Functional phosphoproteomic analysis reveals cold-shock domain protein A to be a Bcr-Abl effector-regulating proliferation and transformation in chronic myeloid leukemia

One proposed strategy to suppress the proliferation of imatinib-resistant cells in chronic myeloid leukemia (CML) is to inhibit key proteins downstream of Bcr-Abl. The PI3K/Akt pathway is activated by Bcr-Abl and is specifically required for the growth of CML cells. To identify targets of this pathway, we undertook a proteomic screen and identified several proteins that differentially bind 14-3-3, dependent on Bcr-Abl kinase activity. An siRNA screen of candidates selected by bioinformatics analysis reveals cold-shock domain protein A (CSDA), shown previously to regulate cell cycle progression in epithelial cells, to be a positive regulator of proliferation in a CML cell line. We show that Akt can phosphorylate the serine 134 residue of CSDA but, downstream of Bcr-Abl activity, this modification is mediated through the activation of MEK/p90 ribosomal S6 kinase (RSK) signaling. Inhibition of RSK, similarly to treatment with imatinib, blocked proliferation specifically in Bcr-Abl-positive leukemia cell lines, as well as cells from CML patients. Furthermore, these primary CML cells showed an increase in CSDA phosphorylation. Expression of a CSDA phospho-deficient mutant resulted in the decrease of Bcr-Abl-dependent transformation in Rat1 cells. Our results support a model whereby phosphorylation of CSDA downstream of Bcr-Abl enhances proliferation in CML cells to drive leukemogenesis

Trends in incidence of childhood cancer in Australia, 1983–2006

Cancer risk is increased substantially in adult kidney transplant recipients, but the long-term risk of cancer in childhood recipients is unclear. Using the Australian and New Zealand Dialysis and Transplant Registry, the authors compared overall and site-specific incidences of cancer after transplantation in childhood recipients with population-based data by using standardized incidence ratios (SIRs). Among 1734 childhood recipients (median age 14 years, 57% male, 85% white), 289 (16.7%) developed cancer (196 nonmelanoma skin cancers, 143 nonskin cancers) over a median follow-up of 13.4 years. The 25-year cumulative incidences of any cancer were 27% (95% confidence intervals 24-30%), 20% (17-23%) for nonmelanoma skin cancer, and 14% (12-17%) for nonskin cancer (including melanoma). The SIR for nonskin cancer was 8.23 (95% CI 6.92-9.73), with the highest risk for posttransplant lymphoproliferative disease (SIR 45.80, 95% CI 32.71-62.44) and cervical cancer (29.4, 95% CI 17.5-46.5). Increasing age at transplantation (adjusted hazard ratio [aHR] per year 1.10, 95% CI 1.06-1.14), white race (aHR 3.36, 95% CI 1.61-6.79), and having a functioning transplant (aHR 2.27, 95% CI 1.47-3.71) were risk factors for cancer. Cancer risk, particularly for virus-related cancers, is increased substantially after kidney transplantation during childhood

The Unknown Risk of Vertical Transmission in Sleeping Sickness—A Literature Review

Children with human African trypanosomiasis (HAT) present with a range of generally non-specific symptoms. Late diagnosis is frequent with often tragic outcomes. Trypanosomes can infect the foetus by crossing the placenta. Unequivocal cases of congenital infection that have been reported include newborn babies of infected mothers who were diagnosed with HAT in the first 5 days of life and children of infected mothers who had never entered an endemic country themselves

Recalibration of the delirium prediction model for ICU patients (PRE-DELIRIC): a multinational observational study

