Prognostic Significance of TRAIL Signaling Molecules in Stage II and III Colorectal Cancer

Purpose: We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer.

Experimental Design: Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil–based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry.

Results: Colorectal tumors displayed significantly higher expression levels of c-FLIP (P < 0.001), caspase 8 (P = 0.01), and DR5 (P < 0.001), but lower levels of TRAIL (P < 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P < 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P < 0.001).

Conclusions: High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse.

PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells

Background: In recent years, much progress has been made in the treatment of multiple myeloma. However, a major limitation of existing chemotherapeutic drugs is the eventual emergence of resistance; hence, the development of novel agents with new mechanisms of action is pertinent. Here, we describe the activity and mechanism of action of pyrrolo-1,5-benzoxazepine-15 (PBOX-15), a novel microtubule-targeting agent, in multiple myeloma cells.

Methods: The anti-myeloma activity of PBOX-15 was assessed using NCI-H929, KMS11, RPMI8226, and U266 cell lines, and primary myeloma cells. Cell cycle distribution, apoptosis, cytochrome c release, and mitochondrial inner membrane depolarisation were analysed by flow cytometry; gene expression analysis was carried out using TaqMan Low Density Arrays; and expression of caspase-8 and Bcl-2 family of proteins was assessed by western blot analysis.

Results: Pyrrolo-1,5-benzoxazepine-15 induced apoptosis in ex vivo myeloma cells and in myeloma cell lines. Death receptor genes were upregulated in both NCI-H929 and U266 cell lines, which displayed the highest and lowest apoptotic responses, respectively, following treatment with PBOX-15. The largest increase was detected for the death receptor 5 (DR5) gene, and cotreatment of both cell lines with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the DR5 ligand, potentiated the apoptotic response. In NCI-H929 cells, PBOX-15-induced apoptosis was shown to be caspase-8 dependent, with independent activation of extrinsic and intrinsic apoptotic pathways. A caspase-8-dependent decrease in expression of Bim(EL) preceded downregulation of other Bcl-2 proteins (Bid, Bcl-2, Mcl-1) in PBOX-15-treated NCI-H929 cells.

Conclusion: PBOX-15 induces apoptosis and potentiates TRAIL-induced cell death in multiple myeloma cells. Thus, PBOX-15 represents a promising agent, with a distinct mechanism of action, for the treatment of this malignancy. British Journal of Cancer (2011) 104, 281-289. doi: 10.1038/sj.bjc.6606035 www.bjcancer.com Published online 21 December 2010 (C) 2011 Cancer Research UK

Right-Wing Violence in Germany: Assessing the Objectives, Personalities and Terror Trail of the National Socialist Underground and the State's Response to It

In the last five years the forces of organised right-wing extremism have made electoral advances across many states in contemporary Europe. Germany has not been immune and the extreme right party, the National Democratic Party of Germany won its first seat in the European Parliament since 1989. The recent successes of the extreme right pose issues for European society about tolerance and immigration policy, but this scene has also been associated with an upsurge in racially motivated political violence and acts of right-wing terrorism. Much of this violence is perpetrated by small neo-Nazi styled groups. This paper looks at the most notorious and recent of such groups to emerge in Germany, the National Socialist Underground. The paper explores the origins and personalities behind this terror cell, provides derails of its criminal activities and murder spree, and questions why it took so long for the authorities to identify the NSU.

'Conditional candour' and 'knowing me': an interpretive description study on patient preferences for physician behaviours during end-of-life communication

OBJECTIVE: To understand patients' preferences for physician behaviours during end-of-life communication.

METHODS: We used interpretive description methods to analyse data from semistructured, one-on-one interviews with patients admitted to general medical wards at three Canadian tertiary care hospitals. Study recruitment took place from October 2012 to August 2013. We used a purposive, maximum variation sampling approach to recruit hospitalised patients aged ≥55 years with a high risk of mortality within 6-12 months, and with different combinations of the following demographic variables: race (Caucasian vs non-Caucasian), gender and diagnosis (cancer vs non-cancer).

