MiRNA 34a: a therapeutic target for castration-resistant prostate cancer

INTRODUCTION: Development of a therapy for bone metastases is of paramount importance for castration-resistant prostate cancer (CRPC). The osteomimetic properties of CRPC confer a propensity to metastasize to osseous sites. Micro-ribonucleic acid (miRNA) is non-coding RNA that acts as a post-transcriptional regulator of multiple proteins and associated pathways. Therefore identification of miRNAs could reveal a valid third generation therapy for CRPC. Areas covered: miR34a has been found to play an integral role in the progression of prostate cancer, particularly in the regulation of metastatic genes involved in migration, intravasation, extravasation, bone attachment and bone homeostasis. The correlation between miR34a down-regulation and metastatic progression has generated substantial interest in this field. Expert opinion: Examination of the evidence reveals that miR34a is an ideal target for gene therapy for metastatic CRPC. We also conclude that future studies should focus on the effects of miR34a upregulation in CRPC with respect to migration, translocation to bone micro-environment and osteomimetic phenotype development. The success of miR34a as a therapeutic is reliant on the development of appropriate delivery systems and targeting to the bone micro-environment. In tandem with any therapeutic studies, biomarker serum levels should also be ascertained as an indicator of successful miR34a delivery.

Secure Wireless Key Establishment Using Retrodirective Array

In this paper a new method of establishing secret keys for wireless communications is proposed. A retrodirective array (RDA) that is configured to receive and re-transmit at different frequencies is utilized as a relay node. Specifically the analogue RDA is able to respond in ‘real-time’, reducing the required number of time slots for key establishment to two, compared with at least three in previous relay key generation schemes. More importantly, in the proposed architecture equivalent reciprocal wireless channels between legitimate keying nodes can be randomly updated within one channel coherence time period, leading to greatly increased key generation rates (KGRs) in slow fading environment. The secrecy performance of this RDA assisted key generation system is evaluated and it is shown that it outperforms previous relay key generation systems.

Targeting treatment resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01

FKBPL and its peptide derivative, AD-01, have already demonstrated well-established inhibitory effects on breast cancer growth and CD44 dependent anti-angiogenic activity1, 2, 3. Since breast cancer stem cells (BCSCs) are CD44 positive, we wanted to explore if AD-01 could specifically target BCSCs. FKBPL stable overexpression or AD-01 treatment were highly effective at reducing the BCSC population measured by inhibiting mammosphere forming efficiency (MFE) in cell lines and primary breast cancer samples from both solid breast tumours and pleural effusions. Flow cytometry, to assess the ESA+/CD44+/CD24- subpopulation, validated these results. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed across three generations of mammospheres, where mammospheres were completely eradicated by the third generation (p<0.001). Clonogenic assays suggested that AD-01 mediated BCSC differentiation, with a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones. In support of this, the stem cell markers, Nanog and Oct4 were significantly reduced following AD-01 treatment, whilst transfection of FKBPL-targeted siRNAs led to an increase in these markers and in mammosphere forming potential, highlighting the endogenous role of FKBPL in stem cell signalling. The clinical relevance of this was confirmed using a publically available microarray data set (GSE7390), where, high FKBPL and low Nanog expression were independently associated with improved overall survival in breast cancer patients (log rank test p=0.03; hazard ratio=3.01). When AD-01 was combined with other agents, we observed synergistic activity with the Notch inhibitor, DAPT and AD-01 was also able to abrogate a chemo- and radiotherapy induced enrichment in BCSCs. Importantly, using ‘gold standard’ in vivo limiting dilution assays we demonstrated a delay in tumour initiation and reoccurrence in AD-01 treated xenografts. In summary, AD-01 appears to have dual anti-angiogenic and anti-BCSC activity which will be advantageous as this agent enters clinical trial.

Targeting treatment resistant cancer stem cells with FKBPL and its peptide therapeutics

