Mapping the regulatory sequences controlling 93 breast cancer-associated miRNA genes leads to the identification of two functional promoters of the Hsa-mir-200b cluster, methylation of which is associated with metastasis or hormone receptor status in advanced breast cancer

MicroRNAs (miRNAs) are small non-coding RNAs of 20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer-associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located 2 kb upstream of the 5′ stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers.

The emerging role of extracellular vesicle-mediated drug resistance in cancers: Implications in advanced prostate cancer

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

The treatment of recurrent abdominal pain in children : a controlled comparison of cognitive-behavioral family intervention and standard pediatric care

This study describes the results of a controlled clinical trial involving 44 7- to 14-year-old children with recurrent abdominal pain who were randomly allocated to either cognitive-behavioral family intervention (CBFI) or standard pediatric care (SPC). Both treatment conditions resulted in significant improvements on measures of pain intensity and pain behavior. However, the children receiving CBFI had a higher rate of complete elimination of pain, lower levels of relapse at 6- and 12-month follow-up, and lower levels of interference with their activities as a result of pain and parents reported a higher level of satisfaction with the treatment than children receiving SPC. After controlling for pretreatment levels of pain, children's active self-coping and mothers' caregiving strategies were significant independent predictors of pain behavior at posttreatment.

Physics beyond Standard Model: Working group 3 report

This is a summary of the beyond the Standard Model (including model building working group of the WHEPP-X workshop held at Chennai from January 3 to 15, 2008.

Standard errors and covariance matrices for smoothed rank estimators

A 'pseudo-Bayesian' interpretation of standard errors yields a natural induced smoothing of statistical estimating functions. When applied to rank estimation, the lack of smoothness which prevents standard error estimation is remedied. Efficiency and robustness are preserved, while the smoothed estimation has excellent computational properties. In particular, convergence of the iterative equation for standard error is fast, and standard error calculation becomes asymptotically a one-step procedure. This property also extends to covariance matrix calculation for rank estimates in multi-parameter problems. Examples, and some simple explanations, are given.

The standard you walk past is the standard you accept

In his 2013 three-minute speech on unacceptable behaviour in the workplace, Lieutenant General David Morrison makes the above insightful statement. While the context of the speech is the defence force, the meaning of the powerful message holds true for perioperative nursing. Perioperative nurses are part of a profession. Professions Australia, a national organisation of professional associations which aims to advance and promote professionalism for the benefit of the community, provides us with a definition of a profession2 and perioperative nurses meet this definition. Perioperative nurses possess special knowledge and skills grounded in a widely recognised body of discipline knowledge derived from research, education and high-level training. We control and regulate our own boundaries of work. We adhere to ethical and professional standards and values. Specialty professional practice standards define perioperative nurses as a community of professionals — assisting perioperative nurses when advocating for consistency in quality patient care3. It is an imperative for every professional perioperative nurse to model practice underpinned by the ACORN Standards throughout their workplace. Hence, Lieutenant General Morrison’s profound statement is a mantra each perioperative nurse could readily adopt and model in their practice environment...

The vaccination-challenge trial: the gold standard test to evaluate the protective efficacy of infectious coryza vaccines

Infectious coryza is an upper respiratory tract disease of chickens with the major impact occurring in multi-age flocks. We investigated the relationship between the level of antibodies, as detected by a haemagglutination-inhibition (HI) assay, in infectious coryza-vaccinated chickens and the protection against challenge in those chickens. In one experiment, chickens given a single dose of either of two infectious coryza vaccines lacked a detectable HI response to vaccination but showed significant levels of protection 11 weeks after vaccination. In contrast, in chickens given two doses of an infectious coryza vaccine and challenged 3 weeks after the second vaccine dose, there was a strong serological response with 36/40 birds having a HI titre of 1/20 or greater. In this trial there was an apparent relationship between titre and subsequent protection, with none of the 32 chickens with a titre of 1/40 or 1/80 showing any clinical signs and only one of the same group yielding the challenge organism on culture. In contrast, three of the four vaccinated chickens with a HI titre less than 1/5 developed the typical clinical signs of coryza and yielded the challenge organism on culture. Overall, our results suggest that HI titres cannot be regarded as a definitive predictor of vaccine efficacy. We suggest that the vaccination-challenge trial is the gold standard for the evaluation of the immune response to infectious coryza vaccines.

