Ab initio calculation of the anomalous Hall conductivity by Wannier interpolation

The intrinsic anomalous Hall effect in ferromagnets depends on subtle spin-orbit-induced effects in the electronic structure, and recent ab-initio studies found that it was necessary to sample the Brillouin zone at millions of k-points to converge the calculation. We present an efficient first-principles approach for computing the anomalous Hall conductivity. We start out by performing a conventional electronic-structure calculation including spin-orbit coupling on a uniform and relatively coarse k-point mesh. From the resulting Bloch states, maximally-localized Wannier functions are constructed which reproduce the ab-initio states up to the Fermi level. The Hamiltonian and position-operator matrix elements, needed to represent the energy bands and Berry curvatures, are then set up between the Wannier orbitals. This completes the first stage of the calculation, whereby the low-energy ab-initio problem is transformed into an effective tight-binding form. The second stage only involves Fourier transforms and unitary transformations of the small matrices set up in the first stage. With these inexpensive operations, the quantities of interest are interpolated onto a dense k-point mesh and used to evaluate the anomalous Hall conductivity as a Brillouin zone integral. The present scheme, which also avoids the cumbersome summation over all unoccupied states in the Kubo formula, is applied to bcc Fe, giving excellent agreement with conventional, less efficient first-principles calculations. Remarkably, we find that more than 99% of the effect can be recovered by keeping a set of terms depending only on the Hamiltonian matrix elements, not on matrix elements of the position operator.Comment: 16 pages, 7 figure

Access to Investigational Drugs: FDA Expanded Access Programs or “Right‐to‐Try” Legislation?

PurposeThe Food and Drug Administration Expanded Access (EA) program and “Right‐to‐Try” legislation aim to provide seriously ill patients who have no other comparable treatment options to gain access to investigational drugs and biological agents. Physicians and institutions need to understand these programs to respond to questions and requests for access.MethodsFDA EA programs and state and federal legislative efforts to provide investigational products to patients by circumventing FDA regulations were summarized and compared.ResultsThe FDA EA program includes Single Patient‐Investigational New Drug (SP‐IND), Emergency SP‐IND, Intermediate Sized Population IND, and Treatment IND. Approval rates for all categories exceed 99%. Approval requires FDA and Institutional Review Board (IRB) approval, and cooperation of the pharmaceutical partner is essential. “Right‐to‐Try” legislation bypasses some of these steps, but provides no regulatory or safety oversight.ConclusionThe FDA EA program is a reasonable option for patients for whom all other therapeutic interventions have failed. The SP‐IND not only provides patient access to new drugs, but also maintains a balance between immediacy and necessary patient protection. Rather than circumventing existing FDA regulations through proposed legislation, it seems more judicious to provide the knowledge and means to meet the EA requirements.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115991/1/cts12255.pd

Potential Impact of Revised Nci Eligibility Criteria Guidance: Prior Malignancy Exclusion in Breast Cancer Clinical Trials

BACKGROUND: Many individuals with cancer have survived a prior cancer and for this reason may have been excluded from clinical trials. Recent NCI guidance recommends including these individuals, especially when the risk of the prior malignancy interfering with either safety or efficacy endpoints is very low. Using breast cancer as an example, we determined the potential effect this policy change may have on clinical trial accrual. PATIENTS AND METHODS: We reviewed protocols of NCI-sponsored breast cancer clinical trials activated in 1991 through 2016. We quantified prevalence of prior cancer-related exclusion criteria and assessed the association with trial characteristics using Fisher\u27s exact tests. Using SEER data, we estimated the prevalence and timing of prior primary (nonbreast) cancer diagnoses among patients with breast cancer. RESULTS: Among 87 clinical trials (total target enrollment, 137,253 patients), 77% excluded individuals with prior cancer, most commonly (79%) within the preceding 5 years. Among trials with radiographic response or toxicity endpoints, 69% excluded prior cancer. In SEER data, the prevalence of a prior (nonbreast) cancer diagnosis ranged from 5.7% to 7.7%, depending on breast cancer stage, of which 39% occurred within 5 years of the incident breast cancer. For trials excluding prior cancer, the estimated proportion of patients excluded for this reason ranged from 1.3% to 5.8%, with the estimated number of excluded patients ranging from 1 to 288. CONCLUSIONS: More than three-fourths of NCI-sponsored breast cancer clinical trials exclude patients with prior cancer, including almost 70% of trials with response or toxicity endpoints. Given that \u3e5% of patients with breast cancer have a history of prior cancer, in large phase III trials this practice may exclude hundreds of patients. Following recent NCI eligibility guidance, the inclusion of patients with prior cancer on breast cancer trials may have a meaningful impact on accrual

Towards the creation of decellularized organ constructs using irreversible electroporation and active mechanical perfusion

<p>Abstract</p> <p>Background</p> <p>Despite advances in transplant surgery and general medicine, the number of patients awaiting transplant organs continues to grow, while the supply of organs does not. This work outlines a method of organ decellularization using non-thermal irreversible electroporation (N-TIRE) which, in combination with reseeding, may help supplement the supply of organs for transplant.</p> <p>Methods</p> <p>In our study, brief but intense electric pulses were applied to porcine livers while under active low temperature cardio-emulation perfusion. Histological analysis and lesion measurements were used to determine the effects of the pulses in decellularizing the livers as a first step towards the development of extracellular scaffolds that may be used with stem cell reseeding. A dynamic conductivity numerical model was developed to simulate the treatment parameters used and determine an irreversible electroporation threshold.</p> <p>Results</p> <p>Ninety-nine individual 1000 V/cm 100-μs square pulses with repetition rates between 0.25 and 4 Hz were found to produce a lesion within 24 hours post-treatment. The livers maintained intact bile ducts and vascular structures while demonstrating hepatocytic cord disruption and cell delamination from cord basal laminae after 24 hours of perfusion. A numerical model found an electric field threshold of 423 V/cm under specific experimental conditions, which may be used in the future to plan treatments for the decellularization of entire organs. Analysis of the pulse repetition rate shows that the largest treated area and the lowest interstitial density score was achieved for a pulse frequency of 1 Hz. After 24 hours of perfusion, a maximum density score reduction of 58.5 percent had been achieved.</p> <p>Conclusions</p> <p>This method is the first effort towards creating decellularized tissue scaffolds that could be used for organ transplantation using N-TIRE. In addition, it provides a versatile platform to study the effects of pulse parameters such as pulse length, repetition rate, and field strength on whole organ structures.</p

Molecular Epidemiology of Adenovirus Type 7 in the United States, 1966–20001

Genetic variation among 166 isolates of human adenovirus 7 (Ad7) obtained from 1966 to 2000 from the United States and Eastern Ontario, Canada, was determined by genome restriction analysis. Most (65%) isolates were identified as Ad7b. Two genome types previously undocumented in North America were also identified: Ad7d2 (28%), which first appeared in 1993 and was later identified throughout the Midwest and Northeast of the United States and in Canada; and Ad7h (2%), which was identified only in the U.S. Southwest in 1998 and 2000. Since 1996, Ad7d2 has been responsible for several civilian outbreaks of Ad7 disease and was the primary cause of a large outbreak of respiratory illness at a military recruit training center. The appearance of Ad7d2 and Ad7h in North America represents recent introduction of these viruses from previously geographically restricted areas and may herald a shift in predominant genome type circulating in the United States

NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers

Purpose: Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLCs) are urgently needed. Here, we investigated the ability of ß-lapachone (ß-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that over-express NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Experimental Design: The mechanism of lethality of low dose IR in combination with sublethal doses of ß-lap were evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograph models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus co-treatments were performed to validate therapeutic efficacy and mechanism of action. Results: ß-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased DSB lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 ß-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (~12 Units) of any normal tissue. PK/PD responses confirm that IR + ß-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, while low NQO1 levels and high levels of Catalase in associated normal tissue were protective. Conclusion: Our data suggest that combination of sublethal doses of ß-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + ß-lapachone against patients with NQO1+ NSCLCs

Discovering transcriptional modules by Bayesian data integration

Motivation: We present a method for directly inferring transcriptional modules (TMs) by integrating gene expression and transcription factor binding (ChIP-chip) data. Our model extends a hierarchical Dirichlet process mixture model to allow data fusion on a gene-by-gene basis. This encodes the intuition that co-expression and co-regulation are not necessarily equivalent and hence we do not expect all genes to group similarly in both datasets. In particular, it allows us to identify the subset of genes that share the same structure of transcriptional modules in both datasets. Results: We find that by working on a gene-by-gene basis, our model is able to extract clusters with greater functional coherence than existing methods. By combining gene expression and transcription factor binding (ChIP-chip) data in this way, we are better able to determine the groups of genes that are most likely to represent underlying TMs

Financing Direct Democracy: Revisiting the Research on Campaign Spending and Citizen Initiatives

The conventional view in the direct democracy literature is that spending against a measure is more effective than spending in favor of a measure, but the empirical results underlying this conclusion have been questioned by recent research. We argue that the conventional finding is driven by the endogenous nature of campaign spending: initiative proponents spend more when their ballot measure is likely to fail. We address this endogeneity by using an instrumental variables approach to analyze a comprehensive dataset of ballot propositions in California from 1976 to 2004. We find that both support and opposition spending on citizen initiatives have strong, statistically significant, and countervailing effects. We confirm this finding by looking at time series data from early polling on a subset of these measures. Both analyses show that spending in favor of citizen initiatives substantially increases their chances of passage, just as opposition spending decreases this likelihood

906-61 Acoustic Quantification in the Infarcted Ventricle: Comparison with Electron Beam Computed Tomography

Assessment of LV size and function by acoustic quantification (AQ) correlates well with other techniques in patients with normally contracting ventricles. This prospective study examined the correlation between AQ and electron beam computed tomography (EBCT) volume measurements in patients with first anterior Q-wave MI and abnormally contracting ventricles. End-diastolic (EDV) and end-systolic (ESV) volumes by AQ were determined from standard four-chamber (4ch) and two-chamber (2ch) apical windows. The AQ tracings were transformed to volumetric measurements using the area-length (AL) and the modified Simpson's (mod.S) methods. EDV and ESV by EBCT were obtained conventionally by summation of manually traced LV areas on each short axis tomograms using Simpson's rule. Thirteen patients were imaged by both EBCT and echocardiography within 24 hours. EBCT-EDV ranged from 129–234ml (mean 173±34 ml and ESV from 58–109ml (mean 82±19 ml). The EDV and ESV by AQ, their correlation to EBCT and the accompanying pvalues are shown below:EDV-2chEDV-4chESV-2chESV-4chVol (ml)88±3097±3043±2050±22ALr0.760.560.580.34p0.0060.0490.0610.258Vol (ml)80±3390±3140±2145±20mod.Sr0.760.700.720.58p0.0060.0080.0120.037Conclusions[1] AQ underestimates absolute EDV and ESV measured by EBCT. [2] AQ-EDV correlates well with EBCT, particularly using the mod.S method. [3] AQ-ESV correlation to EBCT drops due to the asymmetric contraction pattern of infarcted ventricles. [4] The AL method's accuracy is particularly susceptible to asymmetric contraction in distorted ventricles. [5] Correction factors can be applied to account for the offset of EDV and ESV measurements by AQ

A System for Performing High Throughput Assays of Synaptic Function

Unbiased, high-throughput screening has proven invaluable for dissecting complex biological processes. Application of this general approach to synaptic function would have a major impact on neuroscience research and drug discovery. However, existing techniques for studying synaptic physiology are labor intensive and low-throughput. Here, we describe a new high-throughput technology for performing assays of synaptic function in primary neurons cultured in microtiter plates. We show that this system can perform 96 synaptic vesicle cycling assays in parallel with high sensitivity, precision, uniformity, and reproducibility and can detect modulators of presynaptic function. By screening libraries of pharmacologically defined compounds on rat forebrain cultures, we have used this system to identify novel effects of compounds on specific aspects of presynaptic function. As a system for unbiased compound as well as genomic screening, this technology has significant applications for basic neuroscience research and for the discovery of novel, mechanism-based treatments for central nervous system disorders