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Comprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types.
Cancer cell lines are a cornerstone of cancer research but previous studies have shown that not all cell lines are equal in their ability to model primary tumors. Here we present a comprehensive pan-cancer analysis utilizing transcriptomic profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia to evaluate cell lines as models of primary tumors across 22 tumor types. We perform correlation analysis and gene set enrichment analysis to understand the differences between cell lines and primary tumors. Additionally, we classify cell lines into tumor subtypes in 9 tumor types. We present our pancreatic cancer results as a case study and find that the commonly used cell line MIA PaCa-2 is transcriptionally unrepresentative of primary pancreatic adenocarcinomas. Lastly, we propose a new cell line panel, the TCGA-110-CL, for pan-cancer studies. This study provides a resource to help researchers select more representative cell line models
Focused Deterrence and the Prevention of Violent Gun Injuries: Practice, Theoretical Principles, and Scientific Evidence
Focused deterrence strategies are a relatively new addition to a growing portfolio of evidence-based violent gun injury prevention practices available to policy makers and practitioners. These strategies seek to change offender behavior by understanding the underlying violence-producing dynamics and conditions that sustain recurring violent gun injury problems and by implementing a blended strategy of law enforcement, community mobilization, and social service actions. Consistent with documented public health practice, the focused deterrence approach identifies underlying risk factors and causes of recurring violent gun injury problems, develops tailored responses to these underlying conditions, and measures the impact of implemented interventions. This article reviews the practice, theoretical principles, and evaluation evidence on focused deterrence strategies. Although more rigorous randomized studies are needed, the available empirical evidence suggests that these strategies generate noteworthy gun violence reduction impacts and should be part of a broader portfolio of violence prevention strategies available to policy makers and practitioners
Ready or not? Expectations of faculty and medical students for clinical skills preparation for clerkships
Background: Preclerkship clinical-skills training has received increasing attention as a foundational preparation for clerkships. Expectations among medical students and faculty regarding the clinical skills and level of skill mastery needed for starting clerkships are unknown. Medical students, faculty teaching in the preclinical setting, and clinical clerkship faculty may have differing expectations of students entering clerkships. If students' expectations differ from faculty expectations, students may experience anxiety. Alternately, congruent expectations among students and faculty may facilitate integrated and seamless student transitions to clerkships. Aims: To assess the congruence of expectations among preclerkship faculty, clerkship faculty, and medical students for the clinical skills and appropriate level of clinical-skills preparation needed to begin clerkships. Methods: Investigators surveyed preclinical faculty, clerkship faculty, and medical students early in their basic clerkships at a North American medical school that focuses on preclerkship clinical-skills development. Survey questions assessed expectations for the appropriate level of preparation in basic and advanced clinical skills for students entering clerkships. Results: Preclinical faculty and students had higher expectations than clerkship faculty for degree of preparation in most basic skills. Students had higher expectations than both faculty groups for advanced skills preparation. Conclusions: Preclinical faculty, clerkship faculty, and medical students appear to have different expectations of clinical-skills training needed for clerkships. As American medical schools increasingly introduce clinical-skills training prior to clerkships, more attention to alignment, communication, and integration between preclinical and clerkship faculty will be important to establish common curricular agendas and increase integration of student learning. Clarification of skills expectations may also alleviate student anxiety about clerkships and enhance their learning
A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies
A promising direction in drug development is to exploit the ability of
natural killer cells to kill antibody-labeled target cells. Monoclonal
antibodies and drugs designed to elicit this effect typically bind cell-surface
epitopes that are overexpressed on target cells but also present on other
cells. Thus it is important to understand adhesion of cells by antibodies and
similar molecules. We present an equilibrium model of such adhesion,
incorporating heterogeneity in target cell epitope density and epitope
immobility. We compare with experiments on the adhesion of Jurkat T cells to
bilayers containing the relevant natural killer cell receptor, with adhesion
mediated by the drug alefacept. We show that a model in which all target cell
epitopes are mobile and available is inconsistent with the data, suggesting
that more complex mechanisms are at work. We hypothesize that the immobile
epitope fraction may change with cell adhesion, and we find that such a model
is more consistent with the data. We also quantitatively describe the parameter
space in which binding occurs. Our results point toward mechanisms relating
epitope immobility to cell adhesion and offer insight into the activity of an
important class of drugs.Comment: 13 pages, 5 figure
Sparse Matrix-Based HPC Tomography
Tomographic imaging has benefited from advances in X-ray sources, detectors
and optics to enable novel observations in science, engineering and medicine.
