Strong Consistency of the Least-Squares Estimator in Simple Regression Models with Stochastic Regressors

Strong consistency of least squares estimators of the slope parameter in simple linear regression models is established for predetermined stochastic regressors. The main result covers a class of models which falls outside the applicability of what is presently available in the literature. An application to the identification of economic models with adaptive learning is discussed

Consistent estimation of structural parameters in regression models with adaptive learning

In this paper we consider regression models with forecast feedback. Agents' expectations are formed via the recursive estimation of the parameters in an auxiliary model. The learning scheme employed by the agents belongs to the class of stochastic approximation algorithms whose gain sequence is decreasing to zero. Our focus is on the estimation of the parameters in the resulting actual law of motion. For a special case we show that the ordinary least squares estimator is consistent

A Simple Regime-Switching Model for Stochastic Volatilities

In this paper, a simple Markov switching model for the volatility of financial returns is presented. We discuss a moment estimation procedure and develop forecasts for future squared volatilities.Stochastic volatilities, Markov regime switching, Moment estimatior.

Nine months to progression using fourth-line liposomally encapsulated paclitaxel against hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths. Difficulties to diagnose HCC at early stages remain the major obstacle to curative (surgical) therapy. Therapy in advanced stages has to be considered palliative. In this situation, a considerable amount of attention should be paid to innovative treatment strategies, e. g. including antiangiogenetic drugs. Results: We report on the successful treatment of a patient suffering from progressive HCC with a novel drug (EndoTAG (R)-1, formerly named LipoPac (R)) currently investigated in phase II studies. This drug consists of liposomally encapsulated paclitaxel. Its liposomal formulation favors the drug's adherence to the tumor neovasculature, in effect starving the tumor. Conclusions: EndoTAG (R)-1 stopped tumor progression for 9 months in our patient. This, along with successes observed testing this drug against other indications, makes it a suitable candidate for future clinical trials. Copyright (C) 2008 S. Karger AG, Basel

Proteomics of AML1/ETO Target Proteins: AML1–ETO Targets a C/EBP–NM23 Pathway

Abstract Introduction The rational design of targeted therapies for acute myeloid leukemia (AML) requires the discovery of novel protein pathways in the systems biology of a specific AML subtype. We have shown that in the AML subtype with translocation t(8;21), the leukemic fusion protein AML1–ETO inhibits the function of transcription factors PU.1 and C/EBPα via direct protein–protein interaction. In addition, recently using proteomics, we have also shown that the AML subtypes differ in their proteome, interactome, and post-translational modifications. Methods We, therefore, hypothesized that the systematic identification of target proteins of AML1–ETO on a global proteome-wide level will lead to novel insights into the systems biology of t(8;21) AML on a post-genomic functional level. Thus, 6 h after inducible expression of AML1–ETO, protein expression changes were identified by two-dimensional gel electrophoresis and subsequent mass spectrometry analysis. Results Twenty-eight target proteins of AML1–ETO including prohibitin, NM23, HSP27, and Annexin1 were identified by MALDI-TOF mass spectrometry. AML1–ETO upregulated the differentiation inhibitory factor NM23 protein expression after 6 h, and the NM23 mRNA expression was also elevated in t(8;21) AML patient samples in comparison with normal bone marrow. AML1–ETO inhibited the ability of C/EBP transcription factors to downregulate the NM23 promoter. These data suggest a model in which AML1–ETO inhibits the C/EBP-induced downregulation of the NM23 promoter and thereby increases the protein level of differentiation inhibitory factor NM23. Conclusions Proteomic pathway discovery can identify novel functional pathways in AML, such as the AML1–ETO–C/EBP–NM23 pathway, as the main step towards a systems biology and therapy of AML. </jats:sec

Graft-versus-lymphoma effect in a 64-year-old caucasian woman after allogeneic stem-cell transplantation: a case report

<p>Abstract</p> <p>Introduction</p> <p>The existence of a graft-versus-lymphoma effect is well established. When lacking a firm diagnosis, however, the clinician is challenged to to weigh the potential benefits of the graft-versus-lymphoma effect against potential dangers of graft-versus-host disease as well as against generalized (viral) infections.</p> <p>Case presentation</p> <p>We present evidence for a graft-versus-lymphoma effect in a 64-year-old caucasian woman with a transplanted peripheral blood-stem-cell graft from her Human Leukocyte Antigen-identical sister, and propose diagnostic measures to distinguish between graft-versus-host effect, and against viral disease or drug-induced reactions.</p> <p>Conclusion</p> <p>We were able to identify an allogeneic graft-reaction against progressive lymphoma alongside an erythema consistent with acute graft-versus-host disease of the skin. Establishing a firm diagnosis enabled us to decide against T-cell suppression (such as by using cyclosporine). Anti-lymphoma activity was favoured, by means of the allogeneic graft, local radiation and immunotherapy. This illustrates the importance of a sound differential diagnosis of erythema after allogeneic stem-cell transplantation, including assessment of viral disease of the affected tissue.</p

