STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia.Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer.These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood

Effect of a primary care walking intervention with and without nurse support on physical activity levels in 45- to 75-year-olds: The pedometer and consultation evaluation (PACE-UP) cluster randomised clinical trial

Background Pedometers can increase walking and moderate-to-vigorous physical activity (MVPA) levels, but their effectiveness with or without support has not been rigorously evaluated. We assessed the effectiveness of a pedometer-based walking intervention in predominantly inactive adults, delivered by post or through primary care nurse-supported physical activity (PA) consultations. Methods and Findings A parallel three-arm cluster randomised trial was randomised by household, with 12-mo follow-up, in seven London, United Kingdom, primary care practices. Eleven thousand fifteen randomly selected patients aged 45–75 y without PA contraindications were invited. Five hundred forty-eight self-reporting achieving PA guidelines were excluded. One thousand twenty-three people from 922 households were randomised between 2012–2013 to one of the following groups: usual care (n = 338); postal pedometer intervention (n = 339); and nurse-supported pedometer intervention (n = 346). Of these, 956 participants (93%) provided outcome data (usual care n = 323, postal n = 312, nurse-supported n = 321). Both intervention groups received pedometers, 12-wk walking programmes, and PA diaries. The nurse group was offered three PA consultations. Primary and main secondary outcomes were changes from baseline to 12 mo in average daily step-counts and time in MVPA (in ≥10-min bouts), respectively, measured objectively by accelerometry. Only statisticians were masked to group. Analysis was by intention-to-treat. Average baseline daily step-count was 7,479 (standard deviation [s.d.] 2,671), and average time in MVPA bouts was 94 (s.d. 102) min/wk. At 12 mo, mean steps/d, with s.d. in parentheses, were as follows: control 7,246 (2,671); postal 8,010 (2,922); and nurse support 8,131 (3,228). PA increased in both intervention groups compared with the control group; additional steps/d were 642 for postal (95% CI 329–955) and 677 for nurse support (95% CI 365–989); additional MVPA in bouts (min/wk) were 33 for postal (95% CI 17–49) and 35 for nurse support (95% CI 19–51). There were no significant differences between the two interventions at 12 mo. The 10% (1,023/10,467) recruitment rate was a study limitation. Conclusions A primary care pedometer-based walking intervention in predominantly inactive 45- to 75-y-olds increased step-counts by about one-tenth and time in MVPA in bouts by about one-third. Nurse and postal delivery achieved similar 12-mo PA outcomes. A primary care pedometer intervention delivered by post or with minimal support could help address the public health physical inactivity challenge.The PACE-UP trial was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number HTA 10/32/02 ISRCTN42122561) and will be published in full in Health Technology Assessment. The funders had no role in study design (beyond the commissioned call outline), data collection and analysis, decision to publish, or preparation of the manuscript

The induction of senescence-like growth arrest by protein kinase C-activating diterpene esters in solid tumor cells

We previously identified the induction of senescence in melanoma cell lines sensitive to diterpene esters, indicating a therapeutic potential. Here we compared the cytostatic effects of two diterpene esters: the prototypic PKC-activating drug TPA (12-O-tetradecanoylphorbol-13-acetate), and the novel compound PEP008 (20-O-acetyl-ingenol-3-angelate) in cell lines derived from melanoma, breast cancer and colon cancer. The diterpene esters induced permanent growth arrest with characteristics of senescence in a subset of cell lines in all three solid tumor models at 100-1000 ng/ml. Use of the PKC inhibitor bisindolylmaleimide-l demonstrated that activation of PKC was required for growth arrest. Full genome expression profiling identified pivotal genes involved in DNA synthesis and cell cycle control down-regulated by treatment in all three sensitive tumor models. At the protein level, prolonged down-regulation of E2F-1 and proliferating cell nuclear antigen (PCNA), sustained expression of p21(WAF1/CIP1) and dephosphorylation of retinoblastoma (Rb) occurred in the sensitive cells. Additionally, the type II tumor suppressor HRASLS3, which has a role in mitogen-activated protein kinase (MAPK) pathway suppression, was constitutively elevated in cell lines resistant to the senescence effects compared to their sensitive counterparts. Together, these results demonstrate that both TPA and the novel PKC-activating drug PEP008 induce growth arrest with characteristics of senescence in solid tumor cell lines derived from a variety of tissue types, and by a similar mechanism. PKC-activating diterpene esters may therefore have therapeutic potential in a subset of breast cancer, colon cancer and melanoma tumors

Powerful owls : possum assassins move into town

Once thought to live only in large forested areas, the powerful owl (Ninox strenua), Australia’s largest and most iconic of owls (figure 11.1), surprisingly is now turning up frequently in the cities of eastern Australia. Powerful owls require ample prey and large tree cavities for nest sites how this top-order predator is able to survive in human-dominated landscapes is an important question for conservation and the focus of ongoing research. The powerful owl is endemic to Australia, resident in the three eastern mainland states and the Australian Capital Territory, and classified nationally as “rare.”2,3 First described by Gould in 1838, powerful owls are an unusual raptor in that they do not exhibit reversed sexual size dimorphism, the prevalent trait among raptors in which females are larger than males. For reasons still not understood, male powerful owls grow to a height of 65 cm and weigh up to 1,700 g, compared to females, which grow to a height of 54 cm and weigh up to 1,308 g.

What strategies do desk-based workers choose to reduce sitting time and how well do they work? Findings from a cluster randomised controlled trial 11 Medical and Health Sciences 1117 Public Health and Health Services

© 2018 The Author(s). Background: Large amounts of sitting at work have been identified as an emerging occupational health risk, and findings from intervention trials have been reported. However, few such reports have examined participant-selected strategies and their relationships with behaviour change. Methods: The Stand Up Victoria cluster-randomised controlled trial was a workplace-delivered intervention comprising organisational, environmental and individual level behaviour change strategies aimed at reducing sitting time in desk-based workers. Sit-stand workstations were provided, and participants (n = 134; intervention group only) were guided by health coaches to identify strategies for the 'Stand Up', 'Sit Less', and 'Move More' intervention targets, including how long they would stand using the workstation. Three-month workplace sitting and activity changes (activPAL3-assessed total sitting, prolonged sitting (i.e., sitting =30 min continuously) and purposeful walking) were evaluated in relation to the number (regression analysis) and types of strategies (decision-tree analysis). Results: Over 80 different strategies were nominated by participants. Each additional strategy nominated for the 'Stand Up' intervention target (i.e. number of strategies) was associated with a reduction in prolonged sitting of 27.6 min/8-h workday (95% CI: -53.1, - 2.1, p = 0.034). Types of strategies were categorised into 13 distinct categories. Strategies that were task-based and phone-based were common across all three targets. The decision tree models did not select any specific strategy category as predicting changes in prolonged sitting ('Stand Up'), however four strategy categories were identified as important for total sitting time ('Sit Less') and three strategy categories for purposeful walking ('Moving More'). The uppermost nodes (foremost predictors) were nominating > 3 h/day of workstation standing (reducing total workplace sitting) and choosing a 'Move More' task-based strategy (purposeful walking). Conclusions: Workers chose a wide range of strategies, with both strategy choice and strategy quantity appearing relevant to behavioural improvement. Findings support a tailored and pragmatic approach to encourage a change in sitting and activity in the workplace. Evaluating participant-selected strategies in the context of a successful intervention serves to highlight options that may prove feasible and effective in other desk-based workplace environments. Trial registration: This trial was prospectively registered with the Australian New Zealand Clinical Trials register (ACTRN12611000742976) on 15 July 2011