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BACKGROUND: Diffuse midline gliomas (DMG) are highly invasive brain tumors with rare survival beyond two years past diagnosis and limited understanding of the mechanism behind tumor invasion. Previous reports demonstrate upregulation of the protein ID1 with H3K27M and ACVR1 mutations in DMG, but this has not been confirmed in human tumors or therapeutically targeted. METHODS: Whole exome, RNA, and ChIP-sequencing was performed on the ID1 locus in DMG tissue. Scratch-assay migration and transwell invasion assays of cultured cells were performed following shRNA-mediated ID1-knockdown. In vitro and in vivo genetic and pharmacologic [cannabidiol (CBD)] inhibition of ID1 on DMG tumor growth was assessed. Patient-reported CBD dosing information was collected. RESULTS: Increased ID1 expression in human DMG and in utero electroporation (IUE) murine tumors is associated with H3K27M mutation and brainstem location. ChIP-sequencing indicates ID1 regulatory regions are epigenetically active in human H3K27M-DMG tumors and prenatal pontine cells. Higher ID1-expressing astrocyte-like DMG cells share a transcriptional program with oligo/astrocyte-precursor cells (OAPCs) from the developing human brain and demonstrate upregulation of the migration regulatory protein SPARCL1. Genetic and pharmacologic (CBD) suppression of ID1 decreases tumor cell invasion/migration and tumor growth in H3.3/H3.1K27M PPK-IUE and human DIPGXIIIP* in vivo models of pHGG. The effect of CBD on cell proliferation appears to be non-ID1 mediated. Finally, we collected patient-reported CBD treatment data, finding that a clinical trial to standardize dosing may be beneficial. CONCLUSIONS: H3K27M-mediated re-activation of ID1 in DMG results in a SPARCL1+ migratory transcriptional program that is therapeutically targetable with CBD.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFR[alpha] alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFR[alpha]-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFR[alpha]-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFR[alpha] alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor-bearing mice (mutant TP53, mutant PDGFR[alpha], H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFR[alpha]-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population., Introduction High-grade gliomas (HGGs) are common and aggressive pediatric and adult brain tumors. The median overall survival (OS) of adult patients diagnosed with glioblastoma (GBM), grade IV glioma, is 12.6 [...]

We present results of a Hubble Space Telescope (HST) UBVI -band study of star clusters in tidal tails, using new WFC3 and ACS imaging to complement existing WFPC2 data. We survey 12 tidal tails across seven merging systems, deriving ages and masses for 425 star cluster candidates (SCCs). The stacked mass distribution across all systems follows a power law of the form d N /d M  ∝  M β, with β = −2.02 ± 0.15, consistent with what is seen in other star-forming environments. GALEX and Swift UV imaging provide star formation rates (SFRs) for our tidal tails, which when compared with ages and masses of our SCCs, allows for a determination of the cluster formation efficiency (CFE). We find the CFE increases with increasing SFR surface density, matching the theoretical model. We confirm this fit down at SFR densities lower than previously measured (log ΣSFR (M⊙ yr−1 kpc−2) ≈ −4.2), as related to the CFE. We determine the half-light radii for a refined sample of 57 SCCs with our HST WFC3 and ACS imaging, and calculate their dynamical age, finding the majority of them to be gravitationally bound. We also provide evidence of only low-mass (<104 M⊙) cluster formation in our nearest galaxy, NGC 1487, consistent with the theory that this system is a dwarf merger. [ABSTRACT FROM AUTHOR]

Examines the impact of sociodemographic variables on employment retention of 2,078 male and 1,299 female Cambodian, Laotian, Vietnamese, Polish, Romanian, Soviet, and other refugees in greater metropolitan Chicago (Illinois). Labor force participation patterns and experiences are influenced differentially by background characteristics and exposure to U.S. assistance systems. (SLD)

