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.

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.

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.

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.

[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.

[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.

Personalized oncogenomics in the management of gastrointestinal carcinomas-early experiences from a pilot study.

BACKGROUND: Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways. METHODS: We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma. RESULTS: In the first case, genomic profiling revealed an IDH1 somatic mutation, supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin, and further guided therapy by identifying epidermal growth factor receptor amplification. In the second case, a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma. The third case was an appendiceal adenocarcinoma defined by a p53 inactivation; Ras/raf/mek, Akt/mtor, Wnt, and notch pathway activation; and overexpression of ret, erbb2 (her2), erbb3, met, and cell cycle regulators. SUMMARY: We show that whole-genome and transcriptome sequencing can be achieved within clinically effective timelines, yielding clinically useful and actionable information.

[How do citizens in Germany assess their own Health Literacy?]. / Wie bewerten Bürger in Deutschland ihre eigene Health Literacy?

Health literacy is a relatively recent concept in Europe. First international investigations indicate that a substantial part of the population has significantly impaired subjective health literacy. In Germany there is a lack of meaningful data. Therefore, 2 comprehensive studies have been started that will provide population representative results, as well as take the health literacy level of vulnerable groups such as older people and migrants into consideration.

[Health literacy among less well-educated young people: Influencing factors and consequences]. / Gesundheitskompetenz bildungsferner Jugendlicher : Einflussfaktoren und Folgen.

OBJECTIVES: Health literacy is known to influence health. Findings on the unequal distribution of health literacy among less well-educated young people are presented. The influence of socio-demographic factors and the consequences of a low level of health literacy with regard to health-related behaviour are discussed. MATERIALS AND METHODS: Data from a survey on the health literacy of young people with a lower level of education, older people and migrants (n = 1,000) were used. Health literacy was measured using the instruments of the European Health Literacy Survey (HLS-EU-Q47). RESULTS: The results demonstrate a lower level of health literacy among young people with less education and especially among young migrants. Explanations for a lower level of health literacy among young people with less well-educated young people were parents' educational background and parents' wealth. Migration-related factors had no influence on young people. Further correlations between health literacy and health behaviour were explored. CONCLUSION: It is concluded that health literacy is linked to health behaviour and that unequal distributions of health literacy among young people may increase health inequalities.

Proton deflectometry analysis in magnetized plasmas: Magnetic field reconstruction in one dimension.

Proton deflectometry is used in magnetized high-energy-density plasmas to observe electromagnetic fields. We describe a reconstruction algorithm to recover the electromagnetic fields from proton fluence data in 1-D. The algorithm is verified against analytic solutions and applied to example data. Next, we study the role of source fluence uncertainty for 1-D reconstructions. We show that reconstruction boundary conditions can be used to constrain the source fluence profile and use this to develop a reconstruction using a specified pair of boundary conditions on the magnetic field. From these considerations, we experimentally demonstrate a hybrid mesh-fluence reconstruction technique where fields are reconstructed from fluence data in an interior region with boundary conditions supplied by direct mesh measurements at the boundary.

[Health care and regional disparities]. / Versorgungsgestaltung angesichts regionaler Unterschiede.

Municipalities in Germany have to advance health care structures to be resistant to demographic transitions and to the changing health care needs of the regional population in upcoming years. Therefore, it is important to note that needs vary from region to region and that care structures have to be differentiated according to this. Indeed regionality and community care have been increasingly referred to in current debate on improving care structures. But the discussed approaches remain relatively unclear and, moreover, fail to overcome care fragmentation and legal or sectoral perspectives. This paper points out the current lack of systematic knowledge about regional health disparities as well as knowledge about models of health care that are appropriate especially for disadvantaged communities and also rural regions. Moreover, knowledge of steering mechanisms that enforce the development of regional care systems are not developed yet.

[National health target "healthy ageing". Medical, psychosocial and nursing care for elderly people]. / Nationales Gesundheitsziel "Gesund älter werden". Handlungsfeld II: Medizinische, psychosoziale und pflegerische Versorgung älterer Menschen.

What kind of health targets should be pursued concerning the health care of elderly people? What kind of activities should be implemented to ensure good health care with regard to future challenges? The Association for the Continuous Development of the National Health Target Process, health-targets.de, deals with these issues under the new national health target "Healthy Ageing". We develop concrete objectives and proposals for practical implementation in the areas of "outpatient and inpatient care", "nursing" and "rehabilitation in old age". health-targets.de supports a common health target process and initiates interventions in the field of health care for elderly people.

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.

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.

[Self-responsibility in health care using the example of medication management from the chronically ill patient's perspective]. / Selbstverantwortung im Gesundheitswesen, diskutiert am Medikamentenmanagement aus Sicht chronisch kranker Patienten.

With rising costs in health care, especially in the area of pharmaceuticals, patients are expected to be more involved in managing their care. Concepts such as shared decision-making or self-management support in chronic illness have been suggested as a way to facilitate this process and to empower patients. It is unclear however, whether the self-responsible patient role outlined in these concepts aligns with the patient's needs. The aim of this paper is to examine this proposed self-responsible role with regard to the patient's medication management needs and to discuss whether self-responsibility and autonomy are suitable concepts when illness-related challenges become difficult or complex. Selected findings from a qualitative longitudinal study on medication management from the perspective of people with chronic conditions are presented. Results from interviews with 27 patients indicate that both the patient's view and the challenges people with chronic conditions face in everyday life remain a 'blind spot' in health care. Providing information to improve health literacy may not be enough; there is a need to systematically support patients in developing skills to adequately (self-)manage a chronic condition.

[Coping with chronic illness and multiple medicines in older age: self-management support as an obligation in nursing]. / Bewältigung komplexer Medikamentenregime bei chronischer Krankheit im Alter: Förderung des Selbstmanagements als Aufgabe der Pflege.

In later stages of chronic disease and especially in older age, chronically ill people are often dependent on multiple medicines. Coming to terms with complex medication regimes in everyday life is a challenging task. To provide the support actually needed, patient-centered interventions are essential, not only taking into account the patients' needs and preferences, but also promoting their ability to self manage their disease(s) and their medication regime. This paper outlines the results of a research project aimed at developing and evaluating an intervention to integrate self-management support into primary care, based on a qualitative exploration of the patients' and professionals' views. The findings stress that home care nurses should take an active part in self-management support but need to be prepared adequately. Therefore, a two-tier intervention was developed and evaluated in a prospective control study, consisting of a qualified training and guidelines for practice. The intervention serves to expand the nurses' professional competence to provide the needed individually tailored self-management support in home care.

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.