Identification of responders to immune checkpoint therapy : which biomarkers have the highest value?

Evasion of immune recognition by the innate and acquired immune system is a major principle of tumour cells and belongs to the hallmarks of cancer. Immune checkpoint inhibitor-based cancer therapies targeting the co-inhibitory receptors CTLA-4 or PD-1 have received enormous scientific and clinical attention during the last few years, because of promising clinical results observed in the treatment of different cancer entities including melanoma and cutaneous squamous cell carcinoma. However, the enthusiasm about the effects of the immune checkpoint inhibitors is muted as only a subfraction of patients shows a stable clinical response. To predefine the patient cohorts that may benefit from immune checkpoint therapy, rigorous biomarker analyses, which predict the response to these novel therapies, need to be performed. In addition, combination of immune checkpoint therapy with classical DNA-damaging chemotherapy or radiotherapy, which positively affects tumour neo-antigen presentation, appears to be a promising approach in optimizing patients’ response. In this review, we briefly summarize important biomarkers for patient stratification and discuss the current limitations of these biomarkers in defining responders vs. non-responders to immune checkpoint therapy

Quantitative 2D magnetorelaxometry imaging of magnetic nanoparticles using optically pumped magnetometers

For biomagnetical applications exploiting physical properties of magnetic nanoparticles (MNP), e.g., magnetic hyperthermia, knowledge about the quantitative spatial MNP distribution is crucial, which can be extracted by magnetorelaxometry (MRX) imaging. In this paper, we present quantification, quantitative 1D reconstruction, and quantitative 2D imaging of MNP by exploiting optically pumped magnetometers for MRX. While highlighting the potential of commercially available optically pumped magnetometers (OPM) for MRXI, we discuss current limitations of the used OPM. We show, that with our OPM setup, MNP can be precisely quantified with iron amounts down to ≈6 μg, which can be improved easily. With a 1D-reconstruction setup, point-like and complex MNP phantoms can be reconstructed quantitatively with high precision and accuracy. We show that with our developed 2D MRX imaging setup, which measures 12 cm by 8 cm, point-like MNP distributions with clinically relevant iron concentrations can be reconstructed precisely and accurately. Our 2D setup has the potential to be easily extended to a tomography styled (and thus slice-selective) 3D scanner, by adding a mechanical axis to the phantom

Pulsed optically pumped magnetometers: addressing dead time and bandwidth for the unshielded magnetorelaxometry of magnetic nanoparticles

Magnetic nanoparticles (MNP) offer a large variety of promising applications in medicine thanks to their exciting physical properties, e.g., magnetic hyperthermia and magnetic drug targeting. For these applications, it is crucial to quantify the amount of MNP in their specific binding state. This information can be obtained by means of magnetorelaxometry (MRX), where the relaxation of previously aligned magnetic moments of MNP is measured. Current MRX with optically pumped magnetometers (OPM) is limited by OPM recovery time after the shut-off of the external magnetic field for MNP alignment, therewith preventing the detection of fast relaxing MNP. We present a setup for OPM-MRX measurements using a commercially available pulsed free-precession OPM, where the use of a high power pulsed pump laser in the sensor enables a system recovery time in the microsecond range. Besides, magnetometer raw data processing techniques for Larmor frequency analysis are proposed and compared in this paper. Due to the high bandwidth (≥100 kHz) and high dynamic range of our OPM, a software gradiometer in a compact enclosure allows for unshielded MRX measurements in a laboratory environment. When operated in the MRX mode with non-optimal pumping performance, the OPM shows an unshielded gradiometric noise floor of about 600 fT/cm/Hz for a 2.3 cm baseline. The noise floor is flat up to 1 kHz and increases then linearly with the frequency. We demonstrate that quantitative unshielded MRX measurements of fast relaxing, water suspended MNP is possible with the novel OPM-MRX concept, confirmed by the accurately derived iron amount ratios of MNP samples. The detection limit of the current setup is about 1.37 μg of iron for a liquid BNF-MNP-sample (Bionized NanoFerrite) with a volume of 100 μL

Bone Mineral Density Estimations From Routine Multidetector Computed Tomography: A Comparative Study of Contrast and Calibration Effects.