These advances have come with a dramatic increase of input data in the form of
faster frame rates, larger fields of view or higher resolution, so high
performance solutions are currently widely used for analysis. Tomographic
instruments can vary significantly from one to another, including the hardware
employed for reconstruction: from single CPU workstations to large scale hybrid
CPU/GPU supercomputers. Flexibility on the software interfaces and
reconstruction engines are also highly valued to allow for easy development and
prototyping. This paper presents a novel software framework for tomographic
analysis that tackles all aforementioned requirements. The proposed solution
capitalizes on the increased performance of sparse matrix-vector multiplication
and exploits multi-CPU and GPU reconstruction over MPI. The solution is
implemented in Python and relies on CuPy for fast GPU operators and CUDA kernel
integration, and on SciPy for CPU sparse matrix computation. As opposed to
previous tomography solutions that are tailor-made for specific use cases or
hardware, the proposed software is designed to provide flexible, portable and
high-performance operators that can be used for continuous integration at
different production environments, but also for prototyping new experimental
settings or for algorithmic development. The experimental results demonstrate
how our implementation can even outperform state-of-the-art software packages
used at advanced X-ray sources worldwide
Predictability of evolutionary trajectories in fitness landscapes
Experimental studies on enzyme evolution show that only a small fraction of
all possible mutation trajectories are accessible to evolution. However, these
experiments deal with individual enzymes and explore a tiny part of the fitness
landscape. We report an exhaustive analysis of fitness landscapes constructed
with an off-lattice model of protein folding where fitness is equated with
robustness to misfolding. This model mimics the essential features of the
interactions between amino acids, is consistent with the key paradigms of
protein folding and reproduces the universal distribution of evolutionary rates
among orthologous proteins. We introduce mean path divergence as a quantitative
measure of the degree to which the starting and ending points determine the
path of evolution in fitness landscapes. Global measures of landscape roughness
are good predictors of path divergence in all studied landscapes: the mean path
divergence is greater in smooth landscapes than in rough ones. The
model-derived and experimental landscapes are significantly smoother than
random landscapes and resemble additive landscapes perturbed with moderate
amounts of noise; thus, these landscapes are substantially robust to mutation.
The model landscapes show a deficit of suboptimal peaks even compared with
noisy additive landscapes with similar overall roughness. We suggest that
smoothness and the substantial deficit of peaks in the fitness landscapes of
protein evolution are fundamental consequences of the physics of protein
folding.Comment: 14 pages, 7 figure
Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses
<p><b>Background:</b> The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.</p>
<p><b>Methods:</b> The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.</p>
<p><b>Results:</b> Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.</p>
<p><b>Conclusion:</b> With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.</p>
Use of an Anaerobic Chamber Environment for the Assay of Endogenous Cellular Protein-Tyrosine Phosphatase Activities
Protein-tyrosine phosphatases (PTPases) have a catalytic cysteine residue whose reduced state is integral to the reaction mechanism. Since exposure to air can artifactually oxidize this highly reactive thiol, PTPase assays have typically used potent reducing agents to reactivate the enzymes present; however, this approach does not allow for the measurement of the endogenous PTPase activity directly isolated from the in vivo cellular environment. Here we provide a method for using an anaerobic chamber to preserve the activity of the total PTPase complement in a tissue lysate or of an immunoprecipitated PTPase homolog to characterize their endogenous activation state. Comparison with a sample treated with biochemical reducing agents allows the determination of the activatable (reducible) fraction of the endogenous PTPase pool
Spontaneous symmetry breaking in a quenched ferromagnetic spinor Bose condensate
A central goal in condensed matter and modern atomic physics is the
exploration of many-body quantum phases and the universal characteristics of
quantum phase transitions in so far as they differ from those established for
thermal phase transitions. Compared with condensed-matter systems, atomic gases
are more precisely constructed and also provide the unique opportunity to
explore quantum dynamics far from equilibrium. Here we identify a second-order
quantum phase transition in a gaseous spinor Bose-Einstein condensate, a
quantum fluid in which superfluidity and magnetism, both associated with
symmetry breaking, are simultaneously realized. Rb spinor condensates
were rapidly quenched across this transition to a ferromagnetic state and
probed using in-situ magnetization imaging to observe spontaneous symmetry
breaking through the formation of spin textures, ferromagnetic domains and
domain walls. The observation of topological defects produced by this symmetry
breaking, identified as polar-core spin-vortices containing non-zero spin
current but no net mass current, represents the first phase-sensitive in-situ
detection of vortices in a gaseous superfluid.Comment: 6 pages, 4 figure
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