FKBPL and its peptide derivatives have already demonstrated well-established inhibitory effects on cancer growth and CD44-dependent anti-angiogenic activity. Since cancer stem cells (CSCs) are CD44 positive, we wanted to explore if these therapeutics could specifically target CSCs in breast and ovarian cancer. In a tumoursphere assay, FKBPL stable overexpression or FKBPL-based peptide (AD-01, preclinical peptide or ALM201, clinical peptide candidate) treatment were highly effective at reducing the CSC population measured by inhibiting tumoursphere forming efficiency in breast and ovarian cancer cell lines and primary breast cancer samples from both solid breast tumours and pleural effusions. Flow cytometry, to assess the ESA+/CD44+/CD24- and ALDH+ cell subpopulations representative of CSCs, validated these results. The ability of AD-01 and ALM201 to inhibit the self-renewal capacity of CSCs was confirmed across three generations, eradicating CSC completely by the third generation (p<0.001). Furthermore, clonogenic assay demonstrated that FKBPL-based peptides mediated CSC differentiation, with a significant decrease in the number of CSCs or holoclones and an associated increase in differentiated cancer cells or meroclones/paraclones. In addition, AD-01 treatment in vitro and in vivo led to a significant reduction in the stem cell markers, Nanog, Sox2 and Oct4 protein and mRNA levels; whilst transfection of FKBPL-targeted siRNAs led to an increase in these markers and in tumoursphere forming potential, highlighting the endogenous role of FKBPL in stem cell signalling. The clinical relevance of this was confirmed using a publically available microarray data set (GSE7390), where, high FKBPL and low Nanog expression were independently associated with improved overall survival in breast cancer patients (log rank test p=0.03; hazard ratio=3.01). Additionally, when AD-01 was combined with other agents, we observed additive activity with the Notch inhibitor, DAPT and AD-01 was also able to abrogate a chemo- and radiotherapy induced enrichment in CSCs. Importantly, using gold standard in vivo limiting dilution assays we demonstrated a delay in tumour initiation and reoccurrence in AD-01 treated xenografts. In summary, FKBPL-based peptides appear to have dual anti-angiogenic and anti-CSC activity which will be advantageous as this agent enters clinical trial.

Retrodirective Assisted Secure Wireless Key Establishment

In this paper a new type of architecture for secure wireless key establishment is proposed. A retrodirective array (RDA) that is configured to receive and re-transmit at different frequencies is utilized as a relay node. The RDA is able to respond in ‘real-time’, reducing the required number of time slots to two. More importantly, in this architecture equivalent reciprocal wireless channels between legitimate keying nodes can be randomly updated within one channel coherence time period, leading to greatly increased key generation rates (KGRs) in slow fading environment. The secrecy performance of this RDA assisted key generation system is evaluated under several eavesdropping strategies and it is shown that it outperforms previous relay key generation systems.

Optimal generation scheduling of interconnected wind-coal intensive power systems

Large scale wind power generation complicated with restrictions on the tie line plans may lead to significant wind power curtailment and deep cycling of coal units during the valley load periods. This study proposes a dispatch strategy for interconnected wind-coal intensive power systems (WCISs). Wind power curtailment and cycling of coal units are included in the economic dispatch analysis of regional systems. Based on the day-ahead dispatch results, a tie line power plan adjustment strategy is implemented in the event of wind power curtailment or deep cycling occurring in the economic dispatch model, with the objective of reducing such effects. The dispatch strategy is designed based on the distinctive operation characteristics of interconnected WCISs, and dispatch results for regional systems in China show that the proposed strategy is feasible and can improve the overall system operation performance.

Feature recognition & tool path generation for 5 axis step-nc machining of free form / irregular contoured surfaces

This research paper presents a five step algorithm to generate tool paths for machining Free form / Irregular Contoured Surface(s) (FICS) by adopting STEP-NC (AP-238) format. In the first step, a parametrized CAD model with FICS is created or imported in UG-NX6.0 CAD package. The second step recognizes the features and calculates a Closeness Index (CI) by comparing them with the B-Splines / Bezier surfaces. The third step utilizes the CI and extracts the necessary data to formulate the blending functions for identified features. In the fourth step Z-level 5 axis tool paths are generated by adopting flat and ball end mill cutters. Finally, in the fifth step, tool paths are integrated with STEP-NC format and validated. All these steps are discussed and explained through a validated industrial component.

Damping Torque Analysis of Power Systems with DFIGs for Wind Power Generation

A grid-connected DFIG for wind power generation can affect power system small-signal angular stability in two ways: by changing the system load flow condition and dynamically interacting with synchronous generators (SGs). This paper presents the application of conventional method of damping torque analysis (DTA) to examine the effect of DFIG’s dynamic interactions with SGs on the small-signal angular stability. It shows that the effect is due to the dynamic variation of power exchange between the DFIG and power system and can be estimated approximately by the DTA. Consequently, if the DFIG is modelled as a constant power source when the effect of zero dynamic interactions is assumed, the impact of change of load flow brought about by the DFIG can be determined. Thus the total effect of DFIG can be estimated from the result of DTA added on that of constant power source model. Applications of the DTA method proposed in the paper are discussed. An example of multi-machine power systems with grid-connected DFIGs are presented to demonstrate and validate the DTA method proposed and conclusions obtained in the paper.