bluuebunny/crossref_metadata_2025 huggingface dataset:
Measuring dynamical masses from gas kinematics in simulated high-redshift galaxies
Authors: Wellons Sarah , Faucher-Giguère Claude-André , Anglés-Alcázar Daniel , Hayward Christopher C , Feldmann Robert , Hopkins Philip F , Kereš Dušan
Published: August 2020

Advances in instrumentation have recently extended detailed measurements of gas kinematics to large samples of high-redshift galaxies. Relative to most nearby, thin disc galaxies, in which gas rotation accurately traces the gravitational potential, the interstellar medium (ISM) of $z$ ≳ 1 galaxies is typically more dynamic and exhibits elevated turbulence. If not properly modelled, these effects can strongly bias dynamical mass measurements. We use high-resolution FIRE-2 cosmological zoom-in simulations to analyse the physical effects that must be considered to correctly infer dynamical masses from gas kinematics. Our analysis covers a range of galaxy properties from low-redshift Milky-Way-mass galaxies to massive high-redshift galaxies (M⋆ > 1011 M⊙ at $z$ = 1). Selecting only snapshots where a disc is present, we calculate the rotational profile $\bar{v}_\phi (r)$ of the cool ($10^{3.5}\,\lt {\it T}\lt 10^{4.5}~\rm {K}$) gas and compare it to the circular velocity $v_{\rm c}=\sqrt{GM_{\rm enc}/r}$. In the simulated galaxies, the gas rotation traces the circular velocity at intermediate radii, but the two quantities diverge significantly in the centre and in the outer disc. Our simulations appear to over-predict observed rotational velocities in the centres of massive galaxies (likely from a lack of black hole feedback), so we focus on larger radii. Gradients in the turbulent pressure at these radii can provide additional radial support and bias dynamical mass measurements low by up to 40 per cent. In both the interior and exterior, the gas’ motion can be significantly non-circular due to e.g. bars, satellites, and inflows/outflows. We discuss the accuracy of commonly used analytic models for pressure gradients (or ‘asymmetric drift’) in the ISM of high-redshift galaxies.
From parallel to perpendicular – On the orientation of magnetic fields in molecular clouds
Authors: Seifried D , Walch S , Weis M , Reissl S , Soler J D , Klessen R S , Joshi P R
Published: August 2020

We present synthetic dust polarization maps of simulated molecular clouds with the goal to systematically explore the origin of the relative orientation of the magnetic field ($\mathbf {B}$) with respect to the cloud sub-structure identified in density (n; 3D) and column density (N; 2D). The polarization maps are generated with the radiative transfer code polaris, which includes self-consistently calculated efficiencies for radiative torque alignment. The molecular clouds are formed in two sets of 3D magnetohydrodynamical simulations: (i) in colliding flows (CF), and (ii) in the SILCC-Zoom simulations. In 3D, for the CF simulations with an initial field strength below ∼5 μG, $\mathbf {B}$ is oriented either parallel or randomly with respect to the n-structures. For CF runs with stronger initial fields as well as all SILCC-Zoom simulations, which have an initial field strength of 3 μG, a flip from parallel to perpendicular orientation occurs at high densities of $n_\rm {trans}\, \simeq$ 102–103 cm−3. We suggest that this flip happens if the cloud’s mass-to-flux ratio, μ, is close to or below the critical value of 1. This corresponds to a field strength around 3–5 μG, close to the Galactic average. In 2D, we use the method of Projected Rayleigh Statistics (PRS) to study the relative orientation of $\mathbf {B}$. If present, the flip in orientation occurs in the projected maps at $N_\rm {trans}\, \simeq$ 1021 − 21.5 cm−2. This value is similar to the observed transition value from sub- to supercritical magnetic fields in the interstellar medium. However, projection effects can strongly reduce the predictive power of the PRS method: Depending on the considered cloud or line-of-sight, the projected maps of the SILCC-Zoom simulations do not always show the flip, although it is expected given the 3D morphology. Such projection effects can explain the variety of recently observed field configurations, in particular within a single cloud. Finally, we do not find a correlation between the observed orientation of $\mathbf {B}$ and the N-PDF.
Modelling the asymmetry of the halo cross-correlation function with relativistic effects at quasi-linear scales
Authors: Saga Shohei , Taruya Atsushi , Breton Michel-Andrès , Rasera Yann
Published: August 2020

The observed galaxy distribution via galaxy redshift surveys appears distorted due to redshift-space distortions (RSD). While one dominant contribution to RSD comes from the Doppler effect induced by the peculiar velocity of galaxies, the relativistic effects, including the gravitational redshift effect, are recently recognized to give small but important contributions. Such contributions lead to an asymmetric galaxy clustering along the line of sight, and produce non-vanishing odd multipoles when cross-correlating between different biased objects. However, non-zero odd multipoles are also generated by the Doppler effect beyond the distant-observer approximation, known as the wide-angle effect, and at quasi-linear scales, the interplay between wide-angle and relativistic effects becomes significant. In this paper, based on the formalism developed by Taruya et al., we present a quasi-linear model of the cross-correlation function taking a proper account of both the wide-angle and gravitational redshift effects, as one of the major relativistic effects. Our quasi-linear predictions of the dipole agree well with simulations even at the scales below $20\, h^{-1}\,$Mpc, where non-perturbative contributions from the halo potential play an important role, flipping the sign of the dipole amplitude. When increasing the bias difference and redshift, the scale where the sign flip happens is shifted to a larger scale. We derive a simple approximate formula to quantitatively account for the behaviours of the sign flip.
Rapid filamentary accretion as the origin of extended thin discs
Authors: Kretschmer Michael , Agertz Oscar , Teyssier Romain
Published: August 2020

