Bortezomib modulates TRAIL sensitivity in human bladder and prostate cancer

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of the TNF superfamily of cytokines that can induce cell death through engagement of cognate death receptors. Unlike other death receptor ligands, it selectively kills tumor cells while sparing normal cells. Preclinical studies in non-human primates have generated much enthusiasm regarding its therapeutic potential. However, many human cancer cell lines exhibit significant resistance to TRAIL-induced apoptosis, and the molecular mechanisms underling this are controversial. Possible explanations are typically cell-type dependent, but include alterations of receptor expression, enhancement of pro-apoptotic intracellular signaling molecules, and reductions in anti-apoptotic proteins. We show here that the proteasome inhibitor bortezomib (Velcade, PS-341) produces synergistic apoptosis in both bladder and prostate cancer cell lines within 4-6 hours when co-treated with recombinant human TRAIL which is associated with accumulation of p21 and cdk1/2 inhibition. Our data suggest that bortezomib's mechanism of action involves a p21-dependent enhancement of caspase maturation. Furthermore, we found enhanced tumor cell death in in vivo models using athymic nude mice. This is associated with increases in caspase-8 and caspase-3 cleavage as well as significant reductions in microvessel density (MVD) and proliferation. Although TRAIL alone had less of an effect, its biological significance as a single agent requires further investigations. Toxicity studies reveal that the combination of bortezomib and rhTRAIL has fatal consequences that can be circumvented by altering treatment schedules. Based on our findings, we conclude that this strategy has significant therapeutic potential as an anti-cancer agent. ^

The transcription factor nuclear factor kappa B (NFkappaB) maintains TRAIL resistance in human pancreatic cancer cells

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of the TNF family of cytokines that induces apoptosis in a variety of tumor cells while sparing normal cells. However, many human cancer cell lines display resistance to TRAIL-induced apoptosis and the mechanisms contributing to resistance remain controversial. Previous studies have demonstrated that the dimeric transcription factor Nuclear Factor kappa B (NFκB) is constitutively active in a majority of human pancreatic cancer cell lines and primary tumors, and although its role in tumor progression remains unclear it has been suggested that NFκB contributes to TRAIL resistance. Based on this, I examined the effects of NFκB inhibitors on TRAIL sensitivity in a panel of nine pancreatic cancer cell lines. I show here that inhibitors of NFκB, including two inhibitors of the proteasome (bortezomib (Velcade™, PS-341) and NPI-0052), a small molecule inhibitor of IKK (PS1145), and a novel synthetic diterpene NIK inhibitor (NPI-1342) reverse TRAIL resistance in pancreatic cancer cell lines. Further analysis revealed that the expression of the anti-apoptosic proteins BclXL and XIAP was significantly decreased following exposure to these inhibitors alone and in combination with TRAIL. Additionally, treatment with NPI0052 and TRAIL significantly reduced tumor burden relative to the control tumors in an L3.6pl orthotopic pancreatic xenograft model. This was associated with a significant decrease in proliferation and an increase in caspase 3 and 8 cleavage. Combination therapy employing PS1145 or NPI-1342 in combination with TRAIL also resulted in a significant reduction in tumor burden compared to either agent alone in a Panc1 orthotopic xenograft model. My studies show that combination therapy with inhibitors of NFκB alone and TRAIL is effective in pre-clinical models of pancreatic cancer and suggests that the approach should be evaluated in patients. ^

Examining seasonal variations in physical activity among low-income Hispanic walk-trail users living in the Cameron Park Colonia

This study examines variations in physical activity by season, and within seasons by age and gender among park users living in the Cameron Park Colonia, a low-income Hispanic community along the Texas-Mexico border. This is the first study of its kind to evaluate seasonal variations by physical activity among a Hispanic population. We hypothesized that (1) there are no differences in overall physical activity by season; (2) youth engage in more sport-related physical activity compared to adults, (3) males engage in more physical activity than females, and (4) there are differences in physical activity between walk-trail users compared to non walk-trail users in the park.^ Physical activity behavioral data was collected (males n=2,093; females n=1,014) at two time periods (winter 2007; summer 2007) via direct observations and assessed park use, walking trail use, and physical activity (moderate-to-vigorous physical activity (MVPA) by seasons. Frequencies for physical activities were calculated for gender, age groups, and season. Separate Pearson's chi-square analyses were used to address variations in physical activity, age, gender, intensity level of physical activity by season, between walk-trails users and non walk-trail users.^ People visiting the park engaged in more sedentary behavior in winter than summer and a higher percentage engaged in MVPA in the summer than winter (p<.05). More females engaged in light activity compared to males (p<.05). Walk-trail users consisted mostly of females and engaged in more light activity than non walk-trail users (p<.05) who participated in more MVPA.^ Increasing access to parks and walk-trails may be an intervention strategy to increase physical activity among Hispanics. More research is needed to assess promoting trail use and determining long-term effects on physical activity among minority/ethnic groups at greater risk of a sedentary lifestyle and reasons for trail use and non-use. Future studies should focus on the types of activities Hispanics engage in at different parks particularly between men and women. As a result of this study city officials and planners may use this information to build and design parks that cater to the types of activities that Hispanics engage in and may use to meet physical activity guidelines.^

The Trail of No Tears: Traditional Masculinity Ideologies and The Cycle of Dismissing-Avoidant Attachment

Raising boys in accordance with traditional masculinity ideologies is creating a mental health crisis among men. Socialization in accordance with traditional male gender roles causes boys to develop dismissing-avoidant attachments with their primary caregivers. Approaching subsequent relationships with a dismissing-attachment style creates disconnection between men and male peers, female partners, and their children. Many researchers advocate clinical interventions that perpetuate men's traditional fears of intimacy, however attachment theory provides an alternative lens through which clinicians may approach therapy with men. By engaging men in therapeutic attachment relationships, clinicians can inspire implicit and explicit learning of new attachment patterns. This experience by nature challenges traditional definitions of masculinity, and men may develop more congruent, adaptive, and healthy definitions of masculinity.

