Natural linewidth analysis of d-band photoemission from Ag(110)

We report a high-resolution angle-resolved study of photoemission linewidths observed for Ag(110). A careful data analysis yields k$-resolved upper limits for the inverse inelastic lifetimes of$d$-holes at the X-point of the bulk band structure. At the upper$d$-band edge the hole-lifetime is$\tau_h \geq 22 $fs, i.e. more than one order of magnitude larger than predicted for a free-electron gas. Following calculations for$d$-hole dynamics in Cu (I.\ Campillo et al., Phys. Rev. Lett., in press) we interpret the lifetime enhancement by a small scattering cross-section of $d$- and $sp$-states below the Fermi level. With increasing distance to $E_F$ the $d$-hole lifetimes get shorter because of the rapidly increasing density of d-states and contributions of intra-$d$-band scattering processes, but remain clearly above free-electron-model predictions.Comment: 14 pages, 7 figure

Quasiparticles and Energy Scaling in Bi2_2Sr2_2Can−1_{n-1}Cun_nO2n+4_{2n+4} (n\it{n}=1-3): Angle-Resolved Photoemission Spectroscopy

Angle-resolved photoemission spectroscopy (ARPES) has been performed on the single- to triple-layered Bi-family high-{\it T$_c$} superconductors (Bi$_2$Sr$_2$Ca$_{n-1}$Cu$_n$O$_{2n+4}$, $\it{n}$=1-3). We found a sharp quasiparticle peak as well as a pseudogap at the Fermi level in the triple-layered compound. Comparison among three compounds has revealed a universal rule that the characteristic energies of superconducting and pseudogap behaviors are scaled with the maximum {\it T$_c$}.Comment: 4 pages, 4 figure

Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity

In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.We also thank the University of Cambridge, Cancer Research UK, the CRUK Cambridge Institute Core Facilities, and Hutchison Whampoa Limited. This work was also supported by the Lustgarten Foundation for Pancreatic Cancer Research, the Ludwig Institute for Cancer Research, the NIHR Biomedical Research Centre, and the Cambridge ECMC. T.R.F. was supported by the Rosetrees Trust and the Cambridge School of Clinical Medicine’s MB/PhD Programme, T.J. was supported by the Wellcome Trust Translational Medicine and Therapeutics Programme and the University of Cambridge Department of Oncology (RJAG/076), C.M.C. was supported by the Cambridge University Hospitals NHS Foundation Trust, E.W.R. was supported by the CRI Irvington Postdoctoral Fellowship Program, and A.P.C. was supported by the Medical Research Council (MRC) Metabolic Diseases Unit (MRC_MC_UU_12012/1). D.T.F. is a Distinguished Scholar of the Lustgarten Foundation

Cross-sectional analysis of data from the U.S. clinical trials database reveals poor translational clinical trial effort for traumatic brain injury, compared with stroke

Traumatic brain injury (TBI) is an important public health problem, comparable to stroke in incidence and prevalence. Few interventions have proven efficacy in TBI, and clinical trials are, therefore, necessary to advance management in TBI. We describe the current clinical trial landscape in traumatic brain injury and compare it with the trial efforts for stroke. For this, we analysed all stroke and TBI studies registered on the US Clinical Trials (www.clinicaltrials.gov) database over a 10-year period (01/01/2000 to 01/31/2013). This methodology has been previously used to analyse clinical trial efforts in other specialties. We describe the research profile in each area: total number of studies, total number of participants and change in number of research studies over time. We also analysed key study characteristics, such as enrolment number and scope of recruitment. We found a mismatch between relative public health burden and relative research effort in each disease. Despite TBI having comparable prevalence and higher incidence than stroke, it has around one fifth of the number of clinical trials and participant recruitment. Both stroke and TBI have experienced an increase in the number of studies over the examined time period, but the rate of growth for TBI is one third that for stroke. Small-scale (<1000 participants per trial) and single centre studies form the majority of clinical trials in both stroke and TBI, with TBI having significantly fewer studies with international recruitment. We discuss the consequences of these findings and how the situation might be improved. A sustained research effort, entailing increased international collaboration and rethinking the methodology of running clinical trials, is required in order to improve outcomes after traumatic brain injury

A Molecular and Preclinical Comparison of the PD-1 targeted T cell Checkpoint Inhibitors Nivolumab and Pembrolizumab

