Role of intratumoural heterogeneity in cancer drug resistance : molecular and clinical perspectives

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.

Using police crash databases for injury prevention research - a comparison of opt-out and opt-in approaches to study recruitment

Objective: The study aimed to examine the difference in response rates between opt-out and opt-in participant recruitment in a population-based study of heavy-vehicle drivers involved in a police-attended crash. Methods: Two approaches to subject recruitment were implemented in two different states over a 14-week period and response rates for the two approaches (opt-out versus opt-in recruitment) were compared. Results: Based on the eligible and contactable drivers, the response rates were 54% for the optout group and 16% for the opt-in group. Conclusions and Implications: The opt-in recruitment strategy (which was a consequence of one jurisdiction’s interpretation of the national Privacy Act at the time) resulted in an insufficient and potentially biased sample for the purposes of conducting research into risk factors for heavy-vehicle crashes. Australia’s national Privacy Act 1988 has had a long history of inconsistent practices by state and territory government departments and ethical review committees. These inconsistencies can have profound effects on the validity of research, as shown through the significantly different response rates we reported in this study. It is hoped that a more unified interpretation of the Privacy Act across the states and territories, as proposed under the soon-to-be released Australian Privacy Principles will reduce the recruitment challenges outlined in this study.

A qualitative investigation of adolescents’ perceived mechanisms of change from a universal school-based depression prevention program

A recent meta-analysis provides evidence supporting the universal application of school-based prevention programs for adolescent depression. The mechanisms underlying such successful interventions, however, are largely unknown. We report on a qualitative analysis of 109 Grade 9 students’ beliefs about what they gained from an evidence-based depression prevention intervention, the Resourceful Adolescent Program (RAP-A). Fifty-four percent of interviewees articulated at least one specific example of program benefit. A thematic analysis of responses revealed two major themes, improved interpersonal relationships and improved self-regulation, both stronger than originally assumed. A more minor theme also emerged—more helpful cognitions. It is postulated that both improved interpersonal relationships and improved self-regulation are likely to enhance one another, and more helpful cognitions may express its contribution through enhanced self-regulation. These findings broaden our understanding of the impact of depression prevention programs, beginning to illuminate how such programs benefit participants.

Engendering the responsibility to protect : women and the prevention of mass atrocities

This article explores the relationship between the Responsibility to Protect (R2P) and the pursuit of the so-called ‘Women, Peace and Security’ (WPS) agenda at the UN. We ask whether the two agendas should continue to be pursued separately or whether each can make a useful contribution to the other. We argue that while the history of R2P has not included language that deliberately evokes the protection of women and the promotion of gender in preventing genocide and mass atrocities, this does not preclude the R2P and WPS agendas becoming mutually reinforcing. The article identifies cross-cutting areas where the two agendas may be leveraged for the UN and member states to address the concerns of women as both actors in need of protection and active agents in preventing and responding to genocide and mass atrocities, namely in the areas of early warning.

An exploratory study for the development of emergency nurse practitioner specialist clinical practice standards

This thesis presents a mixed methods study to develop specialty specific clinical practice standards for Emergency Nurse Practitioners. This is the first time in Australia that Nurse Practitioners standards have been developed for a clinical specialty. These standards will guide educational preparation for the role and ongoing Continuous Professional Development for endorsed Emergency Nurse Practitioners.

Clinical faculty : major contributors to the education of new CRNAs - Part 2

This study examines the important contributions of clinical faculty toward the education of the future workforce of Certified Registered Nurse Anesthetists (CRNAs). Differences in workload, work activities and income among clinical faculty, academic faculty and nonfaculty are examined. This is Part 2 of a 2-part column. Part 1, published in the April 2008 AANA Journal discussed salaries, recruitment, and retention of CRNA faculty.

Cheating prevention in linear secret sharing

Cheating detection in linear secret sharing is considered. The model of cheating extends the Tompa-Woll attack and includes cheating during multiple (unsuccessful) recovery of the secret. It is shown that shares in most linear schemes can be split into subshares. Subshares can be used by participants to trade perfectness of the scheme with cheating prevention. Evaluation of cheating prevention is given in the context of different strategies applied by cheaters.

Cheating prevention in secret sharing over GF(pt)

The work investigates cheating prevention in secret sharing. It is argued that cheating is immune against cheating if the cheaters gain no advantage over honest participants by submitting invalid shares to the combiner. This work addresses the case when shares and the secret are taken from GF(pt). Two models are considered. The first one examines the case when cheaters consistently submit always invalid shares. The second modeldeal s with cheaters who submit a mixture of valid and invalid shares. For these two models, cheating immunity is defined, properties of cheating immune secret sharing are investigated and their constructions are given.

Development of reverse phase protein microarrays for clinical applications and patient-tailored therapy

While genomics provide important information about the somatic genetic changes, and RNA transcript profiling can reveal important expression changes that correlate with outcome and response to therapy, it is the proteins that do the work in the cell. At a functional level, derangements within the proteome, driven by post-translational and epigenetic modifications, such as phosphorylation, is the cause of a vast majority of human diseases. Cancer, for instance, is a manifestation of deranged cellular protein molecular networks and cell signaling pathways that are based on genetic changes at the DNA level. Importantly, the protein pathways contain the drug targets in signaling networks that govern overall cellular survival, proliferation, invasion and cell death. Consequently, the promise of proteomics resides in the ability to extend analysis beyond correlation to causality. A critical gap in the information knowledge base of molecular profiling is an understanding of the ongoing activity of protein signaling in human tissue: what is activated and “in use” within the human body at any given point in time. To address this gap, we have invented a new technology, called reverse phase protein microarrays, that can generate a functional read-out of cell signaling networks or pathways for an individual patient obtained directly from a biopsy specimen. This “wiring diagram” can serve as the basis for both, selection of a therapy and patient stratification.

The nurse's role in managing chemotherapy-induced nausea and vomiting

Background Nurses play a substantial role in the prevention and management of chemotherapy-induced nausea and vomiting (CINV). Objectives This study set out to describe nurses’ roles in the prevention and management of CINV and to identify any gaps that exist across countries. Methods A self-reported survey was completed by 458 registered nurses who administered chemotherapy to cancer patients in Australia, China, Hong Kong, and 9 Latin American countries. Results More than one-third of participants regarded their own knowledge of CINV as fair to poor. Most participants (>65%) agreed that chemotherapy-induced nausea and chemotherapy-induced vomiting should be considered separately (79%), but only 35% were confident in their ability to manage chemotherapy-induced nausea (53%) or chemotherapy-induced vomiting (59%). Only one-fifth reported frequent use of a standardized CINV assessment tool and only a quarter used international clinical guidelines to manage CINV. Conclusions Participants perceived their own knowledge of CINV management to be insufficient. They recognized the need to develop and use a standardized CINV assessment tool and the importance of adopting international guidelines to inform the management of CINV. Implications for Practice: Findings indicate that international guidelines should be made available to nurses in clinically relevant and easily accessible formats, that a review of chemotherapy assessment tools should be undertaken to identify reliable and valid measures amenable to use in a clinical settings, and that a CINV risk screening tool should be developed as a prompt for nurses to enable timely identification of and intervention for patients at high risk of CINV.

Modeling of protein signaling networks in clinical proteomics

Molecular interactions that underlie pathophysiological states are being elucidated using techniques that profile proteomicend points in cellular systems. Within the field of cancer research, protein interaction networks play pivotal roles in the establishment and maintenance of the hallmarks of malignancy, including cell division, invasion, and migration. Multiple complementary tools enable a multifaceted view of how signal protein pathway alterations contribute to pathophysiological states.One pivotal technique is signal pathway profiling of patient tissue specimens. This microanalysis technology provides a proteomic snapshot at one point in time of cells directly procured from the native context of a tumor micro environment. To study the adaptive patterns of signal pathway events over time, before and after experimental therapy, it is necessary to obtain biopsies from patients before, during, and after therapy. A complementary approach is the profiling of cultured cell lines with and without treatment. Cultured cell models provide the opportunity to study short-term signal changes occurring over minutes to hours. Through this type of system, the effects of particular pharmacological agents may be used to test the effects of signal pathway inhibition or activation on multiple endpoints within a pathway. The complexity of the data generated has necessitated the development of mathematical models for optimal interpretation of interrelated signaling pathways. In combination,clinical proteomic biopsy profiling, tissue culture proteomic profiling, and mathematical modeling synergistically enable a deeper understanding of how protein associations lead to disease states and present new insights into the design of therapeutic regimens.

