Ariel - Volume 6 Number 1

Editors John Lammie Curt Cummings Frank Chervenak J.D. Kanofsky Mark Dembert Entertainment Robert Breckenridge Joe Conti Gary Kaskey Photographer Larry Glazerman Overseas Editor Mike Sinason Circulation Jay Amsterdam Humorist Jim McCann Staff Ken Jaffe Bob Sklaroff Halley Faus

VisIVOWeb: A WWW Environment for Large-Scale Astrophysical Visualization

This article presents a newly developed Web portal called VisIVOWeb that aims to provide the astrophysical community with powerful visualization tools for large-scale data sets in the context of Web 2.0. VisIVOWeb can effectively handle modern numerical simulations and real-world observations. Our open-source software is based on established visualization toolkits offering high-quality rendering algorithms. The underlying data management is discussed with the supported visualization interfaces and movie-making functionality. We introduce VisIVOWeb Network, a robust network of customized Web portals for visual discovery, and VisIVOWeb Connect, a lightweight and efficient solution for seamlessly connecting to existing astrophysical archives. A significant effort has been devoted for ensuring interoperability with existing tools by adhering to IVOA standards. We conclude with a summary of our work and a discussion on future developments

Celiac disease and headache in children: A narrative state of the art

Celiac disease (CD) is one of the most important entity of the wide spectrum of gluten-related disorders (GRDs). It is well known that neurological manifestation can be present either at the onset of CD, or appear during the development of the pathology, and different can be the neurologic findings. Clinical features are very variable, ranging from typical manifestations of gastrointestinal involvement to neurologic symptom. The most frequent neurologic signs reported were headache, epileptic seizure, migraine, mental retardation, ataxia and attention deficit and hyperactive disorder. Headache either in form of migraine, or in non-specific form represents one of the main clinical presentation in CD. The aim of this work is to provide a narrative review of the pediatric literature focused on the cephalalgic features of children with CD evaluating the potential benefits of a gluten free diet (GFD). Papers were identified by searching for related literature in Medline (PubMed) and Embase using the words “Celiac Disease” and “Headache” or “Migraine” by specifying “children”/“paediatric age” for reports published since 1972 till 31th October 2018. According to our inclusion criteria, a total of 25 papers has been evaluated. Although it is still controversial if headache is prevalent in CD children a correct compliance to a GFD seems to improve the neurological symptoms even if the underlying pathogenic relationship between CD and neurologic system involvement is still not fully understood. (www.actabiomedica.it)

BCR-ABL1 doubling-times and halving-times may predict CML response to tyrosine kinase inhibitors

In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene’s expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation

Clinical implications of discordant early molecular responses in CML patients treated with imatinib

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3-and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points

A counterfactual approach to measure the impact of wet grassland conservation on UK breeding bird populations

Wet grassland wader populations in the United Kingdom have experienced severe declines over the last three decades. To help mitigate these declines, the Royal Society for the Protection of Birds (RSPB) has restored and managed lowland wet grassland nature reserves to benefit these and other species. However, the impact that these reserves have on bird population trends has not been experimentally evaluated, as appropriate control populations do not readily exist. In this study, we compare population trends from 1994 ‐ 2018 for five bird species of conservation concern that breed on these nature reserves with counterfactual trends using matched breeding bird survey observations. Our results showed positive effects of conservation interventions for all four wader species that these reserves aim to benefit: Lapwing (Vanellus vanellus), Redshank (Tringa totanus), Curlew (Numenius arquata) and Snipe (Gallinago gallinago). There was no positive effect of conservation interventions on reserves for the passerine, Yellow Wagtail (Motacilla flava). We compared reserve trends with three different counterfactuals, based on different scenarios of how reserve populations could have developed in the absence of conservation, and found that reserve trends performed better regardless of the counterfactual used. Our approach using monitoring data to produce valid counterfactual controls is a broadly applicable method allowing large‐scale evaluation of conservation impact

Correction to: Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial (Cancers, (2022), 14, 2, (374), 10.3390/cancers14020374)

\ua9 2024 by the authors.In the original publication [1], the funder Cancer Research UK, A2524 was not included. Keith Wheatley, Simon Gates, and Victoria Homer were not included as authors in the original publication. The reason we would like to add the authors is that the statistical element of the trial and the trial design were in a large part done by the statistical authors and the team were necessary for the running of the trial. The corrected Author Contributions Statement appears here. Author Contributions: Conceptualization, S.B., N.A., L.G., M.M., K.W., S.R. and S.C.C.; methodology, K.W., S.G. and V.H.; project administration, S.G. and V.H.; resources, S.B., N.A., L.G., M.M., S.R. and S.C.C.; writing—original draft preparation, S.B., N.A., L.G., M.M., S.R. and S.C.C.; writing—review and editing, S.B., N.A., L.G., M.M., S.R. and S.C.C. All authors have read and agreed to the published version of the manuscript. Author Contributions: Conceptualization, S.B., N.A., L.G., M.M., K.W., S.R. and S.C.C.; methodology, K.W., S.G. and V.H.; project administration, S.G. and V.H.; resources, S.B., N.A., L.G., M.M., S.R. and S.C.C.; writing—original draft preparation, S.B., N.A., L.G., M.M., S.R. and S.C.C.; writing—review and editing, S.B., N.A., L.G., M.M., S.R. and S.C.C. All authors have read and agreed to the published version of the manuscript. Cancer Research UK Clinical Trials Unit, University of Birimingham, Birmingham B15 2TT, UK; [email protected](K.W.); [email protected] (S.G.); [email protected] (V.H.) The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells