Interactions between growth factor receptors and adhesion molecules: breaking the rules

Adhesion molecules, although catalytically inactive, are able to translate environmental cues into complex intracellular signals. They can do this by associating with tyrosine kinase receptors for growth factors, which can prime, integrate or feedback adhesion-based signals. Recent results show that reciprocal crosstalk between the two systems is only one facet of such a collaboration, and that unconventional and alternative hierarchies can be established in which, on the one hand, cell adhesion can trigger ligand-independent activation of growth factor receptors, and, on the other, growth factors can induce adhesion molecules to propagate adhesion-independent signals.     

Inhibition of poly(ADP-ribosyl)ation in cancer: Old and new paradigms revisited

Inhibitors of poly(ADP-ribose) polymerases actualized the biological concept of synthetic lethality in the clinical practice, yielding a paradigmatic example of translational medicine. The profound sensitivity of tumors with germline BRCA mutations to PARP1/2 blockade owes to inherent defects of the BRCA-dependent homologous recombination machinery, which are unleashed by interruption of PARP DNA repair activity and lead to DNA damage overload and cell death. Conversely, aspirant BRCA-like tumors harboring somatic DNA repair dysfunctions (a vast entity of genetic and epigenetic defects known as “BRCAness”) not always align with the familial counterpart and appear not to be equally sensitive to PARP inhibition. The acquisition of secondary resistance in initially responsive patients and the lack of standardized biomarkers to identify “BRCAness” pose serious threats to the clinical advance of PARP inhibitors; a feeling is also emerging that a BRCA-centered perspective might have missed the influence of additional, not negligible and DNA repair-independent PARP contributions onto therapy outcome. While regulatory approval for PARP1/2 inhibitors is still pending, novel therapeutic opportunities are sprouting from different branches of the PARP family, although they remain immature for clinical extrapolation. This review is an endeavor to provide a comprehensive appraisal of the multifaceted biology of PARPs and their evolving impact on cancer therapeutics.     

Environmental alteration and allergophytes

Summary The plant recolonization of wasted biotopes was studied in the Karst region in order to evaluate the incidence of allergophytes. The frequency of allergenic species is higher in habitats with low human disturbance, such as wall, ruins, dumps, roadsides and slopes, colonized by ruderal and semi-ruderal plant associations.     

A long-term toxicological investigation on the effect of tris(maltolate)aluminum(III) in rabbits

The toxicity of iv injected hydrophilic aluminum complex tris(maltolate)aluminum(III) was studied in New Zealand white rabbits for a period of time ranging from 5 to 63 wk. Animals were injected 3–5 times a week with 1 mL of 7.5 mM Al(malt)₃ and one rabbit with a dose 10 times higher after 14 wk of treatment. Autopical examination was performed on all animals. Chemoclinical analysis (glucose, urea, creatinine, cholesterol, bilirubin, alanin aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, LDH, CK, total protein, triglycerides, and Ca²⁺) gave no variation in treated animals with respect to the control. The toxicological data show a moderate systemic general toxicity at doses far higher than those used in similar previous experiments using Al(acac)₃ (acac=2,4 pentanedionate), a hydrolytically stable and more lipophilic aluminum(III) complex (1). The diversity of behavior is discussed in terms of metal speciation as well as respect to the thermodynamic and kinetic properties of the two complexes in aqueous solution. The toxicological model presented here emphasizes that neutral, water compatible aluminum(III) complexes are to be considered as promising tools for toxicological experiments providing biological models of human pathologies.     

Salicylate fails to prevent the inhibitory effect of 5,8,11,14-eicosatetraynoic acid on human platelet cyclo-oxygenase and lipoxygenase activities

Sodium salicylate is inactive both on cyclo-oxygenase and lipoxygenase prepared from human platelets. It prevents the inhibition of cyclo-oxygenase induced by aspirin, but does not counteract the inhibitory effect of 5,8,11,14-eicosatetraynoic acid on both enzymes. It also fails to interfere with the inhibitory activity of nordihydroguaiaretic acid on lipoxygenase. These data indicate that, unlike eicosatetraynoic acid, non-steroidal anti-inflammatory drugs interact with a site on cyclo-oxygenase distinct from the catalytic site, although related to it. Such a supplementary binding site is lacking on lipoxygenase.     

Inheritance as Evolved and Evolving Physiological Processes

Acta Biotheoretica - In this paper, we adopt a physiological perspective in order to produce an intelligible overview of biological transmission in all its diversity. This allows us to put forward...     

Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs

Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival motor neuron (SMN) protein. SMN together with Gemins2-8 and unrip proteins form a macromolecular complex that functions in the assembly of small nuclear ribonucleoproteins (snRNPs) of both the major and the minor splicing pathways. It is not known whether the levels of spliceosomal snRNPs are decreased in SMA. Here we analyzed the consequence of SMN deficiency on snRNP metabolism in the spinal cord of mouse models of SMA with differing phenotypic severities. We demonstrate that the expression of a subset of Gemin proteins and snRNP assembly activity are dramatically reduced in the spinal cord of severe SMA mice. Comparative analysis of different tissues highlights a similar decrease in SMN levels and a strong impairment of snRNP assembly in tissues of severe SMA mice, although the defect appears smaller in kidney than in neural tissue. We further show that the extent of reduction in both Gemin proteins expression and snRNP assembly activity in the spinal cord of SMA mice correlates with disease severity. Remarkably, defective SMN complex function in snRNP assembly causes a significant decrease in the levels of a subset of snRNPs and preferentially affects the accumulation of U11 snRNP--a component of the minor spliceosome--in tissues of severe SMA mice. Thus, impairment of a ubiquitous function of SMN changes the snRNP profile of SMA tissues by unevenly altering the normal proportion of endogenous snRNPs. These findings are consistent with the hypothesis that SMN deficiency affects the splicing machinery and in particular the minor splicing pathway of a rare class of introns in SMA.