Galactic outflows driven by stellar feedback are crucial for explaining the inefficiency of star formation in galaxies. Although strong feedback can promote the formation of galactic discs by limiting star formation at early times and removing low angular momentum (AM) gas, it is not understood how the same feedback can result in diverse objects such as elliptical galaxies or razor thin spiral galaxies. We investigate this problem using cosmological zoom-in simulations of two galaxies forming within 1012 M⊙ haloes with almost identical mass accretion histories and halo spin parameters. However, the two resulting galaxies end up with very different bulge-to-disc ratios at z = 0. At z > 1.5, the two galaxies feature a surface density of star formation ΣSFR ≃ 10 M⊙ yr−1 kpc−2, leading to strong outflows. After the last starburst episode, both galaxies feature a dramatic gaseous disc growth from 1 to 5 kpc during 1 Gyr, a decisive event we dub ‘the Grand Twirl’. After this event, the evolutionary tracks diverge strongly, with one galaxy ending up as a bulge-dominated galaxy, whereas the other ends up as a disc-dominated galaxy. The origins of this dichotomy are the AM of the accreted gas, and whether it adds constructively to the initial disc angular momentum. The build-up of this extended disc leads to a rapid lowering of ΣSFR by over two orders of magnitude with ΣSFR ≲ 0.1 M⊙ yr−1 kpc−2, in remarkable agreement with what is derived from Milky Way stellar populations. As a consequence, supernovae explosions are spread out and cannot launch galactic outflows anymore, allowing for the persistence of a thin, gently star-forming, extended disc.
Methanol and glycolaldehyde production from formaldehyde in massive star-forming regions
Authors: Silva Silvia G S , Vichietti Rafael M , Haiduke Roberto L A , Machado Francisco B C , Spada Rene F K
Published: August 2020

Based on typical physical and chemical conditions expected in massive and dense hot cores during the protostar collapse, the formation of glycolaldehyde (CH2OHCHO) and methanol (CH3OH) was investigated from H2 and CO and formaldehyde (H2CO) as an intermediate. Thermochemical properties and rate constants were obtained for gas-phase reactions using high-level electronic structure methods and chemical kinetic calculations, and the concentrations of the molecules were evolved along time. The chemical equilibrium was reached in minutes at 1500 K, a time interval much shorter than that required time for a protostar formation process. The results indicate that the formaldehyde and methanol abundances are always larger than those for glycolaldehyde, for example, at 2000 K and [H2]0 equals to 1023 molecule cm−3, the abundances of H2CO, CH3OH, and CH2OHCHO relative to H2 are equal to 3 × 10−6, 5 × 10−6, and 1 × 10−12, while for [H2]0 equals to 1020 molecule cm−3  these abundances are 3 × 10−9, 5 × 10−12, and 2 × 10−21, respectively. Considering that our results can be applied to explain the proximity of methanol and formaldehyde maser emissions, from the whole set of results, the CH3OH abundance relative to H2CO ranges from 10−3 to 102.
Soft X-ray emission lines in the X-ray binary Swift J1858.6–0814 observed with XMM–Newton Reflection Grating Spectrometer: disc atmosphere or wind?
Authors: Buisson D J K , Altamirano D , Díaz Trigo M , Mendez M , Armas Padilla M , Castro Segura N , Degenaar N D , van den Eijnden J , Fogantini F A , Gandhi P , Knigge C , Muñoz-Darias T , Özbey Arabacı M , Vincentelli F M
Published: August 2020

We find soft X-ray emission lines from the X-ray binary Swift J1858.6–0814 in data from XMM–NewtonReflection Grating Spectrometer (RGS): N vii, O vii, and O viii, as well as notable residuals short of a detection at Ne ix and other higher ionization transitions. These could be associated with the disc atmosphere, as in accretion disc corona sources, or with a wind, as has been detected in Swift J1858.6–0814 in emission lines at optical wavelengths. Indeed, the N vii line is redshifted, consistent with being the emitting component of a P-Cygni profile. We find that the emitting plasma has an ionization parameter log (ξ) = 1.35 ± 0.2 and a density n > 1.5 × 1011 cm−3. From this, we infer that the emitting plasma must be within 1013 cm of the ionizing source, ∼5 × 107 rg for a 1.4 M⊙ neutron star, and from the line width that it is at least 104 rg away [2 × 109(M/1.4 M⊙) cm]. We compare this with known classes of emission-line regions in other X-ray binaries and active galactic nuclei.
Electron–positron pair plasma in TXS 0506+056 and the ‘neutrino flare’ in 2014–2015
Authors: Fraija N , Aguilar-Ruiz E , Galván-Gámez A
Published: August 2020

