Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade

Greater understanding of tumour immunobiology has led to a new era of cancer treatment in which immuno-oncology (IO) therapies are used to boost anti-cancer immune responses. Prominent among these therapies are immune checkpoint inhibitors (ICIs), antibody-based drugs that can unleash the power of tumour-specific CD8 + T-cells. ICIs targeting the Programmed cell death protein 1 (PD-1) cell surface receptor or its ligand PD-L1 are particularly effective, with clinical studies reporting powerful and durable therapeutic impact against many cancer types, including melanoma and non-small cell lung cancer. ICIs have the potential to transform the landscape of cancer treatment, and their development was recognised by the award of the 2018 Nobel Prize in Physiology or Medicine to James Allison and Tasuku Honjo. However, the proportion of patients responding to anti-PD-1/PD-L1 monotherapy can be low. The next major challenge involves understanding and overcoming the innate and acquired resistance that prevents most patients from responding to PD-1/PD-L1 blockade. In this review, we outline the physiological function of PD-1 and its exploitation by developing tumours. We give an overview of current FDA-approved drugs targeting PD-1 or PD-L1 and summarise clinical progress so far. We then discuss key mechanisms thought to underpin resistance to PD-1/PD-L1 blockade, describing biomarkers that could allow patient responses to be predicted before treatment, and tracked once treatment has started. We also present clinical and pre-clinical combination therapies that have been developed to overcome resistance and which have the potential to substantially extend the therapeutic reach of these revolutionary drugs

Development and evaluation of a method to define a tibial coordinate system through the fitting of geometric primitives

Coordinate system definition is a critical element of biomechanical modeling of the knee, and cases of skeletal trauma present major technical challenges. This paper presents a method to define a tibial coordinate system by fitting geometric primitives to surface anatomy requiring minimal user input. The method presented here utilizes a conical fit to both the tibial shaft and femoral condyles to generate independent axes forming the basis of a tibial coordinate system. Definition of the tibial axis showed high accuracy when shape fitting to ≥50 mm of shaft with <3° of angular variation from the axis obtained using the full tibia. Repeatability and reproducibility of the axis was compared using intraclass correlation coefficients which showed excellent intra- and inter-observer agreement across cases. Additionally, shape fitting to the distal femoral condyles showed high accuracy compared to the reference axis established automatically through identifying the medial and lateral epicondyles (<4°). Utilizing geometric primitives to estimate functional axes for the tibia and femur removes reliance on anatomical landmarks that can be displaced by fracture or inaccurately identified by observers. Furthermore, fitting of such primitives provides a more complete understanding of the true bony anatomy, which cannot be done through simple landmark identification.Stuart C. Millar, John B. Arnold, Lucian B. Solomon, Dominic Thewlis and François Frayss

The importance of OH radical–neutral low temperature tunnelling reactions in interstellar clouds using a new model

Recent laboratory experiments using a pulsed Laval nozzle apparatus have shown that reactions between a neutral molecule and the radical OH can occur efficiently at low temperatures despite activation energy barriers if there is a hydrogen-bonded complex in the entrance channel which allows the system to tunnel efficiently under the barrier. Since OH is a major radical in the interstellar medium, this class of reactions may well be important in the chemistry that occurs in the gas phase of interstellar clouds. Using a new gas-grain chemical network with both gas-phase reactions and reactions on the surfaces of dust particles, we studied the role of OH–neutral reactions in dense interstellar clouds at 10, 50, and 100 K. We determined that at least one of these reactions can be significant, especially at the lowest temperatures studied, where the rate constants are large. It was found in particular that the reaction between CH3OH and OH provides an effective and unambiguous gas-phase route to the production of the gaseous methoxy radical (CH3O), which has been recently detected in cold, dense interstsellar clouds. The role of other reactions in this class is explored

The PKC, HOG and Ca2+ signalling pathways co-ordinately regulate chitin synthesis in Candida albicans

