A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1–9) intravenous infusions of 25 μg/m2bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis. © 2001 Cancer Research Campaign http://www.bjcancer.co

Challenges for Coring Deep Permafrost on Earth and Mars

This is the published version. Final publication is available from Mary Ann Liebert, Inc., publishers http://www.dx.doi.org/10.1089/ast.2007.0159.A scientific drilling expedition to the High Lake region of Nunavut, Canada, was recently completed with the goals of collecting samples and delineating gradients in salinity, gas composition, pH, pe, and microbial abundance in a 400 m thick permafrost zone and accessing the underlying pristine subpermafrost brine. With a triple-barrel wireline tool and the use of stringent quality assurance and quality control (QA/QC) protocols, 200 m of frozen, Archean, mafic volcanic rock was collected from the lower boundary that separates the permafrost layer and subpermafrost saline water. Hot water was used to remove cuttings and prevent the drill rods from freezing in place. No cryopegs were detected during penetration through the permafrost. Coring stopped at the 535 m depth, and the drill water was bailed from the hole while saline water replaced it. Within 24 hours, the borehole iced closed at 125 m depth due to vapor condensation from atmospheric moisture and, initially, warm water leaking through the casing, which blocked further access. Preliminary data suggest that the recovered cores contain viable anaerobic microorganisms that are not contaminants even though isotopic analyses of the saline borehole water suggests that it is a residue of the drilling brine used to remove the ice from the upper, older portion of the borehole. Any proposed coring mission to Mars that seeks to access subpermafrost brine will not only require borehole stability but also a means by which to generate substantial heating along the borehole string to prevent closure of the borehole from condensation of water vapor generated by drilling. Astrobiology 8, 623–638

The effect of hyperglycemia on neurovascular coupling and cerebrovascular patterning in zebrafish

Neurovascular coupling (through which local cerebral blood flow changes in response to neural activation are mediated) is impaired in many diseases including diabetes. Current preclinical rodent models of neurovascular coupling rely on invasive surgery and instrumentation, but transgenic zebrafish coupled with advances in imaging techniques allow non-invasive quantification of cerebrovascular anatomy, neural activation, and cerebral vessel haemodynamics. We therefore established a novel non-invasive, non-anaesthetised zebrafish larval model of neurovascular coupling, in which visual stimulus evokes neuronal activation in the optic tectum that is associated with a specific increase in red blood cell speed in tectal blood vessels. We applied this model to the examination of the effect of glucose exposure on cerebrovascular patterning and neurovascular coupling. We found that chronic exposure of zebrafish to glucose impaired tectal blood vessel patterning and neurovascular coupling. The nitric oxide donor sodium nitroprusside rescued all these adverse effects of glucose exposure on cerebrovascular patterning and function. Our results establish the first non-mammalian model of neurovascular coupling, offering the potential to perform more rapid genetic modifications and high throughput screening than is currently possible using rodents. Furthermore, using this zebrafish model we reveal a potential strategy to ameliorate the effects of hyperglycemia on cerebrovascular function

Microwave assisted synthesis of novel bis-flavone dimers as new anticancer agents

In this study we describe a microwave based click chemistry method used to prepare a family of novel bis-flavone dimers. The substituted 7-hydroxy and 4’-hydroxy flavonoids were linked through a triazole ring. The compounds were easily synthesized and purified in high yields. The bis-flavonoids were tested on different cell lines including HCT116, HepG2, MCF7 and MOLT-4. Several analogues showed to have anticancer activity with IC50 values in the range of 20-60 µM. Flavonoids are known for their anticancer properties and this method provides the basis for new medicinal structures