INTRODUCTION Phantom-based (synchronous and asynchronous) and phantomless (internal tissue calibration based) assessment of bone mineral density (BMD) in routine MDCT (multidetector computed tomography) examinations potentially allows for diagnosis of osteoporosis. Although recent studies investigated the effects of contrast-medium application on phantom-calibrated BMD measurements, it remains uncertain to what extent internal tissue-calibrated BMD measurements are also susceptible to contrast-medium associated density variation. The present study is the first to systemically evaluate BMD variations related to contrast application comparing different calibration techniques. PURPOSE To compare predicative performance of different calibration techniques for BMD measurements obtained from triphasic contrast-enhanced MDCT. MATERIALS AND METHODS Bone mineral density was measured on nonenhanced (NE), arterial (AR) and portal-venous (PV) contrast phase MDCT images of 46 patients using synchronous (SYNC) and asynchronous (ASYNC) phantom calibration as well as internal calibration (IC). Quantitative computed tomography (QCT) served as criterion standard. Density variations were analyzed for each contrast phase and calibration technique, and respective linear fitting was performed. RESULTS Both asynchronous calibration-derived BMD values (NE-ASYNC) and values estimated using IC (NE-IC) on NE MDCT images did reasonably well in predicting QCT BMD (root-mean-square deviation, 8.0% and 7.8%, respectively). Average NE-IC BMD was 2.7% lower when compared with QCT (P = 0.017), whereas no difference could be found for NE-ASYNC (P = 0.957). All average BMD estimates derived from contrast-enhanced scans differed significantly from QCT BMD (all P 6.0 mg/mL). All regression fits revealed a consistent linear dependency (R range, 0.861-0.963). Overall accuracy and goodness of fit tended to decrease from AR to PV contrast phase. Highest precision and best linear fit could be reached using a synchronously scanned phantom (root-mean-square deviation, 9.4% for AR and 14.4% for PV). Both ASYNC and IC estimations performed comparably accurate and precise. CONCLUSIONS Our data suggest that internal calibration driven BMD measurements derived from contrast-enhanced MDCT need the same amount of post hoc contrast-effect adjustment as measurements using phantom calibration. Adjustment using linear correction equations can correct for systematic bias of bone density variations related to contrast application, irrespective of the calibration technique used

Micromechanical Properties of Injection-Molded Starch–Wood Particle Composites

The micromechanical properties of injection molded starch–wood particle composites were investigated as a function of particle content and humidity conditions. The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starch–wood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that the wood in the starch composites did not prevent water loss from the samples.Peer reviewe

Gait Stability and Its Influencing Factors in Older Adults

A stable gait pattern is a prerequisite to successfully master various activities of daily living. Furthermore, reduced gait stability is associated with a higher risk of falling. To provide specific intervention strategies to improve gait stability, gaining detailed knowledge of the underlying mechanism and influencing factors is of utmost importance. The effects of relevant influencing factors on gait stability are poorly examined, yet. Therefore, the aim of the current study was to quantify the effects of various influencing factors on gait stability. In a cross-sectional study, we assessed dynamic gait stability and relevant influencing factors in 102 older adults (age >65 years). In addition to dynamic gait stability (largest Lyapunov exponent [LLE] and gait variability measures) during normal over-ground (single-task: ST) and dual-task (DT) walking, we registered the following influencing factors: health status (SF12), pain status (painDETECT, SES), fear of falling (falls efficacy scale), depression (CES-D), cognition performance (Stroop test), physical activity (Freiburger Fragebogen zur körperlichen Aktivität), proprioception (joint position sense), peripheral sensation (mechanical and vibration detection threshold), balance performance (static balance on force plate) and muscular fitness (instrumented sit-to-stand test). We used a principal components regression to link the identified principal components with the gait stability and gait variability responses. The four principal components “strength and gender” (e.g., p = 0.001 for LLE during ST), “physical activity” (e.g., p = 0.006 for LLE during ST), “pain” (e.g., p = 0.030 for LLE during DT) and “peripheral sensation” (e.g., p = 0.002 for LLE during ST) were each significantly associated with at least two of the analyzed gait stability/variability measures. The dimension “balance” was a significant predictor in only one gait measure. While “proprioception” tends to correlate with a gait variability measure, we did not find a dependency of mental health on any gait measure. In conclusion, the participants' ability to recover from small perturbations (as measured with the largest Lyapunov exponent) seems to be related to gender and strength, the amount of physical activity the participants spent every week, peripheral sensation and pain status. Since the explained variance is still rather low, there could be more relevant factors that were not addressed, yet

