Indirect comparisons of brigatinib and alectinib for front-line ALK-positive non-small-cell lung cancer.

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naive ALK-positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK-positive NSCLC.

Patients with advanced non-small-cell lung cancer (NSCLC) who have a genetic marker called rearrangement in the anaplastic lymphoma kinase, or ALK-positive disease, are treated with targeted medications taken by mouth. Two medications, alectinib and brigatinib, are both considered first-line treatment for these patients but have not been compared head-to-head. Recently, updated clinical trial results were published for these medications. The present study utilized these updated results and advanced statistical tests to indirectly compare the effectiveness of the two treatments to help guide clinical treatment choices. Results showed brigatinib and alectinib have a similar magnitude of effect in decreasing the risk of a patient with ALK-positive NSCLC developing worsening disease.

Overall survival indirect treatment comparison between brigatinib and alectinib for the treatment of front-line anaplastic lymphoma kinase-positive non-small cell lung cancer using data from ALEX and final results from ALTA-1L.

BACKGROUND: Second-generation anaplastic lymphoma kinase (ALK) gene targeted tyrosine kinase inhibitors (TKIs) alectinib and brigatinib have shown efficacy as front-line treatments for ALK-positive non-small cell lung cancer (NSCLC). No head-to-head data are currently available for brigatinib vs alectinib in the ALK-TKI-naive population. OBJECTIVE: To estimate the relative overall survival (OS) for brigatinib vs alectinib with indirect treatment comparisons (ITCs) using ALEX and ALTA-1L clinical trial data. METHODS: The latest aggregate data from the ALEX trial and final patient-level data from ALTA-1L were used. ITCs were conducted with/without treatment crossover adjustments to estimate relative OS. Bucher methods, anchored matching-adjusted indirect comparisons (MAICs) and unanchored MAICs were employed in ITCs without treatment crossover adjustments. An inverse probability of censoring weight Cox model, a marginal structure model and rank-preserving structural failure time models (with/without re-censoring) within an anchored MAIC were used in ITCs with treatment crossover adjustments. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. RESULTS: HRs for brigatinib vs alectinib for relative OS generated from ITCs without treatment crossover adjustments ranged from 0.90 (95% CI: 0.59-1.38) in the unanchored MAIC to 1.20 (95% CI: 0.69-2.11) using the Bucher method. Methods employing treatment switching adjustments estimated HRs for relative OS ranging from 0.74 (95% CI: 0.38-1.45) to 1.11 (95% CI: 0.63-1.94). Results from all ITCs did not indicate statistically different survival profiles. CONCLUSION: Regardless of ITC methodology, OS is comparable for brigatinib vs alectinib in patients with ALK+ NSCLC previously untreated with an ALK inhibitor.

Hydrophilic protein associated with desiccation tolerance exhibits broad protein stabilization function.

The ability of certain plants, invertebrates, and microorganisms to survive almost complete loss of water has long been recognized, but the molecular mechanisms of this phenomenon remain to be defined. One phylogenetically widespread adaptation is the presence of abundant, highly hydrophilic proteins in desiccation-tolerant organisms. The best characterized of these polypeptides are the late embryogenesis abundant (LEA) proteins, first described in plant seeds >20 years ago but recently identified in invertebrates and bacteria. The function of these largely unstructured proteins has been unclear, but we now show that a group 3 LEA protein from the desiccation-tolerant nematode Aphelenchus avenae is able to prevent aggregation of a wide range of other proteins both in vitro and in vivo. The presence of water is essential for maintenance of the structure of many proteins, and therefore desiccation stress induces unfolding and aggregation. The nematode LEA protein is able to abrogate desiccation-induced aggregation of the water-soluble proteomes from nematodes and mammalian cells and affords protection during both dehydration and rehydration. Furthermore, when coexpressed in a human cell line, the LEA protein reduces the propensity of polyglutamine and polyalanine expansion proteins associated with neurodegenerative diseases to form aggregates, demonstrating in vivo function of an LEA protein as an antiaggregant. Finally, human cells expressing LEA protein exhibit increased survival of dehydration imposed by osmotic upshift, consistent with a broad protein stabilization function of LEA proteins under conditions of water stress.

Elucidation of the Streptomyces coelicolor pathway to 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde, an intermediate in prodiginine biosynthesis.