The detection of a prolonged flaring activity from blazar TXS 0506+056 in temporal and spatial coincidence with the energetic neutrino IceCube-170922A provided evidence about the photohadronic interactions in this source. However, analysis of the archival neutrino and multiwavelength data from the direction of this blazar between 2014 September and 2015 March revealed a ‘neutrino flare’ without observing quasi-simultaneous activity in the gamma-ray bands, posing challenges to established models. Electron–positron (e±) pairs generated from the accretion discs have been amply proposed as a mechanism of bulk acceleration of sub-relativistic and relativistic jets. These pairs annihilate inside the source producing a line around the electron mass, which is blueshifted in the observed frame (on Earth) and redshifted in the frame of the dissipation region of the jet. The redshifted photons in the dissipation region interact with accelerated protons, producing high-energy neutrinos that contribute significantly to the diffuse neutrino flux in the ∼10–20 TeV energy range in connection with gamma-rays from the photopion process, which can be detected by future MeV orbiting satellites. Based on this phenomenological model, we can explain the ‘neutrino flare’ reported in 2014–1015.
Completeness of the Gaia verse II: what are the odds that a star is missing from Gaia DR2?
Authors: Boubert Douglas , Everall Andrew
Published: August 2020

The second data release of the Gaia mission contained astrometry and photometry for an incredible 1692 919 135 sources, but how many sources did Gaiamiss and where do they lie on the sky? The answer to this question will be crucial for any astronomer attempting to map the Milky Way with Gaia DR2. We infer the completeness of Gaia DR2 by exploiting the fact that it only contains sources with at least five astrometric detections. The odds that a source achieves those five detections depends on both the number of observations and the probability that an observation of that source results in a detection. We predict the number of times that each source was observed by Gaia and assume that the probability of detection is either a function of magnitude or a distribution as a function of magnitude. We fit both these models to the 1.7 billion stars of Gaia DR2, and thus are able to robustly predict the completeness of Gaia across the sky as a function of magnitude. We extend our selection function to account for crowding in dense regions of the sky, and show that this is vitally important, particularly in the Galactic bulge and the Large and Small Magellanic Clouds. We find that the magnitude limit at which Gaiais still 99 per cent complete varies over the sky from G = 18.9 to fainter than G = 21. We have created a new python package selectionfunctions (https://github.com/gaiaverse/selectionfunctions) which provides easy access to our selection functions.
Wind–MRI interactions in local models of protoplanetary discs – I. Ohmic resistivity
Authors: Leung Philip K C , Ogilvie Gordon I
Published: August 2020

A magnetic disc wind is an important mechanism that may be responsible for driving accretion and structure formation in protoplanetary discs. Recent numerical simulations have shown that these winds can take either the traditional ‘hourglass’ symmetry about the mid-plane, or a ‘slanted’ symmetry dominated by a mid-plane toroidal field of a single sign. The formation of this slanted symmetry state has not previously been explained. We use radially local 1D vertical shearing box simulations to assess the importance of large-scale MRI channel modes in influencing the formation and morphologies of these wind solutions. We consider only Ohmic resistivity and explore the effect of different magnetizations, with the mid-plane β parameter ranging from 105 to 102. We find that our magnetic winds go through three stages of development: cyclic, transitive, and steady, with the steady wind taking a slanted symmetry profile similar to those observed in local and global simulations. We show that the cycles are driven by periodic excitation of the n = 2 or 3 MRI channel mode coupled with advective eviction, and that the transition to the steady wind is caused by a much more slowly growing n = 1 mode altering the wind structure. Saturation is achieved through a combination of advective damping from the strong wind, and suppression of the instability due to a strong toroidal field. A higher disc magnetization leads to a greater tendency towards, and more rapid settling into the slanted symmetry steady wind, which may have important implications for mass and flux transport processes in protoplanetary discs.
The distribution of dark galaxies and spin bias
Authors: Jimenez Raul , Heavens Alan F
Published: August 2020

In the light of the discovery of numerous (almost) dark galaxies from the ALFALFA and LITTLE THINGS surveys, we revisit the predictions of the existence of dark galaxies, based on the Toomre stability of rapidly spinning gas discs. We have updated the predictions for Λ-cold dark matter with parameters given by the Planck18 collaboration, computing the expected number densities of dark objects, and their spin parameter and mass distributions. Comparing with the data is more challenging, but where the spins are more reliably determined, the spins are close to the threshold for discs to be stable according to the Toomre criterion, where the expected number density is highest, and reinforces the concept that there is a bias in the formation of luminous galaxies based on the spin of their parent halo.
Zodiacal exoplanets in time – XI. The orbit and radiation environment of the young M dwarf-hosted planet K2-25b
Authors: Gaidos E , Hirano T , Wilson D J , France K , Rockcliffe K , Newton E , Feiden G , Krishnamurthy V , Harakawa H , Hodapp K W , Ishizuka M , Jacobson S , Konishi M , Kotani T , Kudo T , Kurokawa T , Kuzuhara M , Nishikawa J , Omiya M , Serizawa T , Tamura M , Ueda A , Vievard S
Published: August 2020

M dwarf stars are high-priority targets for searches for Earth-size and potentially Earth-like planets, but their planetary systems may form and evolve in very different circumstellar environments than those of solar-type stars. To explore the evolution of these systems, we obtained transit spectroscopy and photometry of the Neptune-size planet orbiting the ≈650-Myr-old Hyades M dwarf K2-25. An analysis of the variation in spectral line shape induced by the Doppler ‘shadow’ of the planet indicates that the planet’s orbit is closely aligned with the stellar equator ($\lambda =-1.7_{-3.7}^{+5.8}$ deg), and that an eccentric orbit found by previous work could arise from perturbations by another planet on a coplanar orbit. We detect no significant variation in the depth of the He i line at 1083 nm during transit. A model of atmospheric escape as an isothermal Parker wind with a solar composition shows that this non-detection is not constraining compared to escape rate predictions of ∼0.1 M⊕  Gyr−1; at such rates, at least several Gyr are required for a Neptune-like planet to evolve into a rocky super-Earth.
Structure and mechanism of CutA, RNA nucleotidyl transferase with an unusual preference for cytosine
Authors: Malik Deepshikha , Kobyłecki Kamil , Krawczyk Paweł , Poznański Jarosław , Jakielaszek Aleksandra , Napiórkowska Agnieszka , Dziembowski Andrzej , Tomecki Rafał , Nowotny Marcin
Published: August 2020

