Clinical report : one year of treatment of Proteus syndrome with miransertib (ARQ 092)

A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the AKT1 c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones, asymmetric spinal overgrowth with thoracolumbar scoliosis, dilatation of the inferior vena cava, testicular cystadenoma, bilateral knee deformities, macrodactyly, and apparent intellectual disability. Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor initially developed for cancer therapeutics, now being evaluated for the treatment of PS. After baseline evaluation, the patient started unblinded treatment of 10 mg oral miransertib daily (∼5 mg/m2/day), escalated to 30 mg daily (∼15 mg/m2/day), and then to 50 mg daily (∼25 mg/m2/day) after 3 mo of treatment. Adverse events included dry mouth, one episode of gingivostomatitis, and loose, painful dentition due to preexisting periodontal disease, all of which resolved spontaneously. After 11 mo of treatment, the patient reported improved general well-being, increased mobility of the ankle, spine, and hands, a subjective decrease in size of the right facial bone overgrowth, and reduced areas of cerebriform connective tissue nevi on the soles. Whole-body MRI findings were stable without apparent disease progression. We conclude that 1 yr of treatment with miransertib was beneficial in this case

3D Cu Pyramid Array Grown on Planar Cu Foil for Stable and Dendrite-free Lithium Deposition

Lithium metal is recognized as the anticipated anode for rechargeable batteries because of its inherent physicochemical properties. Unfortunately, the industrialization of Li metal anodes (LMAs) has been entangled in some intractable problems stemming from the uncontrollable growth of Li dendrites, which could result in the issue of short-circuit, thereby leading to cell failure. Here, a three-dimensional structured Cu pyramid array (CPA@CF) is constructed on planar Cu foil (CF) by the simple electrodeposition method. Owing to the features of large surface area and 3D porous structure, the proposed CPA@CF not only can promote Li-ion diffusion and charge transfer, but also effectively slow down the volume change of Li. Consequently, an even and steady Li plating/stripping process up to 360 h is realized using such a CPA@CF current collector. The Li@CPA@CF|LiFePO4 full cell achieves an excellent Coulombic efficiency (CE) of 99.3 % for 160 cycles at 0.3 C with a superior capacity retention of 84.2 %

The Lantern Vol. 55, No. 1, Fall 1988

• The Third Grade Gorilla • Friend, I Am Not Yet A Poet • Twisted • The Final Journey • Ritu Miltonis • Hearthside • The Ogre • O Indestructible Everlasting • December 1, 1988 • Our Church • Louise • Gazebo For Learned Women • Hanging Mirror • Of Football and Flashlights • The Ragged Brown Peasant • Judgement of the Serpent • Sidewalk Wars • I Guess That\u27s Why I Went Awayhttps://digitalcommons.ursinus.edu/lantern/1133/thumbnail.jp

The Lantern Vol. 55, No. 1, Fall 1988

• The Third Grade Gorilla • Friend, I Am Not Yet A Poet • Twisted • The Final Journey • Ritu Miltonis • Hearthside • The Ogre • O Indestructible Everlasting • December 1, 1988 • Our Church • Louise • Gazebo For Learned Women • Hanging Mirror • Of Football and Flashlights • The Ragged Brown Peasant • Judgement of the Serpent • Sidewalk Wars • I Guess That\u27s Why I Went Awayhttps://digitalcommons.ursinus.edu/lantern/1133/thumbnail.jp

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease

The Science of Sungrazers, Sunskirters, and Other Near-Sun Comets

This review addresses our current understanding of comets that venture close to the Sun, and are hence exposed to much more extreme conditions than comets that are typically studied from Earth. The extreme solar heating and plasma environments that these objects encounter change many aspects of their behaviour, thus yielding valuable information on both the comets themselves that complements other data we have on primitive solar system bodies, as well as on the near-solar environment which they traverse. We propose clear definitions for these comets: We use the term near-Sun comets to encompass all objects that pass sunward of the perihelion distance of planet Mercury (0.307 AU). Sunskirters are defined as objects that pass within 33 solar radii of the Sun’s centre, equal to half of Mercury’s perihelion distance, and the commonly-used phrase sungrazers to be objects that reach perihelion within 3.45 solar radii, i.e. the fluid Roche limit. Finally, comets with orbits that intersect the solar photosphere are termed sundivers. We summarize past studies of these objects, as well as the instruments and facilities used to study them, including space-based platforms that have led to a recent revolution in the quantity and quality of relevant observations. Relevant comet populations are described, including the Kreutz, Marsden, Kracht, and Meyer groups, near-Sun asteroids, and a brief discussion of their origins. The importance of light curves and the clues they provide on cometary composition are emphasized, together with what information has been gleaned about nucleus parameters, including the sizes and masses of objects and their families, and their tensile strengths. The physical processes occurring at these objects are considered in some detail, including the disruption of nuclei, sublimation, and ionisation, and we consider the mass, momentum, and energy loss of comets in the corona and those that venture to lower altitudes. The different components of comae and tails are described, including dust, neutral and ionised gases, their chemical reactions, and their contributions to the near-Sun environment. Comet-solar wind interactions are discussed, including the use of comets as probes of solar wind and coronal conditions in their vicinities. We address the relevance of work on comets near the Sun to similar objects orbiting other stars, and conclude with a discussion of future directions for the field and the planned ground- and space-based facilities that will allow us to address those science topics

Mosaic structural variation in children with developmental disorders

Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Genetics paired with CT angiography in the setting of atherosclerosis

Coronary artery disease (CAD) continues to be the leading cause of morbidity and mortality globally. Although the etiological mechanisms for CAD have not been fully elucidated, however, most would agree that atherosclerotic plaques progressively narrow the coronary arteries are the earliest manifestations and the principal cause of CAD. The emergence of revolutionary imaging technologies such as cardiac CT angiography, noninvasive computed fractional flow reserve and intravascular ultrasound provided the possibility of detecting and monitoring phenotypes associated with subclinical atherosclerosis. Meanwhile, with the widespread use of high-throughput genotyping pipeline such as next-generation sequencing, combined with big data-driven solutions in bioinformatics, translating the emerging genetic technologies into clinical practice and, therefore, provide valuable insight into the CAD study. In this review, we briefly describe the latest noninvasive cardiac imaging techniques for atherosclerosis-related phenotypes' detection, mainly focusing on the coronary artery calcification, plaque burden and stenosis. Furthermore, we highlight the state-of-the-art genotyping techniques and its application in the field of CAD translational study. Finally, we discuss the clinical relevance of genetics paired with noninvasive imaging in the setting of coronary artery atherosclerosis