Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce

Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds, and pentamer assembly after 30-month storage at ambient temperature. Robust suppression of immunoglobulin G (IgG)/inhibitor and IgE formation against intravenous FIX was observed in three of four hemophilia B dogs fed with lyophilized lettuce cells expressing CTB-FIX. No side effects were detected after feeding CTB-FIX-lyophilized plant cells for >300 days. Coagulation times were markedly shortened by intravenous FIX in orally tolerized treated dogs, in contrast to control dogs that formed high-titer antibodies to FIX. Commercial-scale production, stability, prolonged storage of lyophilized cells, and efficacy in tolerance induction in a large, non-rodent model of human disease offer a novel concept for oral tolerance and low-cost production and delivery of biopharmaceuticals

Characterization of halogen-bridged binuclear metal complexes as hybridized two-band materials

We study the electronic structure of halogen-bridged binuclear metal (MMX) complexes with a two-band Peierls-Hubbard model. Based on a symmetry argument, various density-wave states are derived and characterized. The ground-state phase diagram is drawn within the Hartree-Fock approximation, while the thermal behavior is investigated using a quantum Monte Carlo method. All the calculations conclude that a typical MMX compound Pt_2(CH_3CS_2)_4I should indeed be regarded as a d-p-hybridized two-band material, where the oxidation of the halogen ions must be observed even in the ground state, whereas another MMX family (NH_4)_4[Pt_2(P_2O_5H_2)_4X] may be treated as single-band materials.Comment: 16 pages, 11 figures embedded, to be published in Phys. Rev.

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma.

BACKGROUND: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer. METHOD: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters. RESULTS: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas. CONCLUSION: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology

Financial burden of men with localized prostate cancer: a process paper

BackgroundMany individuals undergoing cancer treatment experience substantial financial hardship, often referred to as financial toxicity (FT). Those undergoing prostate cancer treatment may experience FT and its impact can exacerbate disparate health outcomes. Localized prostate cancer treatment options include: radiation, surgery, and/or active surveillance. Quality of life tradeoffs and costs differ between treatment options. In this project, our aim was to quantify direct healthcare costs to support patients and clinicians as they discuss prostate cancer treatment options. We provide the transparent steps to estimate healthcare costs associated with treatment for localized prostate cancer among the privately insured population using a large claims dataset.MethodsTo quantify the costs associated with their prostate cancer treatment, we used data from the Truven Health Analytics MarketScan Commercial Claims and Encounters, including MarketScan Medicaid, and peer reviewed literature. Strategies to estimate costs included: (1) identifying the problem, (2) engaging a multidisciplinary team, (3) reviewing the literature and identifying the database, (4) identifying outcomes, (5) defining the cohort, and (6) designing the analytic plan. The costs consist of patient, clinician, and system/facility costs, at 1-year, 3-years, and 5-years following diagnosis.ResultsWe outline our specific strategies to estimate costs, including: defining complex research questions, defining the study population, defining initial prostate cancer treatment, linking facility and provider level related costs, and developing a shared understanding of definitions on our research team.Discussion and next stepsAnalyses are underway. We plan to include these costs in a prostate cancer patient decision aid alongside other clinical tradeoffs

Quantum Monte Carlo and variational approaches to the Holstein model

Based on the canonical Lang-Firsov transformation of the Hamiltonian we develop a very efficient quantum Monte Carlo algorithm for the Holstein model with one electron. Separation of the fermionic degrees of freedom by a reweighting of the probability distribution leads to a dramatic reduction in computational effort. A principal component representation of the phonon degrees of freedom allows to sample completely uncorrelated phonon configurations. The combination of these elements enables us to perform efficient simulations for a wide range of temperature, phonon frequency and electron-phonon coupling on clusters large enough to avoid finite-size effects. The algorithm is tested in one dimension and the data are compared with exact-diagonalization results and with existing work. Moreover, the ideas presented here can also be applied to the many-electron case. In the one-electron case considered here, the physics of the Holstein model can be described by a simple variational approach.Comment: 18 pages, 11 Figures, v2: one typo correcte

NMR Analysis of the Dynamic Exchange of the NS2B Cofactor between Open and Closed Conformations of the West Nile Virus NS2B-NS3 Protease

Dengue and West Nile virus infections put an estimated 2.5 billion people at risk. Neither drugs nor vaccines are currently available against these diseases. The non-structural protein NS3 is a protease that, together with the cofactor NS2B, is essential for viral maturation. The NS2B-NS3 proteases of dengue and West Nile viruses are highly homologous and present promising drug targets. Crystal structures of the West Nile virus protease with and without bound inhibitor revealed large structural differences in NS2B, while no crystal structure of the dengue virus protease could be determined with a bound inhibitor. We investigated the structural change in solution and found that the C-terminal segment (CTS) of the NS2B cofactor is prone to dissociation from NS3. In the case of the West Nile virus protease, the CTS of NS2B is mostly associated with NS3, especially in the presence of inhibitors. In the case of the dengue virus protease and in the absence of inhibitors, the CTS of NS2B is mostly dissociated from NS3. Finding drug candidates to inhibit the association of the NS2B cofactor may thus be easier for the dengue virus protease

Consistency of high-fidelity two-qubit operations in silicon

The consistency of entangling operations between qubits is essential for the performance of multi-qubit systems, and is a crucial factor in achieving fault-tolerant quantum processors. Solid-state platforms are particularly exposed to inconsistency due to the materials-induced variability of performance between qubits and the instability of gate fidelities over time. Here we quantify this consistency for spin qubits, tying it to its physical origins, while demonstrating sustained and repeatable operation of two-qubit gates with fidelities above 99% in the technologically important silicon metal-oxide-semiconductor (SiMOS) quantum dot platform. We undertake a detailed study of the stability of these operations by analysing errors and fidelities in multiple devices through numerous trials and extended periods of operation. Adopting three different characterisation methods, we measure entangling gate fidelities ranging from 96.8% to 99.8%. Our analysis tools also identify physical causes of qubit degradation and offer ways to maintain performance within tolerance. Furthermore, we investigate the impact of qubit design, feedback systems, and robust gates on implementing scalable, high-fidelity control strategies. These results highlight both the capabilities and challenges for the scaling up of spin-based qubits into full-scale quantum processors

The use of surgery in the treatment of ER+ early stage breast cancer in England: variation by time, age and patient characteristics

AIM: To assess whether the proportion of patients aged 70 and over with ER+ operable breast cancer in England who are treated with surgery has changed since 2002, and to determine whether age and individual level factors including tumour characteristics and co-morbidity influence treatment choice. METHODS: A retrospective cohort analysis of routinely collected cancer registration data from two English regions (West Midlands, Northern & Yorkshire) was carried out (n = 17,129). Trends in surgical use over time for different age groups were assessed graphically and with linear regression. Uni- and multivariable logistic regressions were used to assess the effects of age, comorbidity, deprivation and disease characteristics on treatment choice. Missing data was handled using multiple imputation. RESULTS: There is no evidence of a change in the proportion of patients treated surgically over time. The multivariable model shows that age remains an important predictor of whether or not a woman with ER+ operable breast cancer receives surgery after covariate adjustment (Odds ratio of surgery vs no surgery, 0.82 (per year over 70)). Co-morbidity, deprivation, symptomatic presentation, later stage at diagnosis and low grade are also associated with increased probability of non-surgical treatment. CONCLUSION: Contrary to current NICE guidance in England, age appears to be an important factor in the decision to treat operable ER+ breast cancer non-surgically. Further research is needed to assess the role of other age-related factors on treatment choice, and the effect that current practice has on survival and mortality from breast cancer for older women

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13