Ro 31-6045, the inactive analogue of the protein kinase C inhibitor Ro 31-8220, blocks in vivo activation of p70s6k/p85s6k: implications for the analysis of S6K signalling

AbstractThe mitogen-stimulated protein kinase p70s6k/p85s6k (S6K) plays an essential role in cell proliferation and growth, with inhibitors of the S6K signalling pathway showing promise as anti-tumour therapeutics. Here, we report that the bisindolylmaleimide derivative Ro 31-6045, previously reported to be inactive as a kinase inhibitor, inhibited S6K activity in vivo with an IC50=8 μM. Structure/function analysis using mutant forms of S6K indicates that Ro 31-6045 inhibition is independent of the upstream activator mTOR. Ro 31-6045 will prove useful in elucidating the complex activation mechanism of S6K and its independence from mTOR will allow confirmation of functional data obtained using the mTOR inhibitor rapamycin

AKT-independent PI3-K signaling in cancer - emerging role for SGK3

The phosphoinositide 3-kinase (PI3-K) signaling pathway plays an important role in a wide variety of fundamental cellular processes, largely mediated via protein kinase B/v-akt murine thymoma viral oncogene homolog (PKB/AKT) signaling. Given the crucial role of PI3-K/AKT signaling in regulating processes such as cell growth, proliferation, and survival, it is not surprising that components of this pathway are frequently dysregulated in cancer, making the AKT kinase family members important therapeutic targets. The large number of clinical trials currently evaluating PI3-K pathway inhibitors as a therapeutic strategy further emphasizes this. The serum- and glucocorticoid-inducible protein kinase (SGK) family is made up of three isoforms, SGK1, 2, and 3, that are PI3-K-dependent, serine/threonine kinases, with similar substrate specificity to AKT. Consequently, the SGK family also regulates similar cell processes to the AKT kinases, including cell proliferation and survival. Importantly, there is emerging evidence demonstrating that SGK3 plays a critical role in AKT-independent oncogenic signaling. This review will focus on the role of SGK3 as a key effector of AKT-independent PI3-K oncogenic signaling

Therapeutic Approaches Targeting MYC-Driven Prostate Cancer

The transcript encoding the proto-oncogene MYC is commonly overexpressed in prostate cancer (PC). MYC protein abundance is also increased in the majority of cases of advanced and metastatic castrate-resistant PC (mCRPC). Accordingly, the MYC-directed transcriptional program directly contributes to PC by upregulating the expression of a number of pro-tumorigenic factors involved in cell growth and proliferation. A key cellular process downstream of MYC activity is the regulation of ribosome biogenesis which sustains tumor growth. MYC activity also cooperates with the dysregulation of the phosphoinositol-3-kinase (PI3K)/AKT/mTOR pathway to promote PC cell survival. Recent advances in the understanding of these interactions through the use of animal models have provided significant insight into the therapeutic efficacy of targeting MYC activity by interfering with its transcriptional program, and indirectly by targeting downstream cellular events linked to MYC transformation potentialThis work was supported by Cancer Australia (CA 1084546 to Ross D. Hannan, Richard B. Pearson, and Luc Furic); Prostate Cancer Foundation of Australia (YI 0310 to Luc Furic and CG 1511 to Richard B. Pearson, Ross D. Hannan, and Luc Furic); National Health and Medical Research Council (Program Grant 1053792 and Project Grant 1004881 to R.B. Pearson and Ross D. Hannan; Senior Research Fellowships to Richard B. Pearson and Ross D. Hannan) and the Department of Health and Human Services acting through the Victorian Cancer Agency (MCRF16007 to Luc Furic)

Frequent expansion of Plasmodium vivax Duffy Binding Protein in Ethiopia and its epidemiological significance.

Plasmodium vivax invasion of human erythrocytes depends on the Duffy Binding Protein (PvDBP) which interacts with the Duffy antigen. PvDBP copy number has been recently shown to vary between P. vivax isolates in Sub-Saharan Africa. However, the extent of PvDBP copy number variation, the type of PvDBP multiplications, as well as its significance across broad samples are still unclear. We determined the prevalence and type of PvDBP duplications, as well as PvDBP copy number variation among 178 Ethiopian P. vivax isolates using a PCR-based diagnostic method, a novel quantitative real-time PCR assay and whole genome sequencing. For the 145 symptomatic samples, PvDBP duplications were detected in 95 isolates, of which 81 had the Cambodian and 14 Malagasy-type PvDBP duplications. PvDBP varied from 1 to >4 copies. Isolates with multiple PvDBP copies were found to be higher in symptomatic than asymptomatic infections. For the 33 asymptomatic samples, PvDBP was detected with two copies in two of the isolates, and both were the Cambodian-type PvDBP duplication. PvDBP copy number in Duffy-negative heterozygotes was not significantly different from that in Duffy-positives, providing no support for the hypothesis that increased copy number is a specific association with Duffy-negativity, although the number of Duffy-negatives was small and further sampling is required to test this association thoroughly

