Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells

: The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity

miR-10b*, a master inhibitor of the cell cycle, is down-regulated in human breast tumours

Deregulated proliferation is a hallmark of cancer cells. Here, we show that microRNA-10b* is a master regulator of breast cancer cell proliferation and is downregulated in tumoural samples versus matched peritumoural counterparts. Two canonical CpG islands (5kb) upstream from the precursor sequence are hypermethylated in the analysed breast cancer tissues. Ectopic delivery of synthetic microRNA-10b* in breast cancer cell lines or into xenograft mouse breast tumours inhibits cell proliferation and impairs tumour growth in vivo, respectively. We identified and validated in vitro and in vivo three novel target mRNAs of miR-10b* (BUB1, PLK1 and CCNA2), which play a remarkable role in cell cycle regulation and whose high expression in breast cancer patients is associated with reduced disease-free survival, relapse-free survival and metastasis-free survival when compared to patients with low expression. This also suggests that restoration of microRNA-10b* expression might have therapeutic promise

Targeted disruption of the extracellular polymeric network of Pseudomonas aeruginosa biofilms by alginate oligosaccharides

Acquisition of a mucoid phenotype by Pseudomonas sp. in the lungs of cystic fibrosis (CF) patients, with subsequent over-production of extracellular polymeric substance (EPS), plays an important role in mediating the persistence of multi-drug resistant (MDR) infections. The ability of a low molecular weight (Mn=3200 g mol-1) alginate oligomer (OligoG CF-5/20) to modify biofilm structure of mucoid Pseudomonas aeruginosa (NH57388A) was studied in vitro using scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM) with Texas Red (TxRd®)-labelled OligoG and EPS histochemical staining. Structural changes in treated biofilms were quantified using COMSTAT image-analysis software of CLSM z-stack images, and nanoparticle diffusion. Interactions between the oligomers, Ca2+ and DNA were studied using molecular dynamics simulations (MDS), Fourier transform infrared spectroscopy (FTIR) and isothermal titration calorimetry (ITC). Imaging demonstrated that OligoG treatment (>0.5%) inhibited biofilm formation, demonstrating a significant reduction in both biomass and biofilm height (17.8 vs. 5.5 µm; P <0.05). TxRd®-labelled oligomers readily diffused into established (24 h) biofilms. OligoG treatment (≥2%) induced alterations in the EPS of established biofilms; significantly reducing the structural quantities of sugar residues, and extracellular (e)DNA (P <0.05) with a corresponding increase in nanoparticle diffusion (P<0.05) and antibiotic efficacy against established biofilms. ITC demonstrated an absence of rapid complex formation between DNA and OligoG and confirmed the interactions of OligoG with Ca2+ evident in FTIR and MDS. The ability of OligoG to diffuse into biofilms, potentiate antibiotic activity, disrupt DNA-Ca2+-DNA bridges and biofilm EPS matrix highlights its potential for the treatment of biofilm-related infections

Performance Evaluation of an Optical Packet Switch equipped with FRWCs and LRWCs Shared per Output Fiber

An optical packet switch that shares wavelength converters for contention resolution is introduced. The sharing is partial and both limited and full range wavelength converters are used in the pool of converters shared in each Output Fiber. A parallel scheduling algorithm is defined to manage the optical packet forwarding and the wavelength converters. Performance are evaluated by means of an accurate analytical model validated through simulation

Switching Node with Load Balancing Bursts of Packets

A packet switching node is coupled by links to other nodes of a network, and receives and assembles (74) packets belonging to a specified packet flow, into bursts of packets with a burst control packet indicating a sequence of the burst in the flow. The node determines (78) whether to distribute the flow across several links. If so, the bursts are then forwarded (80) for switching to the output ports (160) of the selected links. Distributing the flow over multiple links can enable more flexible and efficient filling of allocated bandwidth on links, as traffic increases. To reduce the risk of losing the order of packets the sequence of the bursts is indicated for use in reordering at intermediate nodes during transmission through the network

Cost Evaluation of Packet Switches equipped with Limited-Range and Full-Range Converters for Contention Resolution

Two architectures are proposed for a wavelength-division multiplexed optical packet switch equipped with both limited-range wavelength converters (LRWCs) and shared full-range wavelength converters (FRWCs). The FRWCs are used to overcome the performance degradation in terms of packet loss probability due to the use of LRWCs only. Two different sharing strategies of the FRWCs are considered. In the first architecture, a pool of FRWCs is shared among the arriving packets. In the second one, the sharing is only partial and the packets directed to the same output share a same pool of FRWCs. A probabilistic model is proposed to dimension the number of shared FRWCs so that the same packet loss probability of a switch equipped with only shared FRWCs is guaranteed. After introducing a cost model of the converters depending on the conversion range, we show that the architectures may allow a conversion cost savings on the order of 90%

An Analytical Model to Optimally Dimension Resources in OPS Equipped with Heterogeneous Wavelength Converters

An optical packet switch that shares both limited range and full range wavelength converters for contention resolution is proposed with the aim to guarantee an high conversion cost saving. To optimally dimension the number and the conversion range of the wavelength converters, an analytical model, validated by simulation, is introduced to evaluate the packet loss probability of the switch. Numerical results show that the proposed switch architecture allows for a conversion cost saving in the order of 90% with respect to a classical architecture in which only shared full range wavelength converters are used

Cost Evaluation of Optical Packet Switches Using Both Limited-Range and Full-Range Converters for Contention Resolution

An architecture is proposed for a wavelength division multiplexed (WDM) optical packet switch equipped with both limited range wavelength converters (LRWCs) and shared full range wavelength converters (FRWCs). The FRWCs are used to overcome the performance degradation in terms of packet loss probability due to the use of LRWCs only. A probabilistic model is proposed to dimension the number of shared FRWCs so that the same packet loss probability of a switch equipped with only shared FRWCs is guaranteed. After introducing a cost model of the converters depending on the range conversion, we show that the architecture may allow conversion cost saving in the order of 85%