121 research outputs found

    Combinatorial immunotherapies overcome MYC-driven immune evasion in triple negative breast cancer

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    Few patients with triple negative breast cancer (TNBC) benefit from immune checkpoint inhibitors with complete and durable remissions being quite rare. Oncogenes can regulate tumor immune infiltration, however whether oncogenes dictate diminished response to immunotherapy and whether these effects are reversible remains poorly understood. Here, we report that TNBCs with elevated MYC expression are resistant to immune checkpoint inhibitor therapy. Using mouse models and patient data, we show that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, mice experience tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and when strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors. The oncoprotein c-Myc is often overexpressed in triple negative breast cancer and has a role in tumor progression and resistance to therapy. Here the authors show that elevated MYC expression is correlated with low immune infiltration, diminished MHC-I pathway expression and that CpG/aOX40 treatment could overcome resistance to PD-L1 blockade in MYC-high breast tumors.Peer reviewe

    A case study of physical and social barriers to hygiene and child growth in remote Australian Aboriginal communities

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    Background\ud Despite Australia's wealth, poor growth is common among Aboriginal children living in remote communities. An important underlying factor for poor growth is the unhygienic state of the living environment in these communities. This study explores the physical and social barriers to achieving safe levels of hygiene for these children.\ud \ud Methods\ud A mixed qualitative and quantitative approach included a community level cross-sectional housing infrastructure survey, focus groups, case studies and key informant interviews in one community.\ud \ud Results\ud We found that a combination of crowding, non-functioning essential housing infrastructure and poor standards of personal and domestic hygiene underlie the high burden of infection experienced by children in this remote community.\ud \ud Conclusion\ud There is a need to address policy and the management of infrastructure, as well as key parenting and childcare practices that allow the high burden of infection among children to persist. The common characteristics of many remote Aboriginal communities in Australia suggest that these findings may be more widely applicable

    Ethnobotanical study of some of mosquito repellent plants in north-eastern Tanzania

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    The use of plant repellents against nuisance biting insects is common and its potential for malaria vector control requires evaluation in areas with different level of malaria endemicity. The essential oils of Ocimum suave and Ocimum kilimandscharicum were evaluated against malaria vectors in north-eastern Tanzania. An ethnobotanical study was conducted at Moshi in Kilimanjaro region north-eastern Tanzania, through interviews, to investigate the range of species of plants used as insect repellents. Also, bioassays were used to evaluate the protective potential of selected plants extracts against mosquitoes. The plant species mostly used as repellent at night are: fresh or smoke of the leaves of O. suave and O. kilimandscharicum (Lamiaceae), Azadirachta indica (Meliaceae), Eucalyptus globules (Myrtaceae) and Lantana camara (Verbenaceae). The most popular repellents were O. kilimandscharicum (OK) and O. suave (OS) used by 67% out of 120 households interviewed. Bioassay of essential oils of the two Ocimum plants was compared with citronella and DEET to study the repellence and feeding inhibition of untreated and treated arms of volunteers. Using filter papers impregnated with Ocimum extracts, knockdown effects and mortality was investigated on malaria mosquito Anopheles arabiensis and Anopheles gambiae, including a nuisance mosquito, Culex quinquefasciatus. High biting protection (83% to 91%) and feeding inhibition (71.2% to 92.5%) was observed against three species of mosquitoes. Likewise the extracts of Ocimum plants induced KD90 of longer time in mosquitoes than citronella, a standard botanical repellent. Mortality induced by standard dosage of 30 mg/m2 on filter papers, scored after 24 hours was 47.3% for OK and 57% for OS, compared with 67.7% for citronella. The use of whole plants and their products as insect repellents is common among village communities of north-eastern Tanzania and the results indicate that the use of O. suave and O. kilimandscharicum as a repellent would be beneficial in reducing vector biting. The widespread use of this approach has a potential to complement other control measures

    SHANK3 controls maturation of social reward circuits in the VTA.

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    Haploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of autism spectrum disorder. How SHANK3 insufficiency affects specific neural circuits and how this is related to specific symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the ventral tegmental area of mice. We identified dopamine (DA) and GABA cell-type-specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors mGluR1 during the first postnatal week restored DA neuron excitatory synapse transmission and partially rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired ventral tegmental area function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy

    The Gravity Collective: A Search for the Electromagnetic Counterpart to the Neutron Star-Black Hole Merger GW190814

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    We present optical follow-up imaging obtained with the Katzman Automatic Imaging Telescope, Las Cumbres Observatory Global Telescope Network, Nickel Telescope, Swope Telescope, and Thacher Telescope of the LIGO/Virgo gravitational wave (GW) signal from the neutron star-black hole (NSBH) merger GW190814. We searched the GW190814 localization region (19 deg2^{2} for the 90th percentile best localization), covering a total of 51 deg2^{2} and 94.6% of the two-dimensional localization region. Analyzing the properties of 189 transients that we consider as candidate counterparts to the NSBH merger, including their localizations, discovery times from merger, optical spectra, likely host-galaxy redshifts, and photometric evolution, we conclude that none of these objects are likely to be associated with GW190814. Based on this finding, we consider the likely optical properties of an electromagnetic counterpart to GW190814, including possible kilonovae and short gamma-ray burst afterglows. Using the joint limits from our follow-up imaging, we conclude that a counterpart with an rr-band decline rate of 0.68 mag day1^{-1}, similar to the kilonova AT 2017gfo, could peak at an absolute magnitude of at most 17.8-17.8 mag (50% confidence). Our data are not constraining for ''red'' kilonovae and rule out ''blue'' kilonovae with M>0.5MM>0.5 M_{\odot} (30% confidence). We strongly rule out all known types of short gamma-ray burst afterglows with viewing angles <<17^{\circ} assuming an initial jet opening angle of \sim5.25.2^{\circ} and explosion energies and circumburst densities similar to afterglows explored in the literature. Finally, we explore the possibility that GW190814 merged in the disk of an active galactic nucleus, of which we find four in the localization region, but we do not find any candidate counterparts among these sources.Comment: 86 pages, 9 figure

    Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

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    Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

    Rapid Effects of Hearing Song on Catecholaminergic Activity in the Songbird Auditory Pathway

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    Catecholaminergic (CA) neurons innervate sensory areas and affect the processing of sensory signals. For example, in birds, CA fibers innervate the auditory pathway at each level, including the midbrain, thalamus, and forebrain. We have shown previously that in female European starlings, CA activity in the auditory forebrain can be enhanced by exposure to attractive male song for one week. It is not known, however, whether hearing song can initiate that activity more rapidly. Here, we exposed estrogen-primed, female white-throated sparrows to conspecific male song and looked for evidence of rapid synthesis of catecholamines in auditory areas. In one hemisphere of the brain, we used immunohistochemistry to detect the phosphorylation of tyrosine hydroxylase (TH), a rate-limiting enzyme in the CA synthetic pathway. We found that immunoreactivity for TH phosphorylated at serine 40 increased dramatically in the auditory forebrain, but not the auditory thalamus and midbrain, after 15 min of song exposure. In the other hemisphere, we used high pressure liquid chromatography to measure catecholamines and their metabolites. We found that two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, increased in the auditory forebrain but not the auditory midbrain after 30 min of exposure to conspecific song. Our results are consistent with the hypothesis that exposure to a behaviorally relevant auditory stimulus rapidly induces CA activity, which may play a role in auditory responses

    Rare coding variants in ten genes confer substantial risk for schizophrenia

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    Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, PPeer reviewe
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