In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinaseextracellular signal-regulated kinase (ERK) kinase (MEK)ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.Peer Reviewe

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG- binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763

SN 2009E: a faint clone of SN 1987A

In this paper we investigate the properties of SN 2009E, which exploded in a relatively nearby spiral galaxy (NGC 4141) and that is probably the faintest 1987A-like supernova discovered so far. Spectroscopic observations which started about 2 months after the supernova explosion, highlight significant differences between SN 2009E and the prototypical SN 1987A. Modelling the data of SN 2009E allows us to constrain the explosion parameters and the properties of the progenitor star, and compare the inferred estimates with those available for the similar SNe 1987A and 1998A. The light curve of SN 2009E is less luminous than that of SN 1987A and the other members of this class, and the maximum light curve peak is reached at a slightly later epoch than in SN 1987A. Late-time photometric observations suggest that SN 2009E ejected about 0.04 solar masses of 56Ni, which is the smallest 56Ni mass in our sample of 1987A-like events. Modelling the observations with a radiation hydrodynamics code, we infer for SN 2009E a kinetic plus thermal energy of about 0.6 foe, an initial radius of ~7 x 10^12 cm and an ejected mass of ~19 solar masses. The photospheric spectra show a number of narrow (v~1800 km/s) metal lines, with unusually strong Ba II lines. The nebular spectrum displays narrow emission lines of H, Na I, [Ca II] and [O I], with the [O I] feature being relatively strong compared to the [Ca II] doublet. The overall spectroscopic evolution is reminiscent of that of the faint 56Ni-poor type II-plateau supernovae. This suggests that SN 2009E belongs to the low-luminosity, low 56Ni mass, low-energy tail in the distribution of the 1987A-like objects in the same manner as SN 1997D and similar events represent the faint tail in the distribution of physical properties for normal type II-plateau supernovae.Comment: 19 pages, 9 figures (+7 in appendix); accepted for publication in A&A on 3 November 201

Modified Wisconsin Card Sorting Test (M-WCST): Normative data for Spanish-speaking pediatric population

OBJECTIVE: To generate normative data for the Modified Wisconsin Card Sorting Test (M-WCST) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the M-WCST as part of a larger neuropsychological battery. Number of categories, perseverative errors, and total error scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models indicated main effects for age on all scores, such that the number of categories correct increased and total number of perseverative errors and total number of errors decrease linearly as a function of age. Age2 had a significant effect in Chile, Cuba, Ecuador, and Spain for numbers of categories; a significant effect for number of perseverative errors in Chile, Cuba, Mexico, and Spain; and a significant effect for number of total errors in Chile, Cuba, Peru, and Spain. Models showed an effect for MLPE in Cuba (total errors), Ecuador (categories and total errors), Mexico (all scores), Paraguay (perseverative errors and total error), and Spain (categories and total errors). Sex affected number of total errors for Ecuador. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate way to interpret the M-WCST with pediatric populations

A survey for variable young stars with small telescopes: II - mapping a protoplanetary disc with stable structures at 0.15 au

The HOYS citizen science project conducts long term, multifilter, high cadence monitoring of large YSO samples with a wide variety of professional and amateur telescopes. We present the analysis of the light curve of V1490 Cyg in the Pelican Nebula. We show that colour terms in the diverse photometric data can be calibrated out to achieve a median photometric accuracy of 0.02 mag in broadband filters, allowing detailed investigations into a variety of variability amplitudes over timescales from hours to several years. Using Gaia DR2 we estimate the distance to the Pelican Nebula to be 870 +70 −55 pc. V1490 Cyg is a quasi-periodic dipper with a period of 31.447 ± 0.011 d. The obscuring dust has homogeneous properties, and grains larger than those typical in the ISM. Larger variability on short timescales is observed in U and Rc−Hα, with U-amplitudes reaching 3 mag on timescales of hours, indicating the source is accreting. The Hα equivalent width and NIR/MIR colours place V1490 Cyg between CTTS/WTTS and transition disk objects. The material responsible for the dipping is located in a warped inner disk, about 0.15 AU from the star. This mass reservoir can be filled and emptied on time scales shorter than the period at a rate of up to 10−10 M�/yr, consistent with low levels of accretion in other T Tauri stars. Most likely the warp at this separation from the star is induced by a protoplanet in the inner accretion disk. However, we cannot fully rule out the possibility of an AA Tau-like warp, or occultations by the Hill sphere around a forming planet

The evolving landscape of COVID‐19 and post‐COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Summary: Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763. : Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by loss-of-function mutations in the MeCP2 gene. Jorge-Torres et al. show that mice models of RTT display hyperactivation of Gsk3b kinase and neuroinflammation. Inhibition of the Gsk3b pathway partially rescues the phenotype and affects neuronal morphology and synaptic activity. Keywords: Rett syndrome, Gsk3b, Nfkb1, neurons, mice models, SB216763, neuroinflammation, Mecp

First scientific observations with MEGARA at GTC

On June 25th 2017, the new intermediate-resolution optical IFU and MOS of the 10.4-m GTC had its first light. As part of the tests carried out to verify the performance of the instrument in its two modes (IFU and MOS) and 18 spectral setups (identical number of VPHs with resolutions R=6000-20000 from 0.36 to 1 micron) a number of astronomical objects were observed. These observations show that MEGARA@GTC is called to fill a niche of high-throughput, intermediateresolution IFU and MOS observations of extremely-faint narrow-lined objects. Lyman-α absorbers, star-forming dwarfs or even weak absorptions in stellar spectra in our Galaxy or in the Local Group can now be explored to a new level. Thus, the versatility of MEGARA in terms of observing modes and spectral resolution and coverage will allow GTC to go beyond current observational limits in either depth or precision for all these objects. The results to be presented in this talk clearly demonstrate the potential of MEGARA in this regard