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Autoimmunity develops when extracellular DNA released from dying cells is not cleared from serum. While serum DNA is primarily digested by Dnase1 and Dnase1L3, Dnase1 cannot rescue autoimmunity arising from Dnase1L3 deficiencies. Dnase1L3 uniquely degrades antigenic forms of cell-free DNA, including DNA complexed with lipids and proteins. The distinct activity of Dnase1L3 relies on its unique C-terminal Domain (CTD), but the mechanism is unknown. We used multiple biophysical techniques and functional assays to study the interplay between the core catalytic domain and the CTD. While the core domain resembles Dnase1, there are key structural differences between the two enzymes. First, Dnase1L3 is not inhibited by actin due to multiple differences in the actin recognition site. Second, the CTD augments the ability of the core to bind DNA, thereby facilitating the degradation of complexed DNA. Together, these structural insights will inform the development of Dnase1L3-based therapies for autoimmunity. Biophysical, structural, and functional characterization of Dnase1L3 reveals differences in DNA binding and degradation mechanisms between Dnase1 and Dnase1L3 facilitated by Dnase1L3's intrinsically disordered C-terminal domain. [ABSTRACT FROM AUTHOR]

Background: Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis. Whilst being corticosteroid responsive, AIP often masquerades radiologically as pancreatic neoplasia. Our aim is to appraise demographic, radiological and histological features in our cohort in order to differentiate AIP from pancreatic malignancy. Methods: Clinical, biochemical, histological and radiological details of all AIP patients 1997–2016 were analysed. The initial imaging was re-reviewed according to international guidelines by three blinded independent radiologists to evaluate features associated with autoimmune pancreatitis and pancreatic cancer. Results: There were a total of 45 patients: 25 in type 1 (55.5%), 14 type 2 (31.1%) and 6 AIP otherwise not specified (13.3%). The median (IQR) age was 57 (51–70) years. Thirty patients (66.6%) were male. Twenty-six patients (57.8%) had resection for suspected malignancy and one for symptomatic chronic pancreatitis. Three had histologically proven malignancy with concurrent AIP. Two patients died from recurrent pancreatic cancer following resection. Multidisciplinary team review based on radiology and clinical history dictated management. Resected patients (vs. non-resected group) were older (64 vs. 53, p = 0.003) and more frequently had co-existing autoimmune pathologies (22.2 vs. 55.6%, p = 0.022). Resected patients also presented with less classical radiological features of AIP, which are halo sign (0/25 vs. 3/17, p = 0.029) and loss of pancreatic clefts (18/25 vs. 17/17, p = 0.017). There were no differences in demographic features other than age. Conclusion: Despite international guidelines for diagnosing AIP, differentiation from pancreatic cancer remains challenging. Resection remains an important treatment option in suspected cancer or where conservative treatment fails. [ABSTRACT FROM AUTHOR]

This paper describes the development and basic evaluation of decadal predictions produced using the HiGEM coupled climate model. HiGEM is a higher resolution version of the HadGEM1 Met Office Unified Model. The horizontal resolution in HiGEM has been increased to $$1.25^{\circ } \times 0.83^{\circ }$$ in longitude and latitude for the atmosphere, and $$1/3^{\circ } \times 1/3^{\circ }$$ globally for the ocean. The HiGEM decadal predictions are initialised using an anomaly assimilation scheme that relaxes anomalies of ocean temperature and salinity to observed anomalies. 10 year hindcasts are produced for 10 start dates (1960, 1965,..., 2000, 2005). To determine the relative contributions to prediction skill from initial conditions and external forcing, the HiGEM decadal predictions are compared to uninitialised HiGEM transient experiments. The HiGEM decadal predictions have substantial skill for predictions of annual mean surface air temperature and 100 m upper ocean temperature. For lead times up to 10 years, anomaly correlations (ACC) over large areas of the North Atlantic Ocean, the Western Pacific Ocean and the Indian Ocean exceed values of 0.6. Initialisation of the HiGEM decadal predictions significantly increases skill over regions of the Atlantic Ocean, the Maritime Continent and regions of the subtropical North and South Pacific Ocean. In particular, HiGEM produces skillful predictions of the North Atlantic subpolar gyre for up to 4 years lead time (with ACC > 0.7), which are significantly larger than the uninitialised HiGEM transient experiments. [ABSTRACT FROM AUTHOR]

A robust adaptive autopilot for uninhabited surface vehicles (USV) based on a model predictive controller (MPC) is presented in this paper. The novel autopilot is capable of handling sudden changes in system dynamics. In real life situations, very often a sudden change in dynamics results in missions being aborted and the uninhabited vehicles have to be rescued before they cause damage to other marine craft in the vicinity. This problem has been suitably dealt with by this innovative design. The MPC adopts an online adaptive nature by utilising three algorithms, individually: gradient descent, least squares and weighted least squares (WLS). Even with random initialisation, significant improvements over the other algorithmic approach were achieved by WLS by maintaining the intermittent continuous values of system parameters and periodically reinitialising the covariance matrix. Also, a time frame of 25 seconds appears to be the optimum to reinitialise the parameters in simulation studies. This novel approach enables the autopilot to cope well with significant changes in the system dynamics and empowers USVs to accomplish their desired missions. [ABSTRACT FROM AUTHOR]

