Obinutuzumab-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than rituximab-based therapy. High-grade adverse events were more common with obinutuzumab-based chemotherapy. (Funded by F. Hoffmann-La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968 .).

The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.

Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation.

In patients with indolent or mantle cell lymphoma, R-chemo is superior to chemotherapy alone with respect to overall survival.

BP is superior to MP with respect to complete remission rate, TTF, cycles needed to achieve maximum remission and quality of life and should be considered the new standard in first-line treatment of MM patients not eligible for transplantation.

Transgenic potato (Solanum tuberosum) plants expressing Arabidopsis phytochrome B were characterized morphologically and physiologically under white light in a greenhouse to explore their potential for improved photosynthesis and higher tuber yields. As expected, overexpression of functional phytochrome B caused pleiotropic effects such as semidwarfism, decreased apical dominance, a higher number of smaller but thicker leaves, and increased pigmentation. Because of increased numbers of chloroplasts in elongated palisade cells, photosynthesis per leaf area and in each individual plant increased. In addition, photosynthesis was less sensitive to photoinactivation under prolonged light stress. The beginning of senescence was not delayed, but deceleration of chlorophyll degradation extended the lifetime of photosynthetically active plants. Both the higher photosynthetic performance and the longer lifespan of the transgenic plants allowed greater biomass production, resulting in extended underground organs with increased tuber yields.Plant growth, development, and metabolic activities are regulated by a range of environmental factors, including light, which is of central importance. Light is perceived by a variety of photoreceptors that control developmental processes such as germination, photomorphogenesis, flowering, and senescence, as well as metabolic processes such as photosynthesis and assimilate allocation. It has been pointed out before that the agricultural productivity of crop plants might be enhanced by overexpressing one of these central regulators (Smith, 1992), and phytochromes are promising candidates for such an improvement (Robson et al., 1996).Phytochromes represent a family of red-light-absorbing photoreceptors that can exist in the physiologically inactive Pr form and the active Pfr form (for reviews, see Quail et al., 1995;Smith, 1995; Casal et al., 1998). Pr and Pfr are interconvertible by red or FR light, respectively. This absorption profile is extremely useful for the detection of shade or the presence of neighboring plants. At high relative proportions of FR radiation, which occur under shade conditions or in dense plant populations, the photoequilibrium is shifted toward the inactive Pr form. Under these conditions, green plants exhibit various symptoms of the shade-avoidance response, such as promotion of stem and petiole elongation, reduced leaf thickness, reduced chlorophyll synthesis, and increased apical dominance (Smith and Whitelam, 1997). The shade-avoidance response reduces the availability of resources for storage and reproduction.Five PHY genes have been identified in Arabidopsis that have 50% to 80% identity at the amino acid level (Sharrock and Quail, 1989;Clack et al., 1994). The best-characterized members are PHYA and PHYB. phyA accumulates in the dark and is rapidly degraded upon conversion to the labile Pfr form (Pratt et al., 1997). It is responsible for detecting continuous FR light and dampens the shade-avoidance response under high relative proportions of FR light (McCo...

A chemically regulated gene expression system that can be switched on with dexamethasone and switched off with tetracycline was constructed. It is based on a transcriptional activator (TGV) that consists of the Tn10 encoded Tet repressor, the rat glucocorticoid receptor hormone binding domain and the transcriptional activation domain of Herpes simplex virion protein VP16. When stably expressed in transgenic tobacco plants, it mediates dexamethasone-inducible transcription from a synthetic promoter (P Top10 ) consisting of seven tet operators upstream of a TATA-box. Tetracycline interferes with induction by negatively regulating the DNA-binding activity of the TetR moiety of TGV. The boundaries of the expression window of the TGV-driven P Top10 reach from undetectable levels of the reporter enzyme b-glucuronidase in the absence of dexamethasone to induced levels reaching 15±20% of the Cauli¯ower Mosaic Virus 35S promoter (P CaMV35S ). By modifying the sequence of P Top10 , we generated a new target promoter (P Tax ) that is stably expressed over several generations and that can be activated to levels comparable to P CaMV35S , while yielding only slightly elevated background activities.

Liver toxicity is a leading systemic toxicity of drugs and chemicals demanding more human-relevant, high throughput, cost effective in vitro solutions. In addition to contributing to animal welfare, in vitro techniques facilitate exploring and understanding the molecular mechanisms underlying toxicity. New ‘omics technologies can provide comprehensive information on the toxicological mode of action of compounds, as well as quantitative information about the multi-parametric metabolic response of cellular systems in normal and patho-physiological conditions. Here, we combined mass-spectroscopy metabolomics with an in vitro liver toxicity model. Metabolite profiles of HepG2 cells treated with 35 test substances resulted in 1114 cell supernatants and 3556 intracellular samples analyzed by metabolomics. Control samples showed relative standard deviations of about 10–15%, while the technical replicates were at 5–10%. Importantly, this procedure revealed concentration–response effects and patterns of metabolome changes that are consistent for different liver toxicity mechanisms (liver enzyme induction/inhibition, liver toxicity and peroxisome proliferation). Our findings provide evidence that identifying organ toxicity can be achieved in a robust, reliable, human-relevant system, representing a non-animal alternative for systemic toxicology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-017-2079-6) contains supplementary material, which is available to authorized users.