Immune Activation following Irbesartan Treatment in a Colorectal Cancer Patient: A Case Study.

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.

Planar laser induced fluorescence mapping of a carbon laser produced plasma.

We present measurements of ion velocity distribution profiles obtained by laser induced fluorescence (LIF) on an explosive laser produced plasma. The spatiotemporal evolution of the resulting carbon ion velocity distribution was mapped by scanning through the Doppler-shifted absorption wavelengths using a tunable, diode-pumped laser. The acquisition of these data was facilitated by the high repetition rate capability of the ablation laser (1 Hz), which allowed for the accumulation of thousands of laser shots in short experimental times. By varying the intensity of the LIF beam, we were able to explore the effects of fluorescence power against the laser irradiance in the context of evaluating the saturation vs the non-saturation regime. The small size of the LIF beam led to high spatial resolution of the measurement compared to other ion velocity distribution measurement techniques, while the fast-gate operation mode of the camera detector enabled the measurement of the relevant electron transitions.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Proton deflectometry with in situ x-ray reference for absolute measurement of electromagnetic fields in high-energy-density plasmas.

We report a technique of proton deflectometry that uses a grid and an in situ reference x-ray grid image for precise measurements of magnetic fields in high-energy-density plasmas. A D3He fusion implosion provides a bright point source of both protons and x-rays, which is split into beamlets by a grid. The protons undergo deflections as they propagate through the plasma region of interest, whereas the x-rays travel along straight lines. The x-ray image, therefore, provides a zero-deflection reference image. The line-integrated magnetic fields are inferred from the shifts of beamlets between the deflected (proton) and reference (x-ray) images. We developed a system for analysis of these data, including automatic algorithms to find beamlet locations and to calculate their deflections from the reference image. The technique is verified in an experiment performed at OMEGA to measure a nonuniform magnetic field in vacuum and then applied to observe the interaction of an expanding plasma plume with the magnetic field.

Raster Thomson scattering in large-scale laser plasmas produced at high repetition rate.

We present optical Thomson scattering measurements of electron density and temperature in a large-scale (∼2 cm) exploding laser plasma produced by irradiating a solid target with a high-energy (5-10 J) laser pulse at a high repetition rate (1 Hz). The Thomson scattering diagnostic matches this high repetition rate. Unlike previous work performed in single shots at much higher energies, the instrument allows for point measurements anywhere inside the plasma by automatically translating the scattering volume using motorized stages as the experiment is repeated at 1 Hz. Measured densities around 4 × 1016 cm-3 and temperatures around 7 eV result in a scattering parameter near unity, depending on the distance from the target. The measured spectra show the transition from collective scattering close to the target to non-collective scattering at larger distances. Densities obtained by fitting the weakly collective spectra agree to within 10% with an irradiance calibration performed via Raman scattering in nitrogen.

Measurements of electron temperature in high-energy-density plasmas using gated x-ray pinhole imaging.

We present measurements of spatially and temporally resolved electron temperature in high-energy-density plasmas using gated x-ray pinhole imagers. A 2D image of bremsstrahlung x-ray self-emission from laser-driven plasma plumes is detected at the same time through two pinholes covered with different filter materials. By comparing the attenuated signal through each filter, a spatially resolved electron temperature as low as 0.1 keV can be estimated. Measurements of the plasma plume taken from different directions indicate that imaging through extended plasmas has a negligible effect on the temperature estimates. Methods for estimating the expected signal, selecting filters, and incorporating the response of the detector are discussed.

Measurements of ion velocity distributions in a large scale laser-produced plasma.

Laser-produced plasma velocity distributions are an important, but difficult quantity to measure. We present a non-invasive technique for measuring individual charge state velocity distributions of laser-produced plasmas using a high temporal and spectral resolution monochromator. The novel application of this technique is its ability to detect particles up to 7 m from their inception (significantly larger than most laboratory plasma astrophysics experiments, which take place at or below the millimeter scale). The design and assembly of this diagnostic is discussed in terms of maximizing the signal to noise ratio, maximizing the spatial and temporal resolution, and other potential use cases. The analysis and results of this diagnostic are demonstrated by directly measuring the time-of-flight velocity of all ion charge states in a laser produced carbon plasma.

Reference intervals and echocardiographic findings in Leonberger dogs.

