Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer

Background: Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in development of resistance to anti-angiogenic therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850 mg/m Results: Forty-seven patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 23 patients and Arm B enrolled 24 patients. Fifty percent of patients had progressive disease and 62% of patients had stable disease in each arm as best response. There was no demonstrable difference in PFS between the two arms (log-rank test P=0.83). Median time to progression was 3.4 months in Arm A and 3.5 months in Arm B. Conclusions: Median PFS in the trial was comparable to and appeared to be better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine measurement with IL-8 levels did not show any correlation with progression free survival but patients with stable disease showed overall lower levels of IL-8 as compared to patients with progressive disease in the cytokine analysis

Comprehensive Genetic Testing Identifies Targetable Genomic Alterations in Most Patients with Non-Small Cell Lung Cancer, Specifically Adenocarcinoma, Single Institute Investigation

This study reviews extensive genetic analysis in advanced non-small cell lung cancer (NSCLC) patients in order to: describe how targetable mutation genes interrelate with the genes identified as variants of unknown significance; assess the percentage of patients with a potentially targetable genetic alterations; evaluate the percentage of patients who had concurrent alterations, previously considered to be mutually exclusive; and characterize the molecular subset of KRAS. Thoracic Oncology Research Program Databases at the University of Chicago provided patient demographics, pathology, and results of genetic testing. 364 patients including 289 adenocarcinoma underwent genotype testing by various platforms such as FoundationOne, Caris Molecular Intelligence, and Response Genetics Inc. For the entire adenocarcinoma cohort, 25% of patients were African Americans; 90% of KRAS mutations were detected in smokers, including current and former smokers; 46% of EGFR and 61% of ALK alterations were detected in never smokers. 99.4% of patients, whose samples were analyzed by next-generation sequencing (NGS), had genetic alterations identified with an average of 10.8 alterations/tumor throughout different tumor subtypes. However, mutations were not mutually exclusive. NGS in this study identified potentially targetable genetic alterations in the majority of patients tested, detected concurrent alterations and provided information on variants of unknown significance at this time but potentially targetable in the future

Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune- System-Mediated Protection and Subsequent Long-Term Adaptive Immunity

The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigendependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8! T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8! T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity

Col-OSSOS: The Distribution of Surface Classes in Neptune's Resonances

The distribution of surface classes of resonant trans-Neptunian objects (TNOs) provides constraints on the protoplanetesimal disk and giant planet migration. To better understand the surfaces of TNOs, the Colours of the Outer Solar System Origins Survey (Col-OSSOS) acquired multi-band photometry of 102 TNOs, and found that the surfaces of TNOs can be well described by two surface classifications, BrightIR and FaintIR. These classifications both include optically red members and are differentiated predominantly based on whether their near-infrared spectral slope is similar to their optical spectral slope. The vast majority of cold classical TNOs, with dynamically quiescent orbits, have the FaintIR surface classification, and we infer that TNOs in other dynamical classifications with FaintIR surfaces share a common origin with the cold classical TNOs. Comparison between the resonant populations and the possible parent populations of cold classical and dynamically excited TNOs reveal that the 3:2 has minimal contributions from the FaintIR class, which could be explained by the $\nu_8$ secular resonance clearing the region near the 3:2 before any sweeping capture occurred. Conversely, the fraction of FaintIR objects in the 4:3 resonance, 2:1 resonance, and the resonances within the cold classical belt, suggest that the FaintIR surface formed in the protoplanetary disk between 34.6 and 47 au, though the outer bound depends on the degree of resonance sweeping during migration. The presence and absence of the FaintIR surfaces in Neptune's resonances provides critical constraints for the history of Neptune's migration, the evolution of the $\nu_8$, and the surface class distribution in the initial planetesimal diskComment: 19 pages, 8 figures. in Press at PS

Opposite associations between alanine aminotransferase and γ-glutamyl transferase levels and all-cause mortality in type 2 diabetes: analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

