Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling.

In glioblastoma (GBM), the EGF receptor (EGFR) and Src family kinases (SFKs) contribute to an aggressive phenotype. EGFR may be targeted therapeutically; however, resistance to EGFR-targeting drugs such as Erlotinib and Gefitinib develops quickly. In many GBMs, a truncated form of the EGFR (EGFRvIII) is expressed. Although EGFRvIII is constitutively active and promotes cancer progression, its activity is attenuated compared with EGF-ligated wild-type EGFR, suggesting that EGFRvIII may function together with other signaling receptors in cancer cells to induce an aggressive phenotype. In this study, we demonstrate that in EGFRvIII-expressing GBM cells, the urokinase receptor (uPAR) functions as a major activator of SFKs, controlling phosphorylation of downstream targets, such as p130Cas and Tyr-845 in the EGFR in vitro and in vivo. When EGFRvIII expression in GBM cells was neutralized, either genetically or by treating the cells with Gefitinib, paradoxically, the cells demonstrated increased cell migration. The increase in cell migration was explained by a compensatory increase in expression of urokinase-type plasminogen activator, which activates uPAR-dependent cell signaling. GBM cells that were selected for their ability to grow in vivo in the absence of EGFRvIII also demonstrated increased cell migration, due to activation of the uPAR signaling system. The increase in GBM cell migration, induced by genetic or pharmacologic targeting of the EGFR, was blocked by Dasatinib, highlighting the central role of SFKs in uPAR-promoted cell migration. These results suggest that compensatory activation of uPAR-dependent cell signaling, in GBM cells treated with targeted therapeutics, may adversely affect the course of the disease by promoting cell migration, which may be associated with tumor progression

Is cancer associated with polymyalgia rheumatica?: A cohort study in the General Practice Research Database

OBJECTIVE: To investigate the incidence of new cancer diagnoses in a community sample of patients with polymyalgia rheumatica (PMR). METHODS: All incident cases of PMR in the UK General Practice Research Database (GPRD) (1987-99), without pre-existing cancer or vascular disease and treated with corticosteroids (n=2877) were matched with up to five age, sex and GP practice patients without PMR (n=9942). Participants were followed up until first cancer diagnosis, death, transfer out of the database or end of available records. RESULTS: The mean age of the sample was 71.6 years (SD 9.0), 73% were female. Median follow-up time was 7.8 years (IQR 3.4, 12.3). 667 (23.2%) people with a PMR diagnosis developed cancer compared with 1938 (19.5%) of those without PMR. There was an interaction between PMR status and time. In the first 6 months after diagnosis, those with a PMR diagnosis were significantly more likely to receive a cancer diagnosis (adjusted HR (95% CI): 1.69 (1.18 to 2.42)). The number of events was small, but occurrences of prostate, blood, lymph nodes, female reproductive and nervous system cancers may be more common in those with PMR in the first 6 months after PMR diagnosis. CONCLUSIONS: An increase in the rate of cancer diagnoses was noted in the first 6 months of observation, but we were unable to determine whether the cancer incidence in PMR was different from controls, beyond this time point. Clinicians should ensure they fully exclude cancer as a cause of PMR-like symptoms and monitor patients for possible malignancies

A new direction for water management? Indigenous nation building as a strategy for river health

© 2017 by the author(s). Indigenous involvement in Australian water management is conventionally driven by a top-down approach by nonIndigenous government agencies, that asks “how do we engage Indigenous people?” and has culminated in the ineffective “consult” and “service delivery” processes evident in mainstream water management planning. This is a hopeful paper that identifies the critical importance of a “nation-based” approach for effective Indigenous engagement in water planning and policy through the work undertaken by the Ngarrindjeri Regional Authority (NRA) in the Murray Futures program. The NRA is an Indigenous government in the “settled-south” of Australia. Over past decades, the NRA has developed a range of political technologies that act as tools for redeveloping Ngarrindjeri Nationhood after colonial disempowerment and dispossession. These tools enable better collaboration with nonIndigenous governments, especially in natural resource management policy and practice. In turn, this has better enabled the NRA to exercise a decision-making and planning authority over the lands and waters in its jurisdiction, therefore, more effectively exercising its ongoing duty of care as Country. This paper presents a case study of the Sugar Shack Complex Management Plan, codeveloped by the NRA and the South Australian Government in 2015, to demonstrate the benefits that accrue when Indigenous nations are resourced as authorities responsible for reframing water management and planning approaches to facilitate the equitable collaboration of Indigenous and nonIndigenous worldviews. As a marker of the success of this strategy, the Ngarrindjeri Yarluwar-Ruwe Program, in partnership with the South Australian government, recently won the Australian Riverprize 2015 for delivering excellence in Australian river management

