Information Technology Usage In Accounting Firms: The Best Versus The Rest

The purpose of this paper is to analyze information technology expenditures in public accounting firms from a multi-year sample.  This study also focuses on identifying possible IT spending trends in public accounting firms and attempts to determine if additional spending on IT increased the profitability of these firms

The Outburst of V1647 Ori Revealed by Spitzer

We present Spitzer Space Telescope observations of V1647 Ori, the outbursting source lighting McNeil's nebula, taken near the optical peak of the outburst in early March 2004. The source is easily detected in all Spitzer imaging bands from 3.6 - 70 microns. The fluxes at all wavelengths are roughly a factor of 15 brighter than pre-outburst levels; we measure a bolometric luminosity of 44 Lsun. We posit that this event is due to an increase in the accretion luminosity of the source. Simple models of an accretion disk plus tenuous envelope can qualitatively explain the observed pre- and post-outburst spectral energy distributions. The accretion activity implied by our results indicates that the outburst may be intermediate between FUor and EXor-type events. We also report the discovery of a previously unknown mid-infrared counterpart to the nearby Herbig-Haro object HH 22.Comment: 12 pages, 3 figures, accepted by ApJ Letter

Infrared Variability of Evolved Protoplanetary Disks: Evidence for Scale Height Variations in the Inner Disk

We present the results of a multi-wavelength multi-epoch survey of five evolved protoplanetary disks in the IC 348 cluster that show significant infrared variability. Using 3-8micron and 24micron photometry along with 5-40micron spectroscopy from the Spitzer Space Telescope, as well as ground-based 0.8-5micron spectroscopy, optical spectroscopy and near-infrared photometry, covering timescales of days to years, we examine the variability in the disk, stellar and accretion flux. We find substantial variations (10-60%) at all infrared wavelengths on timescales of weeks to months for all of these young stellar objects. This behavior is not unique when compared to other cluster members and is consistent with changes in the structure of the inner disk, most likely scale height fluctuations on a dynamical timescale. Previous observations, along with our near-infrared photometry, indicate that the stellar fluxes are relatively constant; stellar variability does not appear to drive the large changes in the infrared fluxes. Based on our near-infrared spectroscopy of the Pa-beta and Br-gamma lines we find that the accretion rates are variable in most of the evolved disks but the overall rates are probably too small to cause the infrared variability. We discuss other possible physical causes for the variability, including the influence of a companion, magnetic fields threading the disk, and X-ray flares.Comment: Accepted to ApJ. 33 pages, emulate apj forma

Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage

<p>Abstract</p> <p>Background</p> <p>Phase I/II placebo-controlled clinical trials of recombinant Factor VIIa (rFVIIa) suggested that administration of rFVIIa within 4 hours after onset of intracerebral hemorrhage (ICH) is safe, limits ICH growth, and improves outcomes. We sought to determine the cost-effectiveness of rFVIIa for acute ICH treatment, using published Phase II data. We hypothesized that rFVIIa would have a low marginal cost-effectiveness ratio (mCER) given the poor neurologic outcomes after ICH with conventional management.</p> <p>Methods</p> <p>We performed an incremental cost-effectiveness analysis from the societal perspective, considering conventional management vs. 80 ug/kg rFVIIa treatment for acute ICH cases meeting Phase II inclusion criteria. The time frame for the analysis was 1. 25 years: data from the Phase II trial was used for 90 day outcomes and rFVIIa complications – arterial thromboembolic events (ATE). We assumed no substantial cost differences in care between the two strategies except: 1) cost of rFVIIa (for an 80 mcg/kg dose in an 80 kg patient, assumed cost of $6,408); 2) cost of ATE side effects from rFVIIa (which also decrease quality of life and increase the chance of death); and 3) differential monetary costs of outcomes and their impact on quality of life, including disposition (home vs. nursing home), and outpatient vs. inpatient rehabilitation. Sensitivity analyses were performed to explore uncertainty in parameter estimates, impact of rFVIIa cost, direct cost of neurologic outcomes, probability of ATE, and outcomes after ATE.</p> <p>Results</p> <p>In the "base case", treating ICH with rFVIIa dominates the usual care strategy by being more effective and less costly. rFVIIa maintained a mCER <$50,000/QALY over a wide range of sensitivity analyses. Sensitivity analyses showed that the cost of rFVIIa must exceed $14,500, or the frequency of ATE exceed 29$50,000/QALY. Varying the cost and/or reducing the utility of health states following ATE did not impact results.</p> <p>Conclusion</p> <p>Based on data from preliminary trials, treating selected ICH patients with rFVIIa results in lower cost and improved clinical outcomes. This potential cost-effectiveness must be considered in light of the Phase III trial results.</p

Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma

Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. Here, we establish a mechanism of resistance and subsequently identified a suitable drug combination to overcome the resistance. Single treatment of BRAF mutant melanoma cell lines with vemurafenib or dabrafenib (BRAF inhibitors) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1. Overexpression of Mcl-1 in A375 and SK-MEL-28 by transfection completely blocked BRAF and MEK1/2 inhibitor-mediated inhibition of cell survival and apoptosis. Melanoma cells resistant to BRAF inhibitors showed massive expression of Mcl-1 as compared to respective sensitive cell lines. Silencing of Mcl-1 using siRNA completely sensitized resistant melanoma cells to growth suppression and induction of apoptosis by BRAF inhibitors. In vivo, vemurafenib resistant A375 xenografts implanted in athymic nude mice showed substantial tumor growth inhibition when treated with a combination of vemurafenib and Mcl-1 inhibitor or siRNA. Immunohistochemistry and western blot analyses demonstrated enhanced expression of Mcl-1 and activation of ERK1/2 in vemurafenib-resistant tumors whereas level of Mcl-1 or p-ERK1/2 was diminished in the tumors of mice treated with either of the combination. Biopsied tumors from the patients treated with or resistant to BRAF inhibitors revealed overexpression of Mcl-1. These results suggest that the combination of BRAF inhibitors with Mcl-1 inhibitor may have therapeutic advantage to melanoma patients with acquired resistance to BRAF inhibitors alone or in combination with MEK1/2 inhibitors

Galactic bulge giants: probing stellar and galactic evolution I. Catalogue of Spitzer IRAC and MIPS sources

Aims: We aim at measuring mass-loss rates and the luminosities of a statistically large sample of Galactic bulge stars at several galactocentric radii. The sensitivity of previous infrared surveys of the bulge has been rather limited, thus fundamental questions for late stellar evolution, such as the stage at which substantial mass-loss begins on the red giant branch and its dependence on fundamental stellar properties, remain unanswered. We aim at providing evidence and answers to these questions. Methods: To this end, we observed seven 15 times 15 arcmin^2 fields in the nuclear bulge and its vicinity with unprecedented sensitivity using the IRAC and MIPS imaging instruments on-board the Spitzer Space Telescope. In each of the fields, tens of thousands of point sources were detected. Results: In the first paper based on this data set, we present the observations, data reduction, the final catalogue of sources, and a detailed comparison to previous mid-IR surveys of the Galactic bulge, as well as to theoretical isochrones. We find in general good agreement with other surveys and the isochrones, supporting the high quality of our catalogue.Comment: 21 pages, accepted for publication in A&A. A version with high-resolution figures, as well as the data catalogues (including cross-id with GLIMPSE and GALCEN) and image mosaics are available at the anonymous ftp://ftp.ster.kuleuven.be/dist/stefan/Spitzer

A melanocyte lineage program confers resistance to MAP kinase pathway inhibition

BRAFV600E-mutant malignant melanomas depend on RAF/MEK/ERK (MAPK) signaling for tumor cell growth1. RAF and MEK inhibitors show remarkable clinical efficacy in BRAFV600E melanoma2, 3; however, resistance to these agents remains a formidable challenge2, 4. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here, we performed systematic gain-of-function resistance studies by expressing >15,500 genes individually in a BRAFV600E melanoma cell line treated with RAF, MEK, ERK, or combined RAF/MEK inhibitors. These studies revealed a cyclic AMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAFV600E melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF/MEK-inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAP kinase pathway and histone deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF/MEK/ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics

NCI-MATCH Arms N & P: Phase II study of PI3K beta inhibitor GSK2636771 in patients (pts) with cancers (ca) with PTEN mutation/deletion (mut/del) or PTEN protein loss

Background: The NCI-MATCH trial is the largest national study (1173 sites) for ptswith relapsed/ refractory solid tumors, lymphomas and myeloma, which assigns tar-geted therapies based on individual tumor molecular alterations detected using theadapted Oncomine AmpliSeq panel (143 genes) and immunohistochemistry (IHC).We hypothesized that patients with PTEN-deficient cancers enrolled to Arms N and Pmay benefit from treatment with the PI3K beta-selective inhibitor GSK2636771. Methods: Eligibility: relapsed/refractory ca, good end-organ function, and ECOG PS ≤ 1. Pts were screened for molecular alterations by centralized testing on fresh tumor biopsy and had deleterious PTEN mut/del without loss of expression (Arm N) or complete loss of cytoplasmic and nuclear PTEN staining on IHC (Arm P), and no other aberrations activating the PI3K/MTOR and MAPK pathways (mut in PIK3CA, PIK3R1, BRAF, KRAS, AKT1, TSC1/2, mTOR, RHEB, NF2, NRAS, HRAS). Pts received GSK2636771 400mg/day (28-days cycles). RECIST 1.1 overall response rate (ORR) was the primary endpoint. Results: Of 59 enrolled pts, 56 were eligible and received treatment. Of 22 pts with PTEN mut/del (Arm N: 6 uterine, 2 breast, 2 prostate, 2 head/neck ca, 10 other), all are off treatment as of analysis (14 disease progression, 4 for adverse events [AEs], 4 other). One pt (4.5%) with prostate ca (PTEN deletion, MPRSS2-ERG fusion) attained a partial response (-42%). Of 7 (32%) pts with stable disease (SD), 2 had SD \u3e 6 months (uterine leiomyosarcoma; endometrial carcinoma). Of 34 pts with loss of PTEN protein by IHC (Arm P: 7 prostate, 6 breast, 3 squamous anal ca, 2 cholangiocarcinoma, 16 other), all are off treatment as of analysis (26 disease progression, 4 for AE, 4 other). Of 9 (37.5%) pts with SD, 3 had SD \u3e 6 months (prostate cancer; squamous bladder cancer, squamous anal cancer). Median progression-free survival was 1.8 months for both arms. Gr ≥ 3 treatment-related (tr) reversible toxicities were experienced by 30% (7) and 20% (7) of pts in arms N and P, respectively. No tr Gr 5 toxicities were observed in either arm. Conclusions: Single agent GSK2636771 has very modest activity in ca with PTEN gene mutation/deletion and/or PTEN protein loss