Purpose: Brain tumors have become the leading cause of cancer-related mortality in young patients. Novel effective therapies on the basis of the unique biology of each tumor are urgently needed. The goal of this study was to evaluate the feasibility, utility, and clinical impact of integrative clinical sequencing and genetic counseling in children and young adults with high-risk brain tumors. Patients and Methods: Fifty-two children and young adults with brain tumors designated by the treating neuro-oncologist to be high risk (> 25% chance for treatment failure; mean age, 10.2 years; range, 0 to 39 years) were enrolled in a prospective, observational, consecutive case series, in which participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed in a multi-institutional brain tumor precision medicine teleconference. Results: Sequencing revealed a potentially actionable germline or tumor alteration in 25 (63%) of 40 tumors with adequate tissue, of which 21 (53%) resulted in an impact on treatment or change of diagnosis. Platelet-derived growth factor receptor or fibroblast growth factor receptor pathway alterations were seen in nine of 20 (45%) glial tumors. Eight (20%) sequenced tumors harbored an oncogenic fusion isolated on RNA sequencing. Seventeen of 20 patients (85%) with glial tumors were found to have a potentially actionable result, which resulted in change of therapy in 14 (70%) patients. Patients with recurrent brain tumors receiving targeted therapy had a median progression-free survival (from time on therapy) of 4 months. Conclusion: Selection of personalized agents for children and young adults with high-risk brain tumors on the basis of integrative clinical sequencing is feasible and resulted in a change in therapy in more than two thirds of children and young adults with high-risk glial tumors. [ABSTRACT FROM AUTHOR]

We have developed an observing programme using deep, multiband imaging to probe the chaotic regions of tidal tails in search of an underlying stellar population, using NGC 3256's 400 Myr twin tidal tails as a case study. These tails have different colours of u - g = 1.05 ± 0.07 and r - i = 0.13 ± 0.07 for NGC 3256W, and u - g = 1.26 ± 0.07 and r - i = 0.26 ± 0.07 for NGC 3256E, indicating different stellar populations. These colours correspond to simple stellar population ages of 288+11-54 and 841+125-157 Myr for NGC 3256W and NGC 3256E, respectively, suggesting that NGC 3256W's diffuse light is dominated by stars formed after the interaction, while light in NGC 3256E is primarily from stars that originated in the host galaxy. Using a mixed stellar population model, we break our diffuse light into two populations: one at 10 Gyr, representing stars pulled from the host galaxies, and a younger component, whose age is determined by fitting the model to the data. We find similar ages for the young populations of both tails (195-13+0 and 170-70+44 Myr for NGC 3256W and NGC 3256E, respectively), but a larger percentage of mass in the 10 Gyr population for NGC 3256E (98+1-3 per cent versus 90+5-6 per cent). Additionally, we detect 31 star cluster candidates in NGC 3256W and 19 in NGC 2356E, with median ages of 141 and 91 Myr, respectively. NGC 3256E contains several young (<10 Myr), low-mass objects with strong nebular emission, indicating a small, recent burst of star formation. [ABSTRACT FROM AUTHOR]

Current and prospective migration law and policy in Chile does not adequately incorporate the causes, content, and consequences of international migration to and from Chile. We describe and examine migration in-flows, out-flows, migration-related policies, and how those policies drive, and are driven by, notions of development in Chile. We explore contradictions in Chilean nascent migration policy currently under legislative review. We argue that it is imperative that migration, migration policy, and their relationship to development be discussed inclusively and transparently and be explicitly incorporated into the Chilean government's nascent migration and development legal policies and frameworks. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including human trafficking, refugee resettlement in Tanzania, and migration and development of South Korean and Korean Chinese migrants.