It had been proposed that a loop, typically containing 26 or 27 amino acids, which is only present in monomeric, ferredoxin-dependent, 'plant-type' glutamate synthases and is absent from the catalytic α-subunits of both NADPH-dependent, heterodimeric glutamate synthases found in non-photosynthetic bacteria and NADH-dependent heterodimeric cyanobacterial glutamate synthases, plays a key role in productive binding of ferredoxin to the plant-type enzymes. Site-directed mutagenesis has been used to delete the entire 27 amino acid-long loop in the ferredoxin-dependent glutamate synthase from the cyanobacterium Synechocystis sp. PCC 6803. The specific activity of the resulting loopless variant of this glutamate synthase, when reduced ferredoxin serves as the electron donor, is actually higher than that of the wild-type enzyme, suggesting that this loop is not absolutely essential for efficient electron transfer from reduced ferredoxin to the enzyme. These results are consistent with the results of an in-silico study that suggests that the loop is unlikely to interact directly with ferredoxin in the energetically most favorable model of a 1:1 complex of ferredoxin with the wild-type enzyme. [ABSTRACT FROM AUTHOR]

Background:Patients with malignant pleural effusions (MPEs) generally have advanced disease with poor survival and few therapeutic options. Cells within MPEs may be used to stratify patients for targeted therapy. Targeted therapy with poly(ADP ribose) polymerase inhibitors (PARPi) depends on identifying homologous recombination DNA repair (HRR)-defective cancer cells. We aimed to determine the feasibility of assaying HRR status in MPE cells.Methods:A total of 15 MPE samples were collected from consenting patients with non-small-cell lung cancer (NSCLC), mesothelioma and ovarian and breast cancer. Primary cultures were confirmed as epithelial by pancytokeratin, and HRR status was determined by the detection of γH2AX and RAD51 foci following a 24-h exposure to rucaparib, by immunofluorescence microscopy. Massively parallel next-generation sequencing of DNA repair genes was performed on cultured MPE cells.Results:From 15 MPE samples, 13 cultures were successfully established, with HRR function successfully determined in 12 cultures. Four samples - three NSCLC and one mesothelioma - were HRR defective and eight samples - one NSCLC, one mesothelioma, one sarcomatoid, one breast and four ovarian cancers - were HRR functional. No mutations in DNA repair genes were associated with HRR status, but there was probable loss of heterozygosity of FANCG, RPA1 and PARP1.Conclusions:HRR function can be successfully detected in MPE cells demonstrating the potential to stratify patients for targeted therapy with PARPi. [ABSTRACT FROM AUTHOR]

This paper describes a new genetic learning approach to the construction of a local model network (LMN) and design of a local controller network (LCN) with application to a single-link flexible manipulator. A highly nonlinear flexible manipulator system is modelled using an LMN comprising Autoregressive-moving-average model with exogenous inputs (ARMAX) type local models (LMs) whereas linear Proportional-integral-derivative (PID) type local controllers (LCs) are used to design an LCN. In addition to allowing the simultaneous optimisation of the number of LMs and LCs, model parameters and interpolation function parameters, the approach provides a flexible framework for targeting transparency and generalisation. Simulation results confirm the excellent nonlinear modelling properties of an LM network and illustrate the potential benefits of the proposed LM control scheme. [ABSTRACT FROM AUTHOR]

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement. [ABSTRACT FROM AUTHOR]

Loss of function mutation in FBXW7, an E3 ubiquitin ligase, is associated with good prognosis and early glucocorticoid treatment response in childhood T-cell acute lymphoblastic leukemia (T-ALL) by unknown mechanisms. Here, we show that FBXW7 targets the glucocorticoid receptor α (GRα) for ubiquitylation and proteasomal degradation in a manner dependent on glycogen synthase kinase 3 β-mediated phsophorylation. FBXW7 inactivation caused elevated GRα levels, and enhanced the transcriptional response to glucocorticoids. There was significant enhancement of GR transcriptional responses in FBXW7-deficient cell lines and primary T-ALL samples, in particular, for those pro-apoptotic regulatory proteins, BIM and PUMA. Reduced FBXW7 expression or function promoted glucocorticoid sensitivity, but not sensitivity to other chemotherapeutic agents used in T-ALL. Moreover, this was a general feature of different cancer cell types. Taken together, our work defines GRα as a novel FBXW7 substrate and demonstrates that favorable patient prognosis in T-ALL is associated with FBXW7 mutations due to enhanced GRα levels and steroid sensitivity. These findings suggest that inactivation of FBXW7, a putative tumor suppressor protein, may create a synthetic lethal state in the presence of specific anticancer therapies. [ABSTRACT FROM AUTHOR]

