Chemical abundances and radial velocities in the extremely metal-poor galaxy DDO 68

We present chemical abundances and radial velocities of six HII regions in the extremely metal-poor star-forming dwarf galaxy DDO 68. They are derived from deep spectra in the wavelength range 3500 - 10,000 {\AA}, acquired with the Multi Object Double Spectrograph (MODS) at the Large Binocular Telescope (LBT). In the three regions where the [O III]$\lambda$4363 {\AA} line was detected, we inferred the abundance of He, N, O, Ne, Ar, and S through the "direct" method. We also derived the oxygen abundances of all the six regions adopting indirect method calibrations. We confirm that DDO 68 is an extremely metal-poor galaxy, and a strong outlier in the luminosity - metallicity relation defined by star-forming galaxies. With the direct-method we find indeed an oxygen abundance of 12+log(O/H)=7.14$\pm$0.07 in the northernmost region of the galaxy and, although with large uncertainties, an even lower 12+log(O/H)=6.96$\pm$0.09 in the "tail". This is, at face value, the most metal-poor direct abundance detection of any galaxy known. We derive a radial oxygen gradient of -0.06$\pm$0.03 dex/kpc (or -0.30 dex $R_{25}^{-1}$) with the direct method, and a steeper gradient of -0.12$\pm$0.03 dex/kpc (or -0.59 dex $R_{25}^{-1}$) from the indirect method. For the $\alpha$-element to oxygen ratios we obtain values in agreement with those found in other metal-poor star-forming dwarfs. For nitrogen, instead, we infer much higher values, leading to log(N/O)$\sim-1.4$, at variance with the suggested existence of a tight plateau at $-1.6$ in extremely metal poor dwarfs. The derived helium mass fraction ranges from Y=0.240$\pm$0.005 to Y=0.25$\pm$0.02, compatible with standard big bang nucleosynthesis. Finally, we measured HII region radial velocities in the range 479$-$522 km/s from the tail to the head of the "comet", consistent with the rotation derived in the HI.Comment: Accepted for publication in MNRA

Impact of IFN lambda 3/4 single nucleotide polymorphisms on the cytomegalovirus reactivation in autologous stem cell transplant patients

Cytomegalovirus (CMV) infection represents one of the main cause mortality after Stem Cell Transplantation. Recently, a protective effect of the T allele of rs12979860 IL28B Single Nucleotide Polymorphisms (SNPs) against CMV infection in the allogenic stem cell transplantation was suggested. We investigate whether the rs12979860 IL28B SNP and the relative rs368234815 (IFNλ4) genotype may affect the incidence of active CMV infection in Autologous stem cell transplantation (Auto-SCT) setting. The study included 99 patients who underwent to Auto-SCT. IL28 and IFNΔ4 SNPs were correlated with CMV reactivation along with other clinical and treatment parameters. CMV reactivation by CMV DNAemia was evaluated once a week until day 100 from Auto-SCT. CMV reactivation was documented in 50% (TT-ΔG/ΔG), 35% (CC-TT/TT) and 29.2% (CT-TT/ΔG) of the patients respectively. No differences in CMV copies number were recorded at reactivation between different IL28/IFNλ4 genotypes. The analysis of patients older than 60 years showed a significantly higher incidence of active CMV infection in the TT-ΔG/ΔG (83%) population with respect to CC-TT/TT (21%) and CT-TT/ΔG (40%) patients. Our data suggest a negative role of TT-ΔG/ΔG genotype in the CMV reactivation in Auto-SCT. The exposure to rituximab and the pre-infusion presence of anti CMV IgG also significantly influenced CMV reactivation

Star Formation Histories of the LEGUS Dwarf Galaxies (I): recent History of NGC1705, NGC4449 and Holmberg II