Successful treatment of severe sinusoidal obstruction syndrome despite multiple organ failure with defibrotide after allogeneic stem cell transplantation: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report a case of sinusoidal obstruction syndrome, a typical and life-threatening complication after allogeneic stem-cell transplantation, successfully treated with defibrotide despite massive multiple organ failure.</p> <p>Case presentation</p> <p>A 64-year-old Caucasian woman underwent allogeneic peripheral blood stem-cell transplantation from her human leukocyte antigen-identical sister against aggressive lymphoplasmocytoid immunocytoma. Seven days later, the patient developed severe sinusoidal obstruction syndrome according to the modified Seattle criteria. We initiated treatment with defibrotide. Despite early treatment, multiple organ failure with kidney failure requiring dialysis and ventilator-dependent lung failure aggravated the clinical course. Furthermore, central nervous dysfunction occurred as well as transfusion refractory thrombocytopenia.</p> <p>Conclusion</p> <p>As highlighted in our report, defibrotide is the most promising drug in the treatment of the formerly, almost lethal, severe sinusoidal obstruction syndrome to date. This is demonstrated very clearly in our patient. She improved completely, even after renal, cerebral and respiratory failure.</p

Structural insights into TMB-1 and the role of residues 119 and 228 in substrate and inhibitor binding

Source at https://doi.org/10.1128/AAC.02602-16.Metallo-β-lactamases (MBLs) threaten the effectiveness of β-lactam antibiotics, including carbapenems, and are a concern for global public health. β-Lactam/β-lactamase inhibitor combinations active against class A and class D carbapenemases are used, but no clinically useful MBL inhibitor is currently available. Tripoli metallo-β-lactamase-1 (TMB-1) and TMB-2 are members of MBL subclass B1a, where TMB-2 is an S228P variant of TMB-1. The role of S228P was studied by comparisons of TMB-1 and TMB-2, and E119 was investigated through the construction of site-directed mutants of TMB-1, E119Q, E119S, and E119A (E119Q/S/A). All TMB variants were characterized through enzyme kinetic studies. Thermostability and crystallization analyses of TMB-1 were performed. Thiol-based inhibitors were investigated by determining the 50% inhibitory concentrations (IC50) and binding using surface plasmon resonance (SPR) for analysis of TMB-1. Thermostability measurements found TMB-1 to be stabilized by high NaCl concentrations. Steady-state enzyme kinetics analyses found substitutions of E119, in particular, substitutions associated with the penicillins, to affect hydrolysis to some extent. TMB-2 with S228P showed slightly reduced catalytic efficiency compared to TMB-1. The IC50 levels of the new thiol-based inhibitors were 0.66 μM (inhibitor 2a) and 0.62 μM (inhibitor 2b), and the equilibrium dissociation constant (KD) of inhibitor 2a was 1.6 μM; thus, both were more potent inhibitors than L-captopril (IC50 = 47 μM; KD = 25 μM). The crystal structure of TMB-1 was resolved to 1.75 Å. Modeling of inhibitor 2b in the TMB-1 active site suggested that the presence of the W64 residue results in T-shaped π-π stacking and R224 cation-π interactions with the phenyl ring of the inhibitor. In sum, the results suggest that residues 119 and 228 affect the catalytic efficiency of TMB-1 and that inhibitors 2a and 2b are more potent inhibitors for TMB-1 than L-captopril

Major central nervous system complications after allogeneic stem cell transplantation: A large retrospective study on 888 consecutive adult patients.

AbstractObjectivesMajor complications affecting the central nervous system (CNS) present a challenge after allogeneic stem cell transplantation (allo‐SCT).MethodsIncidence, risk factors, and outcome were retrospectively analyzed in 888 patients in a monocentric study.ResultsCumulative incidence (CI) of major CNS complications at 1 year was 14.8% (95%CI 12.3%‐17.2%). Median follow‐up is 11 months. CNS complications were documented in 132 patients: in 36 cases, classified metabolic; 26, drug‐related neurotoxicity (14 attributed to cyclosporine A, 4 to antilymphocyte globulin); 11, cerebrovascular (ischemic n = 8, bleeding n = 3); 9, infections; 9, psychiatric; and 9, malignant. The cause of CNS symptoms remained unclear for 37 patients (28%). Multivariate analysis demonstrated an association of CNS complication with patient age (P < .001). The estimated OS of patients with any CNS complication was significantly lower than in patients without neurological complications (P < .001), and the CI of non‐relapse mortality (NRM) was higher for patients with CNS complication (P < .001). A significant negative impact on survival can only be demonstrated for metabolic CNS complications and CNS infections (NRM, P < .0001 and P = .0003, respectively), and relapse (P < .0001).ConclusionCNS complications after allo‐SCT are frequent events with a major contribution to morbidity and mortality. In particular, the situations of unclear neurological complications need to be clarified by intensive research

Estimating Structural Parameters in Regression Models with Adaptive Learning

This paper investigates the asymptotic properties of the ordinary least squares (OLS) estimator of structural parameters in a stylised macroeconomic model in which agents are boundedly rational and use an adaptive learning rule to form expectations of the endogenous variable. In particular, when the learning recursion is subject to so-called decreasing gain sequences the model does not satisfy, in general, any of the sufficient conditions for consistent estimability available in the literature. The paper demonstrates that, for appropriate parameter sets, the OLS estimator nevertheless remains strongly consistent and asymptotically normally distributed