Decadal predictions have a high profile in the climate science community and beyond, yet very little is known about their skill. Nor is there any agreed protocol for estimating their skill. This paper proposes a sound and coordinated framework for verification of decadal hindcast experiments. The framework is illustrated for decadal hindcasts tailored to meet the requirements and specifications of CMIP5 (Coupled Model Intercomparison Project phase 5). The chosen metrics address key questions about the information content in initialized decadal hindcasts. These questions are: (1) Do the initial conditions in the hindcasts lead to more accurate predictions of the climate, compared to un-initialized climate change projections? and (2) Is the prediction model's ensemble spread an appropriate representation of forecast uncertainty on average? The first question is addressed through deterministic metrics that compare the initialized and uninitialized hindcasts. The second question is addressed through a probabilistic metric applied to the initialized hindcasts and comparing different ways to ascribe forecast uncertainty. Verification is advocated at smoothed regional scales that can illuminate broad areas of predictability, as well as at the grid scale, since many users of the decadal prediction experiments who feed the climate data into applications or decision models will use the data at grid scale, or downscale it to even higher resolution. An overall statement on skill of CMIP5 decadal hindcasts is not the aim of this paper. The results presented are only illustrative of the framework, which would enable such studies. However, broad conclusions that are beginning to emerge from the CMIP5 results include (1) Most predictability at the interannual-to-decadal scale, relative to climatological averages, comes from external forcing, particularly for temperature; (2) though moderate, additional skill is added by the initial conditions over what is imparted by external forcing alone; however, the impact of initialization may result in overall worse predictions in some regions than provided by uninitialized climate change projections; (3) limited hindcast records and the dearth of climate-quality observational data impede our ability to quantify expected skill as well as model biases; and (4) as is common to seasonal-to-interannual model predictions, the spread of the ensemble members is not necessarily a good representation of forecast uncertainty. The authors recommend that this framework be adopted to serve as a starting point to compare prediction quality across prediction systems. The framework can provide a baseline against which future improvements can be quantified. The framework also provides guidance on the use of these model predictions, which differ in fundamental ways from the climate change projections that much of the community has become familiar with, including adjustment of mean and conditional biases, and consideration of how to best approach forecast uncertainty. [ABSTRACT FROM AUTHOR]

Patients commonly present with syncope at emergency departments and other facilities for urgent care. Syncope is understood by physicians to be a transient, self-terminating period of cerebral hypoperfusion that usually results from systemic hypotension, and clinical guidelines for the care of patients with presumed syncope are available. However, the diagnosis and management of such patients continue to pose important diagnostic, therapeutic, and economic challenges, which are the focus of this Review. First, we discuss how to improve symptom characterization to distinguish syncope from other forms of transient loss of consciousness and syncope mimics. Second, we compare methods of risk stratification in patients with suspected syncope, and recommend the introduction of syncope clinics with enhanced interdisciplinary collaboration to optimize patient care at reduced expense. Third, we highlight the importance of the appropriate selection of diagnostic tools and treatment strategies in these syncope clinics. Finally, we address the difficulties associated with therapy for the most-common form of syncope--vasovagal or reflex syncope. [ABSTRACT FROM AUTHOR]

In neurons, SNAREs, synaptotagmin and other factors catalyze Ca2+-triggered fusion of vesicles with the plasma membrane. The molecular mechanism of this process, especially the interaction between synaptotagmin and SNAREs, remains an enigma. Here we characterized this interaction by single-molecule fluorescence microscopy and crystallography. The two rigid Ca2+-binding domains of synaptotagmin 3 (Syt3) undergo large relative motions in solution. Interaction with SNARE complex amplifies a particular state of the two domains that is further enhanced by Ca2+. This state is represented by the first SNARE-induced Ca2+-bound crystal structure of a synaptotagmin fragment containing both domains. The arrangement of the Ca2+-binding loops of this structure of Syt3 matches that of SNARE-bound Syt1, suggesting a conserved feature of synaptotagmins. The loops resemble the membrane-interacting loops of certain viral fusion proteins in the postfusion state, suggesting unexpected similarities between both fusion systems. [ABSTRACT FROM AUTHOR]

Analysis of variance (ANOVA) is a powerful statistical technique for making inferences about experiments that are influenced by multiple factors. Whilst common in many other scientific fields, its use within the climate community has been limited to date. Here we review the basis for ANOVA and how, in particular, it can be applied to partition the variance in a multi-model ensemble of Atmospheric General Circulation Model simulations. We examine an ensemble of four AGCMs forced with observed twentieth century sea surface temperatures (SST). We show that the dominant contributions to the total variance of seasonal mean sea level pressure arise from between-model differences (the bias term) and internal noise (the noise term). However, which term is most important varies from region to region. Of particular interest is the interaction term, which describes differences between the models in their responses to common SST forcing. The interaction term is found to be largest over the Indian Ocean (in all seasons), and over the subtropical Northwest Pacific in boreal summer. The differences between the model responses in these regions suggest differences in their simulation of atmospheric teleconnections, with potentially important implications, e.g. for seasonal predictions of the South and East Asian Monsoons. Examination of these differences may lead to an understanding of the reasons why models respond differently to common forcing, and ultimately to improvements in the performance of climate models. [ABSTRACT FROM AUTHOR]