Template-independent terminal ribonucleotide transferases (TENTs) catalyze the addition of nucleotide monophosphates to the 3′-end of RNA molecules regulating their fate. TENTs include poly(U) polymerases (PUPs) with a subgroup of 3′ CUCU-tagging enzymes, such as CutA in Aspergillus nidulans. CutA preferentially incorporates cytosines, processively polymerizes only adenosines and does not incorporate or extend guanosines. The basis of this peculiar specificity remains to be established. Here, we describe crystal structures of the catalytic core of CutA in complex with an incoming non-hydrolyzable CTP analog and an RNA with three adenosines, along with biochemical characterization of the enzyme. The binding of GTP or a primer with terminal guanosine is predicted to induce clashes between 2-NH2 of the guanine and protein, which would explain why CutA is unable to use these ligands as substrates. Processive adenosine polymerization likely results from the preferential binding of a primer ending with at least two adenosines. Intriguingly, we found that the affinities of CutA for the CTP and UTP are very similar and the structures did not reveal any apparent elements for specific NTP binding. Thus, the properties of CutA likely result from an interplay between several factors, which may include a conformational dynamic process of NTP recognition.
A quantitative binding model for the Apl protein, the dual purpose recombination-directionality factor and lysis-lysogeny regulator of bacteriophage 186
Authors: Cutts Erin E , Barry Egan J , Dodd Ian B , Shearwin Keith E
Published: August 2020

The Apl protein of bacteriophage 186 functions both as an excisionase and as a transcriptional regulator; binding to the phage attachment site (att), and also between the major early phage promoters (pR-pL). Like other recombination directionality factors (RDFs), Apl binding sites are direct repeats spaced one DNA helix turn apart. Here, we use in vitro binding studies with purified Apl and pR-pL DNA to show that Apl binds to multiple sites with high cooperativity, bends the DNA and spreads from specific binding sites into adjacent non-specific DNA; features that are shared with other RDFs. By analysing Apl's repression of pR and pL, and the effect of operator mutants in vivo with a simple mathematical model, we were able to extract estimates of binding energies for single specific and non-specific sites and for Apl cooperativity, revealing that Apl monomers bind to DNA with low sequence specificity but with strong cooperativity between immediate neighbours. This model fit was then independently validated with in vitro data. The model we employed here is a simple but powerful tool that enabled better understanding of the balance between binding affinity and cooperativity required for RDF function. A modelling approach such as this is broadly applicable to other systems.
Semisynthesis of site-specifically succinylated histone reveals that succinylation regulates nucleosome unwrapping rate and DNA accessibility
Authors: Jing Yihang , Ding Dongbo , Tian Gaofei , Kwan Ka Chun Jonathan , Liu Zheng , Ishibashi Toyotaka , Li Xiang David
Published: August 2020

Posttranslational modifications (PTMs) of histones represent a crucial regulatory mechanism of nucleosome and chromatin dynamics in various of DNA-based cellular processes, such as replication, transcription and DNA damage repair. Lysine succinylation (Ksucc) is a newly identified histone PTM, but its regulation and function in chromatin remain poorly understood. Here, we utilized an expressed protein ligation (EPL) strategy to synthesize histone H4 with site-specific succinylation at K77 residue (H4K77succ), an evolutionarily conserved succinylation site at the nucleosomal DNA-histone interface. We then assembled mononucleosomes with the semisynthetic H4K77succ in vitro. We demonstrated that this succinylation impacts nucleosome dynamics and promotes DNA unwrapping from the histone surface, which allows proteins such as transcription factors to rapidly access buried regions of the nucleosomal DNA. In budding yeast, a lysine-to-glutamic acid mutation, which mimics Ksucc, at the H4K77 site reduced nucleosome stability and led to defects in DNA damage repair and telomere silencing in vivo. Our findings revealed this uncharacterized histone modification has important roles in nucleosome and chromatin dynamics.
Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans
Authors: Klämbt Verena , Werth Max , Onuchic-Whitford Ana C , Getwan Maike , Kitzler Thomas M , Buerger Florian , Mao Youying , Deutsch Konstantin , Mann Nina , Majmundar Amar J , Kaminski Michael M , Shen Tian , Schmidt-Ott Kai M , Shalaby Mohamed , El Desoky Sherif , Kari Jameela A , Shril Shirlee , Lienkamp Soeren S , Barasch Jonathan , Hildebrandt Friedhelm
Published: August 2020

Background

An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in ∼20% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis.

Methods

In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD.

Results

We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1 was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1 in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient’s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.

Conclusion

Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.
11. ASSOCIATION OF TUMOR EXPOSURE TO CEREBROSPINAL FLUID SPACES TO LEPTOMENINGEAL DISEASE IN PATIENTS WITH BRAIN METASTASES
Authors: Patel Kunal , Levin-Epstein Rebecca , Pouratian Nader , Kaprealian Tania , Kim Won
Published: August 2020

BACKGROUND

Development of leptomeningeal disease in patients with brain metastases is associated with extremely poor survival. Identification of the underlying pathogenesis of leptomeningeal disease is unknown.