We use HST observations from the Legacy Extragalactic UV Survey to reconstruct the recent star formation histories (SFHs) of three actively star-forming dwarf galaxies, NGC4449, Holmberg II and NGC1705, from their UV color-magnitude diagrams (CMDs). We apply a CMD fitting technique using two independent sets of stellar isochrones, PARSEC-COLIBRI and MIST, to assess the uncertainties related to stellar evolution modelling. Irrespective of the adopted stellar models, all the three dwarfs are found to have had almost constant star formation rates (SFRs) in the last 100-200 Myr, with modest enhancements (a factor of $\sim$2) above the 100 Myr-averaged-SFR. Significant differences among the three dwarfs are found in the overall SFR, the timing of the most recent peak and the SFR$/$area. The Initial Mass Function (IMF) of NGC1705 and Holmberg II is consistent with a Salpeter slope down to $\approx$ 5 M$_{\odot}$, whereas it is slightly flatter, s$=-2.0$, in NGC4449. The SFHs derived with the two different sets of stellar models are consistent with each other, except for some quantitative details, attributable to their input assumptions. They also share the drawback that all synthetic diagrams predict a clear separation in color between upper main sequence and helium burning stars, which is not apparent in the data. Since differential reddening, significant in NGC4449, or unresolved binaries don't appear to be sufficient to fill the gap, we suggest this calls for a revision of both sets of stellar evolutionary tracks.Comment: 22 pages, 17 figures, accepted for publication on Ap

Increased CD8+ T cell responses to apoptotic T cell-associated antigens in multiple sclerosis.

BACKGROUND: Here, we evaluated the hypothesis that CD8(+) T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology. METHODS: The percentage of autoreactive CD8(+) T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer(+) CD8(+) T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo. RESULTS: We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8(+) T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8(+) T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8(+) T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8(+) T cells ex vivo. CONCLUSION: Taken together, these data indicate that apoptotic epitope-specific CD8(+) T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines

Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia

Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ‘tethering’ proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity

Gas, dust, and the CO-to-molecular gas conversion factor in low-metallicity starbursts

The factor relating CO emission to molecular hydrogen column density, XCO, is still subject to uncertainty, in particular at low metallicity. In this paper, to quantify XCO at two different spatial resolutions, we exploited a dust-based method together with ALMA 12-m and ACA data and H I maps of three nearby metal-poor starbursts, NGC 625, NGC 1705, and NGC 5253. Dust opacity at 250 pc resolution was derived based on dust temperatures estimated by fitting two-temperature modified blackbodies to Herschel PACS data. By using the HI maps, we were then able to estimate dust-to-gas ratios in the regions dominated by atomic gas, and, throughout the galaxy, to infer total gas column densities and H2 column densities as the difference with HI. Finally, from the ACA CO(1–0) maps, we derived XCO. We used a similar technique with 40 pc ALMA 12-m data for the three galaxies, but instead derived dust attenuation at 40 pc resolution from reddening maps based on VLT/MUSE data. At 250 pc resolution, we find XCO ∼ 1022 − 1023 cm−2/K km s−1, 5–1000 times the Milky Way value, with much larger values than would be expected from a simple metallicity dependence. Instead, at 40 pc resolution, XCO again shows large variation, but is roughly consistent with a power-law metallicity dependence, given the Z ∼ 1/3 Z⊙ metal abundances of our targets. The large scatter in both estimations could imply additional parameter dependence, which we have investigated by comparing XCO with the observed velocity-integrated brightness temperatures, ICO, as predicted by recent simulations. Indeed, larger XCO is significantly correlated with smaller ICO, but with slightly different slopes and normalizations than predicted by theory. Such behavior can be attributed to the increasing fraction of CO-faint (or dark) H2 gas with lower spatial resolution (larger beams). This confirms the idea the XCO is multivariate, depending not only on metallicity but also on the CO brightness temperature and beam size. Future work is needed to consolidate these empirical results by sampling galaxies with different metal abundances observed at varying spatial resolutions