Despite the widespread use of endoscopic biliary stenting in patients presenting with potentially resectable pancreatic cancer, there is no general consensus regarding whether this represents a superior management approach over expeditious surgical intervention. The objective of this study was to investigate the influence of preoperative biliary stenting and resolution of jaundice on subsequent postoperative survival following resection for pancreatic cancer. 155 patients undergoing partial pancreatoduodenectomy for pancreatic ductal adenocarcinoma between January 1997 and August 2007 were identified from a prospectively maintained database. There was no survival difference when comparing patients undergoing preoperative biliary drainage ( n = 130) with those who did not ( n = 25) (log rank, P = 0.981). When analysing individual prognostic factors as continuous variables in univariate Cox analysis, lower albumin levels ( P = 0.016), elevated alkaline phosphatase levels ( P = 0.011) and elevated CRP levels ( P = 0.021) were associated with poorer overall survival. Multivariable Cox regression demonstrated that both albumin ( P = 0.008) and CRP ( P = 0.038) remained significant independent predictors of overall survival alongside lymph node ratio ( P = 0.018). Although preoperative bilirubin levels were not associated with overall survival when analysed as a continuous variable (Cox, P = 0.786), the presence of jaundice (i.e., bilirubin >35 μmol/l) at the time of surgery was a significant adverse predictor of early survival in patients undergoing preoperative biliary drainage (Breslow–Gehan–Wilcoxon, P = 0.013) and remained a significant predictor of early survival when included in a further Cox analysis with censoring of cases who survived beyond 6 months (Cox, P = 0.017). These results suggest that the presence of jaundice at the time of resection has an adverse impact on early, but not overall, postoperative survival in pancreatic cancer patients undergoing preoperative biliary drainage. [ABSTRACT FROM AUTHOR]

Detection of minimal residual disease (MRD) is the most sensitive method to evaluate treatment response and one of the strongest predictors of outcome in childhood acute lymphoblastic leukemia (ALL). The 10-year update on the I-BFM-SG MRD study 91 demonstrates stable results (event-free survival), that is, standard risk group (MRD-SR) 93%, intermediate risk group (MRD-IR) 74%, and high risk group (MRD-HR) 16%. In multicenter trial AIEOP-BFM ALL 2000, patients were stratified by MRD detection using quantitative PCR after induction (TP1) and consolidation treatment (TP2). From 1 July 2000 to 31 October 2004, PCR target identification was performed in 3341 patients: 2365 (71%) patients had two or more sensitive targets (10−4), 671 (20%) patients revealed only one sensitive target, 217 (6%) patients had targets with lower sensitivity, and 88 (3%) patients had no targets. MRD-based risk group assignment was feasible in 2594 (78%) patients: 40% were classified as MRD-SR (two sensitive targets, MRD negativity at both time points), 8% as MRD-HR (MRD 10−3 at TP2), and 52% as MRD-IR. The remaining 823 patients were stratified according to clinical risk features: HR (n=108) and IR (n=715). In conclusion, MRD-PCR-based stratification using stringent criteria is feasible in almost 80% of patients in an international multicenter trial.Leukemia (2008) 22, 771–782; doi:10.1038/leu.2008.5; published online 31 January 2008 [ABSTRACT FROM AUTHOR]

Secretagogues, such as cholecystokinin and acetylcholine, utilise a variety of second messengers (inositol trisphosphate, cADPR and nicotinic acid adenine dinucleotide phosphate) to induce specific oscillatory patterns of calcium (Ca2+) signals in pancreatic acinar cells. These are tightly controlled in a spatiotemporal manner, and are coupled to mitochondrial metabolism necessary to fuel secretion. When Ca2+ homeostasis is disrupted by known precipitants of acute pancreatitis, for example, hyperstimulation or non-oxidative ethanol metabolites, Ca2+ stores (endoplasmic reticulum and acidic pool) become depleted and sustained cytosolic [Ca2+] elevations replace transient signals, leading to severe consequences. Sustained mitochondrial depolarisation, possibly via opening of the mitochondrial permeability transition pore (MPTP), elicits cellular ATP depletion that paralyses energy-dependent Ca2+ pumps causing cytosolic Ca2+ overload, while digestive enzymes are activated prematurely within the cell; Ca2+-dependent cellular necrosis ensues. However, when stress to the acinar cell is milder, for example, by application of the oxidant menadione, release of Ca2+ from stores leads to oscillatory global waves, associated with partial mitochondrial depolarisation and transient MPTP opening; apoptotic cell death is promoted via the intrinsic pathway, when associated with generation of reactive oxygen species. Apoptosis, induced by menadione or bile acids, is potentiated by inhibition of an endogenous detoxifying enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), suggesting its importance as a defence mechanism that may influence cell fate.Cell Death and Differentiation (2007) 14, 1285–1294; doi:10.1038/sj.cdd.4402150; published online 13 April 2007 [ABSTRACT FROM AUTHOR]