Wormhole Cosmic Censorship

We analyze the properties of a Kerr-like wormhole supported by phantom matter, which is an exact solution of the Einstein-phantom field equations. It is shown that the solution has a naked ring singularity which is unreachable to null geodesics falling freely from the outside. Similarly to Roger Penrose's cosmic censorship, that states that all naked singularities in the Universe must be protected by event horizons, here we conjecture from our results that a naked singularity can also be fully protected by the intrinsic properties of a wormhole's throat

Characterising those with incident polymyalgia rheumatica in primary care: results from the PMR Cohort Study.

BACKGROUND: The aim was to characterise the sociodemographic, general health and polymyalgia rheumatica (PMR)-specific features of participants in a large inception cohort of patients with PMR diagnosed in UK primary care. METHODS: Patients (n = 739) with a new diagnosis of PMR were referred into the study and mailed a questionnaire detailing their general health and sociodemographic characteristics in addition to the symptoms of and treatment for PMR. Characteristics of responders and non-responders were compared and descriptive statistics were used to characterise the health of the cohort. RESULTS: A total of 654 individuals responded to the questionnaire (adjusted response 90.1 %). Responders and non-responders were similar in age, gender and deprivation (based on postcode). The mean (standard deviation) age of the recruited cohort was 72.4 (9.3) years; 62.2 % were female. The sample reported high levels of pain and stiffness (8 out of 10 on numerical rating scales) and reported stiffness that lasted throughout the day. High levels of functional impairment, fatigue, insomnia and polypharmacy were also reported. Overall, women reported worse general and PMR-specific health than did men. CONCLUSIONS: This first primary care cohort of patients with incident PMR is similar in demographic terms to cohorts recruited in secondary care. However, the extent of symptoms, particularly reported stiffness, is higher than has been described previously. Given the majority of patients with PMR are exclusively managed in primary care, this cohort provides important information on the course of PMR in the community that will help clinicians managing this painful and disabling condition

What non-pharmacological treatments do people with polymyalgia rheumatica try: results from the PMR Cohort Study.

Polymyalgia rheumatica (PMR) is common. The mainstay of treatment, glucocorticoids, are associated with significant adverse effects and many patients remain on high doses for a number of years. Little is known about the use of other, non-pharmacological therapies as adjuncts in PMR. The PMR Cohort Study is an inception cohort study of patients diagnosed with PMR in primary care. This analysis presents data on the use and perceived impact of non-pharmacological therapies from a long-term follow-up survey. Non-pharmacological treatments were classified as either diet, exercise, or complementary therapies. Results are presented as adjusted means, medians, and raw counts where appropriate. One hundred and ninety-seven participants completed the long-term follow-up questionnaire, of these 81 (41.1%) reported using non-pharmacological therapy. Fifty-seven people reported using a form of complementary therapy, 35 used exercise and 20 reported changing their diet. No individual non-pharmacological therapy appeared to be associated with long-term outcomes. The use of non-pharmacological therapies is common amongst PMR patients, despite the paucity of evidence supporting their use. This suggests that people perceive a need for treatment options in addition to standard glucocorticoid regimens. Further research is needed to understand patients' aims when seeking additional treatments and to strengthen the evidence base for their use so that patients can be guided towards effective options

P16-39. T cell recognition of autologous and non-autologous HIV-1 protease peptides by HIV-1 infected patients undergoing PI therapy

NIH, ICGEB, FAPESP, CNPqNIH, ICGEB, FAPESP, CNP