Ubiquitin- and MDM2 E3 ligase-independent proteasomal turnover of nucleostemin in response to GTP depletion.

Nucleostemin (NS) is a nucleolar GTP-binding protein essential for ribosomal biogenesis, proliferation, and animal embryogenesis. It remains largely unclear how this protein is regulated. While working on its role in suppression of MDM2 and activation of p53, we observed that NS protein (but not mRNA) levels decreased drastically in response to GTP depletion. When trying to further elucidate the molecular mechanism(s) underlying this unusual phenomenon, we found that NS was degraded independently of ubiquitin and MDM2 upon GTP depletion. First, depletion of GTP by treating cells with mycophenolic acid decreased the level of NS without apparently affecting the levels of other nucleolar proteins. Second, mutant NS defective in GTP binding and exported to the nucleoplasm was much less stable than wild-type NS. Although NS was ubiquitinated in cells, its polyubiquitination was independent of Lys-48 or Lys-63 in the ubiquitin molecule. Inactivation of E1 in E1 temperature-sensitive mouse embryonic fibroblast (MEF) cells failed to prevent the proteasomal degradation of NS. The proteasomal turnover of NS was also MDM2-independent, as its half-life in p53/MDM2 double knock-out MEF cells was the same as that in wild-type MEF cells. Moreover, NS ubiquitination was MDM2-independent. Mycophenolic acid or doxorubicin induced NS degradation in various human cancerous cells regardless of the status of MDM2. Hence, these results indicate that NS undergoes a ubiquitin- and MDM2-independent proteasomal degradation when intracellular GTP levels are markedly reduced and also suggest that ubiquitination of NS may be involved in regulation of its function rather than stability.

Consensus-Derived Quality Performance Indicators for Neuroendocrine Tumour Care.

Quality performance indicators (QPIs) are used to monitor the delivery of cancer care. Neuroendocrine tumours (NETs) are a family of individually uncommon cancers that derive from neuroendocrine cells or their precursors, and can occur in most organs. There are currently no QPIs available for NETs and their heterogeneity makes QPI development difficult. CommNETs is a collaboration between NET clinicians, researchers and advocates in Canada, Australia and New Zealand. We created QPIs for NETs using a three-step consensus process. First, a multidisciplinary team used the nominal group technique to create candidates (n = 133) which were then curated into appropriateness statements (62 statements, 44 sub-statements). A two-stage modified RAND/UCLA Delphi consensus process was conducted: an online survey rated the statement appropriateness then the top-ranked statements (n = 20) were assessed in a face-to-face meeting. Finally, 10 QPIs met consensus criteria; documentation of primary site, proliferative index, differentiation, tumour board review, use of a structured pathology report, presence of distant metastasis, 5- and 10-year disease-free and overall survival. These NET QPIs will be trialed as a method to monitor and improve care for people with NETs and to facilitate international comparison.

Thromboembolism and anticoagulant management in hemodialysis patients: a practical guide to clinical management.

The need for anticoagulation in dialysis patients is common and the incidence of venous thromboembolism (VTE) and atrial fibrillation in this population is high. While direct data are lacking on the management of anticoagulation in dialysis patients, careful weighing of risks and benefits on the basis of evidence from other populations is crucial. VTE should be managed with adjusted dose warfarin for most patients. Placement of an inferior vena cava filter is a reasonable option for those patients with unacceptable bleeding risks. Studies are ongoing to assess the safety of some low-molecular-weight heparins (LMWH), which may potentially be useful for long-term anticoagulation in hemodialysis patients. In atrial fibrillation the available data on risk of bleeding, risk of stroke, and patient preferences should all be taken into account when considering long-term anticoagulation. We have constructed an evidence model to help quantitate the risks and benefits for an individual patient. The impact of dialysis on risk of bleeding is such that the risk of bleeding will outweigh the benefit in many patients, and anticoagulation will not be used: in some of these patients aspirin therapy may be an alternative. Finally, in the area of prevention of graft and access thrombosis, some randomized controlled trials are available, but none have to date shown benefit from anticoagulation for primary or secondary prevention of thrombosis, and the risk of bleeding in these studies was high.

Nucleostemin: Another nucleolar "Twister" of the p53-MDM2 loop.

Several nucleolar proteins, such as ARF, ribosomal protein (RP) L5, L11, L23 and S7, have been shown to induce p53 activation by inhibiting MDM2 E3 ligase activity and consequently to trigger cell cycle arrest and/or apoptosis. Our recent study revealed another nucleolar protein called nucleostemin (NS), a nucleolar GTP binding protein, as a novel regulator of the p53-MDM2 feedback loop. However, unlike other known nucleolar regulators of this loop, NS surprisingly plays a dual role, as both up and downregulations of its levels could turn on p53 activity. Here, we try to offer some prospective views for this unusual phenomenon by reconciling previously and recently published studies in the field in hoping to better depict the role of NS in linking the p53 pathway with ribosomal biogenesis during cell growth and proliferation as well as to propose NS as another potential molecular target for anti-cancer drug development.

Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer.

BACKGROUND: Tumor nodules are occasionally found in adjacent mesentery of colorectal cancer specimens and are felt to reflect a worse prognosis. The clinical significance of mesenteric tumor nodules was investigated. METHODS: A review of 786 patients with stage III colorectal cancer referred between 1995 and 1999 was undertaken. TNM staging was standardized by considering mesenteric nodules separately and not assigning them to T or N categories. Survival analyses were performed. RESULTS: Mesenteric tumor nodules were found in 116 (14.8%) patients: 48 (41.4%) with colon cancer and 68 (58.6%) rectal cancer. Mean age at surgery was 63 years. Adjuvant chemotherapy was given to 84.8% of colon cancer patients. Two (2.9%) rectal cancer patients received neoadjuvant chemoradiation, and 63 (92.6%) received adjuvant therapy (chemotherapy and/or radiation). In the cohort with mesenteric nodules, the median time to progression was 23.1 months, the median 5-year disease-free survival was 35%, and the median overall survival (OS) was 47.9 months, with 44% OS at 5 years. In the 19 (16.4%) patients with mesenteric nodules and no lymph nodes the 5-year OS was 60% (SEER stage II 5-year survival 82.5%), whereas in 97 patients who were lymph node-positive the 5-year OS was 40% (SEER 5-year survival stage IIIc 44.3%; stage IV 8.1%). CONCLUSIONS: In comparison to SEER survival data, the presence of mesenteric nodules appears to worsen the prognosis of any T/N0 disease to that of overall stage III disease. Mesenteric nodules with any T/N+ disease had prognosis similar to that of stage IIIC disease, but the prognosis was better than M1 disease. .

Time to treat: a system redesign focusing on decreasing the time from suspicion of lung cancer to diagnosis.

INTRODUCTION: Multiple investigations often result in a lengthy process from the onset of lung cancer-related symptoms until diagnosis. An unpublished chart audit indicated suboptimal delays in patients' courses from onset of symptoms until diagnosis of cancer. METHODS: The Time to Treat Program was designed for patients with clinical or radiographic suspicion of lung cancer. Pre- and postimplementation data on median wait times were compared. RESULTS: From April 2005 to January 2007, 430 patients were referred. After Time to Treat Program implementation, the median time from suspicion of lung cancer to referral for specialist consultation decreased from 20 days to 6 days, and the median time from such referral to the actual consultation date decreased from 17 days to 4 days. The median time from specialist consultation to computed tomography scan decreased from 52 days to 3 days, and the median time from computed tomography scan to diagnosis decreased from 39 days to 6 days. Overall, the median time from suspicion of lung cancer to diagnosis decreased from 128 days to 20 days. Of all patients in the Time to Treat Program, 33% were eventually diagnosed with lung cancer. CONCLUSIONS: Time to Treat Program was effective in shortening the time from suspicion of lung cancer to diagnosis and reduced time intervals at each step in the process. Earlier diagnosis of lung cancer may allow increased treatment options for patients and may improve outcomes.

Emergency interventions for hyperkalaemia

It brings information about the hyperkalaemia, its incidence, consequences and treatment by using emergency interventions.