A Mercury orbiter mission is challenging from thermal and mass perspectives. The Mercury Surface, Space Environment, Geochemistry, and Ranging (MESSENGER) mission overcomes these challenges while ...avoiding esoteric technologies by using an innovative approach with commonly available materials, minimal moving parts, and maximum heritage. This approach yields a spacecraft with good margins in all categories and low technical risk. The key concepts are a ceramic-cloth sunshade, an integrated lightweight structure and high- performance propulsion system, and a solar array incorporating optical solar reflectors (OSRs). The sunshade maintains the spacecraft at room temperature. The integrated structure and propulsion system provides ample mass margin. The solar array with OSRs, which has already undergone significant testing, provides thermal margin even if the panels are inadvertently pointed directly at the Sun at 0.3 AU.
0.3
AU
.
Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk ...stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS.
We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8).
Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes.
Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms.
We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.
Display omitted
•HBCs display a combination of HB and HCC histological and molecular features.•HBCs are genetically unstable hepatocellular neoplasms with higher mutation and CNA burdens than HBs.•HBCs are associated with poor outcomes and patients may benefit from specialized aggressive therapeutic algorithms.
Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ...'interrogator' that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.
We have investigated the in vivo safety, efficacy, and persistence of autologous Epstein Barr virus (EBV)–specific cytotoxic T lymphocytes (CTLs) for the treatment of solid organ transplant (SOT) ...recipients at high risk for EBV-associated posttransplantation lymphoproliferative disease (PTLD). EBV-CTLs generated from 35 patients expanded with normal kinetics contained both CD8 and CD4 lymphocytes and produced significant specific killing of autologous EBV-transformed B lymphoblastoid cell lines (LCLs). Twelve SOT recipients at high risk for PTLD, or with active disease, received autologous CTL infusions without toxicity. Real-time polymerase chain reaction (PCR) monitoring of EBV-DNA showed a transient increase in plasma EBV-DNA suggestive of lysis of EBV-infected cells, although there was no consistent decrease in virus load in peripheral-blood mononuclear cells. Interferon-γ enzyme-linked immunospot (ELISPOT) assay and tetramer analysis showed an increase in the frequency of EBV-responsive T cells, which returned to preinfusion levels after 2 to 6 months. None of the treated patients developed PTLD. One patient with liver PTLD showed a complete response, and one with ocular disease has had a partial response stable for over one year. These data are consistent with an expansion and persistence of adoptively transferred EBV-CTLs that is limited in the presence of continued immunosuppression but that nonetheless produces clinically useful antiviral activity.
The evaluation of long‐term cellular immunity to EBV in pediatric orthotopic liver transplant (OLT) recipients after treatment with the humanized anti‐CD20 monoclonal antibody (Rituximab) has not yet ...been explored. At our institution, one child with EBV‐related mononucleosis‐like syndrome and five children with polymorphic‐EBV‐PTLD occurring 6–88 months after OLT were treated with Rituximab. Treatment was well tolerated. All children achieved complete remission. After Rituximab, B‐lymphocytes were undetectable in the peripheral blood and EBV‐load, monitored with real‐time PCR, decreased to undetectable levels in all children from >4000 copies/μg DNA at diagnosis. Four to eight months after Rituximab, EBV‐load increased (>4000 copies/μg DNA) in four children, and PTLD recurred in three. Their frequency of EBV‐specific T‐cell precursors, measured by Elispot analysis, remained lower than in healthy controls. Rituximab effectively induced regression of PTLD in OLT recipients. However, EBV‐specific T‐cell immunocompetence, which may be crucial for the long‐term control of EBV‐mediated proliferation, did not improve.
Here we describe of an ‘Interrogator’ instrument that uses liquid-handling robotics, a custom software package, and an integrated mobile microscope to enable automated culture, perfusion, medium ...addition, fluidic linking, sample collection, and
in situ
microscopic imaging of up to 10 Organ Chips inside a standard tissue culture incubator. The automated Interrogator platform maintained the viability and organ-specific functions of 8 different vascularized, 2-channel, Organ Chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier (BBB), and brain) for 3 weeks in culture when intermittently fluidically coupled through their medium reservoirs and endothelium-lined vascular channels using a common blood substitute medium. When an inulin tracer was perfused through the multi-organ Human Body-on-Chips (HuBoC) fluidic network, quantitative distributions of this tracer could be accurately predicted using a physiologically-based multi-compartmental reduced order (MCRO)
in silico
model of the experimental system derived from spatio-temporal transport equations and experimental data. This automated culture platform enables non-invasive imaging of cells within human Organ Chips and repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling, which should facilitate future HuBoc studies and pharmacokinetics (PK) analysis
in vitro
.
Comparison of the professional activities, level of satisfaction, and working conditions reported in a 1966 mailed questionnaire survey of over six hundred NASW hospital-based social workers and ...nearly five hundred NASW social workers who functioned in nonhos- pital settings reveals (a) some notable differences in the configuration of professional ac- tivities (work roles) reported by the two groups, (b) remarkable similarity between the two groups regarding the extent of their satisfaction with their respective work settings, and (c) both similarities and differences in the nature and extent of specific working conditions reported as posing problems for the two groups.
PDF
