Explore the vast range of titles available.

ONYX-015 is an oncolytic virus untested as a treatment for malignant glioma. The NABTT CNS Consortium conducted a dose-escalation trial of intracerebral injections of ONYX-015. Cohorts of six patients at each dose level received doses of vector from 10(7) plaque-forming units (pfu) to 10(10) pfu into a total of 10 sites within the resected glioma cavity. Adverse events were identified on physical exams and testing of hematologic, renal, and liver functions. Efficacy data were obtained from serial MRI scans. None of the 24 patients experienced serious adverse events related to ONYX-015. The maximum tolerated dose was not reached at 10(10) pfu. The median time to progression after treatment with ONYX-015 was 46 days (range 13 to 452 + days). The median survival time was 6.2 months (range 1.3 to 28.0 + months). One patient has not progressed and 1 patient showed regression of interval-increased enhancement. With more than 19 months of follow-up, 1/6 recipients at a dose of 10(9) and 2/6 at a dose of 10(10) pfu remain alive. In 2 patients who underwent a second resection 3 months after ONYX-015 injection, a lymphocytic and plasmacytoid cell infiltrate was observed. Injection of ONYX-015 into glioma cavities is well tolerated at doses up to 10(10) pfu.

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m 2 /day and escalated by 25 mg/m 2 /day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m 2 /day in the −EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. −EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m 2 /day dose level ( P  = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.

Carboxyamido-triazole (CAI) is a synthetic inhibitor of non-voltage-gated calcium channels that reversibly inhibits angiogenesis, tumor cell proliferation, and metastatic potential. This study examined the efficacy, safety and pharmacokinetics of oral CAI in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) in an open-label, single arm non-randomized phase 2 trial. Eligible patients with histologically confirmed GBM started CAI therapy (250 mg daily) on the first day of radiation (6000 cGy in 30 fractions) and continued until progression, unless side effects became intolerable. The primary outcome was survival compared to historical controls within the NABTT CNS Consortium database. Secondary outcomes included toxicity and pharmacokinetic parameters. Fifty-five patients were enrolled with a median Karnofsky performance status of 90 and age of 56 years. Forty-six (84%) of these patients had debulking surgeries and 52 have died. The median survival was 10.3 months (95% confidence interval (CI), 8.5-12.8) compared to 12.1 months (95% CI, 10.3-13.3) in the NABTT reference group (p = 0.97). Significant toxicities included 2 incidents of reversible vision loss. The mean CAI plasma concentration for patients taking enzyme inducing antiepileptic drugs (EIAED) was 1.35 +/-1.22 compared to 4.06 +/- 1.50 (p < 0.001) for subjects not taking these agents. Overall survival and grade > or = 3 toxicities were comparable by EIAED status. This study demonstrated that (1) CAI can be administered safely with concomitant cranial irradiation, (2) the pharmacokinetics of CAI are significantly affected by co-administration of EIAED, and (3) the survival of patients with newly diagnosed GBM was not improved with this novel agent, despite achieving adequate drug levels.

Recent studies demonstrate a short 3–6-month atmospheric lifetime for mercury (Hg). This implies Hg emissions are predominantly deposited within the same hemisphere in which they are emitted, thus placing increasing importance on considering Hg sources, sinks and impacts from a hemispheric perspective. In the absence of comprehensive Hg data from the Southern Hemisphere (SH), estimates and inventories for the SH have been drawn from data collected in the NH, with the assumption that the NH data are broadly applicable. In this paper, we centre the uniqueness of the SH in the context of natural biogeochemical Hg cycling, with focus on the midlatitudes and tropics. Due to its uniqueness, Antarctica warrants an exclusive review of its contribution to the biogeochemical cycling of Hg and is therefore excluded from this review. We identify and describe five key natural differences between the hemispheres that affect the biogeochemical cycling of Hg: biome heterogeneity, vegetation type, ocean area, methylation hotspot zones and occurence of volcanic activities. We review the current state of knowledge of SH Hg cycling within the context of each difference, as well as the key gaps that impede our understanding of natural Hg cycling in the SH. The differences demonstrate the limitations in using NH data to infer Hg processes and emissions in the SH.