RESULTS: A total of 16 participants were recruited, most of whom (69%) were women and 70% had a non-cancer diagnosis. Two major concepts regarding helpful physician behaviour during end-of-life conversations emerged: (1) 'knowing me', which reflects the importance of acknowledging the influence of family roles and life history on values and priorities expressed during end-of-life communication, and (2) 'conditional candour', which describes a process of information exchange that includes an assessment of patients' readiness, being invited to the conversation, and sensitive delivery of information.

CONCLUSIONS: Our findings suggest that patients prefer a nuanced approach to truth telling when having end-of-life discussions with their physician. This may have important implications for clinical practice and end-of-life communication training initiatives.

A collision in 2009 as the origin of the debris trail of asteroid P/2010A2

The peculiar object P/2010A2 was discovered in January 2010 and given a cometary designation because of the presence of a trail of material, although there was no central condensation or coma. The appearance of this object, in an asteroidal orbit (small eccentricity and inclination) in the inner main asteroid belt attracted attention as a potential new member of the recently recognized class of main-belt comets. If confirmed, this new object would expand the range in heliocentric distance over which main-belt comets are found. Here we report observations of P/2010A2 by the Rosetta spacecraft. We conclude that the trail arose from a single event, rather than a period of cometary activity, in agreement with independent results. The trail is made up of relatively large particles of millimetre to centimetre size that remain close to the parent asteroid. The shape of the trail can be explained by an initial impact ejecting large clumps of debris that disintegrated and dispersed almost immediately. We determine that this was an asteroid collision that occurred around 10 February 2009.

The Rainbow Trail due date card

This is a due date card for the book titled The Rainbow Trail, with stamped dates from 1940-1941.

Changing Professional Identity in the Transition from Practitioner to Lecturer in Higher Education: an Interpretive Phenomenological Analysis

This research explores the experiences of five professional practitioners from disciplines including teaching, youth work, sport and health who had become lecturers in Higher Education. Their experiences are considered using Interpretative Phenomenological Analysis and tentative conclusions are reached on the meaning of such experiences for the individuals. The work extends previous studies (Shreeve 2010, 2011; Gourlay 2011a, 2011b; Boyd & Harris 2010) to consider the relationship between knowledge and influence and how institutional preference for knowledge gained from research impacts on the validity of knowledge derived from professional experience. The research finds shared feelings associated with inauthenticity and loss arising from concerns that the contribution of the professional in Higher Education is undervalued. The research challenges the assumption that professional practitioners adopt the professional identity of a lecturer in Higher Education instead finding that they create their own professional identities in the liminal space between the professional and academic domains, but points to difficulties associated with constructed nature of such professional identities within the institutional structure of a Higher Education institution.

The effectiveness of interpretive methods in informal educational facilities : an experimental study with reference to marine parks

Interpretation has been used in many tourism sectors as a technique in achieving building hannony between resources and human needs. The objectives of this study are to identify the types of the interpretive methods used, and to evaluate their effectiveness, in marine parks. This study reviews the design principles of an effective interpretation for marine wildlife tourism, and adopts Drams' five design principles (1997) into a conceptual framework. Enjoyment increase, knowledge gain, attitude and intention change, and behaviour modification were used as key indicators in the assessment of the interpretive effectiveness of the Vancouver Aquarium (VA) and Marineland Canada (MC). Since on-site research is unavailable, a virtual tour is created to represent the interpretive experiences in the two study sites. Self-administered questionnaires are used to measure responses. Through comparing responses to the questionnaires (pre-, post-virtual tours and follow-up), this study found that interpretation increased enjoyment and added to respondents' knowledge. Although the changes in attitudes and intentions are not significant, the findings indicate that attitude and intention changes did occur as a result of interpretation, but only to a limited extent. Overall results suggest that more techniques should be added to enhance the effectiveness of the interpretation in marine parks or self-guiding tours, and with careful design, virtual tours are the innovative interpretation techniques for marine parks or informal educational facilities.