Purpose Recalibration and determining discriminative power, internationally, of the existing delirium prediction model (PRE-DELIRIC) for intensive care patients. Methods A prospective multicenter cohort study was performed in eight intensive care units (ICUs) in six countries. The ten predictors (age, APACHE-II, urgent and admission category, infection, coma, sedation, morphine use, urea level, metabolic acidosis) were collected within 24 h after ICU admission. The confusion assessment method for the intensive care unit (CAM-ICU) was used to identify ICU delirium. CAM-ICU screening compliance and inter-rater reliability measurements were used to secure the quality of the data. Results A total of 2,852 adult ICU patients were screened of which 1,824 (64 %) were eligible for the study. Main reasons for exclusion were length of stay <1 day (19.1 %) and sustained coma (4.1 %). CAM-ICU compliance was mean (SD) 82 ± 16 % and inter-rater reliability 0.87 ± 0.17. The median delirium incidence was 22.5 % (IQR 12.8–36.6 %). Although the incidence of all ten predictors differed significantly between centers, the area under the receiver operating characteristic (AUROC) curve of the eight participating centers remained good: 0.77 (95 % CI 0.74–0.79). The linear predictor and intercept of the prediction rule were adjusted and resulted in improved re-calibration of the PRE-DELIRIC model. Conclusions In this multinational study, we recalibrated the PRE-DELIRIC model. Despite differences in the incidence of predictors between the centers in the different countries, the performance of the PRE-DELIRIC-model remained good. Following validation of the PRE-DELIRIC model, it may facilitate implementation of strategies to prevent delirium and aid improvements in delirium management of ICU patients

Multinational development and validation of an early prediction model for delirium in ICU patients

Rationale Delirium incidence in intensive care unit (ICU) patients is high and associated with poor outcome. Identification of high-risk patients may facilitate its prevention. Purpose To develop and validate a model based on data available at ICU admission to predict delirium development during a patient’s complete ICU stay and to determine the predictive value of this model in relation to the time of delirium development. Methods Prospective cohort study in 13 ICUs from seven countries. Multiple logistic regression analysis was used to develop the early prediction (E-PRE-DELIRIC) model on data of the first two-thirds and validated on data of the last one-third of the patients from every participating ICU. Results In total, 2914 patients were included. Delirium incidence was 23.6 %. The E-PRE-DELIRIC model consists of nine predictors assessed at ICU admission: age, history of cognitive impairment, history of alcohol abuse, blood urea nitrogen, admission category, urgent admission, mean arterial blood pressure, use of corticosteroids, and respiratory failure. The area under the receiver operating characteristic curve (AUROC) was 0.76 [95 % confidence interval (CI) 0.73–0.77] in the development dataset and 0.75 (95 % CI 0.71–0.79) in the validation dataset. The model was well calibrated. AUROC increased from 0.70 (95 % CI 0.67–0.74), for delirium that developed 6 days. Conclusion Patients’ delirium risk for the complete ICU length of stay can be predicted at admission using the E-PRE-DELIRIC model, allowing early preventive interventions aimed to reduce incidence and severity of ICU delirium

Do schistosome vaccine trials in mice have an intrinsic flaw that generates spurious protection data?

The laboratory mouse has been widely used to test the efficacy of schistosome vaccines and a long list of candidates has emerged from this work, many of them abundant internal proteins. These antigens do not have an additive effect when co-administered, or delivered as SWAP homogenate, a quarter of which comprises multiple candidates; the observed protection has an apparent ceiling of 40–50 %. We contend that the low level of maturation of penetrating cercariae (~32 % for Schistosoma mansoni) is a major limitation of the model since 68/100 parasites fail to mature in naïve mice due to natural causes. The pulmonary capillary bed is the obstacle encountered by schistosomula en route to the portal system. The fragility of pulmonary capillaries and their susceptibility to a cytokine-induced vascular leak syndrome have been documented. During lung transit schistosomula burst into the alveolar spaces, and possess only a limited capacity to re-enter tissues. The acquired immunity elicited by the radiation attenuated (RA) cercarial vaccine relies on a pulmonary inflammatory response, involving cytokines such as IFNγ and TNFα, to deflect additional parasites into the alveoli. A principal difference between antigen vaccine protocols and the RA vaccine is the short interval between the last antigen boost and cercarial challenge of mice (often two weeks). Thus, after antigen vaccination, challenge parasites will reach the lungs when both activated T cells and cytokine levels are maximal in the circulation. We propose that “protection” in this situation is the result of physiological effects on the pulmonary blood vessels, increasing the proportion of parasites that enter the alveoli. This hypothesis will explain why internal antigens, which are unlikely to interact with the immune response in a living schistosomulum, plus a variety of heterologous proteins, can reduce the level of maturation in a non-antigen-specific way. These proteins are “successful” precisely because they have not been selected for immunological silence. The same arguments apply to vaccine experiments with S. japonicum in the mouse model; this schistosome species seems a more robust parasite, even harder to eliminate by acquired immune responses. We propose a number of ways in which our conclusions may be tested

