Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma

BACKGROUND: Patients with advanced gallbladder and biliary tract carcinoma face a dismal prognosis, as no effective palliative chemotherapy exists. The antitumor effect of gemcitabine is schedule-dependent rather than dose-dependent. We evaluated the activity of a prolonged infusion of gemcitabine in advanced gallbladder and biliary tract carcinomas. METHODS: Nineteen consecutive eligible patients were enrolled. All patients were required to have histologically confirmed diagnosis and measurable disease. Gemcitabine was infused over 24 hours at a dose of 100 mg/m(2 )on days 1, 8, and 15. Treatment was repeated every 28 days until progression of disease or limiting toxicity. Tumor response was evaluated every second course by computed tomography (CT) scans. RESULTS: Eighteen patients were evaluable for response. A total of 89 cycles of therapy were administered. One partial response was observed (6%; 95% confidence interval (CI): 0–27%) and ten additional patients had stable disease for at least two months (disease control rate 61%; 95% CI: 36–83%). The therapy was well tolerated, with moderate myelosuppression as the main toxicity. The median time to tumor progression and median overall survival was 3.6 months (95% CI 2.6–4.6 months) and 7.5 months (95% CI 6.5–8.5 months), respectively. CONCLUSION: Weekly 24-hour gemcitabine at a dose of 100 mg/m(2 )is well tolerated. There was a relatively high rate of disease control for a median duration of 5.3 months (range 2.8–18.8 months). However, the objective response rate of this regimen in gallbladder and biliary tract carcinomas was limited

Comprehensive Functional Analysis of Mycobacterium tuberculosis Toxin-Antitoxin Systems: Implications for Pathogenesis, Stress Responses, and Evolution

Toxin-antitoxin (TA) systems, stress-responsive genetic elements ubiquitous in microbial genomes, are unusually abundant in the major human pathogen Mycobacterium tuberculosis. Why M. tuberculosis has so many TA systems and what role they play in the unique biology of the pathogen is unknown. To address these questions, we have taken a comprehensive approach to identify and functionally characterize all the TA systems encoded in the M. tuberculosis genome. Here we show that 88 putative TA system candidates are present in M. tuberculosis, considerably more than previously thought. Comparative genomic analysis revealed that the vast majority of these systems are conserved in the M. tuberculosis complex (MTBC), but largely absent from other mycobacteria, including close relatives of M. tuberculosis. We found that many of the M. tuberculosis TA systems are located within discernable genomic islands and were thus likely acquired recently via horizontal gene transfer. We discovered a novel TA system located in the core genome that is conserved across the genus, suggesting that it may fulfill a role common to all mycobacteria. By expressing each of the putative TA systems in M. smegmatis, we demonstrate that 30 encode a functional toxin and its cognate antitoxin. We show that the toxins of the largest family of TA systems, VapBC, act by inhibiting translation via mRNA cleavage. Expression profiling demonstrated that four systems are specifically activated during stresses likely encountered in vivo, including hypoxia and phagocytosis by macrophages. The expansion and maintenance of TA genes in the MTBC, coupled with the finding that a subset is transcriptionally activated by stress, suggests that TA systems are important for M. tuberculosis pathogenesis

Efficiency of compaction and compositional convection during mafic crystal mush solidification: the Sept Iles layered intrusion, Canada

Adcumulate formation in mafic layered intrusions is attributed either to gravity-driven compaction, which expels the intercumulus melt out of the crystal matrix, or to compositional convection, which maintains the intercumulus liquid at a constant composition through liquid exchange with the main magma body. These processes are length-scale and time-scale dependent, and application of experimentally derived theoretical formulations to magma chambers is not straightforward. New data from the Sept Iles layered intrusion are presented and constrain the relative efficiency of these processes during solidification of the mafic crystal mush. Troctolites with meso- to ortho-cumulate texture are stratigraphically followed by Fe–Ti oxide-bearing gabbros with adcumulate texture. Calculations of intercumulus liquid fractions based on whole-rock P, Zr, V and Cr contents and detailed plagioclase compositional profiles show that both compaction and compositional convection operate, but their efficiency changes with liquid differentiation. Before saturation of Fe–Ti oxides in the intercumulus liquid, convection is not active due to the stable liquid density distribution within the crystal mush. At this stage, compaction and minor intercumulus liquid crystallization reduce the porosity to 30%. The velocity of liquid expulsion is then too slow compared with the rate of crystal accumulation. Compositional convection starts at Fe–Ti oxide-saturation in the pore melt due to its decreasing density. This process occurs together with crystallization of the intercumulus melt until the residual porosity is less than 10%. Compositional convection is evidenced by external plagioclase rims buffered at An 61 owing to continuous exchange between the intercumulus melt and the main liquid body. The change from a channel flow regime that dominates in troctolites to a porous flow regime in gabbros results from the increasing efficiency of compaction with differentiation due to higher density contrast between the cumulus crystal matrix and the equilibrium melts and to the bottom-up decreasing rate of crystal accumulation in the magma chamber