Neutron Characterization for Additive Manufacturing

Oak Ridge National Laboratory (ORNL) is leveraging decades of experience in neutron characterization of advanced materials together with resources such as the Spallation Neutron Source (SNS) and the High Flux Isotope Reactor (HFIR) shown in Fig. 1 to solve challenging problems in additive manufacturing (AM). Additive manufacturing, or three-dimensional (3-D) printing, is a rapidly maturing technology wherein components are built by selectively adding feedstock material at locations specified by a computer model. The majority of these technologies use thermally driven phase change mechanisms to convert the feedstock into functioning material. As the molten material cools and solidifies, the component is subjected to significant thermal gradients, generating significant internal stresses throughout the part (Fig. 2). As layers are added, inherent residual stresses cause warping and distortions that lead to geometrical differences between the final part and the original computer generated design. This effect also limits geometries that can be fabricated using AM, such as thin-walled, high-aspect- ratio, and overhanging structures. Distortion may be minimized by intelligent toolpath planning or strategic placement of support structures, but these approaches are not well understood and often "Edisonian" in nature. Residual stresses can also impact component performance during operation. For example, in a thermally cycled environment such as a high-pressure turbine engine, residual stresses can cause components to distort unpredictably. Different thermal treatments on as-fabricated AM components have been used to minimize residual stress, but components still retain a nonhomogeneous stress state and/or demonstrate a relaxation-derived geometric distortion. Industry, federal laboratory, and university collaboration is needed to address these challenges and enable the U.S. to compete in the global market. Work is currently being conducted on AM technologies at the ORNL Manufacturing Demonstration Facility (MDF) sponsored by the DOE's Advanced Manufacturing Office. The MDF is focusing on R&D of both metal and polymer AM pertaining to in-situ process monitoring and closed-loop controls; implementation of advanced materials in AM technologies; and demonstration, characterization, and optimization of next-generation technologies. ORNL is working directly with industry partners to leverage world-leading facilities in fields such as high performance computing, advanced materials characterization, and neutron sciences to solve fundamental challenges in advanced manufacturing. Specifically, MDF is leveraging two of the world's most advanced neutron facilities, the HFIR and SNS, to characterize additive manufactured components

Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling

Chemo/radio-therapy resistance to the deadly pancreatic cancer is mainly due to the failure to kill pancreatic cancer stem cells (CSCs). Signal transducer and activator of transcription 3 (STAT3) is activated in pancreatic CSCs and, therefore, may be a valid target for overcoming therapeutic resistance. Here we investigated the potential of STAT3 inhibition in sensitizing pancreatic cancer to chemo/radio-therapy. We found that the levels of nuclear pSTAT3 in pancreatic cancer correlated with advanced tumor grade and poor patient outcome. Liposomal delivery of a STAT3 inhibitor FLLL32 (Lip-FLLL32) inhibited STAT3 phosphorylation and STAT3 target genes in pancreatic cancer cells and tumors. Consequently, Lip-FLLL32 suppressed pancreatic cancer cell growth, and exhibited synergetic effects with gemcitabine and radiation treatment in vitro and in vivo. Furthermore, Lip-FLLL32 reduced ALDH1-positive CSC population and modulated several potential stem cell markers. These results demonstrate that Lip-FLLL32 suppresses pancreatic tumor growth and sensitizes pancreatic cancer cells to radiotherapy through inhibition of CSCs in a STAT3-dependent manner. By targeting pancreatic CSCs, Lip-FLLL32 provides a novel strategy for pancreatic cancer therapy via overcoming radioresistance

Pathogenesis of aerosolized Eastern Equine Encephalitis virus infection in guinea pigs

Mice and guinea pigs were experimentally exposed to aerosols containing regionally-distinct strains (NJ1959 or ArgM) of eastern equine encephalitis virus (EEEV) at two exclusive particle size distributions. Mice were more susceptible to either strain of aerosolized EEEV than were guinea pigs; however, clinical signs indicating encephalitis were more readily observed in the guinea pigs. Lower lethality was observed in both species when EEEV was presented at the larger aerosol distribution (> 6 μm), although the differences in the median lethal dose (LD50) were not significant. Virus isolation and immunohistochemistry indicated that virus invaded the brains of guinea pigs within one day postexposure, regardless of viral strain or particle size distribution. Immunohistochemistry further demonstrated that neuroinvasion occurred through the olfactory system, followed by transneuronal spread to all regions of the brain. Olfactory bipolar neurons and neurons throughout the brain were the key viral targets. The main microscopic lesions in infected guinea pigs were neuronal necrosis, inflammation of the meninges and neuropil of the brain, and vasculitis in the brain. These results indicate that guinea pigs experimentally infected by aerosolized EEEV recapitulate several key features of fatal human infection and thus should serve as a suitable animal model for aerosol exposure to EEEV

Epigenetic Regulation of Mesenchymal Stem Cells: A Focus on Osteogenic and Adipogenic Differentiation

Stem cells are characterized by their capability to self-renew and terminally differentiate into multiple cell types. Somatic or adult stem cells have a finite self-renewal capacity and are lineage-restricted. The use of adult stem cells for therapeutic purposes has been a topic of recent interest given the ethical considerations associated with embryonic stem (ES) cells. Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into osteogenic, adipogenic, chondrogenic, or myogenic lineages. Owing to their ease of isolation and unique characteristics, MSCs have been widely regarded as potential candidates for tissue engineering and repair. While various signaling molecules important to MSC differentiation have been identified, our complete understanding of this process is lacking. Recent investigations focused on the role of epigenetic regulation in lineage-specific differentiation of MSCs have shown that unique patterns of DNA methylation and histone modifications play an important role in the induction of MSC differentiation toward specific lineages. Nevertheless, MSC epigenetic profiles reflect a more restricted differentiation potential as compared to ES cells. Here we review the effect of epigenetic modifications on MSC multipotency and differentiation, with a focus on osteogenic and adipogenic differentiation. We also highlight clinical applications of MSC epigenetics and nuclear reprogramming

The Giant Radio Array for Neutrino Detection

High-energy neutrino astronomy will probe the working of the most violent phenomena in the Universe. The Giant Radio Array for Neutrino Detection (GRAND) project consists of an array of ∼ 105 radio antennas deployed over ∼ 200 000 km2 in a mountainous site. It aims at detecting high-energy neutrinos via the measurement of air showers induced by the decay in the atmosphere of τ leptons produced by the interaction of cosmic neutrinos under the Earth surface. Our objective with GRAND is to reach a neutrino sensitivity of 5 × 10−11E−2 GeV−1 cm−2 s−1 sr−1 above 3 × 1016 eV. This sensitivity ensures the detection of cosmogenic neutrinos in the most pessimistic source models, and up to 100 events per year are expected for the standard models. GRAND would also probe the neutrino signals produced at the potential sources of UHECRs

Defective Osteogenic Differentiation in the Development of Osteosarcoma

Osteosarcoma (OS) is associated with poor prognosis due to its high incidence of metastasis and chemoresistance. It often arises in areas of rapid bone growth in long bones during the adolescent growth spurt. Although certain genetic conditions and alterations increase the risk of developing OS, the molecular pathogenesis is poorly understood. Recently, defects in differentiation have been linked to cancers, as they are associated with high cell proliferation. Treatments overcoming these defects enable terminal differentiation and subsequent tumor inhibition. OS development may be associated with defects in osteogenic differentiation. While early regulators of osteogenesis are unable to bypass these defects, late osteogenic regulators, including Runx2 and Osterix, are able to overcome some of the defects and inhibit tumor propagation through promoting osteogenic differentiation. Further understanding of the relationship between defects in osteogenic differentiation and tumor development holds tremendous potential in treating OS

Sexual Priming, Gender Stereotyping, and Likelihood to Sexually Harass: Examining the Cognitive Effects of Playing a Sexually-Explicit Video Game

The present study examines the short-term cognitive effects of playing a sexually explicit video game with female “objectification” content on male players. Seventy-four male students from a university in California, U.S. participated in a laboratory experiment. They were randomly assigned to play either a sexually-explicit game or one of two control games. Participants’ cognitive accessibility to sexual and sexually objectifying thoughts was measured in a lexical decision task. A likelihood-to-sexually-harass scale was also administered. Results show that playing a video game with the theme of female “objectification” may prime thoughts related to sex, encourage men to view women as sex objects, and lead to self-reported tendencies to behave inappropriately towards women in social situations

A Pilot Study of Circulating miRNAs as Potential Biomarkers of Early Stage Breast Cancer

To date, there are no highly sensitive and specific minimally invasive biomarkers for detection of breast cancer at an early stage. The occurrence of circulating microRNAs (miRNAs) in blood components (including serum and plasma) has been repeatedly observed in cancer patients as well as healthy controls. Because of the significance of miRNA in carcinogenesis, circulating miRNAs in blood may be unique biomarkers for early and minimally invasive diagnosis of human cancers. The objective of this pilot study was to discover a panel of circulating miRNAs as potential novel breast cancer biomarkers.Using microarray-based expression profiling followed by Real-Time quantitative Polymerase Cycle Reaction (RT-qPCR) validation, we compared the levels of circulating miRNAs in plasma samples from 20 women with early stage breast cancer (10 Caucasian American (CA) and 10 African American (AA)) and 20 matched healthy controls (10 CAs and 10 AAs). Using the significance level of p<0.05 constrained by at least two-fold expression change as selection criteria, we found that 31 miRNAs were differentially expressed in CA study subjects (17 up and 14 down) and 18 miRNAs were differentially expressed in AA study subjects (9 up and 9 down). Interestingly, only 2 differentially expressed miRNAs overlapped between CA and AA study subjects. Using receiver operational curve (ROC) analysis, we show that not only up-regulated but also down-regulated miRNAs can discriminate patients with breast cancer from healthy controls with reasonable sensitivity and specificity. To further explore the potential roles of these circulating miRNAs in breast carcinogenesis, we applied pathway-based bioinformatics exploratory analysis and predicted a number of significantly enriched pathways which are predicted to be regulated by these circulating miRNAs, most of which are involved in critical cell functions, cancer development and progression.Our observations from this pilot study suggest that the altered levels of circulating miRNAs might have great potential to serve as novel, noninvasive biomarkers for early detection of breast cancer