Brentuximab vedotin consolidation after autologous stem cell transplantation for Hodgkin lymphoma: A Fondazione Italiana Linfomi real-life experience

The standard management for relapsed or refractory classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous stem cell transplantation (ASCT). This strategy allows almost 50% of patients to be cured. Post-ASCT maintenance treatment with brentuximab vedotin (BV) confers improved progression-free survival (PFS) to cHL patients at high risk of relapse. We investigated the outcome of 105 cHL patients receiving post-ASCT BV maintenance in the real-life setting of 23 Italian hematology centers. This population included naïve patients and those previously exposed to BV. Median follow-up was 20 months. Patients presented a median of two lines of treatment pre-ASCT, with 51% receiving BV. Twenty-nine percent of patients had at least two high-risk factors (refractory disease, complete response [CR] less than 12 months, extranodal disease at relapse), while 16% presented none. At PET-CT, a Deauville score (DS) of 1–3 was reported in 75% and 78% of pre- and post-ASCT evaluations, respectively. Grade 3–4 adverse events (AEs), mainly peripheral neuropathy, were observed in 16% of patients. Three-year PFS and overall survival (OS) were 62% and 86%, respectively. According to BV exposure, 3-year PFS and OS were 54% and 71%, respectively, for naïve and 77% and 96%, respectively, for previously exposed patients. Refractory disease (hazard ratio [HR] 4.46; p = 0.003) and post-ASCT DS 4–5 (HR 3.14; p = 0.005) were the only two factors significantly associated with PFS reduction in multivariable analysis. Post-ASCT BV maintenance is an effective, safe treatment option for cHL naïve patients and those previously exposed to BV

Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML

Nucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but also sporadically affect exons 9 and 11, causing changes at the protein C-terminal end (tryptophan loss, nuclear export signal [NES] motif creation) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 patients with AML, we found non–exon 12 NPM1 mutations in 5 (1.3%) of 387 NPM1c+ cases. Besides mutations in exons 9 (n = 1) and 11 (n = 1), novel exon 5 mutations were discovered (n = 3). Another exon 5 mutation was identified in an additional 141 patients with AML selected for wild-type NPM1 exon 12. Three NPM1 rearrangements (NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13 979 AML samples screened by cytogenetic/fluorescence in situ hybridization and RNA sequencing. Functional studies demonstrated that in AML cases, new NPM1 proteins harbored an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting AML-associated NPM1 genetic lesions. This study highlights the need to develop new assays for molecular diagnosis and monitoring of NPM1-mutated AML

Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis

We conducted a pooled analysis of two phase III trials, RV-MM-EMN-441 and EMN01, to compare maintenance with lenalidomide-prednisone vs. lenalidomide in newly diagnosed transplant-eligible and -ineligible myeloma patients. Primary endpoints were progression-free survival, progression-free survival 2 and overall survival with both regimens. A secondary aim was to evaluate the impact of duration of maintenance on overall survival and on outcome after relapse. A total of 625 patients (lenalidomide-prednisone arm, n = 315; lenalidomide arm, n = 310) were analyzed. The median follow-up was 58 months. Median progression-free survival (25 vs. 19 months; p = 0.08), progression-free survival 2 (56 vs. 49 months; p = 0.9) and overall survival (73 months vs. NR; p = 0.08) were not significantly different between the two arms. Toxicity profiles of lenalidomide-prednisone and lenalidomide were similar, with the exception of neutropenia that was higher in the lenalidomide arm (grade ≥ 3: 9% vs. 19%, p < 0.001), without an increase in the rate of infections. Overall survival (median NR vs. 49 months, p < 0.001), progression-free survival from relapse (median 35 vs. 24 months, p = 0.004) and overall survival from relapse (median not reached vs. 41 months, p = 0.002) were significantly longer in patients continuing maintenance for ≥2 years. We showed that the addition of prednisone at 25 or 50 mg every other day (eod) to lenalidomide maintenance did not induce any significant advantage