The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events ...that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.
The Sandia Fracture Challenges provide a forum for the mechanics community to assess its ability to predict ductile fracture through a blind, round-robin format where mechanicians are challenged to ...predict the deformation and failure of an arbitrary geometry given experimental calibration data. The Third Challenge (SFC3) required participants to predict fracture in an additively manufactured (AM) 316L stainless steel bar containing through holes and internal cavities that could not have been conventionally machined. The volunteer participants were provided extensive data including tension and notched tensions tests of 316L specimens built on the same build-plate as the Challenge geometry, micro-CT scans of the Challenge specimens and geometric measurements of the feature based on the scans, electron backscatter diffraction (EBSD) information on grain texture, and post-test fractography of the calibration specimens. Surprisingly, the global behavior of the SFC3 geometry specimens had modest variability despite being made of AM metal, with all of the SFC3 geometry specimens failing under the same failure mode. This is attributed to the large stress concentrations from the holes overwhelming the stochastic local influence of the AM voids and surface roughness. The teams were asked to predict a number of quantities of interest in the response based on global and local measures that were compared to experimental data, based partly on Digital Image Correlation (DIC) measurements of surface displacements and strains, including predictions of variability in the resulting fracture response, as the basis for assessment of the predictive capabilities of the modeling and simulation strategies. Twenty-one teams submitted predictions obtained from a variety of methods: the finite element method (FEM) or the mesh-free, peridynamic method; solvers with explicit time integration, implicit time integration, or quasi-statics; fracture methods including element deletion, peridynamics with bond damage, XFEM, damage (stiffness degradation), and adaptive remeshing. These predictions utilized many different material models: plasticity models including J2 plasticity or Hill yield with isotropic hardening, mixed Swift-Voce hardening, kinematic hardening, or custom hardening curves; fracture criteria including GTN model, Hosford-Coulomb, triaxiality-dependent strain, critical fracture energy, damage-based model, critical void volume fraction, and Johnson-Cook model; and damage evolution models including damage accumulation and evolution, crack band model, fracture energy, displacement value threshold, incremental stress triaxiality, Cocks-Ashby void growth, and void nucleation, growth, and coalescence. Teams used various combinations of calibration data from tensile specimens, the notched tensile specimens, and literature data. A detailed comparison of results based of these different methods is presented in this paper to suggest a set of best practices for modeling ductile fracture in situations like the SFC3 AM-material problem. All blind predictions identified the nominal crack path and initiation location correctly. The SFC3 participants generally fared better in their global predictions of deformation and failure than the participants in the previous Challenges, suggesting the relative maturity of the models used and adoption of best practices from previous Challenges. This paper provides detailed analyses of the results, including discussion of the utility of the provided data, challenges of the experimental-numerical comparison, defects in the AM material, and human factors.
Determining the relative energies of transport states in organic semiconductors is critical to understanding the properties of electronic devices and in designing device stacks. Futhermore, defect ...states are also highly important and can greatly impact material properties and device performance. Recently, energy‐resolved electrochemical impedance spectroscopy (ER‐EIS) is developed to probe both the ionization energy (IE) and electron affinity (EA) as well as sub‐bandgap defect states in organic semiconductors. Herein, ER‐EIS is compared to cyclic voltammetry (CV) and photoemission spectroscopies for extracting IE and EA values, and to photothermal deflection spectroscopy (PDS) for probing defect states in both polymer and molecular organic semiconductors. The results show that ER‐EIS determined IE and EA are in better agreement with photoemission spectroscopy measurements as compared to CV for both polymer and molecular materials. Furthermore, the defect states detected by ER‐EIS agree with sub‐bandgap features detected by PDS. Surprisingly, ER‐EIS measurements of regiorandom and regioregular poly(3‐hexylthiophene) (P3HT) show clear defect bands that occur at significantly different energies. In regioregular P3HT the defect band is near the edge of the occupied states while it is near the edge of the unoccupied states in regiorandom P3HT.
Energy resolved electrochemical impedance spectroscopy (ER‐EIS) is compared to ultraviolet and inverse photoemission spectroscopy for HOMO and LUMO energy determination and to photothermal deflection spectroscopy (PDS) for defect state analysis. Defect states in ER‐EIS are directly linked to sub‐bandgap states in PDS, thereby providing information on whether these defect states would serve as hole or electron traps.