In this paper, we propose a structure for organo-mineral associations in soils based on recent insights concerning the molecular structure of soil organic matter (SOM), and on extensive published evidence from empirical studies of organo-mineral interfaces. Our conceptual model assumes that SOM consists of a heterogeneous mixture of compounds that display a range of amphiphilic or surfactant-like properties, and are capable of self-organization in aqueous solution. An extension of this self-organizational behavior in solution, we suggest that SOM sorbs to mineral surfaces in a discrete zonal sequence. In the contact zone, the formation of particularly strong organo-mineral associations appears to be favored by situations where either (i) polar organic functional groups of amphiphiles interact via ligand exchange with singly coordinated mineral hydroxyls, forming stable inner-sphere complexes, or (ii) proteinaceous materials unfold upon adsorption, thus increasing adhesive strength by adding hydrophobic interactions to electrostatic binding. Entropic considerations dictate that exposed hydrophobic portions of amphiphilic molecules adsorbed directly to mineral surfaces be shielded from the polar aqueous phase through association with hydrophobic moieties of other amphiphilic molecules. This process can create a membrane-like bilayer containing a hydrophobic zone, whose components may exchange more easily with the surrounding soil solution than those in the contact zone, but which are still retained with considerable force. Sorbed to the hydrophilic exterior of hemimicellar coatings, or to adsorbed proteins, are organic molecules forming an outer region, or kinetic zone, that is loosely retained by cation bridging, hydrogen bonding, and other interactions. Organic material in the kinetic zone may experience high exchange rates with the surrounding soil solution, leading to short residence times for individual molecular fragments. The thickness of this outer region would depend more on input than on the availability of binding sites, and would largely be controlled by exchange kinetics. Movement of organics into and out of this outer region can thus be viewed as similar to a phase-partitioning process. The zonal concept of organo-mineral interactions presented here offers a new basis for understanding and predicting the retention of organic compounds, including contaminants, in soils and sediments. [ABSTRACT FROM AUTHOR]

Minimal residual disease (MRD) diagnostics is used for treatment stratification in childhood acute lymphoblastic leukemia. We aimed to identify and solve potential problems in multicenter MRD studies to achieve and maintain consistent results between the AIEOP/BFM ALL-2000 MRD laboratories. As the dot-blot hybridization method was replaced by the real-time quantitative polymerase chain reaction (RQ-PCR) method during the treatment protocol, special attention was given to the comparison of MRD data obtained by both methods and to the reproducibility of RQ-PCR data. Evaluation of all key steps in molecular MRD diagnostics identified several pitfalls that resulted in discordant MRD results. In particular, guidelines for RQ-PCR data interpretation appeared to be crucial for obtaining concordant MRD results. The experimental variation of the RQ-PCR was generally less than three-fold, but logically became larger at low MRD levels below the reproducible sensitivity of the assay (<10−4). Finally, MRD data obtained by dot-blot hybridization were comparable to those obtained by RQ-PCR analysis (r2=0.74). In conclusion, MRD diagnostics using RQ-PCR analysis of immunoglobulin/T-cell receptor gene rearrangements is feasible in multicenter studies but requires standardization; particularly strict guidelines for interpretation of RQ-PCR data are required. We further recommend regular quality control for laboratories performing MRD diagnostics in international treatment protocols.Leukemia (2007) 21, 706–713. doi:10.1038/sj.leu.2404535; published online 8 February 2007 [ABSTRACT FROM AUTHOR]

Most modern treatment protocols for acute lymphoblastic leukaemia (ALL) include the analysis of minimal residual disease (MRD). To ensure comparable MRD results between different MRD-polymerase chain reaction (PCR) laboratories, standardization and quality control are essential. The European Study Group on MRD detection in ALL (ESG-MRD-ALL), consisting of 30 MRD-PCR laboratories worldwide, has developed guidelines for the interpretation of real-time quantitative PCR-based MRD data. The application of these guidelines ensures identical interpretation of MRD data between different laboratories of the same MRD-based clinical protocol. Furthermore, the ESG-MRD-ALL guidelines will facilitate the comparison of MRD data obtained in different treatment protocols, including those with new drugs.Leukemia (2007) 21, 604–611. doi:10.1038/sj.leu.2404586; published online 8 February 2007 [ABSTRACT FROM AUTHOR]

The melanoma differentiation-associated gene-7 (mda-7/IL-24) is a unique member of the interleukin 10 (IL-10) family of cytokines, with ubiquitous tumor cell pro-apoptotic activity. Recent data have shown that IL-24 is secreted as a glycosylated protein and functions as a pro-Th1 cytokine and as a potent anti-angiogenic molecule. In this study, we analyzed the activity of Ad-mda7 and its protein product, secreted IL-24, against human breast cancer cells. We show that Ad-mda7 transduction of human breast cancer cells results in G2/M phase cell cycle arrest and apoptotic cell death, which correlates with secretion of IL-24 protein. Neutralizing antibody against IL-24 significantly inhibited Ad-mda7 cytotoxicity. IL-24 and IL-10 both engage their cognate receptors on breast cancer cells resulting in phosphorylation and activation of STAT3, however, IL-10 receptor binding failed to induce cell killing, indicating that tumor cell killing by IL-24 is independent of STAT3 phosphorylation. Treatment with exogenous IL-24 induced apoptosis in breast cancer cells and this effect was abolished by addition of anti-IL-24 antibody or anti-IL-20R1, indicating that bystander cell killing is mediated via IL-24 binding to the IL-20R1/IL-20R2 heterodimeric receptor complex. Co-administration of the related cytokine IL-10 inhibited killing mediated by IL-24 and concomitantly inhibited IL-24 mediated up-regulation of the tumor suppressor proteins, p53 and p27Kip1. In summary, we have defined a tumor-selective cytotoxic bystander role for secreted IL-24 protein and identified a novel receptor-mediated death pathway in breast cancer cells, wherein the related cytokines IL-24 and IL-10 exhibit antagonistic activity. [ABSTRACT FROM AUTHOR]

