On glioblastoma and the search for a cure: where do we stand?

Although brain tumours have been documented and recorded since the nineteenth century, 2016 marked 90 years since Percival Bailey and Harvey Cushing coined the term “glioblastoma multiforme”. Since that time, although extensive developments in diagnosis and treatment have been made, relatively little improvement on prognosis has been achieved. The resilience of GBM thus makes treating this tumour one of the biggest challenges currently faced by neuro-oncology. Aggressive and robust development, coupled with difficulties of complete resection, drug delivery and therapeutic resistance to treatment are some of the main issues that this nemesis presents today. Current treatments are far from satisfactory with poor prognosis, and focus on palliative management rather than curative intervention. However, therapeutic research leading to developments in novel treatment stratagems show promise in combating this disease. Here we present a review on GBM, looking at the history and advances which have shaped neurosurgery over the last century that cumulate to the present day management of GBM, while also exploring future perspectives in treatment options that could lead to new treatments on the road to a cure.     

Activation and inactivation of thyroid hormone by deiodinases: Local action with general consequences

The thyroid hormone plays a fundamental role in the development, growth, and metabolic homeostasis in all vertebrates by affecting the expression of different sets of genes. A group of thioredoxin fold-containing selenoproteins known as deiodinases control thyroid hormone action by activating or inactivating the precursor molecule thyroxine that is secreted by the thyroid gland. These pathways ensure regulation of the availability of the biologically active molecule T3, which occurs in a time-and tissue-specific fashion. In addition, because cells and plasma are in equilibrium and deiodination affects central thyroid hormone regulation, these local deiodinase-mediated events can also affect systemic thyroid hormone economy, such as in the case of non-thyroidal illness. Heightened interest in the field has been generated following the discovery that the deiodinases can be a component in both the Sonic hedgehog signaling pathway and the TGR-5 signaling cascade, a G-protein-coupled receptor for bile acids. These new mechanisms involved in deiodinase regulation indicate that local thyroid hormone activation and inactivation play a much broader role than previously thought. Received 29 August 2007; received after revision 11 October 2007; accepted 16 October 2007     

A new spectrophotometric determination of nitrazepam

Riassunto È stata studiata per via spettrofotometrica la reazione cromatica tra nitrazepam e 1,2-naftochinone in dimetilformammide (DMF) in presenza di ammoniaca. È stato stabilito che in soluzione si forma un addotto molecolare dei due reagenti in rapporto molare 11. Tale reazione viene proposta come metodo di determinazione colorimetrica del nitrazepam in liquidi biologici quali sangue, saliva ed urina.     

High-performance reversed-phase liquid chromatography (HPLC) of favism-inducing factors inVicia faba L.

Summary A HPLC assay for L-Dopa, convicine, and vicine in broad-bean extracts has been developed. The distribution of these compounds in the different organs of the plant has been studied, especially in the seeds, where their presence may cause favism if the beans are used as food.Work supported by C.N.R. through Progetto Finalizzato Miglioramento delle produzioni vegetali per fini alimentari ed industriali mediante interventi genetici. Sottogrogetto leguminose da granella. Paper No. 200.     

Light echoes reveal an unexpectedly cool η Carinae during its nineteenth-century Great Eruption

η?Carinae is one of the most massive binary stars in the Milky Way. It became the second-brightest star in our sky during its mid-nineteenth-century 'Great Eruption', but then faded from view (with only naked-eye estimates of brightness). Its eruption is unique in that it exceeded the Eddington luminosity limit for ten years. Because it is only 2.3 kiloparsecs away, spatially resolved studies of the nebula have constrained the ejected mass and velocity, indicating that during its nineteenth-century eruption, η?Car ejected more than ten solar masses in an event that released ten per cent of the energy of a typical core-collapse supernova, without destroying the star. Here we report observations of light echoes of η?Carinae from the 1838-1858 Great Eruption. Spectra of these light echoes show only absorption lines, which are blueshifted by -210?km?s(-1), in good agreement with predicted expansion speeds. The light-echo spectra correlate best with those of G2-to-G5 supergiants, which have effective temperatures of around 5,000?kelvin. In contrast to the class of extragalactic outbursts assumed to be analogues of the Great Eruption of η?Carinae, the effective temperature of its outburst is significantly lower than that allowed by standard opaque wind models. This indicates that other physical mechanisms such as an energetic blast wave may have triggered and influenced the eruption.     

