Abstract
We perform the first simultaneous Bayesian parameter inference and optimal reconstruction of the gravitational lensing of the cosmic microwave background (CMB), using 100 deg
2
of ...polarization observations from the SPTpol receiver on the South Pole Telescope. These data reach noise levels as low as 5.8
μ
K arcmin in polarization, which are low enough that the typically used quadratic estimator (QE) technique for analyzing CMB lensing is significantly suboptimal. Conversely, the Bayesian procedure extracts all lensing information from the data and is optimal at any noise level. We infer the amplitude of the gravitational lensing potential to be
A
ϕ
=
0.949
±
0.122
using the Bayesian pipeline, consistent with our QE pipeline result, but with 17% smaller error bars. The Bayesian analysis also provides a simple way to account for systematic uncertainties, performing a similar job as frequentist “bias hardening” or linear bias correction, and reducing the systematic uncertainty on
A
ϕ
due to polarization calibration from almost half of the statistical error to effectively zero. Finally, we jointly constrain
A
ϕ
along with
A
L
, the amplitude of lensing-like effects on the CMB power spectra, demonstrating that the Bayesian method can be used to easily infer parameters both from an optimal lensing reconstruction and from the delensed CMB, while exactly accounting for the correlation between the two. These results demonstrate the feasibility of the Bayesian approach on real data, and pave the way for future analysis of deep CMB polarization measurements with SPT-3G, Simons Observatory, and CMB-S4, where improvements relative to the QE can reach 1.5 times tighter constraints on
A
ϕ
and seven times lower effective lensing reconstruction noise.
We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor ...antibiotic) in the treatment of 101 patients > or =60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m(2) for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.
Mylotarg (gemtuzumab ozogamicin, CMA-676; Wyeth-Ayerst Laboratories, Philadelphia, PA) recently was approved by the US Food and Drug Administration for the treatment of patients with CD33-positive ...acute myeloid leukemia in first relapse, age 60 years or older, who are not considered candidates for other types of cytotoxic chemotherapy. In combined phase II studies of 142 patients with CD33-positive acute myeloid leukemia in first relapse, Mylotarg monotherapy was associated with a 30% overall response rate. Although treated patients had relatively high incidences of myelosuppression, hyperbilirubinemia, and elevated hepatic transaminases, the incidences of severe mucositis and infections were low compared with what might be expected in association with conventional chemotherapeutic treatment. Preliminary data in pediatric patients also suggest that the immunoconjugate is reasonably well tolerated. Studies of Mylotarg in combination with anthracycline, cytarabine, and agents that inhibit P-glycoprotein are underway.
Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of ...P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33+ relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibited CSA-sensitive dye efflux compared with 29% (P = .003) or 24% (P < .001) among samples from responders. In vitro gemtuzumab ozogamicin–induced apoptosis was also evaluated using an annexin V–based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to gemtuzumab ozogamicin and suggest that treatment trials combining gemtuzumab ozogamicin with MDR reversal agents are warranted.
We present cosmological constraints based on the cosmic microwave background (CMB) lensing potential power spectrum measurement from the recent 500 deg2 SPTpol survey, the most precise CMB lensing ...measurement from the ground to date. We fit a flat ΛCDM model to the reconstructed lensing power spectrum alone and in addition with other data sets: baryon acoustic oscillations (BAO), as well as primary CMB spectra from Planck and SPTpol. The cosmological constraints based on SPTpol and Planck lensing band powers are in good agreement when analyzed alone and in combination with Planck full-sky primary CMB data. With weak priors on the baryon density and other parameters, the SPTpol CMB lensing data alone provide a 4% constraint on . Jointly fitting with BAO data, we find , , and , up to away from the central values preferred by Planck lensing + BAO. However, we recover good agreement between SPTpol and Planck when restricting the analysis to similar scales. We also consider single-parameter extensions to the flat ΛCDM model. The SPTpol lensing spectrum constrains the spatial curvature to be and the sum of the neutrino masses to be eV at 95% C.L. (with Planck primary CMB and BAO data), in good agreement with the Planck lensing results. With the differences in the signal-to-noise ratio of the lensing modes and the angular scales covered in the lensing spectra, this analysis represents an important independent check on the full-sky Planck lensing measurement.
Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine ...whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33+ AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3,3'-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.
The enediyne antitumor antibiotics are appreciated for their novel molecular architecture, their remarkable biological activity and their fascinating mode of action and many have spawned considerable ...interest as anticancer agents in the pharmaceutical industry. Of equal importance to these astonishing properties, the enediynes also offer a distinct opportunity to study the unparalleled biosyntheses of their unique molecular scaffolds and what promises to be unprecedented modes of self-resistance to highly reactive natural products. Elucidation of these aspects should unveil novel mechanistic enzymology, and may provide access to the rational biosynthetic modification of enediyne structure for new drug leads, the construction of enediyne overproducing strains and eventually lead to an enediyne combinatorial biosynthesis program. This article strives to compile and present the critical research discoveries relevant to the clinically most promising enediyne, calicheamicin, from a historical perspective. Recent progress, particularly in the areas of biosynthesis, self-resistance, bio-engineering analogs and clinical studies are also highlighted.
We present a catalog of galaxy cluster candidates detected in 100 square degrees surveyed with the SPTpol receiver on the South Pole Telescope. The catalog contains 89 candidates detected with a ...signal-to-noise ratio greater than 4.6. The candidates are selected using the Sunyaev-Zel'dovich effect at 95 and 150 GHz. Using both space- and ground-based optical and infrared telescopes, we have confirmed 81 candidates as galaxy clusters. We use these follow-up images and archival images to estimate photometric redshifts for 66 galaxy clusters and spectroscopic observations to obtain redshifts for 13 systems. An additional two galaxy clusters are confirmed using the overdensity of near-infrared galaxies only and are presented without redshifts. We find that 15 candidates (18% of the total sample) are at redshift z ≥ 1.0, with a maximum confirmed redshift of . We expect this catalog to contain every galaxy cluster with and z > 0.25 in the survey area. The mass threshold is approximately constant above z = 0.25, and the complete catalog has a median mass of approximately . Compared to previous SPT works, the increased depth of the millimeter-wave data (11.2 and 6.5 K-arcmin at 95 and 150 GHz, respectively) makes it possible to find more galaxy clusters at high redshift and lower mass.
This paper is concerned with an approximation scheme for rate-independent systems governed by a non-smooth dissipation and a possibly non-convex energy functional. The scheme is based on the local ...minimization scheme introduced in Efendiev and Mielke
J. Convex Anal.
13 (2006) 151–167, but relies on local stationarity of the underlying minimization problem. Under the assumption of Mosco-convergence for the dissipation functional, we show that accumulation points exist and are so-called parametrized BV-solutions of the rate-independent system. In particular, this guarantees the existence of parametrized BV-solutions for a rather general setting. Afterwards, we apply the scheme to a model for the evolution of damage.
PDF