Niagara Bruce Trail Club Fonds, 1962-2014, n.d.

The Bruce trail is Canada’s longest and oldest continuous footpath. The trail runs along the Niagara Escarpment from Niagara to Tobermory through private and public land. The main trail is 890 km long and the side trails measure 400 km. In 1961, a “Save the Escarpment” conference was held in Hamilton. Gerry Wolfram, a writer for the St. Catharines Standard proposed that a committee be formed to develop a hiking trail. The Peninsula Field Naturalists Club formed a committee and President Bert Lowe contacted landowners along the proposed route to gain permission to cross their properties. Through Bert Lowe’s effort and dedication, the trail was completed in October 1963. The trail was officially opened on May 24th, 1964 in a ceremony at Queenston. The Niagara group joined the Bruce Trail Association in 1968 at which time the Niagara Bruce Trail Club was formed. The Bruce Trail Association is a charitable, membership-based volunteer organization. Their goal is to preserve public access to the Niagara Escarpment while restoring its natural habitat. The head office of the Bruce Trail Association is located in Hamilton, Ontario. The Niagara Bruce Trail Club’s goal is to secure and preserve a natural corridor along the Niagara Escarpment while providing education, awareness, and access for the public and the future. The club has organized many hikes including special hikes such as the one to commemorate the St. Catharines Centennial. The club has also hosted children’s hikes, cross country skiing hikes, wildflower hikes, jogging hikes, snowshoe hikes and bike outings. They hold annual events such as the End to End hike which is a 3 day walk from Grimsby to Queenston and the 30 km Laura Secord hike to commemorate Laura Secord’s famous walk. Charity hikes have also been held for the Heart and Stroke Foundation and the Lung Association as well as other causes. Major changes have taken place along the trail throughout the years, some of these include: a reroute which eliminated the tunnel passage (1976) and a bridge which eliminated the need to walk to Mountain Road to cross the Queen Elizabeth Way (2008). Other major changes and clean-up projects have been undertaken by the club. The Bruce Trail Conservancy (formerly Association) is made up of 9 clubs including: Niagara Bruce Trail Club (Queenston to Grimsby), Iroquia Bruce Trail Club (Grimsby to Kelso), Toronto Bruce Trail Club (Kelso to Cheltenham), Caledon Hills Bruce Trail Club (Cheltenham to Mono Centre), Dufferin Hi-Land Bruce Trail Club (Mono Centre to Lavender), Blue Mountains Bruce Trail Club (Lavender to Craigleath), Beaver Valley Bruce Trail Club (Craigleath to Blantyre), Sydenham Bruce Trail Club (Blantyre to Wiarton) and Peninsula Bruce Trail Club (Wiarton to Tobermory). Sources: http://www.niagarabrucetrail.org/index.html and http://brucetrail.org/

Sport Commitment in Wheelchair Basketball: An Interpretive Look into the Lives of Individuals with Physical Disabilities

It is estimated that over 4.4 million people are living in Canada with a reported disability. Due to a number of risk factors associated with potential health concerns and sedentary lifestyles, it is important for people with physical disabilities to lead an active lifestyle. Recreation and leisure pursuits are a great outlet for this to take place. However, in order to gain the long terms benefits of these pursuits one must be committed to an activity. With the use of a collaborative interview method, with the Sport Commitment Model serving as the guiding framework, this study sought to find the underlying factors for continued participation for people with physical disabilities in wheelchair basketball. Through utilizing an interpretive approach it was found that enjoyment, social support, perceived ability and to some extent involvement opportunities, were the main contributors to overall commitment. Criticisms and suggestions for future research are also provided.

Down the Santa Fé trail and into México : the diary of Susan Shelby Magoffin, 1846-1847

UANL