A Computed Tomography Vertebral Segmentation Dataset with Anatomical Variations and Multi-Vendor Scanner Data

With the advent of deep learning algorithms, fully automated radiological image analysis is within reach. In spine imaging, several atlas- and shape-based as well as deep learning segmentation algorithms have been proposed, allowing for subsequent automated analysis of morphology and pathology. The first Large Scale Vertebrae Segmentation Challenge (VerSe 2019) showed that these perform well on normal anatomy, but fail in variants not frequently present in the training dataset. Building on that experience, we report on the largely increased VerSe 2020 dataset and results from the second iteration of the VerSe challenge (MICCAI 2020, Lima, Peru). VerSe 2020 comprises annotated spine computed tomography (CT) images from 300 subjects with 4142 fully visualized and annotated vertebrae, collected across multiple centres from four different scanner manufacturers, enriched with cases that exhibit anatomical variants such as enumeration abnormalities (n=77) and transitional vertebrae (n=161). Metadata includes vertebral labelling information, voxel-level segmentation masks obtained with a human-machine hybrid algorithm and anatomical ratings, to enable the development and benchmarking of robust and accurate segmentation algorithms.Comment: 18 pages, 2 figures, 2 tables; Hans Liebl, David Schinz equally contributed to this manuscrip

Unraveling the microbiome of a thermophilic biogas plant by metagenome and metatranscriptome analysis complemented by characterization of bacterial and archaeal isolates

One of the most promising technologies to sustainably produce energy and to mitigate greenhouse gas emissions from combustion of fossil energy carriers is the anaerobic digestion and biomethanation of organic raw material and waste towards biogas by highly diverse microbial consortia. In this context, the microbial systems ecology of thermophilic industrial-scale biogas plants is poorly understood

International challenges without borders: a descriptive study of family physicians' educational needs in the field of diabetes

<p>Abstract</p> <p>Background</p> <p>The optimal care of persons with diabetes by general practitioners and family physicians (GP/FP) is complex and requires multiple competencies. This is a fairly unrecognized key challenge in the healthcare systems. In some cases, local and national Continuous Professional Development (CPD) initiatives target these challenges; however there have been few international initiatives, possibly because challenges emerging from different studies have not been linked across national boundaries. In this context, the authors have compiled data about gaps and/or barriers inherent to GP/FP care of persons with type 2 diabetes from Austria, Canada, Germany and the United Kingdom.</p> <p>Methods</p> <p>Secondary analyzes of pre-existing studies were conducted to identify challenges in the care of patients with type 2 diabetes as faced by GPs/FPs. Two sources of data were reviewed: unpublished research data from collaborating organizations and articles from a literature search (in English and German). Articles retrieved were scanned by the research team for relevance to the study objectives and to extract existing gaps and barriers. The identified challenges were then categorized along three major axes: (1) phase of the continuum of care {from screening to management}; (2) learning domain {knowledge, skills, attitudes, behavior, context}; and (3) by country/region. Compilation and categorization were performed by qualitative researchers and discrepancies were resolved through discussion until concordance was achieved.</p> <p>Results and discussion</p> <p>Thirteen challenges faced by GPs/FPs in the care for patients with type 2 diabetes were common in at least 3 of the 4 targeted countries/regions. These issues were found across the entire continuum of care and included: pathophysiology of diabetes, diagnostic criteria, treatment targets assessment, drugs' modes of action, decision-making in therapies, treatment guidelines, insulin therapy, adherence, management of complications, lifestyle changes, team integration, bureaucracy and third-party payers. The issues reported were not restricted to the physicians' knowledge, but also related to their skills, attitudes, behaviours and context.</p> <p>Conclusions</p> <p>This study revealed challenges faced by GPs/FPs when caring for patients with diabetes, which were similar across international and health system borders. Common issues might be addressed more efficiently through international educational designs, adapted to each country's healthcare system, helping develop and maintain physicians' competencies.</p

Profiling Trait Anxiety: Transcriptome Analysis Reveals Cathepsin B (Ctsb) as a Novel Candidate Gene for Emotionality in Mice

Behavioral endophenotypes are determined by a multitude of counteracting but precisely balanced molecular and physiological mechanisms. In this study, we aim to identify potential novel molecular targets that contribute to the multigenic trait “anxiety”. We used microarrays to investigate the gene expression profiles of different brain regions within the limbic system of mice which were selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, and also show signs of comorbid depression-like behavior