Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Role of ion channels and subcellular Ca2+ signalling in arachidonic acid induced dilation of pressurised retinal arterioles

Purpose: To investigate the mechanisms responsible for the dilatation of rat retinal arterioles in response to arachidonic acid (AA). Methods: Changes in the diameter of isolated, pressurized rat retinal arterioles were measured in the presence of AA alone and following pre-incubation with pharmacological agents inhibiting Ca2+ sparks and oscillations and K+ channels. Subcellular Ca2+ signals were recorded in arteriolar myocytes using Fluo-4-based confocal imaging. The effects of AA on membrane currents of retinal arteriolar myocytes were studied using whole-cell perforated patch clamp recording. Results: AA dilated pressurised retinal arterioles under conditions of myogenic tone. Eicosatetraynoic acid (ETYA) exerted a similar effect, but unlike AA, its effects were rapidly reversible. AA-induced dilation was associated with an inhibition of subcellular Ca2+ signals. Interventions known to block Ca2+ sparks and oscillations in retinal arterioles caused dilatation and inhibited AA-induced vasodilator responses. AA accelerated the rate of inactivation of the A-type Kv current and the voltage dependence of inactivation was shifted to more negative membrane potentials. It also enhanced voltage-activated and spontaneous BK currents, but only at positive membrane potentials. Pharmacological inhibition of A-type Kv and BK currents failed to block AA-induced vasodilator responses. AA suppressed L-type Ca2+ currents. Conclusions: These results suggest that AA induces retinal arteriolar vasodilation by inhibiting subcellular Ca2+ signalling activity in retinal arteriolar myocytes, most likely through a mechanism involving the inhibition of L-type Ca2+ channel activity. AA actions on K+ currents are inconsistent with a model in which K+ channels contribute to the vasodilator effects of AA.

Pathophysiology and Pathogenesis of Diabetic Retinopathy

Diabetic retinopathy is traditionally viewed as a disease of the retinal blood vessels, although there is increasing evidence that retinal neurons and glial cells are also affected. This article describes the changes in the diabetic retina that precede the development of clinical diabetic retinopathy, including changes in the rate of retinal blood flow, alterations in the electroretinogram and breakdown of the integrity of the blood-retinal barrier. The long term lesions of diabetic retinopathy are characterised by a complex array of vasodegenerative changes that lead directly to areas of retinal ischaemia. This frequently triggers the onset of macular oedema and/or the proliferative stages of diabetic retinopathy with risk of visual impairment and blindness. Neurodegeneration has also been reported in the retina during both human and experimental diabetic retinopathy, although presently it remains unclear to what extent such changes contribute to visual loss in diabetic retinopathy.

Defining the Impact of Non-Native Species

Non-native species cause changes in the ecosystems to which they are introduced. These changes, or some of them, are usually termed impacts; they can be manifold and potentially damaging to ecosystems and biodiversity. However, the impacts of most non-native species are poorly understood, and a synthesis of available information is being hindered because authors often do not clearly define impact. We argue that explicitly defining the impact of non-native species will promote progress toward a better understanding of the implications of changes to biodiversity and ecosystems caused by non-native species; help disentangle which aspects of scientific debates about non-native species are due to disparate definitions and which represent true scientific discord; and improve communication between scientists from different research disciplines and between scientists, managers, and policy makers. For these reasons and based on examples from the literature, we devised seven key questions that fall into 4 categories: directionality, classification and measurement, ecological or socio-economic changes, and scale. These questions should help in formulating clear and practical definitions of impact to suit specific scientific, stakeholder, or legislative contexts.

Potentially inappropriate prescribing among older people in the United Kingdom

Background: Potentially inappropriate prescribing (PIP) in older people is associated with increases in morbidity, hospitalisation and mortality. The objective of this study was to estimate the prevalence of and factors associated with PIP, among those aged ≥70 years, in the United Kingdom, using a comprehensive set of prescribing indicators and comparing these to estimates obtained from a truncated set of the same indicators.

Methods: A retrospective cross-sectional study was carried out in the UK Clinical Practice Research Datalink (CPRD), in 2007. Participants included those aged ≥ 70 years, in CPRD. Fifty-two PIP indicators from the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria were applied to data on prescribed drugs and clinical diagnoses. Overall prevalence of PIP and prevalence according to individual STOPP criteria were estimated. The relationship between PIP and polypharmacy (≥4 medications), comorbidity, age, and gender was examined. A truncated, subset of 28 STOPP criteria that were used in two previous studies, were further applied to the data to facilitate comparison.

Results: Using 52 indicators, the overall prevalence of PIP in the study population (n = 1,019,491) was 29%. The most common examples of PIP were therapeutic duplication (11.9%), followed by use of aspirin with no indication (11.3%) and inappropriate use of proton pump inhibitors (PPIs) (3.7%). PIP was strongly associated with polypharmacy (Odds Ratio 18.2, 95% Confidence Intervals, 18.0-18.4, P < 0.05). PIP was more common in those aged 70–74 years vs. 85 years or more and in males. Application of the smaller subset of the STOPP criteria resulted in a lower PIP prevalence at 14.9% (95% CIs 14.8-14.9%) (n = 151,598). The most common PIP issues identified with this subset were use of PPIs at maximum dose for > 8 weeks, NSAIDs for > 3 months, and use of long-term neuroleptics.