Immune sera recognize on erythrocytes Plasmodium falciparum antigen composed of repeated amino acid sequences

Protective immune responses against the asexual stages of the human malaria parasite, Plasmodium falciparum, are most probably directed against exposed antigenic determinants on the surface of the free merozoite or the infected red blood cell, and therefore antigens in these locations are candidates for testing as components of a defined molecular vaccine. To facilitate the search for such antigens, we recently developed a method for the expression of P. falciparum proteins in Escherichia coli as fused polypeptides. Many clones producing antigens were detected by screening with immune human sera. We show here that antibodies against the fused polypeptide expressed by one such clone react with a P. falciparum protein that is synthesized late in schizogony and is later present on the surface of the ring-infected erythrocyte. The protein is composed of repeating subunits of 8, 4 and 3 amino acids and is present in all isolates of P. falciparum examined.     

Processive translocation and DNA unwinding by individual RecBCD enzyme molecules

RecBCD enzyme is a processive DNA helicase and nuclease that participates in the repair of chromosomal DNA through homologous recombination. We have visualized directly the movement of individual RecBCD enzymes on single molecules of double-stranded DNA (dsDNA). Detection involves the optical trapping of solitary, fluorescently tagged dsDNA molecules that are attached to polystyrene beads, and their visualization by fluorescence microscopy. Both helicase translocation and DNA unwinding are monitored by the displacement of fluorescent dye from the DNA by the enzyme. Here we show that unwinding is both continuous and processive, occurring at a maximum rate of 972 +/- 172 base pairs per second (0.30 microm s(-1)), with as many as 42,300 base pairs of dsDNA unwound by a single RecBCD enzyme molecule. The mean behaviour of the individual RecBCD enzyme molecules corresponds to that observed in bulk solution.     

Two distinct modes of guidance signalling during collective migration of border cells

Although directed migration is a feature of both individual cells and cell groups, guided migration has been studied most extensively for single cells in simple environments. Collective guidance of cell groups remains poorly understood, despite its relevance for development and metastasis. Neural crest cells and neuronal precursors migrate as loosely organized streams of individual cells, whereas cells of the fish lateral line, Drosophila tracheal tubes and border-cell clusters migrate as more coherent groups. Here we use Drosophila border cells to examine how collective guidance is performed. We report that border cells migrate in two phases using distinct mechanisms. Genetic analysis combined with live imaging shows that polarized cell behaviour is critical for the initial phase of migration, whereas dynamic collective behaviour dominates later. PDGF- and VEGF-related receptor and epidermal growth factor receptor act in both phases, but use different effector pathways in each. The myoblast city (Mbc, also known as DOCK180) and engulfment and cell motility (ELMO, also known as Ced-12) pathway is required for the early phase, in which guidance depends on subcellular localization of signalling within a leading cell. During the later phase, mitogen-activated protein kinase and phospholipase Cgamma are used redundantly, and we find that the cluster makes use of the difference in signal levels between cells to guide migration. Thus, information processing at the multicellular level is used to guide collective behaviour of a cell group.     

Translocation step size and mechanism of the RecBC DNA helicase

DNA helicases are ubiquitous enzymes that unwind double-stranded DNA. They are a diverse group of proteins that move in a linear fashion along a one-dimensional polymer lattice--DNA--by using a mechanism that couples nucleoside triphosphate hydrolysis to both translocation and double-stranded DNA unwinding to produce separate strands of DNA. The RecBC enzyme is a processive DNA helicase that functions in homologous recombination in Escherichia coli; it unwinds up to 6,250 base pairs per binding event and hydrolyses slightly more than one ATP molecule per base pair unwound. Here we show, by using a series of gapped oligonucleotide substrates, that this enzyme translocates along only one strand of duplex DNA in the 3'-->5' direction. The translocating enzyme will traverse, or 'step' across, single-stranded DNA gaps in defined steps that are 23 (+/-2) nucleotides in length. This step is much larger than the amount of double-stranded DNA that can be unwound using the free energy derived from hydrolysis of one molecule of ATP, implying that translocation and DNA unwinding are separate events. We propose that the RecBC enzyme both translocates and unwinds by a quantized, two-step, inchworm-like mechanism that may have parallels for translocation by other linear motor proteins.