Conventional therapies deplete Brain-Infiltrating adaptive immune cells in a Mouse Model of Group 3 Medulloblastoma implicating Myeloid Cells as favorable immunotherapy targets

Medulloblastoma is the most common childhood brain cancer. Mainstay treatments of radiation and chemotherapy have not changed in decades and new treatment approaches are crucial for the improvement of clinical outcomes. To date, immunotherapies for medulloblastoma have been unsuccessful, and studies investigating the immune microenvironment of the disease and the impact of current therapies are limited. Preclinical models that recapitulate both the disease and immune environment are essential for understanding immune-tumor interactions and to aid the identification of new and effective immunotherapies. Using an immune-competent mouse model of aggressive Myc-driven medulloblastoma, we characterized the brain immune microenvironment and changes induced in response to craniospinal irradiation, or the medulloblastoma chemotherapies cyclophosphamide or gemcitabine. The role of adaptive immunity in disease progression and treatment response was delineated by comparing survival outcomes in wildtype C57Bl/6J and in mice deficient in Rag1 that lack mature T and B cells. We found medulloblastomas in wildtype and Rag1-deficient mice grew equally fast, and that craniospinal irradiation and chemotherapies extended survival equally in wildtype and Rag1-deficient mice, suggesting that tumor growth and treatment response is independent of T and B cells. Medulloblastomas were myeloid dominant, and in wildtype mice, craniospinal irradiation and cyclophosphamide depleted T and B cells in the brain. Gemcitabine treatment was found to minimally alter the immune populations in the brain, resulting only in a depletion of neutrophils. Intratumorally, we observed an abundance of Iba1+ macrophages, and we show that CD45high cells comprise the majority of immune cells within these medulloblastomas but found that existing markers are insufficient to clearly delineate resident microglia from infiltrating macrophages. Ultimately, brain resident and peripheral macrophages dominate the brain and tumor microenvironment and are not depleted by standard-of-care medulloblastoma therapies. These populations therefore present a favorable target for immunotherapy in combination with front-line treatments

Factors Influencing the Participation of Older People in Clinical Trials : Data Analysis from the MAVIS Trial

Peer reviewedPostprin

DES13S2cmm: the first superluminous supernova from the Dark Energy Survey

We present DES13S2cmm, the first spectroscopically-confirmed superluminous supernova (SLSN) from the Dark Energy Survey (DES). We briefly discuss the data and search algorithm used to find this event in the first year of DES operations, and outline the spectroscopic data obtained from the European Southern Observatory (ESO) Very Large Telescope to confirm its redshift (z = 0.663 +/- 0.001 based on the host-galaxy emission lines) and likely spectral type (type I). Using this redshift, we find M_U_peak = -21.05 +0.10 -0.09 for the peak, rest-frame U-band absolute magnitude, and find DES13S2cmm to be located in a faint, low metallicity (sub-solar), low stellar-mass host galaxy (log(M/M_sun) = 9.3 +/- 0.3); consistent with what is seen for other SLSNe-I. We compare the bolometric light curve of DES13S2cmm to fourteen similarly well-observed SLSNe-I in the literature and find it possesses one of the slowest declining tails (beyond +30 days rest frame past peak), and is the faintest at peak. Moreover, we find the bolometric light curves of all SLSNe-I studied herein possess a dispersion of only 0.2-0.3 magnitudes between +25 and +30 days after peak (rest frame) depending on redshift range studied; this could be important for 'standardising' such supernovae, as is done with the more common type Ia. We fit the bolometric light curve of DES13S2cmm with two competing models for SLSNe-I - the radioactive decay of 56Ni, and a magnetar - and find that while the magnetar is formally a better fit, neither model provides a compelling match to the data. Although we are unable to conclusively differentiate between these two physical models for this particular SLSN-I, further DES observations of more SLSNe-I should break this degeneracy, especially if the light curves of SLSNe-I can be observed beyond 100 days in the rest frame of the supernova.Comment: Accepted by MNRAS (2015 January 23), 13 pages, 6 figures, 2 table

Clustering of dark matter tracers: generalizing bias for the coming era of precision LSS

