Strategies to reduce relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia.

The incidence of acute myeloid leukemia (AML) is expected to increase in conjunction with our ageing population. Although it is proving to be a heterogeneous disease process, the only treatment with proven survival benefit for poor risk AML remains allogeneic hematopoietic cell transplant. Although this is presumed to be a curative strategy, many patients relapse after transplant, prompting us to examine various ways that we can improve outcomes. These efforts involve every step of AML diagnostics and therapy, including the intricate processes of conditioning, graft manipulation and immunomodulation. The hope is that improvement in these steps will ultimately improve survival and decrease relapse rates for AML patients after transplant

Mechanisms of Volatile Anesthetic-Induced Myocardial Protection

Volatile anesthetics protect myocardium against reversible and irreversible ischemic injury. Experimental evidence from several in vitro and in vivo animal models demonstrates that volatile agents enhance the recovery of stunned myocardium and reduce the size of myocardial infarction after brief or prolonged coronary artery occlusion and reperfusion, respectively. This protective effect persists after the anesthetic has been discontinued, a phenomenon known as anesthetic-induced preconditioning (APC). Recent clinical data also demonstrates evidence of APC in patients during cardiac surgery. Thus, administration of volatile anesthetics may represent a novel therapeutic approach that reduces morbidity and mortality associated with perioperative myocardial ischemia and infarction. The mechanisms responsible for APC appear to be similar to those implicated in ischemic preconditioning, but nonetheless have subtle differences. Accumulating evidence indicates that APC is characterized by complex signal transduction pathways that may include adenosine receptors, G proteins, protein kinase C, reactive oxygen species, and sarcolemmal or mitochondrial KATP channels. Opioid analgesics may further enhance APC as well. This article will review recent advances in the understanding of mechanisms responsible for volatile anesthetic-induced myocardial protection

Microfocal X-Ray Computed Tomography Post-Processing Operations for Optimizing Reconstruction Volumes of Stented Arteries During 3D Computational Fluid Dynamics Modeling

Restenosis caused by neointimal hyperplasia (NH) remains an important clinical problem after stent implantation. Restenosis varies with stent geometry, and idealized computational fluid dynamics (CFD) models have indicated that geometric properties of the implanted stent may differentially influence NH. However, 3D studies capturing the in vivo flow domain within stented vessels have not been conducted at a resolution sufficient to detect subtle alterations in vascular geometry caused by the stent and the subsequent temporal development of NH. We present the details and limitations of a series of post-processing operations used in conjunction with microfocal X-ray CT imaging and reconstruction to generate geometrically accurate flow domains within the localized region of a stent several weeks after implantation. Microfocal X-ray CT reconstruction volumes were subjected to an automated program to perform arterial thresholding, spatial orientation, and surface smoothing of stented and unstented rabbit iliac arteries several weeks after antegrade implantation. A transfer function was obtained for the current post-processing methodology containing reconstructed 16 mm stents implanted into rabbit iliac arteries for up to 21 days after implantation and resolved at circumferential and axial resolutions of 32 and 50 μm, respectively. The results indicate that the techniques presented are sufficient to resolve distributions of WSS with 80% accuracy in segments containing 16 surface perturbations over a 16 mm stented region. These methods will be used to test the hypothesis that reductions in normalized wall shear stress (WSS) and increases in the spatial disparity of WSS immediately after stent implantation may spatially correlate with the temporal development of NH within the stented region

An Old Cluster in NGC 6822

We present spectroscopy of two clusters in the dwarf irregular galaxy NGC 6822. From these we deduce an age for Cluster VII of 11 Gyr and [Fe/H] = -1.95 +/- 0.15 dex. Cluster VII appears to be an analog of the metal-poor galactic globular clusters. Cluster VI is found to be much younger and more metal rich, with an age of approximately 2 Gyr. Its derived metallicity, [Fe/H], of approximately -1.0 dex is comparable to that of the gas seen today in NGC 6822. The existence of a metal-poor old cluster in NGC 6822 rules out models for the chemical evolution of this galaxy with significant prompt initial enhancement. We find that a star formation rate which is constant with time and is within a factor of two of the present star formation rate can reproduce the two points on the age-metallicity relationship for NGC 6822 over the past 10 Gyr defined by these two clusters.Comment: 8 pages; accepted for publication in A