INTRODUCTION: Leonbergers are large-breed dogs believed to be predisposed to dilated cardiomyopathy, yet the normal echocardiographic measurements of these dogs are unknown. The aim of this study was to describe echocardiographic findings and propose breed-specific reference intervals (RIs) for Leonbergers. ANIMALS: A total of 42 clinically healthy dogs were involved in this study. MATERIALS AND METHODS: This study was designed as a cross-sectional study of 42 Leonberger dogs undergoing complete transthoracic echocardiographic studies at a national show. Reference intervals were determined using robust method with bootstrapping. The effects of age, sex, and body weight (BW) on linear and volumetric dimensions were evaluated by regression analysis. Intra- and interobserver variability were evaluated by coefficient of variation from 10 of the studies. RESULTS: There were significant linear correlations with BW for many of the cardiac variables evaluated. However, despite the statistical significance, most regression equations had small slopes, necessitating large changes in BW for small changes in two-dimensional echocardiographic variables. As such, this study resulted in breed-specific RIs irrespective of BW. Trace mitral insufficiency (n = 18), trace aortic insufficiency (n = 15), or both (n = 1) was identified in 81% of dogs in this population. Coefficients of variation were <9% for all two-dimensional, volumetric, and motion mode measurements. CONCLUSIONS: This study describes echocardiographic findings and provides RIs, which may be useful in echocardiographic evaluations of Leonbergers and may aid in early identification of heart disease within the breed.

Direct Observations of Particle Dynamics in Magnetized Collisionless Shock Precursors in Laser-Produced Plasmas.

We present the first laboratory observations of time-resolved electron and ion velocity distributions in magnetized collisionless shock precursors. Thomson scattering of a probe laser beam was used to observe the interaction of a laser-driven, supersonic piston plasma expanding through an ambient plasma in an external magnetic field. From the Thomson-scattered spectra we measure time-resolved profiles of electron density, temperature, and ion flow speed, as well as spatially resolved magnetic fields from proton radiography. We observe direct evidence of the coupling between piston and ambient plasmas, including the acceleration of ambient ions driven by magnetic and pressure gradient electric fields, and deformation of the piston ion flow, key steps in the formation of magnetized collisionless shocks. Even before a shock has fully formed, we observe strong density compressions and electron heating associated with the pileup of piston ions. The results demonstrate that laboratory experiments can probe particle velocity distributions relevant to collisionless shocks, and can complement, and in some cases overcome, the limitations of similar measurements undertaken by spacecraft missions.

Quantitative assessment of two- and three-dimensional transthoracic and two-dimensional transesophageal echocardiography, computed tomography, and magnetic resonance imaging in normal canine hearts.

INTRODUCTION: The objective of the study was to evaluate the accuracy of two- and three-dimensional (2D, 3D) transthoracic echocardiography (TTE), 2D transesophageal echocardiography, and computed tomography angiography (CTA) compared with cardiac magnetic resonance imaging (CMR) in normal dogs and to assess repeatability of 2D and 3D TTE for the assessment of left ventricular (LV) and left atrial (LA) dimensions. ANIMALS: The study was performed on six healthy dogs. MATERIALS AND METHODS: Transthoracic echocardiography, transesophageal echocardiography, CTA, and CMR were performed on each dog. Right ventricular (RV) and LV volumes (in systole and diastole), ejection fraction (EF), and LA and right atrial (RA) volumes were assessed. Repeatability and intrarater and interrater measurements of variability were quantified by average coefficient of variation (CV) for 2D and 3D TTE. RESULTS: No clinically relevant differences in LV volume were detected between CMR and all modalities. Importantly, 3D TTE had the lowest CV (6.45%), correlated with (rs = 0.62, p = 0.01), and had the highest overlap in distribution with CMR (OVL >80%). Left ventricular EF and LA size via CTA compared best with CMR and RV and RA volumes were best estimated by 3D TTE. Assessment of LV and LA volumes via 3D TTE had moderate repeatability (15-21%) compared with LV M-mode measurements and 2D LA-to-aortic ratio (<10%), respectively. For LV size, interrater CV for 3D TTE (19.4%) was lower than 2D TTE (23.1%). CONCLUSIONS: Measurements of LV, RV, and RA volumes via 3D TTE and LA volume and LV EF assessed by CTA compared best with CMR. Three-dimensional echocardiography had lower interrater and intrarater CV compared with 2D TTE.

Development of a perceived exertion scale for dogs using selected physiologic parameters.