On very large scales, density fluctuations in the Universe are small, suggesting a perturbative model for large-scale clustering of galaxies (or other dark matter tracers), in which the galaxy density is written as a Taylor series in the local mass density, delta, with the unknown coefficients in the series treated as free "bias" parameters. We extend this model to include dependence of the galaxy density on the local values of nabla_i nabla_j phi and nabla_i v_j, where phi is the potential and v is the peculiar velocity. We show that only two new free parameters are needed to model the power spectrum and bispectrum up to 4th order in the initial density perturbations, once symmetry considerations and equivalences between possible terms are accounted for. One of the new parameters is a bias multiplying s_ij s_ji, where s_ij=[nabla_i nabla_j \nabla^-2 - 1/3 delta^K_ij] delta. The other multiplies s_ij t_ji, where t_ij=[nabla_i nabla_j nabla^-2 - 1/3 delta^K_ij](theta-delta), with theta=-(a H dlnD/dlna)^-1 nabla_i v_i. (There are other, observationally equivalent, ways to write the two terms, e.g., using theta-delta instead of s_ij s_ji.) We show how short-range (non-gravitational) non-locality can be included through a controlled series of higher derivative terms, starting with R^2 nabla^2 delta, where R is the scale of non-locality (this term will be a small correction as long as k^2 R^2 is small, where k is the observed wavenumber). We suggest that there will be much more information in future huge redshift surveys in the range of scales where beyond-linear perturbation theory is both necessary and sufficient than in the fully linear regime.Comment: 24 pg., 5 fi

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

The electromagnetic counterpart of the binary neutron star merger LIGO/Virgo GW170817. I. Discovery of the optical counterpart using the Dark Energy Camera

We present the Dark Energy Camera (DECam) discovery of the optical counterpart of the first binary neutron star merger detected through gravitational wave emission, GW170817. Our observations commenced 10.5 hours post-merger, as soon as the localization region became accessible from Chile. We imaged 70 deg2 in the i and z bands, covering 93% of the initial integrated localization probability, to a depth necessary to identify likely optical counterparts (e.g., a kilonova). At 11.4 hours post-merger we detected a bright optical transient located 10:600 from the nucleus of NGC4993 at redshift z = 0:0098, consistent (for H0 = 70 km s-1 Mpc-1) with the distance of 40±8 Mpc reported by the LIGO Scientific Collaboration and the Virgo Collaboration (LVC). At detection the transient had magnitudes i=17.3 and z=17.4, and thus an absolute magnitude of Mi = -15.7, in the luminosity range expected for a kilonova. We identified 1,500 potential transient candidates. Applying simple selection criteria aimed at rejecting background events such as supernovae, we find the transient associated with NGC4993 as the only remaining plausible counterpart, and reject chance coincidence at the 99.5% confidence level. We therefore conclude that the optical counterpart we have identified near NGC4993 is associated with GW170817. This discovery ushers in the era of multi-messenger astronomy with gravitational waves, and demonstrates the power of DECam to identify the optical counterparts of gravitational-wave sources

Reconsidering the Gospel According to Group Studies: A Neuropsychological Case Study Approach to Schizophrenia

Original article can be found at: http://www.informaworld.com/smpp/title~content=t713659088 Copyright Informa / Taylor and Francis GroupIndividual patterns of performance on tests of: visual perception, language, executive function, memory, and face-processing, were examined in 10 schizophrenic patients who were preselected for having current WAIS IQ and premorbid NART IQ scores in the normal range. Although the patients showed some heterogeneity in the type, pervasiveness, and degree of cognitive impairment, a majority had severely impaired verbal recall and familiar face-naming. This contrasted with the low incidence and severity of impairment on tests of executive function, visual recall, recognition memory, naming, and unfamiliar faceprocessing. Contrasts between individual patients indicated that verbal recall and executive performance are independent in some patients and that memory appears to be the core deficit. The profile of impaired and preserved cognitive function revealed some important dissimilarities from the pattern that has emerged from group studies. Finally, face-naming correlated highly with the learning of unrelated paired associates, confirming a similarity with neurological patients who have person name anomia. It is suggested that both deficits might reflect a problem with learning ''meaninglessness'' associations; this interpretation is discussed with reference to a deficit at the level of the Supervisory Attentional System (Shallice, 1988).Peer reviewe