Astrocytic Mechanisms Explaining Neural-Activity-Induced Shrinkage of Extraneuronal Space

Neuronal stimulation causes ∼30% shrinkage of the extracellular space (ECS) between neurons and surrounding astrocytes in grey and white matter under experimental conditions. Despite its possible implications for a proper understanding of basic aspects of potassium clearance and astrocyte function, the phenomenon remains unexplained. Here we present a dynamic model that accounts for current experimental data related to the shrinkage phenomenon in wild-type as well as in gene knockout individuals. We find that neuronal release of potassium and uptake of sodium during stimulation, astrocyte uptake of potassium, sodium, and chloride in passive channels, action of the Na/K/ATPase pump, and osmotically driven transport of water through the astrocyte membrane together seem sufficient for generating ECS shrinkage as such. However, when taking into account ECS and astrocyte ion concentrations observed in connection with neuronal stimulation, the actions of the Na+/K+/Cl− (NKCC1) and the Na+/HCO3− (NBC) cotransporters appear to be critical determinants for achieving observed quantitative levels of ECS shrinkage. Considering the current state of knowledge, the model framework appears sufficiently detailed and constrained to guide future key experiments and pave the way for more comprehensive astroglia–neuron interaction models for normal as well as pathophysiological situations

The dominant Anopheles vectors of human malaria in Africa, Europe and the Middle East: occurrence data, distribution maps and bionomic précis

<p>Abstract</p> <p>Background</p> <p>This is the second in a series of three articles documenting the geographical distribution of 41 dominant vector species (DVS) of human malaria. The first paper addressed the DVS of the Americas and the third will consider those of the Asian Pacific Region. Here, the DVS of Africa, Europe and the Middle East are discussed. The continent of Africa experiences the bulk of the global malaria burden due in part to the presence of the <it>An. gambiae </it>complex. <it>Anopheles gambiae </it>is one of four DVS within the <it>An. gambiae </it>complex, the others being <it>An. arabiensis </it>and the coastal <it>An. merus </it>and <it>An. melas</it>. There are a further three, highly anthropophilic DVS in Africa, <it>An. funestus</it>, <it>An. moucheti </it>and <it>An. nili</it>. Conversely, across Europe and the Middle East, malaria transmission is low and frequently absent, despite the presence of six DVS. To help control malaria in Africa and the Middle East, or to identify the risk of its re-emergence in Europe, the contemporary distribution and bionomics of the relevant DVS are needed.</p> <p>Results</p> <p>A contemporary database of occurrence data, compiled from the formal literature and other relevant resources, resulted in the collation of information for seven DVS from 44 countries in Africa containing 4234 geo-referenced, independent sites. In Europe and the Middle East, six DVS were identified from 2784 geo-referenced sites across 49 countries. These occurrence data were combined with expert opinion ranges and a suite of environmental and climatic variables of relevance to anopheline ecology to produce predictive distribution maps using the Boosted Regression Tree (BRT) method.</p> <p>Conclusions</p> <p>The predicted geographic extent for the following DVS (or species/suspected species complex*) is provided for Africa: <it>Anopheles </it>(<it>Cellia</it>) <it>arabiensis</it>, <it>An. </it>(<it>Cel.</it>) <it>funestus*</it>, <it>An. </it>(<it>Cel.</it>) <it>gambiae</it>, <it>An. </it>(<it>Cel.</it>) <it>melas</it>, <it>An. </it>(<it>Cel.</it>) <it>merus</it>, <it>An. </it>(<it>Cel.</it>) <it>moucheti </it>and <it>An. </it>(<it>Cel.</it>) <it>nili*</it>, and in the European and Middle Eastern Region: <it>An. </it>(<it>Anopheles</it>) <it>atroparvus</it>, <it>An. </it>(<it>Ano.</it>) <it>labranchiae</it>, <it>An. </it>(<it>Ano.</it>) <it>messeae</it>, <it>An. </it>(<it>Ano.</it>) <it>sacharovi</it>, <it>An. </it>(<it>Cel.</it>) <it>sergentii </it>and <it>An. </it>(<it>Cel.</it>) <it>superpictus*</it>. These maps are presented alongside a bionomics summary for each species relevant to its control.</p

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p