The biosynthetic pathway to 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC), a key intermediate in the biosynthesis of prodiginine antibiotics in Streptomyces coelicolor, has been elucidated using a combination of gene replacements and feeding experiments with chemically synthesised MBC and a synthetic analogue of a pathway intermediate.

LEA proteins prevent protein aggregation due to water stress.

LEA (late embryogenesis abundant) proteins in both plants and animals are associated with tolerance to water stress resulting from desiccation and cold shock. However, although various functions of LEA proteins have been proposed, their precise role has not been defined. Recent bioinformatics studies suggest that LEA proteins might behave as molecular chaperones, and the current study was undertaken to test this hypothesis. Recombinant forms of AavLEA1, a group 3 LEA protein from the anhydrobiotic nematode Aphelenchus avenae, and Em, a group 1 LEA protein from wheat, have been subjected to functional analysis. Heat-stress experiments with citrate synthase, which is susceptible to aggregation at high temperatures, suggest that LEA proteins do not behave as classical molecular chaperones, but they do exhibit a protective, synergistic effect in the presence of the so-called chemical chaperone, trehalose. In contrast, both LEA proteins can independently protect citrate synthase from aggregation due to desiccation and freezing, in keeping with a role in water-stress tolerance; similar results were obtained with lactate dehydrogenase. This is the first evidence of anti-aggregation activity of LEA proteins due to water stress. Again, a synergistic effect of LEA and trehalose was observed, which is significant given that non-reducing disaccharides are known to accumulate during dehydration in plants and nematodes. A model is proposed whereby LEA proteins might act as a novel form of molecular chaperone, or 'molecular shield', to help prevent the formation of damaging protein aggregates during water stress.

Perioperative oxygen toxicity.

This article challenges the use of hyperoxia in the perioperative period. It describes the biochemical and physiologic basis for both the direct and indirect adverse effects of oxygen. The reasons for using hyperoxia in the perioperative period are critically evaluated, and the evidence and guidelines for oxygen use in common acute medical conditions are reviewed.

Mechanisms for incorporation of glycerol-derived precursors into polyketide metabolites.

Several polyketide secondary metabolites are shown by feeding experiments to incorporate glycerol-derived 3-carbon starter units, 2-carbon extender units, or 3-carbon branches into their hydrocarbon chains. In recent years, genetic studies have begun to elucidate the mechanisms by which this occurs. In this article we review the incorporation of glycerol-derived precursors into polyketides and propose new mechanisms for the incorporation processes.

Molecular anhydrobiology: identifying molecules implicated in invertebrate anhydrobiosis.

Studies in anhydrobiotic plants have defined many genes which are upregulated during desiccation, but comparable studies in invertebrates are at an early stage. To develop a better understanding of invertebrate anhydrobiosis, we have begun to characterise dehydration-inducible genes and their proteins in anhydrobiotic nematodes and bdelloid rotifers; this review emphasises recent findings with a hydrophilic nematode protein. Initial work with the fungivorous nematode Aphelenchus avenae led to the identification of two genes, both of which were markedly induced on slow drying (90-98% relative humidity, 24 hr) and also by osmotic stress, but not by heat or cold or oxidative stresses. The first of these genes encodes a novel protein we have named anhydrin; it is a small, basic polypeptide, with no counterparts in sequence databases, which is predicted to be natively unstructured and highly hydrophilic. The second is a member of the Group 3 LEA protein family; this and other families of LEA proteins are widely described in plants, where they are most commonly associated with the acquisition of desiccation tolerance in maturing seeds. Like anhydrin, the nematode LEA protein, Aav-LEA-1, is highly hydrophilic and a recombinant form has been shown to be unstructured in solution. In vitro functional studies suggest that Aav-LEA-1 is able to stabilise other proteins against desiccation-induced aggregation, which is in keeping with a role of LEA proteins in anhydrobiosis. In vivo, however, Aav-LEA-1 is apparently processed into smaller forms during desiccation. A processing activity was found in protein extracts of dehydrated, but not hydrated, nematodes; these shorter polypeptides are also active anti-aggregants and we hypothesise that processing LEA protein serves to increase the number of active molecules available to the dehydrating animal. Other LEA-like proteins are being identified in nematodes and it seems likely therefore that they will play a major role in the molecular anhydrobiology of invertebrates, as they are thought to do in plants.