METHODS

This retrospective case control study included consecutive adult patients with at least one cerebral metastasis from a known extracranial primary solid malignancy and at least 3 month follow up (n=366). Patients were treated with radiotherapy with or without surgical resection and primary outcome was development of leptomeningeal disease.

RESULTS

The overall rate of leptomeningeal disease was 15.0%. Rates of development of leptomeningeal disease correlated with the presence of a dural based lesion (65.7% vs. 9.7%; P<0.0001), intraventricular lesion (29.4% vs. 14.3%; P=0.0897), and with dural based lesions with sulcal or cortical enhancement (100% vs. 12.9%; P<0.0001). Rates of developing leptomeningeal disease were not independently associated with surgical resection (17.2% vs. 14.2%; P=0.4859), however did occur significantly more often with piecemeal, as opposed to en bloc, resection (31.3% vs. 8.1%; P=0.0138) or when the ventricle was entered (61.5% vs. 18.9%; P<0.0001).

CONCLUSIONS

Metastases that are in contact with cerebrospinal fluid spaces are associated with a higher rate of subsequent leptomeningeal disease, with or without surgical resection. Future studies should investigate the use of neoadjuvant radiation, whole brain radiation therapy or adherence to strict surgical technique in high risk brain metastasis patients to mitigate this probability.
20. MELANOMA CELL INTRINSIC GABAA RECEPTOR ENHANCEMENT POTENTIATES RADIATION AND IMMUNE CHECKPOINT INHIBITOR RESPONSE BY PROMOTING DIRECT AND T CELL-MEDIATED ANTI-TUMOR ACTIVITY
Authors: Sengupta Soma , Nasti Tahseen , Kaluzova Milota , Kallay Laura , Melms Johannes , Izar Benjamin , Xu Maxwell , Bhattacharya Debanjan , Burnham Andre , Li Guanguan , Ahmed Taukir , Lawson David , Kowalski Jeanne , Cook James , Medvedovic Mario , Jenkins Andrew , Khan Mohammad , Pomeranz Krummel Daniel
Published: August 2020

Most metastatic melanoma patients exhibit poor and variable response to radiotherapy and targeted therapies, including immune checkpoint inhibitors. There is a need for therapeutics that can potentiate existing treatments to positively impact clinical outcomes of metastatic melanoma patients. We reanalyzed melanoma TCGA transcriptomes and identified, as linked to previously defined molecular subgroups, enhanced expression of genes coding for subunits of the Type A GABA receptor (GABAAR), a chloride ion channel and major inhibitory neurotransmitter receptor. Using whole-cell patch clamp electrophysiology, we find that melanoma cells possess GABAARs that control membrane permeability to anions. Select benzodiazepines, by enhancing GABAAR mediated anion transport, depolarize melanoma cell mitochondrial membrane potential and impair cell viability in vitro. Using a syngeneic melanoma mouse model, we find that a benzodiazepine promotes reduction in tumor volume when administered alone and potentiated radiation or immune checkpoint inhibitor α-PD-L1. When a benzodiazepine is combined with concurrent α-PD-L1 and a sub-lethal radiation dose, there is near complete loss of tumor, beyond what is observed for benzodiazepine with radiation or α-PD-L1. Mechanistically, benzodiazepine with radiation or α-PD-L1 results in ipsilateral and an abscopal tumor volume reduction commensurate with enhanced infiltration into the tumor milieu of polyfunctional CD8 T-cells. There is also an increased expression of genes with roles in the cytokine-cytokine receptor and p53 signaling pathways. This study provides evidence for melanoma cell GABAARs as a therapeutic vulnerability with benzodiazepines promoting both direct and immune-mediated anti-tumor activity.
26. GENETIC CHARACTERIZATION OF SELLAR METASTASIS FROM PRIMARY BRONCHIAL CARCINOID TUMOR OF NEUROENDOCRINE PATHOLOGY
Authors: Hong Christopher , McGuone Declan , Erson-Omay E Zeynep , Bulent Omay Sacit
Published: August 2020