The peculiar spiral NGC 2782 is the result of a minor merger with a mass ratio ~4:1 occurring ~200 Myr ago. This merger produced a molecular and Hi-rich, optically bright eastern tail and an Hi-rich, optically faint western tail. Non-detection of CO in the western tail by Braine et al. suggested that star formation had not yet begun. However, deep UBVR and Hα narrowband images show evidence of recent star formation in the western tail, though it lacks massive star clusters and cluster complexes. Using Herschel PACS spectroscopy, we discover 158μm [Cii] emission at the location of the three most luminous Hα sources in the eastern tail, but not at the location of the even brighter Hα source in the western tail. The western tail is found to have a normal star formation efficiency (SFE), but the eastern tail has a low SFE. The lack of CO and [C ii] emission suggests that the western tail Hii region may have a low carbon abundance and be undergoing its first star formation. The western tail is more efficient at forming stars, but lacks massive clusters. We propose that the low SFE in the eastern tail may be due to its formation as a splash region where gas heating is important even though it has sufficient molecular and neutral gas to make massive star clusters. The western tail, which has lower gas surface density and does not form high-mass star clusters, is a tidally formed region where gravitational compression likely enhances star formation. [ABSTRACT FROM AUTHOR]

We present a spectroscopic survey of 21 young massive clusters and complexes and one tidal dwarf galaxy (TDG) candidate in Stephan's Quintet, an interacting compact group of galaxies. All of the selected targets lie outside the main galaxies of the system and are associated with tidal debris. We find clusters with ages between a few and 125 Myr and confirm the ages estimated through Hubble Space Telescope photometry by Fedotov et al., as well as their modeled interaction history of the Quintet. Many of the clusters are found to be relatively long-lived, given their spectrosopically derived ages, while their high masses suggest that they will likely evolve to eventually become intergalactic clusters. One cluster, T118, is particularly interesting, given its age (~125 Myr), high mass (~2 x 106 M☉), and position in the extreme outer end of the young tidal tail. This cluster appears to be quite extended (Reff ~ 12-15 pc) compared to clusters observed in galaxy disks (Reff ~ 3-4 pc), which confirms an effect we previously found in the tidal tails of NGC 3256, where clusters are similarly extended. We find that star and cluster formation can proceed at a continuous pace for at least ~150 Myr within the tidal debris of interacting galaxies. The spectrum of the TDG candidate is dominated by a young population (~7 Myr), and, assuming a single age for the entire region, has a mass of at least 106 M☉. [ABSTRACT FROM AUTHOR]

ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A -mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype. [Display omitted] • ATRX binds regulatory elements of CHEK1 in glioma and glioma precursor cells • ATRX loss is associated with loss of the cell-cycle regulator Chk1 • Chk1 loss increases reliance on ATM, an alternate cell-cycle checkpoint modulator • ATM inhibition may sensitize ATRX-deficient gliomas to radiation therapy Qin et al. show that ATRX binds the gene regulatory elements and promotes expression of the cell-cycle regulator of CHEK1 in glioma and glioma precursor cells. ATRX loss in high-grade glioma results in decreased Chk1, dysregulation of cell-cycle checkpoints after radiation, and enhanced radio-sensitization with ATM inhibitors. [ABSTRACT FROM AUTHOR]

In this paper we describe and explain a variety of problems experienced by Amerasian youths upon their resettlement in the United States. We examine a matrix of contextual, household and individual behavioral predictors of Amerasian youths' problems and we argue that, taken individually, existing theoretical frameworks do not adequately explain the Amerasian adaptation process. The most significant predictors of Amerasian youths' problems are an unstable home environment, gender (maleness), whether or not the mother reported mental and physical problems, and the type of assistance provider (mutual assistance association). We add to existing research on Amerasians' process of adaptation by incorporating a wider variety of youths' problems into the dependent variable, by including hitherto unavailable independent variables into the analysis, and by suggesting some immediate strategies and new policy initiatives aimed at helping resettlement agencies deal with this specialized immigrant population. In sum, we demonstrate that Amerasians' unofficially "mixed" immigration status -- they are designated as immigrants who are treated as refugees but are simultaneously half-American -- compounds theorists and policy makers' difficulties in dealing conceptually with this population. [ABSTRACT FROM AUTHOR]