OBJECTIVE: To develop a perceived exertion scale for dogs exercising on a treadmill and to assess intra- and inter-observer variability. MATERIALS AND METHODS: Fifteen healthy client-owned dogs participated in paired exercise trials. Measurements of lactate, glucose, heart rate, temperature, respiratory rate and regional tissue oximetry were obtained before, during and after exercise. Perceived exertion scale scores were recorded during exercise and using video recordings to evaluate inter-observer variability. Correlations were evaluated using the Spearman's non-parametric method. RESULTS: Thirteen dogs completed both trials. Dogs walked or trotted on the treadmill with an average perceived exertion score of 2 in both trials. Holter heart rate was positively correlated with perceived exertion scale scores from all observers for both trials. In trial 1, plasma glucose decreased in association with increase in perceived exertion and, in trial 2, cutaneous oximetry decreased, respiratory rate increased and temperature increased with increases on the perceived exertion scale. Inter-observer perceived exertion scale scores were positively correlated in both trials. There was no intra-observer variability between trials. CLINICAL SIGNIFICANCE: The perceived exertion scale correlated with the measured physiologic parameters in dogs exercising at mild to moderate intensity. The perceived exertion scale was consistent and repeatable but larger study numbers and further validation are needed before it can be widely applied.

Biermann-Battery-Mediated Magnetic Reconnection in 3D Colliding Plasmas.

Recent experiments have demonstrated magnetic reconnection between colliding plasma plumes, where the reconnecting magnetic fields were self-generated in the plasma by the Biermann-battery effect. Using fully kinetic 3D simulations, we show the full evolution of the magnetic fields and plasma in these experiments, including self-consistent magnetic field generation about the expanding plume. The collision of the two plasmas drives the formation of a current sheet, where reconnection occurs in a strongly time- and space-dependent manner, demonstrating a new 3D reconnection mechanism. Specifically, we observe a fast, vertically localized Biermann-mediated reconnection, an inherently 3D process where the temperature profile in the current sheet coupled with the out-of-plane ablation density profile conspires to break inflowing field lines, reconnecting the field downstream. Fast reconnection is sustained by both the Biermann effect and the traceless electron pressure tensor, where the development of plasmoids appears to modulate the contribution of the latter. We present a simple and general formulation to consider the relevance of Biermann-mediated reconnection in general astrophysical scenarios.

Effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor velagliflozin, a new drug with therapeutic potential to treat diabetes in cats.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used in the treatment of human diabetics. They increase glucose excretion and correct hyperglycemia. We examined the investigational SGLT2 inhibitor velagliflozin in two groups of six neutered adult obese cats (equal gender distribution). Placebo (Pl) or drug (D; 1 mg/kg) was administered for 35 days. Routine blood examinations, fructosamine, beta-hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), glucagon, adiponectin, and leptin were measured before and after treatment, also water intake, and urinary electrolytes, glucose, and volume. Indirect calorimetry, an intravenous glucose tolerance test (IVGTT; 0.8 g/kg) and insulin tolerance test (IVITT) were conducted. All cats tolerated treatment well. Significant changes with D included a decrease in the respiratory exchange ratio, an increase in cholesterol, a small increase in albumin, and a rise in BHB and NEFA. Glucose clearance was unaltered, although less insulin was secreted during the IVGTT (p = .056) suggesting improved insulin sensitivity. IVITT was unchanged. Treatment did not affect glucagon, leptin, or adiponectin. Water intake, urine output, urinary glucose excretion, and the glucose/creatinine ratio but not urinary electrolytes were significantly higher post-D. We conclude that velagliflozin is a promising drug, which increases urinary glucose excretion in cats and could thereby be beneficial for the treatment of hyperglycemia.

Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.

BACKGROUND: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown. PATIENTS AND METHODS: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization. RESULTS: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib. CONCLUSION: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin. CLINICAL TRIAL INFORMATION: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).

Generation and Evolution of High-Mach-Number Laser-Driven Magnetized Collisionless Shocks in the Laboratory.

We present the first laboratory generation of high-Mach-number magnetized collisionless shocks created through the interaction of an expanding laser-driven plasma with a magnetized ambient plasma. Time-resolved, two-dimensional imaging of plasma density and magnetic fields shows the formation and evolution of a supercritical shock propagating at magnetosonic Mach number M_{ms}≈12. Particle-in-cell simulations constrained by experimental data further detail the shock formation and separate dynamics of the multi-ion-species ambient plasma. The results show that the shocks form on time scales as fast as one gyroperiod, aided by the efficient coupling of energy, and the generation of a magnetic barrier between the piston and ambient ions. The development of this experimental platform complements present remote sensing and spacecraft observations, and opens the way for controlled laboratory investigations of high-Mach number collisionless shocks, including the mechanisms and efficiency of particle acceleration.