Metal Abundances of KISS Galaxies III. Nebular Abundances for Fourteen Galaxies and the Luminosity-Metallicity Relationship for HII Galaxies

We report results from the third in a series of nebular abundance studies of emission-line galaxies from the KPNO International Spectroscopic Survey (KISS). Galaxies with coarse metallicity estimates of 12 + log(O/H) less than 8.2 dex were selected for observation. Spectra of 14 galaxies, which cover the full optical region from [OII]3727,3729 to beyond [SII]6717,6731, are presented, and abundance ratios of N, O, Ne, S, and Ar are computed. The auroral [OIII]4363 line is detected in all 14 galaxies. Oxygen abundances determined through the direct electron temperature T_e method confirm that the sample is metal-poor with 7.61 <= 12 + log(O/H) <= 8.32. By using these abundances in conjunction with other T_e-based measurements from the literature, we demonstrate that HII galaxies and more quiescent dwarf irregular galaxies follow similar metallicity-luminosity (L-Z) relationships. The primary difference is a zero-point shift between the correlations such that HII galaxies are brighter by an average of 0.8 B magnitudes at a given metallicity. This offset can be used as evidence to argue that low-luminosity HII galaxies typically undergo factor of two luminosity enhancements, and starbursts that elevate the luminosities of their host galaxies by 2 to 3 magnitudes are not as common. We also demonstrate that the inclusion of interacting galaxies can increase the scatter in the L-Z relation and may force the observed correlation towards lower metallicities and/or larger luminosities. This must be taken into account when attempting to infer metal abundance evolution by comparing local L-Z relations with ones based on higher redshift samples since the fraction of interacting galaxies should increase with look-back time.Comment: 36 pages, 5 figures. ApJ, in pres

HII Region Oxygen Abundances in Starbursting Transition Dwarf Galaxies

We present empirical HII region oxygen abundances for a sample of low-luminosity starburst galaxies which are in a short lived evolutionary state. All five galaxies are characterized by centrally concentrated star formation, which is embedded in smooth stellar envelopes resembling dE-like systems. The galaxies also have small gas contents with typical M_{HI}/L_{B} ~ 0.1 resulting in gas exhaustion timescales less than 1 Gyr, even when molecular gas is considered. We find, compared to other morphologically similar systems, the galaxies of this sample have surprisingly high oxygen abundances with 12 + log(O/H) ~ 9.0. We propose that these objects are a subclass of evolved blue compact dwarfs, which have exhausted most of their gas supply while retaining their metals. We further propose that we are seeing these objects during a short phase in which they are nearing the end of their starburst activity, and could become early-type dwarfs.Comment: 13 pages, 3 figures, accepted by ApJ Letter

Detection of Cold Atomic Clouds in the Magellanic Bridge

We report a detection of cold atomic hydrogen in the Magellanic Bridge using 21-cm absorption spectroscopy toward the radio source B0312-770. With a column density of N_HI=1.2E20 cm^-2, a maximum absorption optical depth of tau=0.10 and a maximum 21-cm emission brightness temperature of 1.4 K, this line of sight yields a spin temperature, T_s, between 20 K and 40 K. H I 21-cm absorption and emission spectroscopy toward 7 other low column density sightlines on the periphery of the LMC and SMC reveal absorption toward one additional background radio source behind the SMC with tau=0.03. The data have typical sensitivities of sigma_tau=0.005 to 0.070 in absorption and sigma_{T_B}=0.03 K in emission. These data demonstrate the presence of a cold atomic phase which is probably accompanied by molecular condensations in the tenuous interstellar medium of the Bridge region. Young OB stars observed in the Magellanic Bridge could form "in situ" from these cold condensations rather than migrate from regions of active star formation in the main body of the SMC. The existence of cold condensations and star formation in the Magellanic Bridge might be understood as a small scale version of the mechanism that produces star formation in the tidal tails of interacting galaxies.Comment: 25 pages, uses AASTeX and psfig; Accepted for Publication in the Astronomical Journa

Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B‐cell lymphoma

This phase 1b/2, multicenter, open‐label study evaluated ibrutinib plus durvalumab in relapsed/refractory follicular lymphoma (FL) or diffuse large B‐cell lymphoma (DLBCL). Patients were treated with once‐daily ibrutinib 560 mg plus durvalumab 10 mg/kg every 2 weeks in 28‐day cycles in phase 1b without dose‐limiting toxicities, confirming the phase 2 dosing. Sixty‐one patients with FL (n = 27), germinal center B‐cell (GCB) DLBCL (n = 16), non‐GCB DLBCL (n = 16), and unspecified DLBCL (n = 2) were treated. Overall response rate (ORR) was 25% in all patients, 26% in patients with FL, 13% in patients with GCB DLBCL, and 38% in patients with non‐GCB DLBCL. Overall, median progression‐free survival was 4.6 months and median overall survival was 18.1 months; both were longer in patients with FL than in patients with DLBCL. The most frequent treatment‐emergent adverse events (AEs) in patients with FL and DLBCL, respectively, were diarrhea (16 [59%]; 16 [47%]), fatigue (12 [44%]; 16 [47%]), nausea (9 [33%]; 12 [35%]), peripheral edema (7 [26%]; 13 [38%]), decreased appetite (8 [30%]; 11 [32%]), neutropenia (6 [22%]; 11 [32%]), and vomiting (5 [19%]; 12 [35%]). Investigator‐defined immune‐related AEs were reported in 12/61 (20%) patients. Correlative analyses were conducted but did not identify any conclusive biomarkers of response. In FL, GCB DLBCL, and non‐GCB DLBCL, ibrutinib plus durvalumab demonstrated similar activity to single‐agent ibrutinib with the added toxicity of the PD‐L1 blockade; the combination resulted in a safety profile generally consistent with those known for each individual agent.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152736/1/ajh25659_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152736/2/ajh25659.pd

Mechanism of Preconditioning by Isoflurane in Rabbits: A Direct Role for Reactive Oxygen Species

LARGE quantities of reactive oxygen species (ROS) released during reperfusion after coronary artery occlusion damage proteins responsible for intracellular homeostasis, produce tissue injury, depress contractile function, and increase myocardial infarct size. In contrast, small quantities of ROS may exert beneficial effects during ischemia and reperfusion when released before a prolonged ischemic event. ROS derived from mitochondria during a brief ischemic episode produce preconditioning. Free radical scavengers administered during ischemic preconditioning (IPC) markedly attenuate the protective effect of the preconditioning stimulus on infarct size. These data suggest that IPC is mediated in part by small quantities of ROS released during preconditioning. Volatile anesthetics protect myocardium against infarction through a signal transduction pathway that includes adenosine type 1 receptors, protein kinase C, inhibitory guanine regulatory proteins, and mitochondrial and sarcolemmal adenosine triphosphate-regulated potassium (KATP) channels. A recent investigation by Müllenheim et al . provides compelling evidence that ROS also mediate myocardial protection produced by volatile anesthetics. We sought to confirm and extend these important results by examining the hypothesis that ROS scavengers inhibit isoflurane-induced protection against irreversible ischemic injury. We further tested the hypothesis that isoflurane directly generates ROS in rabbit ventricular myocardium in vivo using a confocal microscopic technique combined with the superoxide anion-specific fluorescent probe dihydroethidium