The surface heat flux feedback is estimated in the Atlantic and the extra-tropical Indo-Pacific, using monthly heat flux and sea surface temperature anomaly data from control simulations with five global climate models, and it is compared to estimates derived from COADS and the NCEP reanalysis. In all data sets, the heat flux feedback is negative nearly everywhere and damps the sea surface temperature anomalies. At extra-tropical latitudes, it is strongly dominated by the turbulent fluxes. The radiative feedback can be positive or negative, depending on location and season, but it remains small, except in some models in the tropical Atlantic. The negative heat flux feedback is strong in the mid-latitude storm tracks, exceeding 40 W m–2 K–1 at place, but in the Northern Hemisphere it is substantially underestimated in several models. The negative feedback weakens at high latitudes, although the models do not reproduce the weak positive feedback found in NCEP in the northern North Atlantic. The main differences are found in the tropical Atlantic where the heat flux feedback is weakly negative in some models , as in the observations, and strongly negative in others where it can exceed 30 W m–2 K–1 at large scales, in part because of a strong contribution of the radiative fluxes, in particular during spring. A comparison between models with similar atmospheric or oceanic components suggests that the atmospheric model is primarily responsible for the heat flux feedback differences at extra-tropical latitudes. In the tropical Atlantic, the ocean behavior plays an equal role. The differences in heat flux feedback in the tropical Atlantic are reflected in the sea surface temperature anomaly persistence, which is too small in models where the heat flux damping is large. A good representation of the heat flux feedback is thus required to simulate climate variability realistically. [ABSTRACT FROM AUTHOR]

A coupled ocean–atmosphere general circulation model has been used to study the variations of North Atlantic upper ocean heat content (OHC), sea surface temperature (SST) and ocean heat transport (OHT), and the relationships between these three quantities. We find that OHC anomalies, and salinity anomalies, propagate anti-cyclonically around the North Atlantic subtropical gyre. They propagate eastward in midlatitudes and westward in low latitudes. Both the advection of mean temperature by anomalous currents and the advection of temperature anomalies by mean currents are responsible for these zonal propagations. In addition to zonal propagations, upper ocean temperature anomalies propagate southward in the eastern North Atlantic, where subduction plays a dominant role. Variability in the northward OHT in the Atlantic is primarily governed by variability in the ocean circulation rather than variability in temperatures. Fluctuations in OHT are the major cause of anomalies in OHC and SST in the Gulf Stream extension region. This is true both for interannual variability and for decadal variability. On interannual time scales, however, surface fluxes also make a significant contribution. Analysis of the relationships of OHT with OHC and SST suggests that a knowledge of OHT fluctuations could be used to predict variations in OHC, and therefore sea surface temperatures, several years in advance. [ABSTRACT FROM AUTHOR]

The enantioseparation capabilities of three different functionalized β-cyclodextrins, two sulfated β-cyclodextrins with 4 and 15 nominal degrees of substitution and a phosphated β-cyclodextrin with 8 degrees of substitution, were compared. While anodic detection was used with both sulfated cyclodextrins, the phosphated cyclodextrin required cathodic detection suggesting either lower ionization of the phosphated cyclodextrin or generally lower affinity of the analytes for the phosphated cyclodextrin. The effects of several experimental parameters were evaluated with respect to enantioseparation. The degrees of substitution of the cyclodextrin, pH of the background electrolyte as well as the concentration of the functionalized β-cyclodextrin, each had a significant influence on the successful enantiomeric separation of the chiral drugs investigated. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for the seasonal cycle in the tropical central and eastern Pacific sea surface temperature (SST) are investigated using a coupled general circulation model. We find that the annual westward propagation of SST anomalies along the equator is explained by a two-stage process. The first stage sets the phase of the variation at the eastern boundary. The strengthening of the local Hadley Circulation in boreal summer leads to a strengthening of the northward winds that blow across the equator. These stronger winds drive enhanced evaporation and entrainment cooling of the oceanic mixed layer. The resulting change in SST is greatest in the east because the mixed layer is at its shallowest there. As the east Pacific SST cools the zonal SST gradient in the central Pacific becomes more negative. This development signals the onset of the second stage in the seasonal variation of equatorial SST. In response to the anomalous SST gradient the local westward wind stress increases. This increase drives cooling of the oceanic mixed layer in which no single mechanism dominates: enhanced evaporation, wind-driven entrainment, and westward advection all contribute. We discuss the role that equatorial upwelling plays in modulating mixed layer depth and hence the entrainment cooling, and we highlight the importance of seasonal variations in mixed layer depth. In sum these processes act to propagate the SST anomaly westward. [ABSTRACT FROM AUTHOR]

The current ICD-O classification of carcinomas of the oesophagus and stomach causes epidemiological and clinical confusion. This study compares the epidemiological and clinical features of each subtype and subsite of adenocarcinomas of the oesophagus and stomach, to assess requirements for a new classification of these carcinomas. Data were extracted with appropriate validity checks on all cases of oesophageal and gastric carcinomas identified throughout the period 1974-1993 by the Merseyside and Cheshire Cancer Registry, which covers a population of 2.5 million. The incidence of adenocarcinomas of the lower oesophagus and cardia trebled in males, and doubled in females, whereas adenocarcinoma of the subcardia region of the stomach declined in both sexes. Adenocarcinomas of the lower oesophagus and of the cardia were similar for median age at diagnosis, male to female ratio, percentage of patients who smoked and survival; both were significantly different from carcinomas of the subcardia in these respects. These data imply that adenocarcinomas of the lower oesophagus and cardia are the same disease. A new subsite classification of oesophageal and gastric carcinomas is proposed that includes the gastro-oesophageal junction as a distinct subsite, to facilitate surveillance, management and research. [ABSTRACT FROM AUTHOR]

Presents a study which examined the X-ray crystal structure at 2.4 angstrom resolution of a core synaptic fusion complex containing syntaxin-1A, synaptobrevin-II and SNAP-25B. Structure determination; Surface structure of the synaptic fusion complex; Mechanistic implications for fusion.

Twelve Barrett's adenocarcinomas have been analysed for the occurrence of allelic imbalance (LOH) on chromosome 17 using 41 microsatellite markers. This study provides evidence for 13 minimal regions of LOH, six on 17p and seven on 17q. Four of these centre in the vicinity of the known tumour suppressor genes (TSGs) TP53 (17p13.1), NF1 (17q11.2), BRCA1 (17q21.1), and a putative TSG (17p13.3). The tumours all displayed relatively small regions of LOH (1 – 10 cM), and in several tumours extensive regions of LOH were detected. One tumour displayed only two very small regions of LOH; 17p11.2 and 17p13.1. The frequency of allelic imbalance has been calculated based on the LOH encompassing only one minimal region, and based on all the LOH observations. By both evaluations the highest LOH frequencies were found for regions II (p53), III (17p13.1 centromeric to p53), IV (17p12), V (17p11.2) and VII (NF1, 17q11.2). Our data supports the existence of multiple TSGs on chromosome 17 and challenges the view that p53 is the sole target of LOH on 17p in Barrett's adenocarcinoma. [ABSTRACT FROM AUTHOR]

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The effect of the calcium antagonist verapamil, and of thiazide, a well accepted treatment in the prevention of calcium oxalate renal stones, were examined in an experimental renal stone model. Calcium oxalate stones were induced by the synthetic metabolite of vitamin D, the alpha-OH-vitamin D plus ethylene glycol fed rats. A significant decrease in urinary calcium and oxalate was observed following verapamil treatment. Thiazide significantly decreased urinary calcium, but unlike verapamil, did not decrease urinary oxalate. However, no differences in the radiological findings or in the calcium or magnesium content of the kidneys were observed. Although several animal models have been described for the study of calcium oxalate stones, none has yet been proven useful for the evaluation of stone therapy. [ABSTRACT FROM AUTHOR]

Objectives: To investigate: 1) the rate of gastric emptying of portal hypertensive patients and 2) whether alterations in gastric emptying play any role in the development of portal hypertensive gastropathy. Methods: Fifty patients (37 with esophageal varices) with cirrhosis and seven with extrahepatic portal hypertension underwent upper GI endoscopy followed by radionuclide gastric emptying studies using a semi-solid meal. Twenty-six patients also underwent corrected wedged hepatic venous pressure measurement. Sixteen normal subjects underwent gastric emptying studies only. Results: Varices were completely obliterated by sclerotherapy in 17 patients and were patent in 27. Thirty-seven patients had portal hypertensive gastropathy, 25 of whom had mild changes and 12 severe. No significant difference in gastric emptying was observed between patients with mild and severe portal hypertensive gastropathy and between those with portal hypertensive gastropathy and a normal gastric mucosa. There was no significant difference in gastric emptying between normal subjects and portal hypertensive patients although the latter group showed a tendency for faster gastric emptying. No difference in the rate of gastric emptying was observed between portal hypertensive patients with intrahepatic and extrahepatic pathology. However, patients with esophageal varices (patent and obliterated) emptied their stomachs significantly faster than those without (p = 0.01). There was no correlation between the rate of gastric emptying and corrected wedged hepatic venous pressure. Conclusions: It would appear that, although alterations in gastric emptying are common in portal hypertension, gastric emptying docs not appear to play a causative role in the mucosal changes characteristic of portal hypertensive gastropathy. [ABSTRACT FROM AUTHOR]

The segment polarity gene engrailed is involved in the determination of segment posterior identity in Drosophila. engrailed has been largely used for comparative developmental studies due to its evolutionary conservation from nematodes to humans. By in situ hybridization of an engrailed cDNA probe from Drosophila to polytene chromosomes of fourth instar larvae of Rhynchosciara americana we have shown that engrailed-like sequences must be localized in band 6 of chromosome A in this species. The pattern of engrailed protein expression during R. americana embryo development is diffuse at first evolving into a nuclear striped pattern after quite a length of time. In addition, our results suggest a possible developmentally regulated molecular modification of engrailed protein in R. americana embryos. [ABSTRACT FROM AUTHOR]