CBCT-guided radiotherapy for locally advanced head and cancer: dosimetric impact of weight loss on VMAT and IMRT plans for selected organs at risk structures (OARs)

Purpose: It is common for head and neck patients to be affected by time trend errors as a result of weight loss during a course of radiation treatment. The objective of this planning study was to investigate the impact of weight loss on Volumetric Modulated Arc Therapy (VMAT) as well as Intensity modulated radiation therapy (IMRT) for locally advanced head and neck cancer using automatic co-registration of the CBCT. Methods and Materials: A retrospective analysis of previously treated IMRT plans for 10 patients with locally advanced head and neck cancer patients was done. A VMAT plan was also produced for all patients. We calculated the dose–volume histograms (DVH) indices for spinal cord planning at risk volumes (PRVs), the brainstem PRVs (SC+0.5cm and BS+0.5cm, respectively) as well as mean dose to the parotid glands. Results: The results show that the mean difference in dose to the SC+0.5cm was 1.03% and 1.27% for the IMRT and VMAT plans, respectively. As for dose to the BS+0.5, the percentage difference was 0.63% for the IMRT plans and 0.61% for the VMAT plans. The analysis of the parotid gland doses shows that the percentage change in mean dose to left parotid was -8.0% whereas that of the right parotid was -6.4% for the IMRT treatment plans. In the VMAT plans, the percentages change for the left and the right parotid glands were -6.6% and -6.7% respectively. Conclusions: This study shows a clinically significant impact of weight loss on DVH indices analysed in head and neck organs at risk. It highlights the importance of adaptive radiotherapy in head and neck patients if organ at risk sparing is to be maintained.

Standard yet unusual mechanisms of long-distance dispersal: Seed dispersal of Corymbia torelliana by bees

Mellitochory, seed dispersal by bees, has been implicated in long-distance dispersal of the tropical rain forest tree, Corymbia torelliana (Myrtaceae). We examined natural and introduced populations of C. torelliana for 4 years to determine the species of bees that disperse seeds, and the extent and distance of seed dispersal. The mechanism of seed dispersal by bees was also investigated, including fruit traits that promote dispersal, foraging behaviour of bees at fruits, and the fate of seeds. The fruit structure of C. torelliana, with seed presented in a resin reward, is a unique trait that promotes seed dispersal by bees and often results in long-distance dispersal. We discovered that a guild of four species of stingless bees, Trigona carbonaria, T. clypearis, T. sapiens, and T. hockingsi, dispersed seeds of C. torelliana in its natural range. More than half of the nests found within 250 m of fruiting trees had evidence of seed transport. Seeds were transported minimum distances of 20-220 m by bees. Approximately 88% of seeds were dispersed by gravity but almost all fruits retained one or two seeds embedded in resin for bee dispersal. Bee foraging for resin peaked immediately after fruit opening and corresponded to a peak of seed dispersal at the hive. There were strong correlations between numbers of seeds brought in and taken out of each hive by bees (r = 0.753-0.992, P < 0.05), and germination rates were 95 ± 5%. These results showed that bee-transported seeds were effectively dispersed outside of the hive soon after release from fruits. Seed dispersal by bees is a non-standard dispersal mechanism for C. torelliana, as most seeds are dispersed by gravity before bees can enter fruits. However, many C. torelliana seeds are dispersed by bees, since seeds are retained in almost all fruits, and all of these are dispersed by bees.

Double-authentication-preventing signatures

Digital signatures are often used by trusted authorities to make unique bindings between a subject and a digital object; for example, certificate authorities certify a public key belongs to a domain name, and time-stamping authorities certify that a certain piece of information existed at a certain time. Traditional digital signature schemes however impose no uniqueness conditions, so a trusted authority could make multiple certifications for the same subject but different objects, be it intentionally, by accident, or following a (legal or illegal) coercion. We propose the notion of a double-authentication-preventing signature, in which a value to be signed is split into two parts: a subject and a message. If a signer ever signs two different messages for the same subject, enough information is revealed to allow anyone to compute valid signatures on behalf of the signer. This double-signature forgeability property discourages signers from misbehaving—a form of self-enforcement—and would give binding authorities like CAs some cryptographic arguments to resist legal coercion. We give a generic construction using a new type of trapdoor functions with extractability properties, which we show can be instantiated using the group of sign-agnostic quadratic residues modulo a Blum integer; we show an additional application of these new extractable trapdoor functions to standard digital signatures.

