BRIDGE: An Open-Label Phase II Trial Evaluating the Safety of Bevacizumab + Carboplatin/Paclitaxel as First-Line Treatment for Patients with Advanced, Previously Untreated, Squamous Non-small Cell Lung Cancer

Background:Patients with predominantly squamous non-small cell lung cancer (NSCLC) have been generally excluded from studies of bevacizumab treatment, because squamous histology was identified as a possible risk factor for severe (grade ≥3) pulmonary hemorrhage (PH) in a phase II study. BRIDGE was designed to determine whether delaying initiation of bevacizumab treatment and selecting patients without baseline risk factors for PH would lower the incidence of severe PH among patients with squamous NSCLC.Methods:Patients in this open-label, single-arm study were treated with carboplatin/paclitaxel for two cycles, followed by carboplatin/paclitaxel and bevacizumab in cycles 3 to 6, followed by bevacizumab until progression or unacceptable toxicity. Eligible patients had stage IIIb, stage IV, or recurrent squamous NSCLC. The primary end point was incidence of grade ≥3 PH.Results:Grade ≥3 PH occurred in 1 of 31 patients who received ≥1 dose of bevacizumab: estimated incidence was 3.2% (90% confidence interval 0.3–13.5%). The patient experienced grade 3 PH, discontinued from the study, then experienced grade 4 PH 10 days later, and died of progressive disease. No other serious bleeding events occurred. Nine patients (29.0%) experienced grade 3 adverse events, including five with hypertension; five patients experienced grade 4 adverse events (dyspnea, PH, basal ganglia infarction, cerebral ischemia, and pain). Median progression-free survival was 6.2 months (95% confidence interval 5.32–7.62 months).Conclusions:The incidence of grade ≥3 PH was 3.2% (one patient). No new safety signals were identified. Although the rate of PH was low, the number of patients in this study was also low. Treatment of squamous NSCLC with bevacizumab should be considered experimental

Functionally Stable and Phylogenetically Diverse Microbial Enrichments from Microbial Fuel Cells during Wastewater Treatment

Microbial fuel cells (MFCs) are devices that exploit microorganisms as biocatalysts to recover energy from organic matter in the form of electricity. One of the goals of MFC research is to develop the technology for cost-effective wastewater treatment. However, before practical MFC applications are implemented it is important to gain fundamental knowledge about long-term system performance, reproducibility, and the formation and maintenance of functionally-stable microbial communities. Here we report findings from a MFC operated for over 300 days using only primary clarifier effluent collected from a municipal wastewater treatment plant as the microbial resource and substrate. The system was operated in a repeat-batch mode, where the reactor solution was replaced once every two weeks with new primary effluent that consisted of different microbial and chemical compositions with every batch exchange. The turbidity of the primary clarifier effluent solution notably decreased, and 97% of biological oxygen demand (BOD) was removed after an 8–13 day residence time for each batch cycle. On average, the limiting current density was 1000 mA/m2, the maximum power density was 13 mW/m2, and coulombic efficiency was 25%. Interestingly, the electrochemical performance and BOD removal rates were very reproducible throughout MFC operation regardless of the sample variability associated with each wastewater exchange. While MFC performance was very reproducible, the phylogenetic analyses of anode-associated electricity-generating biofilms showed that the microbial populations temporally fluctuated and maintained a high biodiversity throughout the year-long experiment. These results suggest that MFC communities are both self-selecting and self-optimizing, thereby able to develop and maintain functional stability regardless of fluctuations in carbon source(s) and regular introduction of microbial competitors. These results contribute significantly toward the practical application of MFC systems for long-term wastewater treatment as well as demonstrating MFC technology as a useful device to enrich for functionally stable microbial populations

Protein Oxidation Implicated as the Primary Determinant of Bacterial Radioresistance

In the hierarchy of cellular targets damaged by ionizing radiation (IR), classical models of radiation toxicity place DNA at the top. Yet, many prokaryotes are killed by doses of IR that cause little DNA damage. Here we have probed the nature of Mn-facilitated IR resistance in Deinococcus radiodurans, which together with other extremely IR-resistant bacteria have high intracellular Mn/Fe concentration ratios compared to IR-sensitive bacteria. For in vitro and in vivo irradiation, we demonstrate a mechanistic link between Mn(II) ions and protection of proteins from oxidative modifications that introduce carbonyl groups. Conditions that inhibited Mn accumulation or Mn redox cycling rendered D. radiodurans radiation sensitive and highly susceptible to protein oxidation. X-ray fluorescence microprobe analysis showed that Mn is globally distributed in D. radiodurans, but Fe is sequestered in a region between dividing cells. For a group of phylogenetically diverse IR-resistant and IR-sensitive wild-type bacteria, our findings support the idea that the degree of resistance is determined by the level of oxidative protein damage caused during irradiation. We present the case that protein, rather than DNA, is the principal target of the biological action of IR in sensitive bacteria, and extreme resistance in Mn-accumulating bacteria is based on protein protection