An oxygen isotope test for the origin of Archean mantle roots

The origin of the peridotites that form cratonic mantle roots is a central issue in understanding the history and survival of Earth’s oldest continents. A long-standing hypothesis holds that the unusual bulk compositions of some cratonic peridotites stem from their origin as subducted oceanic serpentinite, dehydrated during subduction to form rigid buoyant keels (Schulze, 1986; Canil and Lee, 2009). We present oxygen isotope data from 93 mantle peridotites from five different Archean cratons to evaluate their possible origin as serpentinites. Cratonic mantle peridotite shows remarkably uniform δ18O values, identical to modern MORB-source mantle, that do not vary with bulk rock Si-enrichment or Ca-depletion. These data clearly conflict with any model for cratonic lithosphere that invokes serpentinite as a protolith for cratonic peridotite, and place additional constraints on cratonic mantle origins. We posit that the uniform δ18O was produced by sub-arc and/or MOR depletion processes and that the Si-enriched nature of some samples is unlikely to be related to slab melt infiltration. Instead, we suggest a peridotitic source of Si-enrichment, derived from ascending mantle melts, or a water-fluxed depleted mantle. These variably Si-enriched, cratonic mantle protoliths were then collisionally compressed into the thick cratonic roots that have protected Earth’s oldest continental crust for over 2.5 Gyr

List of Tasmanian Hepaticae

List of sixty Tasmanian Hepaticae collected by R. A. Bastow, Esq., F.L.S., near Hobart, at Mt Wellington, Mount Nelson, Proctors Road, Huon Road, Jonathans Track, St. Crispin’s Well, and Wellington Falls, Tasmania, 1885-6 ; and catalogued by B. Carrington, M.D., E.E.S.E., and W. H. Pearson, from Eccles, England

Description of new or rare Tasmanian Hepaticae

Eight new species of Tasmanian Hepaticae, with accompanying detailed botanical drawings, collected by Richard Bastow from Mount Knocklofty, Mount Wellington and St Crispin's Well, Hobart. Specimens are described in great detail and by Carrington and Pearson. Includes Plates XXXVI - XLII

Relative Expression Levels Rather Than Specific Activity Plays the Major Role in Determining In Vivo AKT Isoform Substrate Specificity

The AKT protooncogene mediates many cellular processes involved in normal development and disease states such as cancer. The three structurally similar isoforms: AKT1, AKT2, and AKT3 exhibit both functional redundancy and isoform-specific functions; however the basis for their differential signalling remains unclear. Here we show that in vitro, purified AKT3 is ∼47-fold more active than AKT1 at phosphorylating peptide and protein substrates. Despite these marked variations in specific activity between the individual isoforms, a comprehensive analysis of phosphorylation of validated AKT substrates indicated only subtle differences in signalling via individual isoforms in vivo. Therefore, we hypothesise, at least in this model system, that relative tissue/cellular abundance, rather than specific activity, plays the dominant role in determining AKT substrate specificity in situ

Tritium supply and use: a key issue for the development of nuclear fusion energy

Full power operation of the International Thermonuclear Experimental Reactor (ITER) has been delayed and will now begin in 2035. Delays to the ITER schedule may affect the availability of tritium for subsequent fusion devices, as the global CANDU-type fission reactor fleet begins to phase out over the coming decades. This study provides an up to date account of future tritium availability by incorporating recent uncertainties over the life extension of the global CANDU fleet, as well as considering the potential impact of tritium demand by other fusion efforts. Despite the delays, our projections suggest that CANDU tritium remains sufficient to support the full operation of ITER. However, whether there is tritium available for a DEMO reactor following ITER is largely uncertain, and is subject to numerous uncontrollable externalities. Further tritium demand may come from any number of private sector “compact fusion” start-ups which have emerged in recent years, all of which aim to accelerate the development of fusion energy. If the associated technical challenges can be overcome, compact fusion programmes have the opportunity to use tritium over the next two decades whilst it is readily available, and before full power DT operation on ITER starts in 2035. Assuming a similar level of performance is achievable, a compact fusion development programme, using smaller reactors operating at lower fusion power, would require smaller quantities of tritium than the ITER programme, leaving sufficient tritium available for multiple concepts to be developed concurrently. The development of concurrent fusion concepts increases the chances of success, as it spreads the risk of failure. Additionally, if full tritium breeding capability is not expected to be demonstrated in DEMO until after 2050, an opportunity exists for compact fusion programmes to incorporate tritium breeding technology in nearer-term devices. DD start-up, which avoids the need for external tritium for reactor start-up, is dependent upon full tritium breeding capability, and may be essential for large-scale commercial roll-out of fusion energy. As such, from the standpoint of availability and use of external tritium, a compact route to fusion energy may be more advantageous, as it avoids longer-term complications and uncertainties in the future supply of tritium