alpha(v)beta(3)-integrin binding site containing the L-isoDGR sequence, which is enzymatically "deactivated" to DGR by protein-L-isoAsp-O-methyltransferase. Furthermore, rapid NGR-to-isoDGR sequence transition in fibronectin fragments generates alpha(v)beta(3) antagonists ( named "isonectins") that competitively bind RGD binding sites and inhibit endothelial cell adhesion, proliferation, and tumor growth. Time-dependent generation of isoDGR may represent a sort of molecular clock for activating latent integrin binding sites in proteins

Lung anatomy, energy load, and ventilator-induced lung injury

High tidal volume can cause ventilator-induced lung injury (VILI), but positive end-expiratory pressure (PEEP) is thought to be protective. We aimed to find the volumetric VILI threshold and see whether PEEP is protective per se or indirectly

SMARCB1 regulates the hypoxic stress response in sickle cell trait during the pathogenesis of renal medullary carcinoma.

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Engineered bone for probing organotypic growth and therapy response of prostate cancer tumoroids in vitro

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Examination of the foreign body response to biomaterials by nonlinear intravital microscopy

Implanted biomaterials often fail because they elicit a foreign body response (FBR) and concomitant fibrotic encapsulation. To design clinically relevant interference approaches, it is crucial to first examine the FBR mechanisms. Here, we report the development and validation of infrared-excited nonlinear microscopy to resolve the three-dimensional (3D) organization and fate of 3D-electrospun scaffolds implanted deep into the skin of mice and the following step-wise FBR process. We observed that immigrating myeloid cells (predominantly macrophages of the M1 type) engaged and became immobilized along the scaffold/tissue interface, before forming multinucleated giant cells. Both macrophages and giant cells locally produced vascular endothelial growth factor (VEGF), which initiated and maintained an immature neovessel network, followed by the formation of a dense collagen capsule two- to four-weeks post-implantation. Elimination of the macrophage/giant-cell compartment, by clodronate and/or neutralization of VEGF by VEGF Trap, significantly diminished giant-cell accumulation, neovascularization and fibrosis. Our findings identify macrophages and giant cells as incendiaries of the fibrotic encapsulation of engrafted biomaterials via VEGF release and neovascularization, and therefore as targets for therapy

Examination of the foreign body response to biomaterials by nonlinear intravital microscopy

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Radium 223-mediated zonal cytotoxicity of prostate cancer in bone

Background Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (∼100 µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Rad-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome. Methods We tested Rad-223 overall response by PC3 and C4–2B human PCa cell lines in mouse bones (n = 5–18 tibiae per group). Rad-223 efficacy at subcellular resolution was determined by intravital microscopy analysis of dual-color fluorescent PC3 cells (n = 3–4 mice per group) in tissue-engineered bone constructs. In vivo data were fed into an in silico model to predict Rad-223 effectiveness in lesions of different sizes (1–27, 306 initial cells; n = 10–100 simulations) and the predictions validated in vivo by treating PCa tumors of varying sizes in bones (n = 10–14 tibiae per group). Statistical tests were performed by two-sided Student t test or by one-way ANOVA followed by Tukey’s post-hoc test. Results Rad-223 (385 kBq/kg) delayed the growth (means [SD]; comparison with control-treated mice) of PC3 (6.7 × 105 [4.2 × 105] vs 2.8 × 106 [2.2 × 106], P = .01) and C4–2B tumors in bone (7.7 × 105 [4.0 × 105] vs 3.5 × 106 [1.3 × 106], P 300 µm distance; P = .01). In silico simulations predicted greater efficacy of Rad-223 on single-cell lesions (eradication rate: 88.0%) and minimal effects on larger tumors (no eradication, 16.2% growth reduction in tumors of 27 306 cells), as further confirmed in vivo for PC3 and C4–2B tumors. Conclusions Micro-tumors showed severe growth delay or eradication in response to Rad-223, whereas macro-tumors persisted and expanded. The relative inefficacy in controlling large tumors points to application of Rad-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core