Our understanding of the formation and evolution of the primary lunar crust is based on geochemical systematics from the lunar ferroan anorthosite (FAN) suite. Recently, much effort has been made to understand this suite’s petrologic history to constrain the timing of crystallisation and to interpret FAN chemical diversity. We investigate the shock histories of lunar anorthosites by combining Optical Microscope (OM) ‘cold’ cathodoluminescence (CL)-imaging and Fourier Transform Infrared (FTIR) spectroscopy analyses. In the first combined study of its kind, this study demonstrates that over ~4.5 Ga of impact processing, plagioclase is on average weakly shocked (<15 GPa) and examples of high shock states (>30 GPa; maskelynite) are uncommon. To investigate how plagioclase trace-element systematics are affected by moderate to weak shock (~5 to 30 GPa) we couple REE+Y abundances with FTIR analyses for FAN clasts from lunar meteorite Northwest Africa (NWA) 2995. We observe weak correlations between plagioclase shock state and some REE+Y systematics ( e.g ., La/Y and Sm/Nd ratios). This observation could prove significant to our understanding of how crystallisation ages are evaluated ( e.g ., plagioclase-whole rock Sm-Nd isochrons) and for what trace-elements can be used to differentiate between lunar lithologies and assess magma source compositional differences.

Up-to-date information on the causes of child deaths is crucial to guide global efforts to improve child survival. We report new estimates for 2008 of the major causes of death in children younger than 5 years. We used multicause proportionate mortality models to estimate deaths in neonates aged 0–27 days and children aged 1–59 months, and selected single-cause disease models and analysis of vital registration data when available to estimate causes of child deaths. New data from China and India permitted national data to be used for these countries instead of predictions based on global statistical models, as was done previously. We estimated proportional causes of death for 193 countries, and by application of these proportions to the country-specific mortality rates in children younger than 5 years and birth rates, the numbers of deaths by cause were calculated for countries, regions, and the world. Of the estimated 8·795 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (5·970 million), with the largest percentages due to pneumonia (18%, 1·575 million, uncertainty range [UR] 1·046 million–1·874 million), diarrhoea (15%, 1·336 million, 0·822 million–2·004 million), and malaria (8%, 0·732 million, 0·601 million–0·851 million). 41% (3·575 million) of deaths occurred in neonates, and the most important single causes were preterm birth complications (12%, 1·033 million, UR 0·717 million–1·216 million), birth asphyxia (9%, 0·814 million, 0·563 million–0·997 million), sepsis (6%, 0·521 million, 0·356 million–0·735 million), and pneumonia (4%, 0·386 million, 0·264 million–0·545 million). 49% (4·294 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China. These country-specific estimates of the major causes of child deaths should help to focus national programmes and donor assistance. Achievement of Millennium Development Goal 4, to reduce child mortality by two-thirds, is only possible if the high numbers of deaths are addressed by maternal, newborn, and child health interventions. WHO, UNICEF, and Bill & Melinda Gates Foundation.

The eruption of Mount St. Helens in 1980 resulted in a cataclysmic restructuring of its surrounding landscapes. The Pumice Plain is one of these landscapes, where tree species such as Sitka willow (Salix sitchensis) and their dependent communities have been established along newly-formed streams. Thus, the study of these dependent communities provides a unique and rare opportunity to investigate factors influencing metacommunity assembly during true primary succession. We analyzed the influence of landscape connectivity on metacommunity assembly through a novel application of circuit theory, alongside the effects of other factors such as stream locations, willow leaf chemistry, and leaf area. We found that landscape connectivity structures community composition on willows across the Pumice Plain, where the least connected willows favored active flyers such as the western tent caterpillar (Malacosoma fragilis) or the Pacific willow leaf beetle (Pyrrhalta decora carbo). We also found that multiple levels of spatial habitat structure linked via landscape connectivity can predict the presence of organisms lacking high rates of dispersal, such as the invasive stem-boring poplar weevil (Cryptorhynchus lapathi). This is critical for management as we show that the maintenance of a heterogeneous mixture of landscape connectivity and resource locations can facilitate metacommunity dynamics to promote ecosystem function and mitigate the influences of invasive species.