Metastasis to the pituitary gland and surrounding sellar region from systemic tumors is a rare occurrence. Patients may present with signs of endocrine dysfunction secondary to pituitary involvement, as well as mass effect-related symptoms including headaches and visual deficits. Despite a small but accumulating body of literature describing the clinical and histopathological correlates for sellar metastases from systemic tumors, the genetic alterations underlying sellar spread have not been previously described. We describe a 68 year-old female with history of a resected lung carcinoid tumor, followed by chemoradiation, who was diagnosed with a sellar lesion on surveillance PET-CT and subsequent brain MRI. Her tumor was resected via an endoscopic endonasal approach, and final pathology was consistent with neuroendocrine origin, including positive immunohistochemistry for synpatophysin, CK7, TTF-1, and CAM5.2 with a Ki-67 index of 8–12%. Whole-exome sequencing of the sellar specimen demonstrated large-scale deletions of chromosomes 3, 6, and 9 and focal deletions on chromosomes 1,2, 11, 15, and 16. Mutational signature analysis was enriched for COSMIC Signature 4, seen in multiple primary lung cancers. Among 91 total somatic alterations, 7 had been previously associated with oncogenesis (MYO18A, PTCH1, BCOR, CLIC6, TLL2, COL1A1, PTPRK). Notably, mutations in BCOR and PTCH1 have been previously implicated in both systemic neuroendocrine tumors as well as primary tumors of the pituitary gland, while MYO18A, FGF4, and PTPRK mutations had not been reported in systemic neuroendocrine tumors but have been implicated in tumor migration and pituitary adenoma progression. In summary, these data demonstrated an expected mutational pattern indicating a systemic lung neuroendocrine origin but also revealed new mutations previously implicated in primary pituitary pathologies that may have evolutionarily drove divergence from the primary tumor. Further genome studies of these rare lesions may yield further insight into the genetic alterations underlying metastasis to the sellar region.
32. TREATMENT MONITORING OF IMMUNOTHERAPY AND TARGETED THERAPY USING AMINO ACID PET IN PATIENTS WITH BRAIN METASTASES
Authors: Galldiks Norbert , Abdulla Diana , Scheffler Matthias , Wolpert Fabian , Werner Jan-Michael , Hüllner Martin , Stoffels Gabriele , Schweinsberg Viola , Schlaak Max , Kreuzberg Nicole , Landsberg Jennifer , Lohmann Philipp , Ceccon Garry , Baues Christian , Trommer Maike , Celik Eren , Ruge Maximilian , Kocher Martin , Marnitz Simone , Fink Gereon , Tonn Jörg-Christian , Weller Michael , Langen Karl-Josef , Wolf Jürgen , Mauch Cornelia
Published: August 2020

PURPOSE

Recently, the RANO group has analyzed the additional diagnostic value of amino acid PET in patients with primary and secondary brain tumors and recommended the use of this imaging technique in addition to conventional MRI. Here, we investigated the value of PET using the radiolabled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastases (BM) since contrast-enhanced MRI often remains inconclusive.

METHODS

We retrospectively identified 40 patients with 107 BM secondary to melanoma (n=29 with 75 BM) or non-small cell lung cancer (n=11 with 32 BM) treated with ICI or TT who had FET PET (n=60 scans) for treatment monitoring from 2015–2019. The majority of patients (n=37; 92.5%) had radiotherapy during the course of disease. In 27 patients, FET PET was used for the differentiation of treatment-related changes from BM relapse following ICI or TT. In 13 patients, FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 months). In all lesions, static and dynamic FET PET parameters were obtained (i.e., mean tumour-to-brain ratios (TBR), time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathological findings as reference.

RESULTS

A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P=0.003). Metabolic Responders to ICI or TT on FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P=0.004). Furthermore, at follow-up, time-to-peak values in metabolic responders increased significantly (P=0.019).

CONCLUSIONS

FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.
38. INNOVATIVE USE OF A CUSTOM MOBILE APPLICATION (APP) BY A BRAIN METASTASES PROGRAM FACILITATES MULTIDISCIPLINARY MANAGEMENT OF PATIENTS AND DECREASED LENGTH OF HOSPITAL STAY (LOS)
Authors: Bovi Joseph , Lindstedt Jennifer , Santos-Pinheiro Fernando , Mueller Wade , Michael Straza , Puckett Lindsay , Thompson Jonathon , Nelson Ariel , Peltier Wendy , Brausch Carolyn , Erlitz Tracy , Meerstein Heather , Atkinson David , Crabb Marianne , Leuck Julianne , Roller-Voigt Kimberly , Schultz Christopher
Published: August 2020

INTRODUCTION

Patients with Brain Metastases (BM) are complex, mandating multidisciplinary care. Our BM patients are discussed at in-person, weekly Brain Tumor Boards (BTB). However, BM patients diagnosed outside weekly BTBs wait several days for the next BTB, causing delays in generating multidisciplinary plans-of-care, prolonging LOS. We created a custom mobile app for our Brain Metastases Program to have a ‘Brain Metastases Virtual Tumor Board’ (BMVTB) discussion, in real-time, resulting in faster plans-of-care, decreasing LOS.

METHODS

The current pathway for navigating multidisciplinary discussions for patients with BM was examined by members of our Brain Metastases Program. We identified the need for all disciplines to participate in a BMVTB, outside of our in-person, weekly BTB. We developed a secure app that can be downloaded on any provider’s mobile device. The app includes a digital BM treatment algorithm for providers to understand comprehensive, data-driven, BM management. The app also gives our multidisciplinary Brain Metastases Program access to a BMVTB messenging tool to securely communicate and generate real-time consensus plans-of-care. Using a Vizient Clinical Database, we retrospectively calculated LOS index (observed LOS/expected LOS) for 184 BM patients over 21 months, creating a baseline. After launching our app and BMVTB workflow we prospectively evaluated LOS index in 45 BM patients over 6 months.

RESULTS

Over 21-months, 184 patients demonstrated baseline LOS index of 1.073. After launching our mobile app and BMVTB workflow, 45 patient admissions over 6-months demonstrated LOS index of 0.850. Using Levene’s test for equal variances, LOS variance with the app and BMVTB was lower than LOS variance at baseline (p = 0.049). This demonstrates a 38% reduction in LOS when the app and BMVTB generated real-time plans-of-care.

