HIF-transcribed p53 chaperones HIF-1α.

Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.

The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53.

p53 is an important tumor-suppressor protein that is mutated in more than 50% of cancers. Strategies for restoring normal p53 function are complicated by the oncogenic properties of mutant p53 and have not met with clinical success. To counteract mutant p53 activity, a variety of drugs with the potential to reconvert mutant p53 to an active wildtype form have been developed. However, these drugs are associated with various negative effects such as cellular toxicity, nonspecific binding to other proteins, and inability to induce a wildtype p53 response in cancer tissue. Here, we report on the effects of a curcumin analog, HO-3867, on p53 activity in cancer cells from different origins. We found that HO-3867 covalently binds to mutant p53, initiates a wildtype p53-like anticancer genetic response, is exclusively cytotoxic toward cancer cells, and exhibits high anticancer efficacy in tumor models. In conclusion, HO-3867 is a p53 mutant-reactivating drug with high clinical anticancer potential.

Magneto-mechanical actuation of magnetic responsive fibrous scaffolds boosts tenogenesis of human adipose stem cells.

Tendons are highly specialized load-bearing tissues with very limited healing capacity. Given their mechanosensitive nature, the combination of tendon mimetic scaffolds with remote mechanical actuation could synergistically contribute to the fabrication of improved tissue engineered alternatives for the functional regeneration of tendons. Here, hybrids of cellulose nanocrystals decorated with magnetic nanoparticles were produced to simultaneously reinforce and confer magnetic responsiveness to tendon mimetic hierarchical fibrous scaffolds, resulting in a system that enables remote stimulation of cells in vitro and, potentially, in vivo after construct transplantation. The biological performance and functionality of these scaffolds were evaluated using human adipose stem cells (hASCs) cultured under or in the absence of magnetic actuation. It was demonstrated that magneto-mechanical stimulation of hASCs promotes higher degrees of cell cytoskeleton anisotropic organization and steers the mechanosensitive YAP/TAZ signaling pathway. As feedback, stimulated cells show increased expression of tendon-related markers, as well as a pro-healing profile in genes related to their inflammatory secretome. Overall, these results support the use of the proposed magnetic responsive fibrous scaffolds as remote biointegrated actuators that can synergistically boost hASC tenogenesis through mechanosensing mechanisms and may modulate their pro-healing paracrine signaling, thus collectively contributing to the improvement of the regenerative potential of engineered tendon grafts.

Injectable and Magnetic Responsive Hydrogels with Bioinspired Ordered Structures.

Injectable hydrogels are particularly interesting for applications in minimally invasive tissue engineering and regenerative medicine strategies. However, the typical isotropic microstructure of these biomaterials limits their potential for the regeneration of ordered tissues. In the present work, we decorated rod-shaped cellulose nanocrystals with magnetic nanoparticles and coated these with polydopamine and polyethylene glycol polymer brushes to obtain chemical and colloidal stable nanoparticles. Then, these nanoparticles (0.1-0.5 wt %) were incorporated within gelatin hydrogels, creating injectable and magnetically responsive materials with potential for various biomedical applications. Nanoparticle alignment within the hydrogel matrix was achieved under exposure to uniform low magnetic fields (108 mT), resulting in biomaterials with directional microstructure and anisotropic mechanical properties. The biological performance of these nanocomposite hydrogels was studied using adipose tissue derived human stem cells. Cells encapsulated in the nanocomposite hydrogels showed high rates of viability demonstrating that the nanocomposite biomaterials are not cytotoxic. Remarkably, the microstructural patterns stemming from nanoparticle alignment induced the directional growth of seeded and, to a lower extent, encapsulated cells in the hydrogels, suggesting that this injectable system might find application in both cellular and acellular strategies targeting the regeneration of anisotropic tissues.

Evaluation of ERBB2 gene status and chromosome 17 anomalies in male breast cancer.

Male breast cancer (MBC) is an uncommon neoplasm that shares several biologic characteristics with its female counterpart. In the latter, abnormalities in the expression and/or copy number of the ERBB2 gene are present in 10% to 30% of invasive carcinoma and behave as poor prognostic markers. ERBB2 abnormalities have also been reported in MBC, yet at lower frequency, but their prognostic significance remains controversial. Furthermore, no study has addressed the impact of chromosome 17 abnormalities in MBC survival. In this study, the ERBB2-gene status (overexpression and amplification) and chromosome 17 numerical abnormalities were investigated in a series of 50 archival cases of MBC. The results, together with patient's age, histologic grade, pathologic stage, and estrogen receptor status were correlated with overall survival. ERBB2-protein overexpression was present in 7 cases (14%), ERBB2-gene amplification in 4 (8%), and aneuploidy of chromosome 17 in 12 cases (33.3%). The pathologic stage, ERBB2 overexpression and ERBB2 amplification were significantly correlated with overall survival (P=0.002, 0.016, and 0.009, respectively). No correlation was observed between chromosome 17 aneuploidy and overall survival. Therefore, despite their low incidence in MBC, expression abnormalities of ERBB2 behave, together with the pathologic stage of the tumor, as predictors of overall survival, akin to what has been reported for its female counterpart.