Open Access via PMC2649417Peer reviewedPublisher PD

Oceanic Anoxic Event 2 triggered by Kerguelen volcanism

Large Igneous Provinces (LIPs) are associated with global warming and carbon cycle perturbations during Oceanic Anoxic Event 2 (OAE2, ~94 Ma) and the Mid-Cenomanian Event (MCE, ~96.5 Ma). However, there is still no consensus on the role volcanism played as a trigger, or its source – previously ascribed to the Caribbean LIP or High Arctic LIP. Here, we use Mentelle Basin sedimentary mercury (Hg) concentrations to determine the timing of volcanism, and neodymium (Nd) and strontium (Sr) isotopes for sedimentary provenance. High Hg concentrations compared to Northern Hemisphere records, and a shift to radiogenic Nd isotopes, indicates Kerguelen LIP volcanic activity and plateau uplift occurred in the lead up to and within OAE2. Whilst we find limited evidence that a volcanic event caused the MCE, pulsed Hg spikes before and during OAE2 imply volcanic emissions were key in driving climate and carbon cycle changes and triggering OAE2

Grain Surface Models and Data for Astrochemistry

AbstractThe cross-disciplinary field of astrochemistry exists to understand the formation, destruction, and survival of molecules in astrophysical environments. Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. A broad consensus has been reached in the astrochemistry community on how to suitably treat gas-phase processes in models, and also on how to present the necessary reaction data in databases; however, no such consensus has yet been reached for grain-surface processes. A team of ∼25 experts covering observational, laboratory and theoretical (astro)chemistry met in summer of 2014 at the Lorentz Center in Leiden with the aim to provide solutions for this problem and to review the current state-of-the-art of grain surface models, both in terms of technical implementation into models as well as the most up-to-date information available from experiments and chemical computations. This review builds on the results of this workshop and gives an outlook for future directions

The roles of the formal and informal sectors in the provision of effective science education

For many years, formal school science education has been criticised by students, teachers, parents and employers throughout the world. This article presents an argument that a greater collaboration between the formal and the informal sector could address some of these criticisms. The causes for concern about formal science education are summarised and the major approaches being taken to address them are outlined. The contributions that the informal sector currently makes to science education are identified. It is suggested that the provision of an effective science education entails an enhanced complementarity between the two sectors. Finally, there is a brief discussion of the collaboration and communication still needed if this is to be effective

Correction: Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial

BACKGROUND: Acute exacerbations contribute to the morbidity and mortality associated with chronic obstructive pulmonary disease (COPD). This proof-of-concept study evaluates whether intermittent pulsed moxifloxacin treatment could reduce the frequency of these exacerbations. METHODS: Stable patients with COPD were randomized in a double-blind, placebo-controlled trial to receive moxifloxacin 400 mg PO once daily (N = 573) or placebo (N = 584) once a day for 5 days. Treatment was repeated every 8 weeks for a total of six courses. Patients were repeatedly assessed clinically and microbiologically during the 48-week treatment period, and for a further 24 weeks' follow-up. RESULTS: At 48 weeks the odds ratio (OR) for suffering an exacerbation favoured moxifloxacin: per-protocol (PP) population (N = 738, OR 0.75, 95% confidence interval (CI) 0.565-0.994, p = 0.046), intent-to-treat (ITT) population (N = 1149, OR 0.81, 95% CI 0.645-1.008, p = 0.059), and a post-hoc analysis of per-protocol (PP) patients with purulent/mucopurulent sputum production at baseline (N = 323, OR 0.55, 95% CI 0.36-0.84, p = 0.006).There were no significant differences between moxifloxacin and placebo in any pre-specified efficacy subgroup analyses or in hospitalization rates, mortality rates, lung function or changes in St George's Respiratory Questionnaire (SGRQ) total scores. There was, however, a significant difference in favour of moxifloxacin in the SGRQ symptom domain (ITT: -8.2 vs -3.8, p = 0.009; PP: -8.8 vs -4.4, p = 0.006). Moxifloxacin treatment was not associated with consistent changes in moxifloxacin susceptibility. There were more treatment-emergent, drug related adverse events with moxifloxacin vs placebo (p < 0.001) largely due to gastrointestinal events (4.7% vs 0.7%). CONCLUSIONS: Intermittent pulsed therapy with moxifloxacin reduced the odds of exacerbation by 20% in the ITT population, by 25% among the PP population and by 45% in PP patients with purulent/mucopurulent sputum at baseline. There were no unexpected adverse events and there was no evidence of resistance development. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00473460 (ClincalTrials.gov)

Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements