Claire Rome

We demonstrate here, for the first time, formation of injectable dynamic covalent hydrogels at physiological pH using benzoxaborin-saccharide complexation as a reversible cross-linking method. The gels were prepared by simply mixing hyaluronic acid modified with an original boronic acid derivative, 3,4-dihydro-2H-benzo[e][1,2]oxaborinin-2-ol (1,2-ABORIN), and HA functionalized with 1-amino-1-deoxy-d-fructose. Dynamic rheological experiments confirmed the gel-like behavior (storage modulus (G′) > loss modulus (G″) in the frequency window explored) for the designed HA-1,2-ABORIN/HA-fructose network. Furthermore, this hydrogel exhibited excellent self-healing and injectability behaviors in aqueous conditions and was found to be responsive to pH. Additionally, fibroblast cells encapsulated in the HA network showed high viability (>80% after 7 days of cell culture), as monitored by Live/Dead staining. Taken together, this new class of boronate ester cross-linked hydrogel provides promising future for diverse biomedical applications.

The endothelial CCM complex regulates blood vessel stability and permeability. Loss-of-function mutations in CCM genes are responsible for human cerebral cavernous malformations (CCMs), which are characterized by clusters of hemorrhagic dilated capillaries composed of endothelium lacking mural cells and altered sub-endothelial extracellular matrix (ECM). Association of the CCM1/2 complex with ICAP-1, an inhibitor of β1 integrin, prompted us to investigate whether the CCM complex interferes with integrin signaling. We demonstrate that CCM1/2 loss resulted in ICAP-1 destabilization, which increased β1 integrin activation and led to increased RhoA-dependent contractility. The resulting abnormal distribution of forces led to aberrant ECM remodeling around lesions of CCM1- and CCM2-deficient mice. ICAP-1-deficient vessels displayed similar defects. We demonstrate that a positive feedback loop between the aberrant ECM and internal cellular tension led to decreased endothelial barrier function. Our data support that up-regulation of β1 integrin activation participates in the progression of CCM lesions by destabilizing intercellular junctions through increased cell contractility and aberrant ECM remodeling.

Immuno-chemotherapy elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumours in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that autonomously drives aggressive tumour growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma.