Abstract
A vertical slice of the CMS Outer Tracker has been tested at the tracker integration facility and at the M2 muon beam facility at CERN. It includes the final prototype of the 2S module with ...an optical link to the back-end ATCA system. The performance of the system will be described, including cooling limits of racks, robustness of 25 Gbit/s trigger optical links, and readiness of firmware.
Silver-Russell syndrome (SRS MIM180860) is a disorder characterised by intrauterine and/or postnatal growth restriction and typical facies. However, the clinical picture is extremely diverse due to ...numerous diagnostic features reflecting a heterogeneous genetic disorder. The mode of inheritance is variable with sporadic cases also being described. Maternal uniparental disomy (mUPD) of chromosome 7 accounts for 10% of SRS cases and many candidate imprinted genes on 7 have been investigated. Chromosome 11 has moved to the forefront as the key chromosome in the aetiology, with reports of methylation defects in the H19 imprinted domain associated with the phenotype in 35-65% of SRS patients. Methylation aberrations have been described in a number of other imprinted growth related disorders such as Beckwith-Wiedmann syndrome. This review discusses these recent developments as well as the previous work on chromosome 7. Other candidate genes/chromosomal regions previously investigated are tabled.
Genomic imprinting is limited to a subset of genes that play critical roles in fetal growth, development and behaviour. One of the most studied imprinted genes encodes insulin-like growth factor 2, ...and aberrant imprinting and DNA methylation of this gene is associated with the growth disorders Beckwith–Wiedemann and Silver–Russell syndromes and many human cancers. Specific isoforms of this gene have been shown to be essential for normal placental function, as mice carrying paternal null alleles for the Igf2-P0 transcript are growth restricted at birth. We report here the identification of three novel human transcripts from the IGF2 locus. One is equivalent to the mouse Igf2-P0 transcript, whereas the two others (INSIGF long and short) originate from the upstream INS gene that alternatively splices to downstream IGF2 exons. In order to elucidate the molecular mechanisms involved in the complex imprinting of these novel IGF2 transcripts, both the allele-specific expression and methylation for all the IGF2 promoters including P0 and the INSIGF transcripts were analysed in human tissues. Similar to the mouse, the human IGF2-P0 transcript is paternally expressed; however, its expression is not limited to placenta. This expression correlates with tissue-specific promoter methylation on the maternal allele. The two novel INSIGF transcripts reported here use the INS promoter and show highly restricted tissue expression profiles including the pancreas. As previously reported for INS in the yolk sac, we demonstrate complex, tissue-specific imprinting of these transcripts. The finding of additional transcripts within this locus will have important implications for IGF2 regulation in both cancer and metabolism.
IMPORTANCE: Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to ...cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion. OBJECTIVE: To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk. DESIGN, SETTING, AND PARTICIPANTS: This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women’s Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion. MAIN OUTCOMES AND MEASURES: The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria. RESULTS: Two hundred four patients (127 men 62.2%; mean SD age, 60.0 12.1 years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26). CONCLUSIONS AND RELEVANCE: The score developed in this study may help predict which patients are likely to experience CAR T-cell–associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.
The design and configuration of a multi-layered imaging system with the ability to detect thermal neutrons, fast neutrons and gamma rays has been developed and its efficacy demonstrated. The work ...presented here numerically determines the systems efficiency and spatial resolution, using
252
Cf and
137
Cs as a case study. The novelty of this detection system lies in the use of small form factor detectors in a three-layer design, which utilises neutron elastic scattering and Compton scattering simultaneously. The current configuration consists of 10 mm thick natural lithium glass (GS10) scintillator integrated with a 20 mm thick plastic scintillator (EJ-204) in the first layer, a 15 mm thick lithium glass (GS10) scintillator in the second and a 30 mm thick CsI(Tl) scintillator forming the final layer. Each of these layers is backed with an 8 x 8 silicon photomultiplier diode (SiPM) array. The overall size of the imaging system is 27 mm x 27 mm x 135 mm. MCNPv6.1 and Geant4-10.04 were alternatively used to optimise the overall configuration and to investigate detection modalities. Results show promising performance with high precision source localisation and characterization abilities. Measurements were virtually obtained of two gamma-ray sources within steel enclosures at angles of 15°, 30° and 50° separation in order to test spatial resolution ability of the system. With the current active size of the system and the 8x8 SiPM configuration, the results estimate the spatial resolution to be close to 30°. The ability of the system to characterise and identify sources based on the type and energy of the radiation emitted, has been investigated and results show that for all radiation types the system can identify the source energy within the energy range of typical reported sources in literature.
Patients treated with chimeric antigen receptor (CAR) T cell therapy often develop severe neurological toxicities associated with focal neurological deficits that are incompletely understood. Rubin ...et al. catalogue the neurological symptoms in 100 consecutive patients receiving CAR T cell therapy, characterizing the common clinical features and diagnostic findings.
Abstract
Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population.
Effective therapeutics given early to high-risk ambulatory patients with coronavirus disease 2019 (COVID-19) could improve outcomes and reduce overall healthcare burden. However, conducting site ...visits in non-hospitalised patients, who should remain isolated, is problematic.
To evaluate the feasibility of a purely remote (virtual) study in non-hospitalised patients with COVID-19; and the efficacy and safety of nebulised recombinant interferon-β1a (SNG001) in this setting.
Randomised, double-blind, parallel-group study, which was conducted remotely.
Eligible patients aged ≥65 years (or ≥50 years with risk factors) with COVID-19 and not requiring hospital admission were recruited remotely. They were randomised to SNG001 or placebo once-daily via nebuliser for 14 days. The main outcomes were assessments of feasibility and safety, which were all conducted remotely.
Of 114 patients treated, 111 (97.4%) completed 28 days of follow-up. Overall compliance to study medication was high, with ≥13 doses taken by 89.7% and 92.9% of treated patients in the placebo and SNG001 groups, respectively. Over the course of the study, only two patients were hospitalised, both in the placebo group; otherwise there were no notable differences between treatments for the efficacy parameters. No patients withdrew owing to an adverse event, and a similar proportion of patients experienced on-treatment adverse events in the two treatment groups (64.3% and 67.2% with SNG001 and placebo, respectively); most were mild or moderate and not treatment-related.
This study demonstrated that it is feasible to conduct a purely virtual study in community-based patients with COVID-19, when the study included detailed daily assessments and with medication administered via nebuliser.
Despite the availability of vaccines and therapies, patients are being hospitalised with coronavirus disease 2019 (COVID-19). Interferon (IFN)-β is a naturally occurring protein that stimulates host ...immune responses against most viruses, including severe acute respiratory syndrome coronavirus 2. SNG001 is a recombinant IFN-β1a formulation delivered to the lungs
nebuliser. SPRINTER assessed the efficacy and safety of SNG001 in adults hospitalised due to COVID-19 who required oxygen
nasal prongs or mask.
Patients were randomised double-blind to SNG001 (n=309) or placebo (n=314) once daily for 14 days plus standard of care (SoC). The primary objective was to evaluate recovery after administration of SNG001
placebo, in terms of times to hospital discharge and recovery to no limitation of activity. Key secondary end-points were progression to severe disease or death, progression to intubation or death and death.
Median time to hospital discharge was 7.0 and 8.0 days with SNG001 and placebo, respectively (hazard ratio (HR) 1.06 (95% CI 0.89-1.27); p=0.51); time to recovery was 25.0 days in both groups (HR 1.02 (95% CI 0.81-1.28); p=0.89). There were no significant SNG001-placebo differences for the key secondary end-points, with a 25.7% relative risk reduction in progression to severe disease or death (10.7% and 14.4%, respectively; OR 0.71 (95% CI 0.44-1.15); p=0.161). Serious adverse events were reported by 12.6% and 18.2% patients with SNG001 and placebo, respectively.
Although the primary objective of the study was not met, SNG001 had a favourable safety profile, and the key secondary end-points analysis suggested that SNG001 may have prevented progression to severe disease.
Large animals could be important drivers of spatial nutrient subsidies when they ingest resources in some habitats and release them in others, even moving nutrients against elevational gradients. In ...high Andean deserts, vicuñas (Vicugna vicugna) move daily between nutrient‐rich wet meadows, where there is abundant water and forage but high risk of predation by pumas (Puma concolor), and nutrient‐poor open plains with lower risk of predation. In all habitats, vicuñas defecate and urinate in communal latrines. We investigated how these latrines impacted soil and plant nutrient concentrations across three habitats in the Andean ecosystem (meadows, plains, and canyons) and used stable isotope analysis to explore the source of fecal nutrients in latrines. Latrine soils had higher concentrations of nitrogen, carbon, and other nutrients than did nonlatrine soils across all habitats. These inputs corresponded with an increase in plant quality (lower C:N) at latrine sites in plains and canyons, but not in meadows. Stable isotope mixing models suggest that ~7% of nutrients in plains latrines originated from vegetation in meadows, which is disproportionately higher than the relative proportion of meadow habitat (2.6%) in the study area. In contrast, ~68% of nutrients in meadow latrines appear to originate from plains and canyon vegetation, though these habitats made up nearly 98% of the study area. Vicuña diel movements thus appear to concentrate nutrients in latrines within habitats and to drive cross‐habitat nutrient subsidies, with disproportionate transport from low‐lying, nutrient‐rich meadows to more elevated, nutrient‐poor plains. When these results are scaled up to the landscape scale, the amount of nitrogen and phosphorus subsidized in soil at plains latrines was of the same order of magnitude as estimates of annual atmospheric nitrogen and phosphorus deposition for this region (albeit far more localized and patchy). Thus, vicuña‐mediated nutrient redistribution and deposition appears to be an important process impacting ecosystem functioning in arid Andean environments, on par with other major inputs of nutrients to the system.
The critical role played by IgE in allergic asthma is well-documented and clinically precedented, but some patients in whom IgE neutralization may still offer clinical benefit are excluded from ...treatment with the existing anti-IgE therapy, omalizumab, due to high total IgE levels or body mass. In this study, we sought to generate a novel high affinity anti-IgE antibody (MEDI4212) with potential to treat a broad severe asthma patient population. Analysis of body mass, total and allergen-specific IgE levels in a cohort of severe asthmatics was used to support the rationale for development of a high affinity IgE-targeted antibody therapeutic. Phage display technology was used to generate a human IgG1 lead antibody, MEDI4212, which was characterized in vitro using binding, signaling and functional assay systems. Protein crystallography was used to determine the details of the interaction between MEDI4212 and IgE. MEDI4212 bound human IgE with an affinity of 1.95 pM and was shown to target critical residues in the IgE Cε3 domain critical for interaction with FcεRI. MEDI4212 potently inhibited responses through FcεRI and also prevented the binding of IgE to CD23. When used ex vivo at identical concentration, MEDI4212 depleted free-IgE from human sera to levels ~1 log lower than omalizumab. Our results thus indicate that MEDI4212 is a novel, high affinity antibody that binds specifically to IgE and prevents IgE binding to its receptors. MEDI4212 effectively depleted free-IgE from human sera ex vivo to a level (1 IU/mL) anticipated to provide optimal IgE suppression in severe asthma patients.
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