MOE and MOR assessment technologies for improving graded recovery of exotic pines in Australia.

This project was designed to provide the structural softwood processing industry with the basis for improved green and dry grading to allow maximise MGP grade yields, consistent product performance and reduced processing costs. To achieve this, advanced statistical techniques were used in conjunction with state-of-the-art property measurement systems. Specifically, the project aimed to make two significant steps forward for the Australian structural softwood industry: • assessment of technologies, both existing and novel, that may lead to selection of a consistent, reliable and accurate device for the log yard and green mill. The purpose is to more accurately identify and reject material that will not make a minimum grade of MGP10 downstream; • improved correlation of grading MOE and MOR parameters in the dry mill using new analytical methods and a combination of devices. The three populations tested were stiffness-limited radiata pine, strength-limited radiata pine and Caribbean pine. Resonance tests were conducted on logs prior to sawmilling, and on boards. Raw data from existing in-line systems were captured for the green and dry boards. The dataset was analysed using classical and advanced statistical tools to provide correlations between data sets and to develop efficient strength and stiffness prediction equations. Stiffness and strength prediction algorithms were developed from raw and combined parameters. Parameters were analysed for comparison of prediction capabilities using in-line parameters, off-line parameters and a combination of in-line and off-line parameters. The results show that acoustic resonance techniques have potential for log assessment, to sort for low stiffness and/or low strength, depending on the resource. From the log measurements, a strong correlation was found between the average static MOE of the dried boards within a log and the predicted value. These results have application in segregating logs into structural and non-structural uses. Some commercial technologies are already available for this application such as Hitman LG640. For green boards it was found that in-line and laboratory acoustic devices can provide a good prediction of dry static MOE and moderate prediction for MOR.There is high potential for segregating boards at this stage of processing. Grading after the log breakdown can improve significantly the effectiveness of the mill. Subsequently, reductions in non-structural volumes can be achieved. Depending on the resource it can be expected that a 5 to 8 % reduction in non structural boards won’t be dried with an associated saving of $70 to 85/m3. For dry boards, vibration and a standard Metriguard CLT/HCLT provided a similar level of prediction on stiffness limited resource. However, Metriguard provides a better strength prediction in strength limited resources (due to this equipment’s ability to measure local characteristics). The combination of grading equipment specifically for stiffness related predictors (Metriguard or vibration) with defect detection systems (optical or X-ray scanner) provides a higher level of prediction, especially for MOR. Several commercial technologies are already available for acoustic grading on board such those from Microtec, Luxscan, Falcon engineering or Dynalyse AB for example. Differing combinations of equipment, and their strategic location within the processing chain, can dramatically improve the efficiency of the mill, the level of which will vary depending of the resource. For example, an initial acoustic sorting on green boards combined with an optical scanner associated with an acoustic system for grading dry board can result in a large reduction of the proportion of low value low non-structural produced. The application of classical MLR on several predictors proved to be effective, in particular for MOR predictions. However, the usage of a modern statistics approach(chemometrics tools) such as PLS proved to be more efficient for improving the level of prediction. Compared to existing technologies, the results of the project indicate a good improvement potential for grading in the green mill, ahead of kiln drying and subsequent cost-adding processes. The next stage is the development and refinement of systems for this purpose.

Advanced practice: A survey of current perspectives of Australian pharmacists

Background An Advanced Pharmacy Practice Framework for Australia (the ‘APPF’) was published in October 2012. Further to the release of the APPF, the Advanced Pharmacy Practice Framework Steering Committee planned to develop an advanced practice recognition model for Australian pharmacists. Aim To gauge the perspectives of the pharmacy profession relating to advanced practice, via an online survey, in order to inform the design of the model. Method A survey was developed and administered to Australian pharmacists through SurveyMonkey . The survey content was based on findings from a review of national and international initiatives for recognition of advanced practice in pharmacy and other health disciplines, including medicine and nursing. Results The results of the survey showed that a high proportion of respondents considered they were already working at, or working towards achieving, an advanced level of practice. The responses relating to the assessment methods showed a clear preference for ‘submission of a professional portfolio’. A ‘written examination’ had a low level of support and in relation to an ‘oral examination by a panel’ there was a marked preference for a panel of multidisciplinary health professionals over a panel of pharmacists. Conclusion The survey outcomes will inform the development of an advanced pharmacy practice recognition model for Australian pharmacists, particularly in relation to the assessment methods. Survey outcomes also demonstrated that there is scope to further enhance the application of the APPF in the development and recognition of advanced practitioners, and to build greater awareness of the breadth of competencies encompassed by ‘advanced practice’.

An Advanced Pharmacy Practice Framework for Australia

The need to develop An Advanced Pharmacy Practice Framework for Australia (the “APPF”) was identified during the 2010 review of the competency standards for Australian pharmacists. The Advanced Pharmacy Practice Framework Steering Committee, a collaborative profession-wide committee comprised of representatives of ten pharmacy organisations, examined and adapted existing advanced practice frameworks, all of which were found to have been based on the Competency Development and Evaluation Group (CoDEG) Advanced and Consultant Level Framework (the “CoDEG Framework”) from the United Kingdom. Its competency standards were also found to align well with the Domains of the National Competency Standards Framework for Pharmacists in Australia (the “National Framework”). Adaptation of the CoDEG Framework created an APPF that is complementary to the National Framework, sufficiently flexible to customise for recognising advanced practice in any area of professional practice and has been approved by the boards/councils of all participating organisations. The primary purpose of the APPF is to assist the development of the profession to meet the changing health care needs of the community. However, it is also a valuable tool for assuring members of the public of the competence of an advanced practice pharmacist and the quality and safety of the services they deliver.

Australian pharmacists' self-perceptions in relation to the 'Advanced Pharmacy Practice Framework'

Background The Australian Pharmacy Practice Framework was developed by the Advanced Pharmacy Practice Steering Committee and endorsed by the Pharmacy Board of Australia in October 2012. The Steering Committee conducted a study that found practice portfolios to be the preferred method to assess and credential Advanced Pharmacy Practitioner, which is currently being piloted by the Australian Pharmacy Council. Credentialing is predicted to open to all pharmacists practising in Australia by November 2015. Objective To explore how Australian pharmacists self-perceived being advanced in practice and how they related their level of practice to the Australian Advanced Pharmacy Practice Framework. Method This was an explorative, cross-sectional study with mixed methods analysis. Advanced Pharmacy Practice Framework, a review of the recent explorative study on Advanced Practice conducted by the Advanced Pharmacy Practice Framework Steering Committee and semi-structured interviews (n = 10) were utilized to create, refine and pilot the questionnaire. The questionnaire was advertised across pharmacy-organizational websites via a purposive sampling method. The target population were pharmacists currently registered in Australia. Results Seventy-two participants responded to the questionnaire. The participants were mostly female (56.9%) and in the 30–40 age group (26.4%). The pharmacists self-perceived their levels of practice as either entry, transition, consolidation or advanced, with the majority selecting the consolidation level (38.9%). Although nearly half (43.1%) of the participants had not seen the Framework beforehand, they defined Advanced Pharmacy Practice similarly to the definition outlined in the Framework, but also added specialization as a requirement. Pharmacists explained why they were practising at their level of practice, stating that not having more years of practice, lacking experience, or postgraduate/post-registration qualifications, and more involvement and recognition in practice were the main reasons for not considering themselves as an Advanced Pharmacy Practitioner. To be considered advanced by the Framework, pharmacists would need to fulfill at least 70% of the Advanced Practice competency standards at an advanced level. More than half of the pharmacists (64.7%) that self-perceived as being advanced managed to fulfill 70% or more of these Advanced Practice competency standards at the advanced level. However, none of the self-perceived entry level pharmacists managed to match at least 70% of the competencies at the entry level. Conclusion Participants' self-perception of the term Advanced Practice was similar to the definition in the Advanced Pharmacy Practice Framework. Pharmacists working at an advanced level were largely able to demonstrate and justify their reasons for being advanced practitioners. However, pharmacists practising at the other levels of practice (entry, transition, consolidation) require further guidance regarding their advancement in practice.