The effect of hyperglycaemia on islet transplantation in the rat has been examined in two ways, using syngeneic transplantation of 400 islets to the kidney capsule and subsequent measurement of kidney insulin content as a measurement of B-cell survival. Firstly, islets were transplanted into either diabetic or normal rats, then 6 months later the composite kidney/islet graft was transplanted into a normal rat. The insulin content was measured after a further 6 months and was found to be significantly reduced in islets exposed to hyperglycaemia in the primary recipient. These findings are interpreted as showing that long-term exposure of islets to hyperglycaemia results in B-cell loss. In the second experiment 400 islets were transplanted into either a long-term (6 months) diabetic or a normal rat. Two weeks later the composite kidney/islet graft was transplanted into a normal rat. The insulin content was measured after a further 6 months and no significant difference was found, whether the primary recipient was diabetic or not. These results are interpreted as showing that islet graft implantation is not impaired in long-term diabetic rats. [ABSTRACT FROM AUTHOR]

The ATP- and sulphonylurea-sensitivity of the ATP-sensitive K-channel was measured in human pancreatic B cells. In inside-out patches, half-maximal inhibition of channel activity was produced by 10 μmol/l ATP (with 2 mM Mg) and ATP-inhibition was partially antagonised by ADP. A significantly lower sensitivity to ATP was found in whole-cell recordings. Tolbutamide inhibited whole-cell ATP-sensitive K-currents half-maximally at 18 μmol/l; the sensitivity to tolbutamide was somewhat less in the inside-out patch. Ca-activated K-channels were unaffected by tolbutamide (10 mmol/l). These results resemble those found for rodent B cells and suggest that sulphonylureas exert their therapeutic effects in Type 2 (non-insulin dependent) diabetes by inhibition of the ATP-sensitive K-channel. [ABSTRACT FROM AUTHOR]

In Malaysia, Tinospora crispa extract is taken orally by Type 2 (non-insulin-dependent) diabetic patients to treat hyperglycaemia. We have evaluated the claimed hypoglycaemic property by adding aqueous extract to the drinking water of normal and alloxan-diabetic rats. After one week, fasting blood glucose levels were significantly ( p<0.01) lower and serum insulin levels were significantly ( p<0.01) higher in treated diabetic animals (10.4±1.0 mmol/l and 12.8±1.1 μU/ml respectively) compared to untreated diabetic controls (17.4±1.7 mmol/l and 8.0±0.7 μU/ml respectively). The insulinotropic action of T. crispa was further investigated in vitro using isolated human or rat islets of Langerhans and HIT-T15 cells. In static incubations with rat islets and HIT-T15 B cells, the extract induced a dosage dependent stimulation and potentiation of basal and glucose-stimulated insulin secretion respectively. This insulinotropic effect was also evident in perifused human and rat islets and HIT-T5 B-cells. The observations that (i) in all three models insulin secretory rates rapidly returned to basal levels on removal of the extract and (ii) in rat islets, a second challenge with T. crispa induced an additional, stimulated response, are all consistent with physiological release of insulin by B cells. Moreover, the rate of HIT-T15 glucose utilisation was not affected by incubation with T. crispa, suggesting that the cells were viable throughout. These are the first studies to provide biochemical evidence which substantiates the traditional claims for an oral hypoglycaemic effect of Tinospora crispa, and which also show that the hypoglycaemic effect is associated with increased insulin secretion. [ABSTRACT FROM AUTHOR]

Thickening of alveolar septa was seen in a dog given subcutaneous D. immitis antigen, whereas control animals had normal lung structure at autopsy. [ABSTRACT FROM AUTHOR]

This paper describes the application of neurofuzzy techniques in the design of autopilots for controlling the yaw dynamics of an autonomous underwater vehicle. Autopilots are designed using an Adaptive-Network-based Fuzzy Inference System (ANFIS), a chemotaxis tuning methodology and a fixed fuzzy rule-based approach. To describe the yaw dynamic characteristics of an autonomous underwater vehicle, a realistic simulation model is employed. Results are presented which demonstrate the superiority of the ANFIS approach. It is concluded that the approach offers a viable alternative method for designing such autopilots. [ABSTRACT FROM AUTHOR]

Squamous papillomas obtained from bovine facial skin yielded viral DNA indistinguishable from that of bovine papillomavirus type 5. It was separated from recognised bovine papillomaviruses by its restriction endonuclease pattern and hybridization tests with DNA. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented depicting the isolated testicular relapse (ITR) after allo-stem cell transplantation (SCT) as a rare event and an important management dilemma.

A letter to the editor in response to the article "Improving minimal residual disease detection in precursor B-ALL based on immunoglobulin-k and heavy-chain gene rearrangements" published online on May 22, 2008 is presented.

This article discusses cases of acute lymphoblastic leukemia (ALL) and symptomatic eosinophilia in children. In these cases, the patients received chemotherapy and bone marrow transplants, with the eosinophilia coming from the donor marrow. These cases are described as a rare and aggressive variation in eosinophilia, and regular polymerase chain reaction testing of minimal residual disease (MRD) is recommended for these patients.