Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1^−/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1^+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.Subject terms: Targeted therapies, Non-small-cell lung cancer     

A RAPID BIOASSAY TO DETECT MYCOTOXINS USING A MELANIN PRECURSOR OVERPRODUCER MUTANT OF THE CILIATETETRAHYMENA THERMOPHILA

Four different mycotoxins (patulin, T-2 toxin, diacetoxyscirpenol and roquefortine) were used to study growth inhibitory effects on a melanin precursor overproducer mutant of the ciliateTetrahymena thermophilaThis strain is especially sensitive to diacetoxyscirpenol and T-2 toxin. The secretion capacity of melanin precursors into the culture medium by this mutant and its biosensor capacity are very useful characteristics to elaborate a rapid bioassay to detect some specific mycotoxins.     

A minimal spliceosomal complex A recognizes the branch site and polypyrimidine tract.

The association of U2 snRNP with the pre-mRNA branch region is a critical step in the assembly of spliceosomal complexes. We describe an assembly process that reveals both minimal requirements for formation of a U2 snRNP-substrate RNA complex, here designated the Amin complex, and specific interactions with the branch site adenosine. The substrate is a minimal RNA oligonucleotide, containing only a branch sequence and polypyrimidine tract. Interactions at the branch site adenosine and requirements for polypyrimidine tract-binding proteins for the Amin complex are the same as those of authentic prespliceosome complex A. Surprisingly, Amin complex formation does not require U1 snRNP or ATP, suggesting that these factors are not necessary for stable binding of U2 snRNP per se, but rather are necessary for accessibility of components on longer RNA substrates. Furthermore, there is an ATP-dependent activity that releases or destabilizes U2 snRNP from branch sequences. The simplicity of the Amin complex will facilitate a detailed understanding of the assembly of prespliceosomes.     

GABAergic modulation of primary gustatory afferent synaptic efficacy

Modulation of synaptic transmission at the primary sensory afferent synapse is well documented for the somatosensory and olfactory systems. The present study was undertaken to test whether GABA impacts on transmission of gustatory information at the primary afferent synapse. In goldfish, the vagal gustatory input terminates in a laminated structure, the vagal lobes, whose sensory layers are homologous to the mammalian nucleus of the solitary tract. We relied on immunoreactivity for the GABA-transporter, GAT-1, to determine the distribution of GABAergic synapses in the vagal lobe. Immunocytochemistry showed dense, punctate GAT-1 immunoreactivity coincident with the layers of termination of primary afferent fibers. The laminar nature and polarized dendritic structure of the vagal lobe make it amenable to an in vitro slice preparation to study early synaptic events in the transmission of gustatory input. Electrical stimulation of the gustatory nerves in vitro produces synaptic field potentials (fEPSPs) predominantly mediated by ionotropic glutamate receptors. Bath application of either the GABA(A) receptor agonist muscimol or the GABA(B) receptor agonist baclofen caused a nearly complete suppression of the primary fEPSP. Coapplication of the appropriate GABA(A) or GABA(B) receptor antagonist bicuculline or CGP-55845 significantly reversed the effects of the agonists. These data indicate that GABAergic terminals situated in proximity to primary gustatory afferent terminals can modulate primary afferent input via both GABA(A) and GABA(B) receptors. The mechanism of action of GABA(B) receptors suggests a presynaptic locus of action for that receptor.     

Home range, association and related aspects of elephants in the eastern Transvaal Lowveld

Home range and association patterns of elephants Loxodonta africana in private nature reserves adjacent to the Kruger National Park, South Africa, were determined over a period of six years by using radio telemetry. The minimum convex polygon (MCP) and harmonic mean (HM) methods were used for data processing. The minimum and maximum range areas required by females were estimated at 115 and 465 km², respectively, whilst those of males varied between 157 and 342 km². Core areas of females comprised on average 10·1% of the range areas as calculated by the MCP method. Range areas between females in the Klaserie and Timbavati Private Nature Reserves differed significantly. A significant difference in range size was also found between the male population (pooled data) and the females of the Klaserie Private Nature Reserve. Range areas increased from the wet to the dry season. Three male elephant categories were established, namely males utilizing the same area during the study period, those who shifted their range areas and individuals with very large range areas which frequented the area on an irregular basis. A loose relationship existed between males. Association between females can be attributed to kinship and not to the overlapping of range areas. Results indicated avoidance behaviour between females in their core areas, which might partially explain the ability of elephants to tolerate high densities. It is concluded that male elephant hunting should be approached with caution.