Darbepoetin alfa: An Effective Treatment with Flexible and Simplified Dosing for Anemia in Patients with Cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90361/1/phco.27.3.434.pd

Validity and Reliability of Firefighting Simulation Test Performance

To assess the validity and reliability of a firefighting simulation test (FFST). Sixty-nine operational firefighters completed a best-effort FFST on one occasion and twenty-two participants completed a further FFST. All participants completed a maximal treadmill test to determine cardiorespiratory fitness (VO2max). Time to complete the FFST demonstrated a strong inverse relationship with VO2max (r = -0.73), although the prediction error was high. Reliability of the FFST was high (r = 0.84, p = 0.01), demonstrating a coefficient of variation of 4.5%. The FFST demonstrated reasonable validity as a surrogate assessment of cardiorespiratory fitness for firefighting. The FFST also demonstrated good reliability. Given the apparent magnitude of the prediction error, the FFST would be best used as a training tool, rather than as a primary means of assessing cardiorespiratory fitness for firefighting

Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses.

Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8(+) T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.C.E.R. was supported by Wellcome Trust 092627/Z/10/Z, J.A.H. by an Irvington Institute Postdoctoral Fellowship from the Cancer Research Institute (New York), and E.I.Z. by a Leukemia and Lymphoma Society Scholar Award and a grant from the NIH AI081923. We thank Dr. Graham Lord (King’s College London) for the kind gift of the Ifng CNS-12 promoter.This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.immuni.2016.01.01

Family Variables and Reading

others of poor and average readers in Japan, Taiwan and the United States were iterviewed about their child-rearing practices, attitudes, and beliefs, and their children's current and earlier experiences. Poor readers represented the lowest fifth percentile in reading scores; they were matched by classroom, sex, and age with average readers; i.e., children who obtained reading scores within one standard deviation from the mean. The groups seldom differed significantly according to environmental variables and parent-child interactions. Maternal ratings of cognitive and achievement variables differentiated both the children in the two groups and the mothers themselves. Maternal beliefs and descriptions of how children use time also differed between the two groups. Notable was the absence of significant interactions between country and reading level.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68579/2/10.1177_002221948401700305.pd

Resetting of ventricular tachycardia: Implications for localizing the area of slow conduction

AbstractAnalysis of local endocardial electrograms recorded during reentrant ventricular tachycardia does not provide direct information as to the participation of the recording site in the tachycardia circuit. To determine if programmed electrical stimulation at the recording site can assist in localizing areas of slow conduction that are participating in the tachycardia circuit, seven patients with sustained monomorphic ventricular tachycardia were studied. The cardiac cycle was scanned with single stimuli delivered during ventricular tachycardia at multiple endocardial sites.In four patients, an endocardial site was identified at which stimuli advanced the tachycardia with marked conduction delay and without alteration of the ventricular activation sequence, as indicated by a lack of change in the configuration of the QRS complex and endocardial electrograms distant from the stimulation site. This finding was seen only during stimulation at sites displaying abnormal electrograms and is consistent with premature depolarization of an area of slow conduction within the tachycardia focus by stimuli delivered at or near that area. Attempted endocardial catheter ablation at or adjacent to these sites in three patients was followed by persistent noninducibility of ventricular tachycardia in one patient, marked modification of the configuration and cycle length of inducible tachycardia in one patient and transient noninducibility of tachycardia in one patient.Programmed electrical stimulation during ventricular tachycardia at sites with abnormal electrograms may provide information about the proximity of the stimulation site to the tachycardia circuit

Clinical and Economic Effectiveness of an Inpatient Anticoagulation Service

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90256/1/phco.19.13.1064.31591.pd

Circulating levels of anti-angiogenic VEGF-A isoform (VEGF-Axxxb) in colorectal cancer patients predicts tumour VEGF-A ratios

Purpose: Bevacizumab as an adjunct to chemotherapy improves survival for some patients with metastatic colorectal cancer. Immunohistochemical staining of samples from the registration ECOG E3200 trial of bevacizumab with FOLFOX demonstrated that only patients with carcinomas expressing low levels of VEGF-A(165)b, an anti-angiogenic splice variant of the Vascular Endothelial Growth Factor family of proteins, benefited from bevacizumab treatment. To identify a more useful biomarker of response we tested the hypothesis that circulating VEGF-A(165)b levels correlate with immunohistochemical staining. Experimental Design: 17 patients with biopsy proven colorectal adenocarcinoma had pre-operative blood samples drawn. They underwent resection and had post-resection blood drawn. The plasma was analysed for levels of VEGF-A(xxx)b using enzyme-linked immunosorbent assay (ELISA) and the tumour blocks stained for VEGF-A(xxx)b and pan-VEGF-A. The normalised ratio of VEGF-A(xxx)b expression to that of panVEGF-A expression scored by IHC was calculated and correlated with plasma VEGF-A(165)b levels. Results: Plasma levels of VEGF-A(xxx)b significantly correlated with the VEGF-A(xxx)b:panVEGF-A ratio (r=0.594, P<0.02) in colorectal cancers. Median plasma VEGF-A(xxx)b levels were 151 pg/ml. The mean (1.5±0.17) and median, IQR (1.8, 1-2) IHC scores of the patients with greater than median plasma VEGF-A(xxx)b were significantly greater than those with less than median plasma VEGF-A(xxx)b levels (mean ± SEM=0.85±10.12, median, IQR=1, 0.54-1). Conclusion: These results suggest that plasma VEGF-A(xxx)b levels could be an effective biomarker of response to Bevacizumab. These results indicate that a prospective trial is warranted to explore the use of plasma VEGF-A(xxx)b levels to stratify patients for colorectal cancer treatment by bevacizumab

