Analogue peptides for the immunotherapy of human acute myeloid leukemia

Accepted manuscript. The final publication is available at: http://link.springer.com/article/10.1007%2Fs00262-015-1762-9The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Dopaminergic Polymorphisms Associated with Time-on-Task Declines and Fatigue in the Psychomotor Vigilance Test

Prolonged demands on the attention system can cause a decay in performance over time known as the time-on-task effect. The inter-subject differences in the rate of this decline are large, and recent efforts have been made to understand the biological bases of these individual differences. In this study, we investigate the genetic correlates of the time-on-task effect, as well as its accompanying changes in subjective fatigue and mood. N = 332 subjects performed a 20-minute test of sustained attention (the Psychomotor Vigilance Test) and rated their subjective states before and after the test. We observed substantial time-on-task effects on average, and large inter-individual differences in the rate of these declines. The 10-repeat allele of the variable number of tandem repeats marker (VNTR) in the dopamine transporter gene and the Met allele of the catechol-o-methyl transferase (COMT) Val158Met polymorphism were associated with greater vulnerability to time-on-task. Separately, the exon III DRD4 48 bp VNTR of the dopamine receptor gene DRD4 was associated with subjective decreases in energy. No polymorphisms were associated with task-induced changes in mood. We posit that the dopamine transporter and COMT genes exert their effects by increasing dopaminergic tone, which may induce long-term changes in the prefrontal cortex, an important mediator of sustained attention. Thus, these alleles may affect performance particularly when sustained dopamine release is necessary

Phantom headache: pain-memory-emotion hypothesis for chronic daily headache?

The neurobiology of chronic pain, including chronic daily headache (CDH) is not completely understood. “Pain memory” hypothesis is one of the mechanisms for phantom limb pain. We reviewed the literature to delineate a relation of “pain memory” for the development of CDH. There is a direct relation of pain to memory. Patients with poor memory have less chance to develop “pain memory”, hence less possibility to develop chronic pain. Progressive memory impairment may lead to decline in headache prevalence. A similar relation of pain is also noted with emotional or psychiatric symptoms. Literature review suggests that there is marked overlap in the neural network of pain to that of memory and emotions. We speculate that pain, memory, and emotions are interrelated in triangular pattern, and each of these three is related to other two in bidirectional pattern, i.e., stimulation of one of these will stimulate other symptoms/networks and vice versa (triangular theory for chronic pain). Longstanding or recurrent noxious stimuli will strengthen this interrelation, and this may be responsible for chronicity of pain. Reduction of both chronic pain and psychological symptoms by cognitive behavioral therapy or psychological interventions further suggests a bidirectional interrelation between pain and emotion. Longitudinal studies are warranted on the prevalence of headache and other painful conditions in patients with progressive memory impairment to delineate the relation of pain to memory. Interrelation of headache to emotional symptoms should also be explored

Cucurbitacin I Inhibits Cell Motility by Indirectly Interfering with Actin Dynamics

Cucurbitacins are plant natural products that inhibit activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway by an unknown mechanism. They are also known to cause changes in the organization of the actin cytoskeleton. actin depolymerization experiments, cucurbitacin I had no effect on the rate of actin filament disassembly at the nanomolar concentrations that inhibit cell migration. At elevated concentrations, the depolymerization rate was also unaffected, although there was a delay in the initiation of depolymerization. Therefore, cucurbitacin I targets some factor involved in cellular actin dynamics other than actin itself. Two candidate proteins that play roles in actin depolymerization are the actin-severing proteins cofilin and gelsolin. Cucurbitacin I possesses electrophilic reactivity that may lead to chemical modification of its target protein, as suggested by structure-activity relationship data. However, mass spectrometry revealed no evidence for modification of purified cofilin or gelsolin by cucurbitacin I.Cucurbitacin I results in accumulation of actin filaments in cells by a unique indirect mechanism. Furthermore, the proximal target of cucurbitacin I relevant to cell migration is unlikely to be the same one involved in activation of the JAK2/STAT3 pathway

The rise of multiple imputation: a review of the reporting and implementation of the method in medical research

BACKGROUND: Missing data are common in medical research, which can lead to a loss in statistical power and potentially biased results if not handled appropriately. Multiple imputation (MI) is a statistical method, widely adopted in practice, for dealing with missing data. Many academic journals now emphasise the importance of reporting information regarding missing data and proposed guidelines for documenting the application of MI have been published. This review evaluated the reporting of missing data, the application of MI including the details provided regarding the imputation model, and the frequency of sensitivity analyses within the MI framework in medical research articles. METHODS: A systematic review of articles published in the Lancet and New England Journal of Medicine between January 2008 and December 2013 in which MI was implemented was carried out. RESULTS: We identified 103 papers that used MI, with the number of papers increasing from 11 in 2008 to 26 in 2013. Nearly half of the papers specified the proportion of complete cases or the proportion with missing data by each variable. In the majority of the articles (86%) the imputed variables were specified. Of the 38 papers (37%) that stated the method of imputation, 20 used chained equations, 8 used multivariate normal imputation, and 10 used alternative methods. Very few articles (9%) detailed how they handled non-normally distributed variables during imputation. Thirty-nine papers (38%) stated the variables included in the imputation model. Less than half of the papers (46%) reported the number of imputations, and only two papers compared the distribution of imputed and observed data. Sixty-six papers presented the results from MI as a secondary analysis. Only three articles carried out a sensitivity analysis following MI to assess departures from the missing at random assumption, with details of the sensitivity analyses only provided by one article. CONCLUSIONS: This review outlined deficiencies in the documenting of missing data and the details provided about imputation. Furthermore, only a few articles performed sensitivity analyses following MI even though this is strongly recommended in guidelines. Authors are encouraged to follow the available guidelines and provide information on missing data and the imputation process. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12874-015-0022-1) contains supplementary material, which is available to authorized users

Self-medication of migraine and tension-type headache: summary of the evidence-based recommendations of the Deutsche Migräne und Kopfschmerzgesellschaft (DMKG), the Deutsche Gesellschaft für Neurologie (DGN), the Österreichische Kopfschmerzgesellschaft (ÖKSG) and the Schweizerische Kopfwehgesellschaft (SKG)

The current evidence-based guideline on self-medication in migraine and tension-type headache of the German, Austrian and Swiss headache societies and the German Society of Neurology is addressed to physicians engaged in primary care as well as pharmacists and patients. The guideline is especially concerned with the description of the methodology used, the selection process of the literature used and which evidence the recommendations are based upon. The following recommendations about self-medication in migraine attacks can be made: The efficacy of the fixed-dose combination of acetaminophen, acetylsalicylic acid and caffeine and the monotherapies with ibuprofen or naratriptan or acetaminophen or phenazone are scientifically proven and recommended as first-line therapy. None of the substances used in self-medication in migraine prophylaxis can be seen as effective. Concerning the self-medication in tension-type headache, the following therapies can be recommended as first-line therapy: the fixed-dose combination of acetaminophen, acetylsalicylic acid and caffeine as well as the fixed combination of acetaminophen and caffeine as well as the monotherapies with ibuprofen or acetylsalicylic acid or diclofenac. The four scientific societies hope that this guideline will help to improve the treatment of headaches which largely is initiated by the patients themselves without any consultation with their physicians