An investigative and interpretive study, with paintings, drawings and prints, of "All Saints' Day" and "All Souls" Day" in Mexico

"In Mexico, the first two days of November are set aside each year for the commemoration of the dead. This fete, called All Saints' Day and All Souls' Day, is observed throughout the world; however, in Mexico, it is celebrated in a manner peculiar to that country and to the various localities within that country . This holiday is sanctioned by both government and church; and is celebrated by practically all Mexicans, whether they be Catholic, pagan, relilious or irreligious. These are the two days when that contrast which is the essence of Mexico becomes obvious: the "triste~alegria" (sad-happiness). During these days , art objects are abundant and arresting ; and religious ceremonies, rites and fiestas blossom forth! Urban and folk arts, in every field, find full expression at this time. The religious, social, political, and artistic manifestations of the holiday are not only stimulating in themselves, but are exciting as subjects for painting, drawings, prints, and any other form of artistic expression!"

A Physical and Social Study of Mountain Bike Use on Five Segments of the Continental Divide National Scenic Trail in Colorado

This capstone reviews uses of the Continental Divide National Scenic Trail. Policies governing use of the trail appear to be ambiguous, especially regarding mountain bicycles. Mountain biking has grown since the trail was created, but is not fully addressed in existing or proposed policy. 382 people on five segments of the trail in Colorado were interviewed for this capstone. Mountain bikes, hiking, and motorized recreation were observed uses. User conflict, overcrowding, degraded recreation experiences, or user displacement was not reported. User satisfaction was high and most would return. Interviewees requested increased public involvement and recognition of user needs in setting policy. Trail degradation occurs, but is unassociated with any particular use. Recommendations for trail improvement and maintenance are presented.

Managing Recreational Impacts on the Northeast corner of the Lake Fayetteville Nature Trail in Fayetteville, AR

Increased population growth of the Northwest Corner of Arkansas is straining the natural resources of the Lake Fayetteville Nature Trail, Fayetteville, AR. Recreational activities conducted on this single track multi-use trail are mountain biking, walking, jogging and wildlife viewing. Impacts evident on the NE section of the trail consist of erosion, vegetation, wildlife and conflict disturbances. Throughout this paper recommendations of management solutions and maintenance ideas are presented. Control of recreation impacts will help the longevity of the trail and maintain the aesthetics for present and future trail users.

The Political and Judicial Life of Metadata: Digital Rights Ireland and the Trail of the Data Retention Directive. CEPS Paper in Liberty and Security No. 65, May 2014

This paper examines the challenges facing the EU regarding data retention, particularly in the aftermath of the judgment Digital Rights Ireland by the Court of Justice of the European Union (CJEU) of April 2014, which found the Data Retention Directive 2002/58 to be invalid. It first offers a brief historical account of the Data Retention Directive and then moves to a detailed assessment of what the judgment means for determining the lawfulness of data retention from the perspective of the EU Charter of Fundamental Rights: what is wrong with the Data Retention Directive and how would it need to be changed to comply with the right to respect for privacy? The paper also looks at the responses to the judgment from the European institutions and elsewhere, and presents a set of policy suggestions to the European institutions on the way forward. It is argued here that one of the main issues underlying the Digital Rights Ireland judgment has been the role of fundamental rights in the EU legal order, and in particular the extent to which the retention of metadata for law enforcement purposes is consistent with EU citizens’ right to respect for privacy and to data protection. The paper offers three main recommendations to EU policy-makers: first, to give priority to a full and independent evaluation of the value of the data retention directive; second, to assess the judgment’s implications for other large EU information systems and proposals that provide for the mass collection of metadata from innocent persons, in the EU; and third, to adopt without delay the proposal for Directive COM(2012)10 dealing with data protection in the fields of police and judicial cooperation in criminal matters.

The private sector, the public sector, and donor assistance in economic development : an interpretive essay /

"PN-AAL-007"--Cover.

Herbert Hoover national historic site, interpretive prospectus (1971) B1; Natural resources management plan (1980) B2; Cultural resources management plan (1981) B3; Annual statement for interpretation and visitor services B4; Snowmobile use, environmental assessment (EA) : environmental impact statement.

Mode of access: Internet.

Pipe Spring National Monument (N.M.), interim interpretive plan, second draft (1977) B1; Master plan (1978) B2; Development concept plan, environmental assessment (EA) B3; Statement for management (1981) B4; Record of decision, draft development concept plan and Finding of no significant impact (FONSI) (1982) : environmental impact statement.

Mode of access: Internet.

The trail drivers of Texas : interesting sketches of early cowboys and their experiences on the range and on the trail during the days that tried men's souls: true narratives related by real cow-punchers and men who fathered the cattle industry in Texas /

Mode of access: Internet.

On the trail of the Russian famine

Maps on lining papers.