CONCLUSION

We demonstrated utility of a custom BM app coupled with a BMVTB to generate real-time plans-of-care for BM patients, reducing LOS.
64. AN ENT2-DEPENDENT, CELL-PENETRATING, AND DNA-DAMAGING LUPUS AUTOANTIBODY CROSSES THE BLOOD-BRAIN BARRIER TO TARGET BRAIN TUMORS
Authors: Rattray Zahra , Deng Gang , Zhang Shenqi , Shirali Anupama , May Christopher , Liu Jun , Zou Pan , Cuffari Benedette , Rattray Nicholas , Johnson Caroline , Dubljevic Valentina , Campbell James , Huttner Anita , Baehring Joachim , Zhou Jiangbing , Hansen James
Published: August 2020

The blood-brain barrier (BBB) limits conventional antibody-based approaches to brain tumors. ENT2, an equilibrative nucleoside transporter, facilitates penetration of autoantibodies into live cells and is expressed in the BBB. PAT-DX1 (also known as Deoxymab-1 or DX1) is an ENT2-dependent, cell-penetrating, and DNA-damaging lupus autoantibody that is synthetically lethal to cancer cells with defects in the DNA damage response. PTEN loss renders sensitivity to DX1 and is common in primary and metastatic brain tumors. We show that DX1 is toxic to spheroids derived from primary PTEN-deficient glioblastoma (GBM), and crosses the BBB to suppress the growth of orthotopic GBM and breast cancer brain metastases. Mechanistically, we find the ENT2 inhibitor dipyridamole blocks DX1 penetration into brain endothelial cells and transport across the BBB in vitro and in vivo, consistent with ENT2-mediated uptake of DX1 into brain tumors. Autoantibodies that hijack nucleoside transporters to cross cell membranes may open new frontiers in brain tumor therapy.
75. PROGRAMMED DEATH RECEPTOR LIGAND ONE EXPRESSION MAY INDEPENDENTLY PREDICT SURVIVAL IN NON-SMALL CELL LUNG CARCINOMA BRAIN METASTASES PATIENTS RECEIVING IMMUNOTHERAPY
Authors: Hulsbergen Alexander , Mammi Marco , Nagtegaal Steven , Malk Asad , Kavouridis Vasileios , Smith Timothy , Iorgulescu Bryan , Mekary Rania , Verhoeff Joost , Broekman Marike , Phillips John
Published: August 2020

BACKGROUND

Programmed death receptor ligand one (PD-L1) expression is known to predict response to PD-1/PD-L1 inhibitors in non-small cell lung cancer (NSCLC). However, the predictive role of this biomarker in brain metastases (BMs) is unknown. The aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with PD-1/PD-L1 inhibitors, after adjusting for established prognostic models.

METHODS

In this multi-institutional retrospective cohort study, we identified NSCLC-BM patients treated with PD-1/PD-L1 inhibitors after local BM treatment (radiotherapy or neurosurgery) but before intracranial progression. Cox proportional hazards models were used to assess predictive value PD-L1 expression for overall survival (OS) and intracranial progression free survival (IC-PFS).

RESULTS

Forty-eight BM patients with available PD-L1 expression were identified. PD-L1 expression was positive in 33 patients (69%). Median survival was 26 months. In univariable analysis, PD-L1 predicted favorable OS (HR = 0.44; 95% CI 0.19 – 1.02; p = 0.055). This effect persisted after correcting for lung-graded prognostic assessment (lung-GPA) and other identified potential confounders (HR = 0.24; 95% CI = 0.10 – 0.61; p = 0.002). Moreover, when modeled as a continuous variable, there appeared to be a proportional relationship between percentage of PD-L1 expression and survival (HR = 0.86 per 10% expression, 95% CI 0.77 – 0.98, p = 0.02). In contrast, PD-L1 expression did not predict IC-PFS in uni- or multivariable analysis (adjusted HR = 0.54, 95% CI 0.26 – 1.14, p = 0.11).

CONCLUSIONS

In patients with NSCLC-BMs treated with PD-1/PD-L1 checkpoint inhibitors and local treatment, PD-L1 expression may predict OS independent of lung-GPA. IC-PFS did not show association with PD-L1 expression, although the present analysis may lack power to assess this. Larger studies are required to validate these findings.
Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to the glo Tobacco Heating Product: A Randomized, Controlled Ambulatory Study
Authors: Gale Nathan , McEwan Michael , Camacho Oscar M , Hardie George , Murphy James , Proctor Christopher J
Published: August 2020

Introduction

Tobacco heating products (THPs) generate lower machine yields of toxicants compared to those found in conventional cigarette smoke. During use, these products are likely to expose users to lower levels of particulate matter and harmful and potentially harmful compounds compared with smoking cigarettes.

Aims and Methods

This randomized, controlled study is investigating whether biomarkers of exposure (BoE) to smoke toxicants are reduced when smokers switch from smoking cigarettes to using the glo THP in a naturalistic, ambulatory setting. Control groups include smokers who are abstaining from cigarette smoking and never-smokers. At a baseline study visit, 24-hour urine samples and spot blood samples were taken for BoE analysis, and exhaled carbon monoxide was also measured. N-(2-cyanoethyl) valine (CEVal) was used as a marker of compliance in subjects asked to refrain from combustible cigarette smoking. Subjects are being followed up at periodic intervals for 360 days; this article presents data following a planned interim analysis at day 90.

Results

In continuing smokers, BoE remained stable between baseline (day 1) and day 90. In both per-protocol and CEVal-compliant analysis populations, reductions in BoE were observed in subjects switching to using glo or undergoing smoking cessation. These reductions were statistically significant for a number of BoE when switching to glo was compared with continued smoking. Furthermore, in both populations, reductions observed in subjects switching to using glo were comparable to those seen with smoking cessation and were also to levels similar to those seen in never-smokers.

