Incidence and Predictors of Neurologic Death in Patients with Brain Metastases.

OBJECTIVE: Neurologic death is the most serious consequence of intracranial disease among patients with brain metastases. Identifying patients with brain metastases at increased risk of neurologic death can improve care and guide further research. We sought to delineate factors predictive of neurologic death among patients with brain metastases. METHODS: We identified 1218 patients with newly diagnosed brain metastases managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2008-2015. Factors predictive of neurologic death were assessed via univariable and multivariable Fine and Gray competing risks regression. RESULTS: On multivariable analysis, neurologic death was associated with number of brain metastases (hazard ratio [HR] 1.01 per 1 metastasis increase, 95% confidence interval [CI] 1.01-1.02, P < 0.001) and 3 primary tumor sites (reference=non-small cell lung cancer): melanoma (HR 4.67, 95% CI 3.27-6.68, P < 0.001), small cell lung cancer (HR 2.33, 95% CI 1.47-3.68, P < 0.001), and gastrointestinal cancer (HR 2.21, 95% CI 1.28-3.82, P = 0.005). Conversely, a reduction in neurologic death was found in patients with good Karnofsky performance status (90-100 vs. 30-80, HR 0.67, 95% CI 0.48-0.95, P = 0.03) and progressive extracranial metastases at diagnosis of intracranial disease (HR 0.50, 95% CI 0.38-0.67, P = 0.001). Among patients with breast primaries, HER2+ patients displayed increased neurologic death relative to the reference of HR+/HER2- (univariable analysis only: HR 2.41, 95% CI 1.00-5.84, P = 0.05). CONCLUSIONS: Patients with melanoma, small cell lung cancer, gastrointestinal cancer, and HER2+ breast cancer primaries, as well as greater intracranial versus extracranial disease burden, harbor significant risk of neurologic death. Future research investigating novel intracranial approaches should focus on these populations.

The molecular basis of interaction domains of full-length PrP with lipid membranes.

PrP-lipid membrane interactions are critical to PrP structural conversion and neurotoxicity, but its molecular mechanism remains unclear. A two-dimensional histogram of force-distance curves and a worm-like chain model revealed three binding regions at the PrP N-terminal, providing the molecular basis for understanding the interactions between full-length PrP and lipid membranes.

Supersnowflakes: Stepwise Self-Assembly and Dynamic Exchange of Rhombus Star-Shaped Supramolecules.

With the goal of increasing the complexity of metallo-supramolecules, two rhombus star-shaped supramolecular architectures, namely, supersnowflakes, were designed and assembled using multiple 2,2':6',2″-terpyridine (tpy) ligands in a stepwise manner. In the design of multicomponent self-assembly, ditopic and tritopic ligands were bridged through Ru(II) with strong coordination to form metal-organic ligands for the subsequent self-assembly with a hexatopic ligand and Zn(II). The combination of Ru(II)-organic ligands with high stability and Zn(II) ions with weak coordination played a key role in the self-assembly of giant heteroleptic supersnowflakes, which encompassed three types of tpy-based organic ligands and two metal ions. With such a stepwise strategy, the self-sorting of individual building blocks was prevented from forming the undesired assemblies, e.g., small macrocycles and coordination polymers. Furthermore, the intra- and intermolecular dynamic exchange study of two supersnowflakes by NMR and mass spectrometry revealed the remarkable stability of these giant supramolecular complexes.

Multifunctional Surface Manipulation Using Orthogonal Click Chemistry.

Polymer brushes are excellent substrates for the covalent immobilization of a wide variety of molecules due to their unique physicochemical properties and high functional group density. By using reactive microcapillary printing, poly(pentafluorophenyl acrylate) brushes with rapid kinetic rates toward aminolysis can be partially patterned with other click functionalities such as strained cyclooctyne derivatives and sulfonyl fluorides. This trireactive surface can then react locally and selectively in a one pot reaction via three orthogonal chemistries at room temperature: activated ester aminolysis, strain promoted azide-alkyne cycloaddition, and sulfur(VI) fluoride exchange, all of which are tolerant of ambient moisture and oxygen. Furthermore, we demonstrate that these reactions can also be used to create areas of morphologically distinct surface features on the nanoscale, by inducing buckling instabilities in the films and the grafting of nanoparticles. This approach is modular, and allows for the development of highly complex surface motifs patterned with different chemistry and morphology.