Natural history of murine gamma-herpesvirus infection

Murine gamma-herpesvirus 68 (MHV-68) is a natural pathogen of small rodents and insectivores (mice, voles and shrews). The primary infection is characterized by virus replication in lung epithelial cells and the establishment of a latent infection in B lymphocytes. The virus is also observed to persist in lung epithelial cells, dendritic cells and macrophages. Splenomegaly is observed two weeks after infection, in which there is a CD4+ T-cell-mediated expansion of B and T cells in the spleen. At three weeks post-infection an infectious mononucleosis-like syndrome is observed involving a major expansion of Vbeta4+CD8+ T cells. Later in the course of persistent infection, ca. 10% of mice develop lymphoproliferative disease characterized as lymphomas of B-cell origin. The genome from MHV-68 strain g2.4 has been sequenced and contains ca. 73 genes, the majority of which are collinear and homologous to other gamma-herpesviruses. The genome includes cellular homologues for a complement-regulatory protein, Bcl-2, cyclin D and interleukin-8 receptor and a set of novel genes M1 to M4. The function of these genes in the context of latent infections, evasion of immune responses and virus-mediated pathologies is discussed. Both innate and adaptive immune responses play an active role in limiting virus infection. The absence of type I interferon (IFN) results in a lethal MHV-68 infection, emphasizing the central role of these cytokines at the initial stages of infection. In contrast, type II IFN is not essential for the recovery from infection in the lung, but a failure of type II IFN receptor signalling results in the atrophy of lymphoid tissue associated with virus persistence. Splenic atrophy appears to be the result of immunopathology, since in the absence of CD8+ T cells no pathology occurs. CD8+ T cells play a major role in recovery from the primary infection, and also in regulating latently infected cells expressing the M2 gene product. CD4+ T cells have a key role in surveillance against virus recurrences in the lung, in part mediated through 'help' in the genesis of neutralizing antibodies. In the absence of CD4+ T cells, virus-specific CD8+ T cells are able to control the primary infection in the respiratory tract, yet surprisingly the memory CD8+ T cells generated are unable to inhibit virus recurrences in the lung. This could be explained in part by the observations that this virus can downregulate major histocompatibility complex class I expression and also restrict inflammatory cell responses by producing a chemokine-binding protein (M3 gene product). MHV-68 provides an excellent model to explore methods for controlling gamma-herpesvirus infection through vaccination and chemotherapy. Vaccination with gp150 (a homologue of gp350 of Epstein-Barr virus) results in a reduction in splenomegaly and virus latency but does not block replication in the lung, nor the establishment of a latent infection. Even when lung virus infection is greatly reduced following the action of CD8+ T cells, induced via a prime-boost vaccination strategy, a latent infection is established. Potent antiviral compounds such as the nucleoside analogue 2'deoxy-5-ethyl-beta-4'-thiouridine, which disrupts virus replication in vivo, cannot inhibit the establishment of a latent infection. Clearly, devising strategies to interrupt the establishment of latent virus infections may well prove impossible with existing methods

The First Substellar Subdwarf? Discovery of a Metal-poor L Dwarf with Halo Kinematics

We present the discovery of the first L-type subdwarf, 2MASS J05325346+8246465. This object exhibits enhanced collision-induced H$_2$ absorption, resulting in blue NIR colors ($J-K_s = 0.26{\pm}0.16$). In addition, strong hydride bands in the red optical and NIR, weak TiO absorption, and an optical/J-band spectral morphology similar to the L7 DENIS 0205$-$1159AB imply a cool, metal-deficient atmosphere. We find that 2MASS 0532+8246 has both a high proper motion, $\mu$ = 2\farcs60\pm0\farcs15 yr$^{-1}$, and a substantial radial velocity, $v_{rad} = -195{\pm}11$ km s$^{-1}$, and its probable proximity to the Sun (d = 10--30 pc) is consistent with halo membership. Comparison to subsolar-metallicity evolutionary models strongly suggests that 2MASS 0532+8246 is substellar, with a mass of 0.077 $\lesssim$ M $\lesssim$ 0.085 M_{\sun} for ages 10--15 Gyr and metallicities $Z = 0.1-0.01$ Z_{\sun}. The discovery of this object clearly indicates that star formation occurred below the Hydrogen burning mass limit at early times, consistent with prior results indicating a flat or slightly rising mass function for the lowest-mass stellar subdwarfs. Furthermore, 2MASS 0532+8246 serves as a prototype for a new spectral class of subdwarfs, additional examples of which could be found in NIR proper motion surveys.Comment: 9 pages, 3 figures, accepted to Ap