Aims Reported associations between liver enzymes and mortality may not hold true in type 2 diabetes, owing to a high prevalence of non-alcoholic fatty liver disease, which has been linked to cardiovascular disease and mortality in its own right. Our study aimed to determine whether alanine aminotransferase (ALT) or γ-glutamyl transferase (GGT) levels predict mortality in type 2 diabetes, and to examine possible mechanisms. Methods Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were analysed to examine the relationship between liver enzymes and all-cause and cause-specific mortality over 5 years. Results Over 5 years, 679 (6.9%) individuals died. After adjustment, for every standard deviation increase in ALT (13.2U/L), the HR for death on study was 0.85 (95% CI 0.78-0.93), p70 U/L, compared with GGT ≤70 U/L, had HR 1.82 (1.48−2.24), p70 U/L was associated with higher risks of death due to cardiovascular disease, cancer and non-cancer/non-cardiovascular causes. The relationship for ALT persisted after adjustment for indirect measures of frailty but was attenuated by elevated hsCRP. Conclusions As in the general population, ALT has a negative, and GGT a positive, correlation with mortality in type 2 diabetes when ALT is less than two times the upper limit of normal. The relationship 4 for ALT appears specific for death due to cardiovascular disease. Links of low ALT with frailty, as a potential mechanism for relationships seen, were neither supported nor conclusively refuted by our analysis and other factors are also likely to be important in those with type 2 diabetes

The second set of pulsar discoveries by CHIME/FRB/Pulsar: 14 Rotating Radio Transients and 7 pulsars

The Canadian Hydrogen Mapping Experiment (CHIME) is a radio telescope located in British Columbia, Canada. The large field of view (FOV) of $\sim$ 200 square degrees has enabled the CHIME/FRB instrument to produce the largest FRB catalog to date. The large FOV also allows CHIME/FRB to be an exceptional pulsar and Rotating Radio Transient (RRAT) finding machine, despite saving only the metadata information of incoming Galactic events. We have developed a pipeline to search for pulsars/RRATs using DBSCAN, a clustering algorithm. Output clusters are then inspected by a human for pulsar/RRAT candidates and follow-up observations are scheduled with the more sensitive CHIME/Pulsar instrument. The CHIME/Pulsar instrument is capable of a near-daily search mode observation cadence. We have thus developed the CHIME/Pulsar Single Pulse Pipeline to automate the processing of CHIME/Pulsar search mode data. We report the discovery of 21 new Galactic sources, with 14 RRATs, 6 regular slow pulsars and 1 binary system. Owing to CHIME/Pulsar's daily observations we have obtained timing solutions for 8 of the 14 RRATs along with all the regular pulsars. This demonstrates CHIME/Pulsar's ability at finding timing solutions for transient sources

CHIME Discovery of a Binary Pulsar with a Massive Non-Degenerate Companion

Of the more than 3000 radio pulsars currently known, only ∼300 are in binary systems, and only five of these consist of young pulsars with massive nondegenerate companions. We present the discovery and initial timing, accomplished using the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope, of the sixth such binary pulsar, PSR J2108+4516, a 0.577 s radio pulsar in a 269 day orbit of eccentricity 0.09 with a companion of minimum mass 11 M⊙. Notably, the pulsar undergoes periods of substantial eclipse, disappearing from the CHIME 400–800 MHz observing band for a large fraction of its orbit, and displays significant dispersion measure and scattering variations throughout its orbit, pointing to the possibility of a circumstellar disk or very dense stellar wind associated with the companion star. Subarcsecond resolution imaging with the Karl G. Jansky Very Large Array unambiguously demonstrates that the companion is a bright, V ≃ 11 OBe star, EM* UHA 138, located at a distance of 3.26(14) kpc. Archival optical observations of EM* UHA 138 approximately suggest a companion mass ranging from 17.5 M⊙ < Mc < 23 M⊙, in turn constraining the orbital inclination angle to 50fdg3 ≲ i ≲ 58fdg3. With further multiwavelength follow-up, PSR J2108+4516 promises to serve as another rare laboratory for the exploration of companion winds, circumstellar disks, and short-term evolution through extended-body orbital dynamics

Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg k

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Genomic Tools in Biological Invasions: Current State and Future Frontiers

Human activities are accelerating rates of biological invasions and climate-driven range expansions globally, yet we understand little of how genomic processes facilitate the invasion process. Although most of the literature has focused on underlying phenotypic correlates of invasiveness, advances in genomic technologies are showing a strong link between genomic variation and invasion success. Here, we consider the ability of genomic tools and technologies to (i) inform mechanistic understanding of biological invasions and (ii) solve real-world issues in predicting and managing biological invasions. For both, we examine the current state of the field and discuss how genomics can be leveraged in the future. In addition, we make recommendations pertinent to broader research issues, such as data sovereignty, metadata standards, collaboration, and science communication best practices that will require concerted efforts from the global invasion genomics community