T cell checkpoint inhibition has a profound impact on cancer care and the two Programmed cell death protein 1 (PD-1) targeted antibodies nivolumab and pembrolizumab have been leading this therapeutic revolution. Their clinical comparability is a highly relevant topic of discussion, but to a significant degree is a consequence of their molecular properties. Here we provide a molecular, preclinical, and early clinical comparison of the two antibodies, based on the available data and recent literature. We acknowledge the limitations of such comparisons, but suggest that based on the available data, differences in clinical trial outcomes between nivolumab and pembrolizumab are more likely drug-independent than drug-dependent.Wellcome Trust Translational Medicine and Therapeutics Grant RJAG/07

Strong spin triplet contribution of the first removal state in the insulating regime of Bi2Sr2Ca1-xYxCu2O8+delta

The experimental dispersion of the first removal state in the insulating regime of Bi2Sr2Ca1-xYxCu2O8+delta is found to differ significantly from that of other parent materials: oxyclorides and La2CuO4 . For Y-contents of 0.92 > x > 0.55 due to nonstoichiometric effects in the Bi-O layers, the hole concentration in the CuO2 -layers is almost constant and on the contrary the crystal lattice parameters a,b,c change very strongly. This (a,b) parameter increase and c parameter decrease results in an unconventional three peak structure at (0,0);(pi/2, pi/2);(pi,pi) for x=0.92. We can describe the experimental data only beyond the framework of the 3-band pd-model involving the representations of a new triplet counterpart for the Zhang-Rice singlet state.Comment: 16 pages, 4 figure

Cross-sectional and longitudinal analysis of cancer vaccination trials registered on the US Clinical Trials Database demonstrates paucity of immunological trial endpoints and decline in registration since 2008

INTRODUCTION: Cancer vaccination has been researched as a means of treating and preventing cancer, but successful translational efforts yielding clinical therapeutics have been limited. Numerous reasons have been offered in explanation, pertaining both to the vaccine formulation, and the clinical trial methodology used. This study aims to characterize the tumor vaccine clinical trial landscape quantitatively, and explore the possible validity of the offered explanations including the translational obstacles posed by the current common endpoints. METHODS: We performed a detailed cross-sectional and longitudinal analysis of tumor vaccine trials (n=955) registered in the US Clinical Trials database. RESULTS: The number of tumor vaccine trials initiated per annum has declined 30% since a peak in 2008. In terms of vaccine formulation, 25% of trials use tumor cell/lysate preparations; whereas, 73% of trials vaccinate subjects against defined protein/peptide antigens. Also, 68% of trials do not use vectors for antigen delivery. Both these characteristics of tumor vaccines have remained unchanged since 1996. The top five types of cancer studied are: melanoma (22.6%); cervical cancer (13.0%); breast cancer (11.3%); lung cancer (9.5%); and prostate cancer (9.4%). In addition, 86% of the trials are performed where there is established disease rather than prophylactically, of which 67% are performed exclusively in the adjuvant setting. Also, 42% of Phase II trials do not measure any survival-related endpoint, and only 23% of Phase III trials assess the immune response to vaccination. CONCLUSION: The clinical trial effort in tumor vaccination is declining, necessitating a greater urgency in identifying and removing the obstacles to clinical translation. These obstacles may include: 1) vaccination against a small range of antigens; 2) naked delivery of antigen; 3) investigation of less immunogenic cancer types; and 4) investigation in the setting of established disease. In addition, the prevalence of late phase failure may be due to inadequate assessment of survival-related endpoints in Phase II trials. The clinical trial development of tumor vaccines should include mechanism-based translational endpoints, as well as the discovery of immune biomarkers with which to stratify, monitor, and prognosticate patients

Novel Fine-Structure in the Low-Energy Excitation Spectrum of a High-Tc Superconductor by Polarization Dependent Photoemission

Angle-resolved photoemission spectroscopy is performed on single crystals of the single-layer high-Tc superconductor Bi(2)Sr(2-x)La(x)CuO(6+d) at optimal doping (x=0.4) in order to study in great detail the Zhang-Rice (ZR) singlet band at the Fermi level. Besides the high crystal quality the advantages of a single-layer material are the absence of bilayer effects and the distinct reduction of thermal broadening. Due to the high energy and angle resolution and, most important, due to the controlled variation of the polarization vector of the synchrotron radiation the emission from the ZR singlet band reveals a distinct fine-structure. It consists of two maxima, the first showing only weak and the second at EF extremely strong polarization dependence. However, our observation has enormous consequences for line shape analyses and the determination of pseudo gaps by photoemission.Comment: 10 pages, 2 figures. to appear in PRB (Rapid Comm.