Impaired Cognitive Flexibility After Neonatal Perirhinal Lesions in Rhesus Macaques

Previous research indicated that monkeys with neonatal perirhinal lesions (Neo-PRh) were impaired on working memory (WM) tasks that generated proactive interference, but performed normally on WM tasks devoid of interference (Weiss et al., 2016). This finding suggested that the early lesions disrupted cognitive processes important for resolving proactive interference, such as behavioral inhibition and cognitive flexibility. To distinguish between these possibilities, the same Neo-PRh monkeys and their controls were tested using the Intradimensional/Extradimensional attentional set-shifting task (Roberts et al., 1988; Dias et al., 1997). Neo-PRh monkeys completed the Simple and Compound Discrimination stages, the Intradimensional Shift stage, and all Reversal stages comparably to controls, but made significantly more errors on the Extradimensional Shift stage of the task. These data indicate that impaired cognitive flexibility was the likely source of increased perseverative errors made by Neo-PRh monkeys when performing WM tasks, rather than impaired behavioral inhibition, and imply that the perirhinal cortex and its interactions with the PFC may play a unique and critical role in the development of attentional set shifting abilities

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

Molecular Superbubbles in the Starburst Galaxy NGC 253

The central 2x1 kpc of the starburst galaxy NGC 253 has been imaged using the Submillimeter Array at a 60 pc resolution in the J=2-1 transitions of 12CO, 13CO, and C18O as well as in the 1.3 mm continuum. Molecular gas and dust are mainly in the circumnuclear disk of ~500 pc radius, with warm (~40 K) and high area-filling factor gas in its central part. Two gas shells or cavities have been discovered in the circumnuclear disk. They have ~100 pc diameters and have large velocity widths of 80-100 km/s, suggestive of expansion at ~50 km/s. Modeled as an expanding bubble, each shell has an age of ~0.5 Myr and needed kinetic energy of ~1E46 J as well as mean mechanical luminosity of ~1E33 W for its formation. The large energy allows each to be called a superbubble. A ~10^6 Msun super star cluster can provide the luminosity, and could be a building block of the nuclear starburst in NGC 253. Alternatively, a hypernova can also be the main source of energy for each superbubble, not only because it can provide the mechanical energy and luminosity but also because the estimated rate of superbubble formation and that of hypernova explosions are comparable. Our observations indicate that the circumnuclear molecular disk harboring the starburst is highly disturbed on 100 pc or smaller scales, presumably by individual young clusters and stellar explosions, in addition to globally disturbed in the form of the well-known superwind.Comment: Accepted by ApJ. 33 pages, 8 figure

Side effects of analgesia may significantly reduce quality of life in symptomatic multiple myeloma: a cross-sectional prevalence study

Background Pain is a common symptom in patients with multiple myeloma (MM). Many patients are dependent on analgesics and in particular opioids, but there is limited information on the impact of these drugs and their side effects on health-related quality of life (HRQoL). Method In a cross-sectional study, semi-structured interviews were performed in 21 patients attending the hospital with symptomatic MM on pain medications. HRQoL was measured using items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. Results Patients were able to recall a median of two (range 0–4) analgesics. They spontaneously identified a median of two (range 1–5) side effects attributable to their analgesic medications. Patients’ assessment of HRQoL based on the EORTC QLQ-C30 questions 29/30 was mean 48.3 (95 % CI; 38.7–57.9) out of 100. Patients’ assessment of their HRQoL in the hypothetical situation, in which they would not experience any side effects from analgesics, was significantly higher: 62.6 (53.5–71.7) (t test, p=0.001). Conclusion This study provides, for the first time, evidence that side effects of analgesics are common in symptomatic MM and may result in a statistically and clinically significant reduction of self-reported HRQoL

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Funding Information: We thank Dr. David James, Dr. Frederick Lang, Dr. Cameron Brennan, and Dr. Harley Kornblum for GBM-PDX neurospheres. We thank Dr. Karen Arden for continuous support and critical evaluation of the results. We thank Dr. Robert Davis, Dr. German Gomez, Dr. Tiffany Taylor, Dr. Rachel Reed, Dr. Melissa Mcalonis, and Dr. Sora Lee for technical support. In memory of Rosa Lupo. This work was supported by the Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society (F.B.F. and P.S.M.), R01-NS080939 (F.B.F.), the James S. McDonnell Foundation (F.B.F.), the National Cancer Institute (2T32CA009523-29A1) (A.H.T), and 1RO1NS097649-01 (C.C.C.). C.Z. was partially supported by an American-Italian Cancer Foundation post-doctoral research fellowship. F.L. received a Gao Feng Gao Yuan Scholarship Award. T.C.G., A.K.S., P.S.M., W.K.C., and F.B.F. receive salary and additional support from the Ludwig Institute for Cancer Research. Publisher Copyright: © 2017 Zanca et al.In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.publishersversionPeer reviewe

Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines that Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase

Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure–activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC₅₀ for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice

Body composition impacts appetite regulation in middle childhood. A prospective study of Norwegian community children

Background Research suggests a role for both fat mass and muscle mass in appetite regulation, but the longitudinal relationships between them have not yet been examined in children. The present study therefore aimed to explore the prospective relationships between fat mass, muscle mass and the appetitive traits food responsiveness and satiety responsiveness in middle childhood. Methods Food responsiveness and satiety responsiveness were measured using the parent-reported Children’s Eating Behavior Questionnaire in a representative sample of Norwegian 6 year olds, followed up at 8 and 10 years of age (n = 807). Body composition was measured by bioelectrical impedance. Results Applying a structural equation modeling framework we found that higher fat mass predicted greater increases in food responsiveness over time, whereas greater muscle mass predicted decreases in satiety responsiveness. This pattern was consistent both from ages 6 to 8 and from ages 8 to 10 years. Conclusions Our study is the first to reveal that fat mass and muscle mass predict distinct changes in different appetitive traits over time. Replication of findings in non-European populations are needed, as are studies of children in other age groups. Future studies should also aim to reveal the underlying mechanisms

Latent class analysis of sexual health markers among men and women participating in a British probability sample survey.

BACKGROUND: Despite known associations between different aspects of sexual health, it is not clear how patterning of adverse sexual health varies across the general population. A better understanding should contribute towards more effective problem identification, prevention and treatment. We sought to identify different clusters of sexual health markers in a general population, along with their socio-demographic, health and lifestyle correlates. METHODS: Data came from men (N = 5113) and women (N = 7019) aged 16-74 who reported partnered sexual activity in the past year in Britain's third National Survey of Sexual Attitudes and Lifestyles, undertaken in 2010-2012. Latent class analysis used 18 self-reported variables relating to adverse sexual health outcomes (STI and unplanned pregnancy, non-volitional sex, and sexual function problems). Correlates included socio-demographics, early debut, alcohol/drug use, depression, and satisfaction/distress with sex life. RESULTS: Four classes were found for men (labelled Good Sexual Health 83%, Wary Risk-takers 4%, Unwary Risk-takers 4%, Sexual Function Problems 9%); six for women (Good Sexual Health 52%, Wary Risk-takers 2%, Unwary Risk-takers 7%, Low Interest 29%, Sexual Function Problems 7%, Highly Vulnerable 2%). Regardless of gender, Unwary Risk-takers reported lower STI/HIV risk perception and more condomless sex than Wary Risk-takers, but both were more likely to report STI diagnosis than Good Sexual Health classes. Highly Vulnerable women reported abortion, STIs and functional problems, and more sexual coercion than other women. Distinct socio-demographic profiles differentiated higher-risk classes from Good Sexual Health classes, with depression, alcohol/drug use, and early sexual debut widely-shared correlates of higher-risk classes. Females in higher-risk classes, and men with functional problems, evaluated their sex lives more negatively than those with Good Sexual Health. CONCLUSIONS: A greater prevalence and diversity of poor sexual health appears to exist among women than men in Britain, with more consistent effects on women's subjective sexual well-being. Shared health and lifestyle characteristics of higher-risk groups suggest widespread benefits of upstream interventions. Several groups could benefit from tailored interventions: men and women who underestimate their STI/HIV risk exposure, women distressed by low interest in sex, and women experiencing multiple adverse outcomes. Distinctive socio-demographic profiles should assist with identification and targeting

Luminous Infrared Galaxies with the Submillimeter Array: II. Comparing the CO(3-2) Sizes and Luminosities of Local and High-Redshift Luminous Infrared Galaxies

We present a detailed comparison of the CO(3-2) emitting molecular gas between a local sample of luminous infrared galaxies (U/LIRGs) and a high redshift sample that comprises submm selected galaxies (SMGs), quasars, and Lyman Break Galaxies (LBGs). The U/LIRG sample consists of our recent CO(3-2) survey using the Submillimeter Array while the CO(3-2) data for the high redshift population are obtained from the literature. We find that the L(CO(3-2)) and L(FIR) relation is correlated over five orders of magnitude, which suggests that the molecular gas traced in CO(3-2) emission is a robust tracer of dusty star formation activity. The near unity slope of 0.93 +/- 0.03 obtained from a fit to this relation suggests that the star formation efficiency is constant to within a factor of two across different types of galaxies residing in vastly different epochs. The CO(3-2) size measurements suggest that the molecular gas disks in local U/LIRGs (0.3 - 3.1 kpc) are much more compact than the SMGs (3 - 16 kpc), and that the size scales of SMGs are comparable to the nuclear separation (5 - 40 kpc) of the widely separated nuclei of U/LIRGs in our sample. We argue from these results that the SMGs studied here are predominantly intermediate stage mergers, and that the wider line-widths arise from the violent merger of two massive gas-rich galaxies taking place deep in a massive halo potential.Comment: 16 pages, 5 figures, ApJ Accepte

Genome-wide association study of endometrial cancer in E2C2

Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility. Electronic supplementary material The online version of this article (doi:10.1007/s00439-013-1369-1) contains supplementary material, which is available to authorized users