Potent pro-apoptotic combination therapy is highly effective in a broad range of cancers

Primary or acquired therapy resistance is a major obstacle to the effective treatment of cancer. Resistance to apoptosis has long been thought to contribute to therapy resistance. We show here that recombinant TRAIL and CDK9 inhibition cooperate in killing cells derived from a broad range of cancers, importantly without inducing detectable adverse events. Remarkably, the combination of TRAIL with CDK9 inhibition was also highly effective on cancers resistant to both, standard-of-care chemotherapy and various targeted therapeutic approaches. Dynamic BH3 profiling revealed that, mechanistically, combining TRAIL with CDK9 inhibition induced a drastic increase in the mitochondrial priming of cancer cells. Intriguingly, this increase occurred irrespective of whether the cancer cells were sensitive or resistant to chemo- or targeted therapy. We conclude that this pro-apoptotic combination therapy has the potential to serve as a highly effective new treatment option for a variety of different cancers. Notably, this includes cancers that are resistant to currently available treatment modalities.Subject terms: Cancer models, Cell biology, Preclinical research     

Changes in the uptake and assimilation efficiency for sulfate and nitrate in maize hybrids selected during the period 1930 through 1975

Sulfate and nitrate uptake capacity, ATP sulfurylase (ATPS) and nitrate reductase (NR) activity were determined in a set of maize hybrids representative of selection cycles carried out during the period 1930 through 1975. All the above metabolic parameters together with the grain yield were improved by the selection. The annual rate of the improvement was higher (double) for sulfate uptake than for ATPS and similar for NR and nitrate uptake. Significant correlations were evidenced between the uptake efficiency of the roots and the enzyme activity in the leaves both for sulfate and nitrate pathways, and also between the uptake and enzyme steps of nitrate and those of sulfate. This offered good evidence of a coupled genetic regulation between nitrogen and sulfur metabolism in maize.     

A nonelectrogenic H+ pump in plasma membranes of hog stomach.

Differential and density gradient centrifugation were used to prepare a vesicular membrane fraction from hog gastric mucosa enriched 17-fold with respect to cation-activated ATPase and 5'-AMPase. Fractionation of the gradient material by free flow electrophoresis resulted in a fraction 35-fold enriched in cation-activated ATPase and essentially free of 5'-AMPase and Mg2+ATPase. The addition of ATP to either fraction resulted in H+ uptake and Rb+ efflux. The ionophoric and osmotic sensitivity showed that these ion movements were due to transport rather than binding. The cation selectivity sequences, substrate specificities and action of inhibitors indicated that the transport was a function of K+ATPase activity. The characteristics of the ATP-dependent enhancement of SCN- uptake and 8-anilinonapthalene-1-sulfonate fluorescence in the presence of valinomycin and the action of ionophores and lipid-permeable ions suggested that the energy dependent K+:H+ exchange was effectively nonelectrogenic. Thus these vesicles contain a nonelectrogenic (H+ + K+)-ATPase, hence acid secretion by the stomach is probably due to an ATP-dependent H+ + K+ exchange.     

Efficiency of the first steps of sulfate utilization by maize hybrids in relation to their productivity

The genetic variability of the efficiency of the first steps of sulfate utilization and its correlation with productivity were evaluated in nine maize hybrids. ³⁵SO₄²⁻ uptake by excised roots, uptake by intact plant roots, translocation to leaves, and ATP sulfurylase in leaves were taken into account. Uptake rate by roots of intact plants did not show any pulse within 7 to 12 days from emergence, in contrast with the previously observed behaviour of excised roots during root elongation. The uptake rate of intact plants was positively correlated with that of excised roots, but the variability within the nine genotypes tested was less. Productivity was positively correlated with sulfate uptake by both intact plant and excised roots, the level of significance being higher in the first case. Translocation to leaves and ATP sulfurylase activity were not correlated to productivity. Therefore, in the case of sulfate, the grain yield of commonly cultivated maize hybrids appeared to be controlled more by the root uptake step than by the activation and translocation steps.     

Target molecular weight of the gastric (H+ + K+)-ATPase functional and structural molecular size

The state of assembly of the (H+ + K+)-ATPase in purified hog gastric mucosa membranes was studied by target size analysis applied to radiation-induced enzyme inactivation and polypeptide degradation data. Radiation inactivated the Mg2+-ATPase, K+-stimulated ATPase, and p-nitrophenyl phosphatase activities of the membrane preparation with a dose dependence characteristic of a target size of 270,000-daltons. Radiation also bleached the major 100,000-dalton sodium dodecyl sulfate-gel electrophoresis band of this preparation, indicating a radiation-induced degradation. This apparent polypeptide degradation exhibited a dose dependency corresponding to a target size of 250,000 daltons in situ. It is suggested that the gastric ATPase is a trimeric assembly of the 100,000-dalton polypeptides.     

Sterol content and efficiency of ion uptake by roots of maize genotypes

Data of compartmental analysis of sulphate were compared with the sterol content of roots of differently yielding maize genotypes. In conditions of steady state nutrient supply, sterol content was significantly correlated only with sulphate efflux (co). This increased at increasing concentration of sterols in the roots. Influx to cytoplasm (oc) was evaluated after sulphate deprivation leading to an induced rate of sulphate uptake. This was negatively correlated with sterol content, which was lower in the high than in the low yielding genotypes. When the highest yield genotype was grown at different sulphate concentrations, influx, efflux, root content of sulphate and sterols were positively correlated with the concentration of sulphate in the nutrient medium. Sterol content in roots appears to be controlled by both the genetic settlement and the nutritional status in maize. Low sterol content is connected with a high efficiency of sulphate utilization.     

Protein networking: insights into global functional organization of proteomes

The formulation of network models from global protein studies is essential to understand the functioning of organisms. Network models of the proteome enable the application of Complex Network Analysis, a quantitative framework to investigate large complex networks using techniques from graph theory, statistical physics, dynamical systems and other fields. This approach has provided many insights into the functional organization of the proteome so far and will likely continue to do so. Currently, several network concepts have emerged in the field of proteomics. It is important to highlight the differences between these concepts, since different representations allow different insights into functional organization. One such concept is the protein interaction network, which contains proteins as nodes and undirected edges representing the occurrence of binding in large-scale protein-protein interaction studies. A second concept is the protein-signaling network, in which the nodes correspond to levels of post-translationally modified forms of proteins and directed edges to causal effects through post-translational modification, such as phosphorylation. Several other network concepts were introduced for proteomics. Although all formulated as networks, the concepts represent widely different physical systems. Therefore caution should be taken when applying relevant topological analysis. We review recent literature formulating and analyzing such networks.     

Developing a multimetric index of ecological integrity based on macroinvertebrates of mountain ponds in central Italy

The lack of biological systems for the assessment of ecological quality specific to mountain ponds prevents the effective management of these natural resources. In this article we develop an index based on macroinvertebrates sensitive to the gradient of nutrient enrichment. With this aim, we sampled 31 ponds along a gradient of trophy and with similar geomorphological characteristics and watershed use in protected areas of the central Apennines. A bioassessment protocol was adopted to collect and process benthic samples and key-associated physical, chemical, and biological variables during the summer growth season of 1998. We collected 61 genera of macroinvertebrates belonging to 31 families. We calculated 31 macroinvertebrate metrics based on selected and total taxa richness, richness of some key groups, abundance, functional groups and tolerance to organic pollution. The gradient of trophy was quantified with summer concentrations of chlorophyll a. We followed a stepwise procedure to evaluate the effectiveness of a given metric for use in the multimetric index. Those were the pollution tolerance metric ASPT, three metrics based on taxonomic richness (the richness of macroinvertebrate genera, the richness of chironomid taxa, and the percentage of total richness composed by Ephemeroptera, Odonata, and Trichoptera), two metrics based on FFG attributes (richness of collector gatherer taxa and richness of scraper taxa) and the habit-based metric richness of burrowers. The 95th percentile of each metric distribution among all ponds was trisected for metric scoring. The final Pond Macroinvertebrate Integrity Index ranged from 7 to 35 and had a good correlation (R ² = 0.71) with the original gradient of environmental degradation. Guest editors: R. Céréghino, J. Biggs, B. Oertli & S. Declerck The ecology of European ponds: defining the characteristics of a neglected freshwater habitat     

Single nucleotide polymorphism markers linked to root elongation rate in sugar beet

The aim of this study was to identify single nucleotide polymorphism (SNP) markers genetically linked to root elongation rate (RER) in sugar beet (Beta vulgaris L.). A population of 244 F₃ individuals, obtained from the cross between lines L01 (a low RER) and L18 (a high RER), was phenotyped by measuring RER of 11-d-old seedlings grown in a hydroponic culture. Two DNA bulks of 50 F₃ individuals with extreme phenotypes were used for bulk segregant analysis by restriction-associated DNA sequencing. A total of 20 376 SNPs were identified. Single nucleotide polymorphisms were filtered to reduce the number of the false positive and mapped on candidate chromosomal regions of the B. vulgaris reference genome. One of the total of SNPs selected, SNP10139, was strongly linked to RER (P < 0.01). The pattern of association between the SNP10139 genotype and RER was also evaluated on a breeding line panel comprising 40 low and 40 high RER individuals with different allele frequencies between groups (P < 0.01). The SNP10139 sequence was mapped on the B. vulgaris peptide transporter (PTR) gene, a carrier that influences root elongation in Arabidopsis thaliana. Our results suggest that SNP10139 influence RER in sugar beet, and sequence information can be used in marker-assisted selection programs.