A major debate continues about whether immigrants receive benefits by virtue of their attachment to ethnic communities and ethnic organizations. On one side of the controversy, a large body of literature suggests that the ethnic community, which often contains resources that promote immigrants' adaptation and assimilation, actually hinders adaptation because the resources of mainstream institutions are less accessible to immigrants (often because they are also minorities). On the opposite side of the argument, critics contend that the ethnic solidarity school emphasizes the positive effects of ethnic communities and ethnic organizations on immigrant populations, while ignoring many of the negative consequences of migrants' involvement in ethnic groups and ethnic institutions. The purpose of this article is to reconsider whether ethnic communities and ethnic institutions facilitate immigrants' socio-economic adaptation. Specifically, the study analyses the impact of ethnic organizations on public assistance utilization among South-East Asian and Eastern European refugees in the Chicago metropolitan area in the late 1980s. The paper proceeds in five stages. As a background to the overall study, the literature on ethnic communities and ethnic organizations is reviewed. This is followed by a discussion of the development of mutual assistance associations (MAAs) in the US. Third is a concise description of the data and methods. Fourth is a presentation of the results. The article concludes with an assessment of the implications of the findings and suggestions for future research. [ABSTRACT FROM AUTHOR]

The causes and consequences of human migration and population distribution are difficult to specify. They involve not only population growth or decline and demographic disturbances, but they also have very deep social, economic and political dimensions that often seem to defy most sophisticated analytical techniques and theoretical models. Economic betterment is a dominant motive for migration. Migration flows are the cumulative results of individual decisions based on a rational evaluation of the benefits and costs of moving. The expected net return to an individual can be calculated to predict his or her migration. But this neoclassical perspective has been strongly criticized by structuralists. They believe that individual and structural elements are simultaneously involved in determining human migration patterns and processes. Migration decisions are inevitably made by actors who weigh the costs and benefits of movement, but these decisions are always made with reference to social and economic realities.

T-type voltage-gated Ca 2+ channels (CaV3.2 VGCC) have been hypothesized to control spontaneous transient outward currents (STOCs) through large-conductance Ca 2+ -activated K + channels (BK Ca ), and contribute to the negative-feedback regulation of myogenic tone. We tested this hypothesis in superior epigastric arteries (SEAs) isolated from male C57BL/6 mice. SEAs were isolated and enzymatically dissociated to obtain single smooth muscle cells (SMCs) for whole-cell recording of paxilline-sensitive (PAX, 1  μ mol/L) STOCs at -30 mV, or cannulated and studied by pressure myography (80 cm H 2 O, 37°C). The CaV3.2 blocker Ni 2+ (30  μ mol/L) had no effect on STOC amplitude (20.1 ± 1.7 pA vs. 20.6 ± 1.7 pA; n  = 12, P  = 0.6), but increased STOC frequency (0.79 ± 0.15 Hz vs. 1.21 ± 0.22 Hz; n  = 12, P  = 0.02). Although Ni 2+ produced concentration-dependent constriction of isolated, pressurized SEAs (logEC 50  = -5.8 ± 0.09; E max  = 72 ± 5% constriction), block of BK Ca with PAX had no effect on vasoconstriction induced by 30  μ mol/L Ni 2+ (in the absence of PAX = 66 ± 4% constriction vs. in the presence of 1  μ mol/L PAX = 65 ± 4% constriction; n  = 7, P  = 0.06). In contrast to Ni 2+ , the nonselective T-type blocker, mibefradil, produced only vasodilation (logEC 50  = -6.9 ± 0.2; E max  = 74 ± 8% dilation), whereas the putative T-type blocker, ML218, had no significant effect on myogenic tone between 10 nmol/L and 10  μ mol/L ( n  = 6-7, P  = 0.59). Our data do not support a role for CaV3.2 VGCC in the negative-feedback regulation of myogenic tone in murine SEAs and suggest that Ni 2+ may constrict SEAs by means other than block of CaV3.2 VGCC.