An open-label multi-center phase 1 safety study of BXQ-350 in children and young adults with relapsed solid tumors, including recurrent malignant brain tumors

BACKGROUND: BXQ-350 is a novel anti-neoplastic agent composed of saposin C (SapC) and phospholipid dioleoylphosphatidyl-serine sodium (DOPS) that selectively binds tumor cell phosphatidylserine (PS), inducing apoptosis. BXQ-350 has demonstrated preclinical antitumor effects in high-grade gliomas (HGG) and clinical activity in adult patients with recurrent HGG. METHODS: A phase 1 study was conducted in pediatric patients with relapsed/refractory solid tumors, including recurrent brain tumors. Primary objectives were to characterize safety and determine maximum tolerated dose (MTD) and preliminary antitumor activity. Sequential dose cohorts were assessed up to 3.2 mg/kg using an accelerated titration design. Each cycle was 28 days; dosing occurred on days 1-5, 8, 10, 12, 15, and 22 of cycle 1, and day 1 of subsequent cycles, until disease progression or toxicity. RESULTS: Nine patients, median age 10 years (range: 4-23), were enrolled. Seven patients (78%) had central nervous system (CNS) and two (22%) had non-CNS tumors. Eight patients completed cycle 1. No dose limiting toxicity (DLT) or BXQ-350-related serious adverse events (SAEs) were observed. Six patients experienced at least one adverse event (AE) considered possibly BXQ-350-related, most were grade ≤2. One patient with diffuse intrinsic pontine glioma experienced stable disease for 5 cycles. The study was terminated after part 1 to focus development on the frontline setting. CONCLUSION: No DLTs or BXQ-350-related SAEs were reported, and the maximal planned dose of 3.2 mg/kg IV was tolerable. Limited safety and efficacy data support continued BXQ-350 development in pediatric HGG; however, early discontinuations for progression suggest novel therapies be assessed at earlier disease stages

Test of two prototype high-temperature superconducting transmission cables

Two 500-A class prototype high-temperature superconducting cables have been constructed by Southwire Company and tested at Oak Ridge National Laboratory (ORNL). In the first cable, no insulation was used to separate the individual HTS tapes. In the second cable, Kapton tape was used to insulate the HTS tapes between successive layers for the study of AC loss and current distribution. The cables were tested with both DC and AC currents in liquid nitrogen from 77 to 69 K. Both cables achieved DC critical current, I{sub c} greater than 500 A. A calorimetric technique that measures the cable temperature rise under ac currents was used to measure the ac loss of the cables. The un-insulated cable showed a cryoresistive behavior under the 60 Hz AC currents. The insulated cable started to show measurable loss at current where there was corresponding resistive loss

Communications Biophysics

Contains reports on five research projects.National Institutes of Health (Grant 5 P01 GM14940-03)National Institutes of Health (Grant 5 TOl GM01555-03)National Aeronautics and Space Administration (Grant NGL 22-009-304

Informatics Enhanced SNP Microarray Analysis of 30 Miscarriage Samples Compared to Routine Cytogenetics

Purpose: The metaphase karyotype is often used as a diagnostic tool in the setting of early miscarriage; however this technique has several limitations. We evaluate a new technique for karyotyping that uses single nucleotide polymorphism microarrays (SNP). This technique was compared in a blinded, prospective fashion, to the traditional metaphase karyotype. Methods: Patients undergoing dilation and curettage for first trimester miscarriage between February and August 2010 were enrolled. Samples of chorionic villi were equally divided and sent for microarray testing in parallel with routine cytogenetic testing. Results: Thirty samples were analyzed, with only four discordant results. Discordant results occurred when the entire genome was duplicated or when a balanced rearrangement was present. Cytogenetic karyotyping took an average of 29 days while microarray-based karytoyping took an average of 12 days. Conclusions: Molecular karyotyping of POC after missed abortion using SNP microarray analysis allows for the ability to detect maternal cell contamination and provides rapid results with good concordance to standard cytogenetic analysis

Impact of high-risk prenatal screening results for 22q11.2 deletion syndrome on obstetric and neonatal management: Secondary analysis from the SMART study

Objective One goal of prenatal genetic screening is to optimize perinatal care and improve infant outcomes. We sought to determine whether high-risk cfDNA screening for 22q11.2 deletion syndrome (22q11.2DS) affected prenatal or neonatal management. Methods This was a secondary analysis from the SMART study. Patients with high-risk cfDNA results for 22q11.2DS were compared with the low-risk cohort for pregnancy characteristics and obstetrical management. To assess differences in neonatal care, we compared high-risk neonates without prenatal genetic confirmation with a 1:1 matched low-risk cohort. Results Of 18,020 eligible participants enrolled between 2015 and 2019, 38 (0.21%) were high-risk and 17,982 (99.79%) were low-risk for 22q11.2DS by cfDNA screening. High-risk participants had more prenatal diagnostic testing (55.3%; 21/38 vs. 2.0%; 352/17,982, p < 0.001) and fetal echocardiography (76.9%; 10/13 vs. 19.6%; 10/51, p < 0.001). High-risk newborns without prenatal diagnostic testing had higher rates of neonatal genetic testing (46.2%; 6/13 vs. 0%; 0/51, P < 0.001), echocardiography (30.8%; 4/13 vs. 4.0%; 2/50, p = 0.013), evaluation of calcium levels (46.2%; 6/13 vs. 4.1%; 2/49, P < 0.001) and lymphocyte count (53.8%; 7/13 vs. 15.7%; 8/51, p = 0.008). Conclusions High-risk screening results for 22q11.2DS were associated with higher rates of prenatal and neonatal diagnostic genetic testing and other 22q11.2DS-specific evaluations. However, these interventions were not universally performed, and >50% of high-risk infants were discharged without genetic testing, representing possible missed opportunities to improve outcomes for affected individuals

Science Communication as a Collective Intelligence Endeavor: A Manifesto and Examples for Implementation

Effective science communication is challenging when scientific messages are informed by a continually updating evidence base and must often compete against misinformation. We argue that we need a new program of science communication as collective intelligence—a collaborative approach, supported by technology. This would have four key advantages over the typical model where scientists communicate as individuals: scientific messages would be informed by (a) a wider base of aggregated knowledge, (b) contributions from a diverse scientific community, (c) participatory input from stakeholders, and (d) better responsiveness to ongoing changes in the state of knowledge

Heritability and Phenotypic Variation of Canine Hip Dysplasia Radiographic Traits in a Cohort of Australian German Shepherd Dogs

Canine Hip Dysplasia (CHD) is a common, painful and debilitating orthopaedic disorder of dogs with a partly genetic, multifactorial aetiology. Worldwide, potential breeding dogs are evaluated for CHD using radiographically based screening schemes such as the nine ordinally-scored British Veterinary Association Hip Traits (BVAHTs). The effectiveness of selective breeding based on screening results requires that a significant proportion of the phenotypic variation is caused by the presence of favourable alleles segregating in the population. This proportion, heritability, was measured in a cohort of 13,124 Australian German Shepherd Dogs born between 1976 and 2005, displaying phenotypic variation for BVAHTs, using ordinal, linear and binary mixed models fitted by a Restricted Maximum Likelihood method. Heritability estimates for the nine BVAHTs ranged from 0.14–0.24 (ordinal models), 0.14–0.25 (linear models) and 0.12–0.40 (binary models). Heritability for the summed BVAHT phenotype was 0.30±0.02. The presence of heritable variation demonstrates that selection based on BVAHTs has the potential to improve BVAHT scores in the population. Assuming a genetic correlation between BVAHT scores and CHD-related pain and dysfunction, the welfare of Australian German Shepherds can be improved by continuing to consider BVAHT scores in the selection of breeding dogs, but that as heritability values are only moderate in magnitude the accuracy, and effectiveness, of selection could be improved by the use of Estimated Breeding Values in preference to solely phenotype based selection of breeding animals

Local flexibility in feeding behaviour and contrasting microhabitat use of an omnivore across latitudes

As the environment is getting warmer and species are redistributed, consumers can be forced to adjust their interactions with available prey, and this could have cascading effects within food webs. To better understand the capacity for foraging flexibility, our study aimed to determine the diet variability of an ectotherm omnivore inhabiting kelp forests, the sea urchin Echinus esculentus, along its entire latitudinal distribution in the northeast Atlantic. Using a combination of gut content and stable isotope analyses, we determined the diet and trophic position of sea urchins at sites in Portugal (42° N), France (49° N), southern Norway (63° N), and northern Norway (70° N), and related these results to the local abundance and distribution of putative food items. With mean estimated trophic levels ranging from 2.4 to 4.6, omnivory and diet varied substantially within and between sites but not across latitudes. Diet composition generally reflected prey availability within epiphyte or understorey assemblages, with local affinities demonstrating that the sea urchin adjusts its foraging to match the small-scale distribution of food items. A net “preference” for epiphytic food sources was found in northern Norway, where understorey food was limited compared to other regions. We conclude that diet change may occur in response to food source redistribution at multiple spatial scales (microhabitats, sites, regions). Across these scales, the way that key consumers alter their foraging in response to food availability can have important implication for food web dynamics and ecosystem functions along current and future environmental gradients

Communications Biophysics

Contains research objectives, summary of research and reports on three research projects.National Institutes of Health (Grant 5 PO1 GM14940-04)National Institutes of Health (Grant 5 TOl GM01555-04)National Aeronautics and Space Administration (Grant NGL 22-009-304