The anaphase-promoting complex: a key factor in the regulation of cell cycle

Events controlling cell division are governed by the degradation of different regulatory proteins by the ubiquitin-dependent pathway. In this pathway, the attachment of a polyubiquitin chain to a substrate by an ubiquitin-ligase targets this substrate for degradation by the 26S proteasome. Two different ubiquitin ligases play an important role in the cell cycle: the SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC). In this review, we describe the present knowledge about the APC. We pay particular attention to the latest results concerning APC structure, APC regulation and substrate recognition, and we discuss the implication of these findings in the understanding the APC function.     

T-cell lymphomas mask slower developing B-lymphoid and myeloid tumours in transgenic mice with broad haemopoietic expression of MYC

Deregulation of MYC expression occurs in many haematological malignancies. Previous studies modelling MYC-induced lymphomagenesis in the mouse used transgenic vectors that directed MYC overexpression in a lineage-specific manner. Here, we describe a transgenic mouse strain in which constitutive MYC expression is driven broadly in haemopoiesis by a vector containing regulatory elements of the Vav gene. Healthy young VavP-MYC17 mice had multiple haemopoietic abnormalities, most notably increased size and numbers of B-lymphoid cells, monocytes and megakaryocytes. The mice rapidly developed tumours and, surprisingly, these were exclusively T-cell lymphomas, mostly of mature CD4(+) CD8(-) T cells, a tumour type that is seldom seen in mouse models. To examine tumour development in the absence of the susceptible T cells, we bred VavP-MYC17 mice lacking the Rag1 recombinase. They survived longer and succumbed to tumours of several different haemopoietic cell types: pre-T cells, pro-B cells, macrophages and unusual progenitor cells. Thus, although T-lineage cells have the shortest latent period to transformation, the VavP-MYC17 transgene drives malignant transformation of multiple cell types and VavP-MYC17 mice provide a new model for tumours of multiple haemopoietic lineages.     

Women's decision-making roles regarding contralateral prophylactic mastectomy

BACKGROUND: Contralateral prophylactic mastectomy (CPM) is the removal of a nonaffected breast in a woman with unilateral breast cancer and is effective in reducing the risk of recurrences. Little is known about women's decision-making roles regarding CPM. METHODS: Women aged 18-80 years with CPM performed at one of six health maintenance organizations between 1979 and 1999 were surveyed. We determined women's reported decision-making roles at the time of CPM, analyzed their trends over time, and explored the association between decision-making roles and psychosocial outcomes following CPM. RESULTS: We received 562 responses (response rate = 73%); 431 completed items needed for this analysis. Most respondents were white, younger than 55 years at CPM, married, and had CPM within 10 years of completing the survey. Forty-five percent made the decision to undergo CPM alone, 37% considered their doctor's opinion, 15% shared the decision with their doctor and only 3% reported their doctor primarily made the decision. Women reporting active roles were more likely to be younger (P<.0008), college educated (P<.0001) and have CPM more recently (P = .002). Compared with those sharing the decision with their doctors, women with active roles were twice as likely to be satisfied 6 months following CPM (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.1 to 4.2) and report current concern about breast cancer (OR = 1.9, 95% CI = 1.0 to 3.4). CONCLUSIONS: Most women reported active or shared roles in decision making regarding CPM, particularly younger women, those with college education, and those with recent CPM. Women with active roles were more often satisfied in the short term but were also more likely to report current concern about breast cancer. Whether higher concern is related to insufficient input from clinicians should be explored. Prospective data are needed.     

Complications following bilateral prophylactic mastectomy

BACKGROUND: Bilateral prophylactic mastectomy significantly decreases breast cancer risk, but complications of the procedure have only been described in single-site studies. We describe the frequency and type of complications in women who underwent bilateral prophylactic mastectomy in a multisite community-based cohort. METHODS: Women aged 18-80 years undergoing bilateral prophylactic mastectomy without a personal history of breast cancer at one of six health plans were eligible. We identified women from automated data sources, then reviewed hospital data, ambulatory notes, and other chart elements to confirm eligibility and obtain all charted information about complications and surgeries performed after prophylactic mastectomy, including reconstructive procedures. Reconstructions were characterized by type (implant vs. tissue graft). Complications were noted for a 1-year period after any surgical procedure. RESULTS: We identified 269 women with prophylactic mastectomy who were followed for a mean of 7.4 years. Their mean age was 44.9 years. Nearly 80% undertook reconstruction, most with prosthetic implants. One or more complications occurred in 64%. The most common complications were pain (35% of women), infection (17%), and seroma (17%). Women with no reconstruction had fewer complications (mean of .93) than women who had implant (2.0) or tissue graft (2.4) reconstruction procedures (differences from no reconstruction: 1.07 [95% confidence interval = 0.36 to 1.77] and 1.50 [95% confidence interval = 0.44 to 2.56] respectively). Delay of reconstruction after mastectomy was associated with a borderline-significant higher risk of complications (80.6%) compared to simultaneous reconstruction (64.0%, P = .055). CONCLUSION: We found that almost two-thirds of women undergoing bilateral prophylactic mastectomy had at least one complication following surgery. Further work should be done to minimize and to understand the effect of complications of bilateral prophylactic mastectomy.     

Single-agent gefitinib in patients with untreated advanced non-small-cell lung cancer and poor performance status: a Minnie Pearl Cancer Research Network Phase II Trial

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) and poor performance status (PS) are often excluded from trials. Gefitinib is a safe oral agent that may benefit these patients. PATIENTS AND METHODS: Seventy-two patients with poor PS and advanced NSCLC were enrolled onto this study of gefitinib 250 mg per day given orally until disease progression, with evaluation at 8 weeks. Eligible patients had no previous chemotherapy, an Eastern Cooperative Oncology Group PS of 2/3, and stage IIIB/IV NSCLC. Quality of life (QOL) and symptom response (SR) scores were calculated using the Functional Assessment of Cancer-Lung questionnaire. Patient characteristics included a median age of 75 years; PS of 2/3; and bronchoalveolar (n=3), adenocarcinoma (n=29), squamous cell (n=21), large-cell (n=11), and unspecified histology (n=6). Mean treatment duration was 4 months (range, 3 days to 18 months), and median duration of follow-up was 12 months. Grade 3/4 toxicities included rash and diarrhea. RESULTS: Among 70 patients assessed for response, there were 3 partial responses (4%), 32 patients with stable disease (46%), and 18 with progressive disease (26%). Median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.3 months, respectively. Six-month and 1-year PFS and OS rates were 35% and 21% and 50% and 24%, respectively. Eighty-two percent and 48% of patients reported improvements or no change in QOL and SR, respectively. CONCLUSION: Gefitinib demonstrates modest efficacy and is well tolerated as initial therapy in advanced NSCLC for patients with poor PS.     

Killing cancer cells by flipping the Bcl-2/Bax switch

Impairment of apoptosis, the physiologic cell death process, is central to cancer development and renders tumors refractory to cytotoxic therapy. Bcl-2, the oncoprotein activated in follicular lymphoma, inhibits the conserved cell death pathway triggered by diverse cytotoxic agents, as do several close relatives. A small-molecule antagonist of these proteins has now been designed by Oltersdorf et al. Strikingly, ABT-737 sensitizes many tumors to cytotoxic agents and is effective as a single agent against certain lymphomas and solid tumors, provoking stable regression in some tumor xenografts. Hence, this work validates Bcl-2-like proteins as important new targets in cancer therapy.     

Amyloidosis: diagnosis and management

Amyloidosis is a rare plasma cell proliferative disorder. The annual incidence in Olmsted County, Minnesota, is 8 in 1,000,000 patients. This is a difficult disorder to diagnose, because the symptoms at presentation are vague and include dyspnea, paresthesias, edema, weight loss, and fatigue. The clinical syndromes at the time of presentation include nephrotic-range proteinuria with or without renal failure, cardiomyopathy, "atypical multiple myeloma," hepatomegaly, and autonomic or peripheral neuropathy. The serum immunoglobulin free light chain assay has been an important step forward in classifying systemic amyloidosis as an immunoglobulin light chain form and in monitoring therapy. Recently, the importance of serum cardiac biomarkers in assessing outcome has been recognized. New therapies developed over the past 5 years include high-dose chemotherapy with stem cell reconstitution, combinations of alkylating agents with dexamethasone, and, most recently, thalidomide.     

Societal discounting of health effects in cost-effectiveness analyses: the influence of life expectancy

BACKGROUND: Increasing life expectancy and decreasing marginal valuation of additional QALYs over time may serve as a basis for discounting future health effects from a societal perspective. Therefore, we tested the hypothesis that societal time preference for health is related to perceived future life expectancy. METHODS: A sample of 223 people from the general population prioritised healthcare programmes with differential timing of health benefits and costs from a societal perspective. Furthermore, we asked respondents to estimate future life expectancy. RESULTS: The relationship between future life expectancy and time preference for health is ambiguous. We observed that people who expected a higher future life expectancy elicited higher discount rates for health effects than those with lower life expectancy growth expectations for all four time periods (5, 10, 20 and 40 years into the future), but the differences were never significant. On average, providing explicit information on growth in life expectancy did significantly alter discount rates in the expected direction but, on an individual level, the results were rather inconsistent. We observed a significantly stronger time preference (i.e. higher discount rates) for health effects than for costs. As commonly observed, discount rates for health and money decreased with time delay following a hyperbolic function. CONCLUSION: Our data indicate that it is troublesome to elicit societal discount rates empirically, especially rates that are in line with the theoretical arguments on societal discounting. The influence of life expectancy remains ambiguous, but there seems to be at least some positive relationship between growth in life expectancy and discount rates that deserves additional attention.     

Hyperbaric oxygen for carbon monoxide poisoning : a systematic review and critical analysis of the evidence

Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.     

Olanzapine: a critical review of recent literature

The purpose of this review is to critically review the current literature on olanzapine with an emphasis on emergent themes and key findings in the use of this agent for the treatment of mood disorders and schizophrenia. New information continues to emerge on the impact of olanzapine on schizophrenia and on aspects of the course of mood disorders. There are also continued efforts to understand, predict and manage the side-effect risk with olanzapine.