Well-posed continuum equations for granular flow with compressibility and µ(I)-rheology.

Continuum modelling of granular flow has been plagued with the issue of ill-posed dynamic equations for a long time. Equations for incompressible, two-dimensional flow based on the Coulomb friction law are ill-posed regardless of the deformation, whereas the rate-dependent µ(I)-rheology is ill-posed when the non-dimensional inertial number I is too high or too low. Here, incorporating ideas from critical-state soil mechanics, we derive conditions for well-posedness of partial differential equations that combine compressibility with I-dependent rheology. When the I-dependence comes from a specific friction coefficient µ(I), our results show that, with compressibility, the equations are well-posed for all deformation rates provided that µ(I) satisfies certain minimal, physically natural, inequalities.

[Current Status of Medical Care for Nursing Home Residents in Germany - Results of an Empirical Study]. / Zur Entwicklung der ärztlichen Versorgung in stationären Pflegeeinrichtungen ­ Ergebnisse einer empirischen Untersuchung.

Following recent studies revealing deficits in general and specialised medical care of nursing home residents in Germany, the discussion on the quality of medical care of residents in residential care facilities has intensified in the past years. As a result, political efforts have been undertaken to facilitate improvements in this context. We collected data on the health status and medical care of 778 residents from 8 nursing homes in order to investigate the current situation regarding medical care for nursing home residents in Germany. Most of them were multimorbid, taking several prescribed medications. Our results showed that about 91% of the residents had personal contact to general practitioners or internists quarterly and only 1.3% had no such contacts within a year. The frequency of contacts to other medical specialists was comparably low. For example, within a year, only 18.9% of the residents had contact to urologists; only 16.7% had contact to ophthalmologists; only 39.6% had contact to dentists and only 10.6% of the female residents had contact to gynaecologists. Despite the fact that many of the residents showed specific medical care needs, these rates were below the utilisation rates of older population groups not living in long-term care homes. This leads to the conclusion that previous efforts to optimise medical care in nursing homes were only partially successful. Well known deficits are still remaining. Considering potential consequences for residents, further and consequent actions are required to improve the general and specialised medical care in institutionalised long-term care.

Spatially resolved Thomson scattering measurements of the transition from the collective to the non-collective regime in a laser-produced plasma.

We present optical Thomson scattering results that image for the first time in a single measurement the spatial transition from collective to non-collective scattering. Data were taken in the Phoenix laser laboratory at the University of California, Los Angeles. The Raptor laser was used to ablate a carbon plasma, which was diagnosed with the frequency-doubled Phoenix laser serving as a Thomson scattering probe. Scattered light was collected from the laser plasma up to 10 cm from the target surface and up to 10 us after ablation, and imaged with high spatial and spectral resolutions. The results show a strong Thomson collective feature close to the target surface that smoothly transitions to a non-collective feature over several mm.

[Differences in Health Literacy of Adolescents with Lower Educational Attainment, Older People and Migrants]. / Unterschiede der Gesundheitskompetenz von Jugendlichen mit niedriger Bildung, Älteren und Menschen mit Migrationshintergrund.

Not everyone seems to have adequate health literacy to take care of their own health. Especially older people, people with migration background, and adolescents with lower educational attainment face challenges when dealing with the healthcare system. Our cross-sectional study focuses on these vulnerable groups. We found that vulnerable populations showed high prevalence of limited health literacy, and there were considerable differences between these groups. Older people were more likely to have limited health literacy compared to younger people. Older people with migration background had the lowest health literacy.

Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways.

The cascade that culminates in macrometastases is thought to be mediated by phenotypic plasticity, including epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET). Although there is substantial support for the role of EMT in driving cancer cell invasion and dissemination, much less is known about the importance of MET in the later steps of metastatic colonization. We created novel reporters, which integrate transcriptional and post-transcriptional regulation, to test whether MET is required for metastasis in multiple in vivo cancer models. In a model of carcinosarcoma, metastasis occurred via an MET-dependent pathway; however, in two prostate carcinoma models, metastatic colonization was MET independent. Our results provide evidence for both MET-dependent and MET-independent metastatic pathways.