A typology of technological enablers of website service failure prevention

An increasing range of services are now offered via online applications and e-commerce websites. However, problems with online services still occur at times, even for the best service providers due to the technical failures, informational failures, or lack of required website functionalities. Also, the widespread and increasing implementation of web services means that service failures are both more likely to occur, and more likely to have serious consequences. In this paper we first develop a digital service value chain framework based on existing service delivery models adapted for digital services. We then review current literature on service failure prevention, and provide a typology of technolo- gies and approaches that can be used to prevent failures of different types (functional, informational, system), that can occur at different stages in the web service delivery. This makes a contribution to theory by relating specific technologies and technological approaches to the point in the value chain framework where they will have the maximum impact. Our typology can also be used to guide the planning, justification and design of robust, reliable web services.

BRAF inhibitors : from the laboratory to clinical trials

BRAF is one of the most commonly mutated proto-oncogenes and plays a significant role in the development of numerous cancers of high clinical impact. Due to the commonality of BRAF mutations, a number of BRAF inhibitors have been developed as tools in the management of patients with cancers dependent on the action of mutant BRAF to drive cellular proliferation. In this review, we examine the current state of clinical trials and laboratory research concerning BRAF inhibitors in development and available for clinical use. We contrast the effectiveness of type-I and type-II BRAF inhibitors, the former typically showing much more restricted inhibitory selectivity and greater patient response rates.

miR-126 in human cancers : clinical roles and current perspectives

miR-126 has been implicated in the processes of inflammation and angiogenesis. Through these processes, miR-126 is implicated in cancer biology, but its role there has not been well reviewed. The aim of this review is to examine the molecular mechanisms and clinicopathological significance of miR-126 in human cancers. miR-126 was shown to have roles in cancers of the gastrointestinal tract, genital tracts, breast, thyroid, lung and some other cancers. Its expression was suppressed in most of the cancers studied. The molecular mechanisms that are known to cause aberrant expression of miR-126 include alterations in gene sequence, epigenetic modification and alteration of dicer abundance. miR-126 can inhibit progression of some cancers via negative control of proliferation, migration, invasion, and cell survival. In some instances, however, miR-126 supports cancer progression via promotion of blood vessel formation. Downregulation of miR-126 induces cancer cell proliferation, migration, and invasion via targeting specific oncogenes. Also, reduced levels of miR-126 are a significant predictor of poor survival of patients in many cancers. In addition, miR-126 can alter a multitude of cellular mechanisms in cancer pathogenesis via suppressing gene translation of numerous validated targets such as PI3K, KRAS, EGFL7, CRK, ADAM9, HOXA9, IRS-1, SOX-2, SLC7A5 and VEGF. To conclude, miR-126 is commonly down-regulated in cancer, most likely due to its ability to inhibit cancer cell growth, adhesion, migration, and invasion through suppressing a range of important gene targets. Understanding these mechanisms by which miR-126 is involved with cancer pathogenesis will be useful in the development of therapeutic targets for the management of patients with cancer.

Clinical impacts of mammalian target of rapamycin expression in human colorectal cancers

This study investigated the clinicopathologic roles of mammalian target of rapamycin (mTOR) expression and its relationship to carcinogenesis and tumor progression in a colorectal adenoma-adenocarcinoma model. Two colon cancer cell lines with different pathologic stages (SW480 and SW48) and 1 normal colonic epithelial cell line (FHC) were used, in addition to 119 colorectal adenocarcinomas and 32 adenomas. mTOR expression profiles at messenger RNA (mRNA) and protein levels were investigated in the cells and tissues using real-time quantification polymerase chain reaction and immunohistochemistry. The findings were correlated with the clinicopathologic features of the tumors. The colon cell line from stage III cancer (SW48) showed higher expression of mTOR mRNA than that from stage II cancer (SW480). At the tissue level, mTOR showed higher mRNA and protein expression in colorectal carcinoma than in adenoma. The mRNA and protein expression was correlated with each other in approximately one-third of the carcinomas and adenomas. High levels of mTOR mRNA expression were noted more in carcinoma or adenoma arising from the distal portion of the large intestine (P = .025 and .019, respectively). Within the colorectal cancer population, a high level of expression of mTOR mRNA was related to the presence of lymph node metastases (P = .031), advanced pathologic stage (P = .05), and presence of persistent disease or tumor recurrence (P = .035). To conclude, the study has indicated that mTOR is likely to be involved in the development and progression of colorectal cancer and is linked to cancer initiation, invasiveness, and progression.