The National Academies of Sciences, Engineering, and Medicine 2016 report on the trauma care system recommended establishing a National Trauma Research Action Plan to strengthen and guide future ...trauma research. To address this recommendation, the Department of Defense funded a study to generate a comprehensive research agenda spanning the trauma and burn care continuum. Panels were created to conduct a gap analysis and identify high-priority research questions. The National Trauma Research Action Plan panel reported here addressed trauma systems and informatics.
Experts were recruited to identify current gaps in trauma systems research, generate research questions, and establish the priorities using an iterative Delphi survey approach from November 2019 through August 2020. Panelists were identified to ensure heterogeneity and generalizability, including military and civilian representation. Panelists were encouraged to use a PICO format to generate research questions: patient/population, intervention, compare/control, and outcome. In subsequent surveys, panelists prioritized each research question on a 9-point Likert scale, categorized as low-, medium-, and high-priority items. Consensus was defined as ≥60% agreement.
Twenty-seven subject matter experts generated 570 research questions, of which 427 (75%) achieved the consensus threshold. Of the consensus reaching questions, 209 (49%) were rated high priority, 213 (50%) medium priority, and 5 (1%) low priority. Gaps in understanding the broad array of interventions were identified, including those related to health care infrastructure, technology products, education/training, resuscitation, and operative intervention. The prehospital phase of care was highlighted as an area needing focused research.
This Delphi gap analysis of trauma systems and informatics research identified high-priority research questions that will help guide investigators and funding agencies in setting research priorities to continue to work toward Zero Preventable Deaths after trauma.
Therapeutic/Care Management; Level IV.
The functional role of human derived stromal cells in the tumor microenviornment of CNS metastases (CM) remain understudied. The purpose of the current study was to isolate and characterize stromal ...cells of the tumor microenvironment in CM. Four different patient-derived cell lines (PDCs) of stromal and one PDC of tumorigenic origin were generated from breast or lung CM. PDCs were analyzed by DNA/RNA sequencing, DNA methylation profiling, and immunophenotypic assays. The stromal derived PDCs were termed CNS metastasis-associated stromal cells (cMASCs). Functional analysis of cMASCs was tested by co-implanting them with tumorigenic cells in mice. cMASCs displayed normal genotypes compared with tumorigenic cell lines. RNA-seq and DNA methylation analyses demonstrated that cMASCs highly resembled each other, suggesting a common cell of origin. Additionally, cMASCs revealed gene expression signatures associated with cancer associated fibroblasts (CAFs), epithelial to mesenchymal transition, mesenchymal stem cells and expressed high levels of collagen. Functionally, cMASCs restricted tumor growth, and induced desmoplasia in vivo, suggesting that cMASCs may promote a protective host response to impede tumor growth. In summary, we demonstrated the isolation, molecular characterization and functional role of human derived cMASCs, a subpopulation of cells in the microenvironment of CM that have tumor inhibitory functions.
The detection of E-cyanomethanimine (E-HNCHCN) toward Sagittarius B2(N) is made by comparing the publicly available Green Bank Telescope (GBT) PRIMOS survey spectra to laboratory rotational spectra ...from a reaction product screening experiment. The experiment uses broadband molecular rotational spectroscopy to monitor the reaction products produced in an electric discharge source using a gas mixture of NH sub(3) and CH sub(3)CN. Several transition frequency coincidences between the reaction product screening spectra and previously unassigned interstellar rotational transitions in the PRIMOS survey have been assigned to E-cyanomethanimine. A total of eight molecular rotational transitions of this molecule between 9 and 50 GHz are observed with the GBT. E-cyanomethanimine, often called the HCN dimer, is an important molecule in prebiotic chemistry because it is a chemical intermediate in proposed synthetic routes of adenine, one of the two purine nucleobases found in DNA and RNA. New analyses of the rotational spectra of both E-cyanomethanimine and Z-cyanomethanimine that incorporate previous millimeter-wave measurements are also reported.
Studies suggest that exercise may be neuroprotective when implemented before the clinical presentation of Parkinson's disease (PD). Levels of brain-derived neurotrophic factor (BDNF), theorized to ...play a role in neuroprotection, are affected by its genotype and exercise. Here we explore this previously unstudied interaction on age at diagnosis and severity of symptoms.
76 participants with PD submitted buccal cells to determine BDNF genotype, completed the modified Lifetime Physical Activity Questionnaire to determine exercise habits, and were assessed using the Movement Disorder Society – Unified Parkinson's Disease Rating Scale III (MDS-UPDRS-III) and the Mini-Balance Evaluations Test (MBT). For aim 1 (age at diagnosis), 60 participants (age = 69.6 ± 7.4; males = 45, females = 15) were analyzed. For aim 2 (severity of symptoms), 54 participants (age = 70.0 ± 7.6; males = 41, females = 13) were analyzed.