Conclusions: PIP was prevalent in the UK and increased with polypharmacy. Application of the comprehensive set of STOPP criteria allowed more accurate estimation of PIP compared to the subset of criteria used in previous studies. These findings may provide a focus for targeted interventions to reduce PIP.

Relationship between genome and epigenome - challenges and requirements for future research

Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set the vision for future policies and research agendas at the European level.

Predictors and dynamics of postpartum relapses in women with multiple sclerosis

Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies.

The role of adiposity in cardiometabolic traits:a Mendelian randomization analysis

The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

The Pan-STARRS Moving Object Processing System

We describe the Pan-STARRS Moving Object Processing System (MOPS), a modern software package that produces automatic asteroid discoveries and identifications from catalogs of transient detections from next-generation astronomical survey telescopes. MOPS achieves >99.5% efficiency in producing orbits from a synthetic but realistic population of asteroids whose measurements were simulated for a Pan-STARRS4-class telescope. Additionally, using a nonphysical grid population, we demonstrate that MOPS can detect populations of currently unknown objects such as interstellar asteroids. MOPS has been adapted successfully to the prototype Pan-STARRS1 telescope despite differences in expected false detection rates, fill-factor loss, and relatively sparse observing cadence compared to a hypothetical Pan-STARRS4 telescope and survey. MOPS remains highly efficient at detecting objects but drops to 80% efficiency at producing orbits. This loss is primarily due to configurable MOPS processing limits that are not yet tuned for the Pan-STARRS1 mission. The core MOPS software package is the product of more than 15 person-years of software development and incorporates countless additional years of effort in third-party software to perform lower-level functions such as spatial searching or orbit determination. We describe the high-level design of MOPS and essential subcomponents, the suitability of MOPS for other survey programs, and suggest a road map for future MOPS development.

The chronostratigraphy of the Haua Fteah cave (Cyrenaica, northeast Libya)

The 1950s excavations by Charles McBurney in the Haua Fteah, a large karstic cave on the coast of northeast Libya, revealed a deep sequence of human occupation. Most subsequent research on North African prehistory refers to his discoveries and interpretations, but the chronology of its archaeological and geological sequences has been based on very early age determinations. This paper reports on the initial results of a comprehensive multi-method dating program undertaken as part of new work at the site, involving radiocarbon dating of charcoal, land snails and marine shell, cryptotephra investigations, optically stimulated luminescence (OSL) dating of sediments, and electron spin resonance (ESR) dating of tooth enamel. The dating samples were collected from the newly exposed and cleaned faces of the upper 7.5m of the ~14.0m-deep McBurney trench, which contain six of the seven major cultural phases that he identified. Despite problems of sediment transport and reworking, using a Bayesian statistical model the new dating program establishes a robust framework for the five major lithostratigraphic units identified in the stratigraphic succession, and for the major cultural units. The age of two anatomically modern human mandibles found by McBurney in Layer XXXIII near the base of his Levalloiso-Mousterian phase can now be estimated to between 73 and 65ka (thousands of years ago) at the 95.4% confidence level, within Marine Isotope Stage (MIS) 4. McBurney's Layer XXV, associated with Upper Palaeolithic Dabban blade industries, has a clear stratigraphic relationship with Campanian Ignimbrite tephra. Microlithic Oranian technologies developed following the climax of the Last Glacial Maximum and the more microlithic Capsian in the Younger Dryas. Neolithic pottery and perhaps domestic livestock were used in the cave from the mid Holocene but there is no certain evidence for plant cultivation until the Graeco-Roman period. © 2013 Elsevier Ltd.

Ecological Impacts of Alien Species: Quantification, Scope, Caveats, and Recommendations

Despite intensive research during the past decade on the effects of alien species, invasion science still lacks the capacity to accurately predict the impacts of those species and, therefore, to provide timely advice to managers on where limited resources should be allocated. This capacity has been limited partly by the context-dependent nature of ecological impacts, research highly skewed toward certain taxa and habitat types, and the lack of standardized methods for detecting and quantifying impacts. We review different strategies, including specific experimental and observational approaches, for detecting and quantifying the ecological impacts of alien species. These include a four-way experimental plot design for comparing impact studies of different organisms. Furthermore, we identify hypothesis-driven parameters that should be measured at invaded sites to maximize insights into the nature of the impact. We also present strategies for recognizing high-impact species. Our recommendations provide a foundation for developing systematic quantitative measurements to allow comparisons of impacts across alien species, sites, and time.

The Second Lesson of the Anatomists

A single poem in a collection of the best poems published in the journal Poetry London, 1988-2013.

ARTD1/PARP1 Negatively Regulates Glycolysis by Inhibiting Hexokinase 1 Independent of NAD(+) Depletion

ARTD1 (PARP1) is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose) (PAR) in response to strand breaks, and it plays an important role in cell death following excessive DNA damage. ARTD1-induced cell death is associated with NAD(+) depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD(+) depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD(+) depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.

The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. a randomized trial

Rationale: Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-b. Exogenous IFN-b restores antiviral activity.

Objectives: To compare the efficacy and safety of inhaled IFN-b with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses.

Methods: A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2–5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-b (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses.

Measurements and Main Results: A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse
(mean change in six-item Asthma Control Questionnaire ,0.5) and IFN-b treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset ofmore difficult-to-treat, Step 4-5 peoplewith asthma (n = 27 IFN-b; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-b (P = 0.004).

Conclusions: Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-b is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the needforfurther, adequately powered, trialsin this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).