Conclusion

glo is a reduced-exposure tobacco product.

Implications

This clinical study builds on a previous 5-day confinement study and demonstrates that when smokers switched from smoking combustible cigarettes to using the glo THP in a naturalistic, ambulatory setting, their exposure to tobacco smoke toxicants was significantly decreased. For most BoE examined, this was to the same extent as that seen when a control group of smokers ceased cigarette smoking, or even to levels seen in never-smoker controls. This indicates that glo is a reduced-exposure product with the potential to be a reduced-risk tobacco product, when used by smokers whose cigarette consumption is displaced completely.

Clinical trial registration

ISRCTN81075760.
Nicotine, Cotinine, and Tobacco-Specific Nitrosamines Measured in Children’s Silicone Wristbands in Relation to Secondhand Smoke and E-cigarette Vapor Exposure
Authors: Quintana Penelope J E , Lopez-Galvez Nicolas , Dodder Nathan G , Hoh Eunha , Matt Georg E , Zakarian Joy M , Vyas Mansi , Chu Linda , Akins Brittany , Padilla Samuel , Anderson Kim A , Hovell Melbourne F
Published: August 2020

Introduction

Simple silicone wristbands (WB) hold promise for exposure assessment in children. We previously reported strong correlations between nicotine in WB worn by children and urinary cotinine (UC). Here, we investigated differences in WB chemical concentrations among children exposed to secondhand smoke from conventional cigarettes (CC) or secondhand vapor from electronic cigarettes (EC), and children living with nonusers of either product (NS).

Methods

Children (n = 53) wore three WB and a passive nicotine air sampler for 7 days and one WB for 2 days, and gave a urine sample on day 7. Caregivers reported daily exposures during the 7-day period. We determined nicotine, cotinine, and tobacco–specific nitrosamines (TSNAs) concentrations in WB, nicotine in air samplers, and UC through isotope-dilution liquid chromatography with triple-quadrupole mass spectrometry.

Results

Nicotine and cotinine levels in WB in children differentiated between groups of children recruited into NS, EC exposed, and CC exposed groups in a similar manner to UC. WB levels were significantly higher in the CC group (WB nicotine median 233.8 ng/g silicone, UC median 3.6 ng/mL, n = 15) than the EC group (WB nicotine median: 28.9 ng/g, UC 0.5 ng/mL, n = 19), and both CC and EC group levels were higher than the NS group (WB nicotine median: 3.7 ng/g, UC 0.1 ng/mL, n = 19). TSNAs, including the known carcinogen NNK, were detected in 39% of WB.

Conclusions

Silicone WB show promise for sensitive detection of exposure to tobacco-related contaminants from traditional and electronic cigarettes and have potential for tobacco control efforts.

Implications

Silicone WB worn by children can absorb nicotine, cotinine, and tobacco-specific nitrosamines, and amounts of these compounds are closely related to the child’s urinary cotinine. Levels of tobacco-specific compounds in the silicone WB can distinguish patterns of children’s exposure to secondhand smoke and e-cigarette vapor. Silicone WB are simple to use and acceptable to children and, therefore, may be useful for tobacco control activities such as parental awareness and behavior change, and effects of smoke-free policy implementation.
Smoking During Pregnancy Among Immigrant Women With Same-Origin and Swedish-Born Partners
Authors: Urquia Marcelo L , Juarez Sol , Wall-Wieler Elizabeth , Hjern Anders
Published: August 2020

Introduction

Although ethnically mixed couples are on the rise in industrialized countries, their health behaviors are poorly understood. We examined the associations between partner’s birthplace, age at immigration, and smoking during pregnancy among foreign-born women.

Methods

Population-based register study including all pregnancies resulting in a livebirth or stillbirth in Sweden (1991–2012) with complete information on smoking and parental country of birth. We compared the prevalence of smoking during pregnancy between women in dual same-origin foreign-born unions (n = 213 111) and in mixed couples (immigrant women with a Swedish-born partner) (n = 111 866) using logistic regression. Swedish-born couples were used as a benchmark.

Results

The crude smoking rate among Swedish women whose partners were Swedish was 11%. Smoking rates of women in dual same-origin foreign-born unions varied substantially by birthplace, from 1.3% among women from Asian countries to 23.2% among those from other Nordic countries. Among immigrant groups with prevalences of pregnancy smoking higher than that of women in dual Swedish-born unions, having a Swedish-born partner was associated with lower odds of smoking (adjusted odds ratios: 0.72–0.87) but with higher odds among immigrant groups with lower prevalence (adjusted odds ratios: 1.17–5.88). These associations were stronger among women immigrating in adulthood, whose smoking rates were the lowest.

Conclusions

Swedish-born partners “pull” smoking rates of immigrant women toward the level of smoking of Swedish-born women, particularly among women arrived during adulthood. Consideration of a woman’s and her partner’s ethnic background and life stage at migration may help understand smoking patterns of immigrant women.

Implications

We found that having a Swedish-born partner is associated with higher rates of smoking during pregnancy among immigrants from regions where women smoke less than Swedish women, but with lower smoking rates among immigrants from regions where women smoke more. This implies that prevention efforts should concentrate on newly arrived single women from low prevalence regions, such as Africa and Asia, whereas cessation efforts may target women from high prevalence regions, such as other European countries. These findings suggest that pregnancy smoking prevention or cessation interventions may benefit from including partners and approaches culturally tailored to mixed unions.