The final hierarchical regression model for age at diagnosis produced an R2 = 0.146, p = .033; however, the only significant variable in the final model was average moderate physical activity from ages 20s to 40s (p = .009). The regression for MDS-UPDRS III was not significant; however, the regression for MBT was, p = .0499. In the final model, 23.1% of the variance was explained. Years since diagnosis (p = .014) and average vigorous physical activity from ages 20s to 40s (p = .047) were the only predictors in the final model.
While a strong interaction between BDNF genotype and lifetime physical activity was not observed, our results suggest that lifetime exercise may be neuroprotective in PD. Specifically, higher amounts of moderate PA were associated with an older age at diagnosis.
•This is the first study to show that pre-diagnosis exercise is associated with age at diagnosis.•Higher amounts of moderate physical activity were associated with an older age at diagnosis.•Every hour increase in weekly moderate physical activity from ages 20–40 was associated with a PD diagnosis 3 months later.
Evidence-based treatment and manualized psychotherapy have a recent but rich history. As interest and research have progressed, defining the role of treatment manuals in resident training and ...clinical practice has become more important. Although there is not a universal definition of treatment manual, most clinicians and researchers agree that treatment manuals are an essential piece of evidence-based therapy, and that despite several limitations, they offer advantages in training residents in psychotherapy. Requirements for resident training in psychotherapy have changed over the years, and treatment manuals offer a simple and straightforward way to meet training requirements. In a search limited to only depression, two treatment manuals emerged with the support of research regarding both clinical practice and resident training. In looking toward the future, it will be important for clinicians to remain updated on further advances in evidence based manualized treatment as a tool for training residents in psychotherapy, including recent developments in online and smartphone based treatments.
Trainees can easily access these psychopharmacologic treatment resources on evidence-based websites (e.g., Up-to-Date) as well as in evidence-based journals. ...the topics presented at grand rounds ...and journal club meetings in many general psychiatry residency training programs are nearly exclusively related to psychopharmacologic treatment. Cohen et al. also emphasize similar factors regarding dissemination: “a detailed description of the tested treatment, training in the treatment, and the compatibility of the treatment with a clinician’s usual intervention strategy” (5, p. 198). In response to this call to champion EBT, our goals for this project are to discover which psychotherapy manuals for the treatment of major depressive disorder (MDD) have evidence supporting their effectiveness, to highlight those which are available free of cost, and to promote the use of these resources in psychiatry residency training. Using manuals to train residents provides a structured approach which builds confidence and competence equipping residents with a solid foundation with the expectation that they will learn to use manuals flexibly, combine this activity with appropriate supervision, and build upon their foundation with relevant adjunctive materials throughout their careers.
There is an urgent need to introduce novel therapies that prevent death due to lung cancer CNS metastasis, which remains a clinically unmet need. Targeted molecular therapies and prophylactic ...measures might shift the current strategy and improve outcomes. Accordingly our study has focused on identifying novel monotherapies and combination therapies that are based on causal, actionable molecular derangements in lung cancer CNS metastasis, and which can be effectively targeted within the context of the brain microenvironment. We have recently established 6 novel patient-derived cell-lines and matching mouse xenograft models of lung CNS metastasis for preclinical testing of novel therapeutic approaches. Cell-lines were implanted intra-cardiacally for confirmation of CNS homing potential. Therapeutic selections for in vivo testing were based on systems biology-based analyses of the matching clinical material using genomic, epigenomic and phosphoproteomic analyses, which revealed systemic biochemical changes that are druggable. Matching datasets were generated for each cell-line and xenograft to ensure the effectiveness of models in representing the human disease. Primary lung tumors were analyzed when available (2/6 cases). Data analysis revealed defects in KRAS activation due to amplifications, mutations and signaling. Therefore, we proceeded to examine the anti-tumor effects of the MEK inhibitor, PD032591 for in vivo targeting of KRAS. There was >90% inhibition of tumor growth and prolonged survival of animals when treated for 14-30 days with PD032591 in an ectopic or orthotopic setting. Signaling architecture was analyzed pre and post treatment and demonstrated strong attenuation of phospho-ERK without concomitant activation of compensatory mechanisms. We are also currently performing a comprehensive functional screen to identify a synergistic combination strategy for use with PD032591 by testing over 300 clinically available compounds. This first-of-its-kind study has demonstrated a strong preclinical rationale for targeting MEK in lung cancer CNS metastasis with KRAS alterations.
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