CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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Web-Based Immersive Virtual Patient Simulators: Positive Effect on Clinical Reasoning in Medical Education

Background

Clinical reasoning is based on the declarative and procedural knowledge of workflows in clinical medicine. Educational approaches such as problem-based learning or mannequin simulators support learning of procedural knowledge. Immersive patient simulators (IPSs) go one step further as they allow an illusionary immersion into a synthetic world. Students can freely navigate an avatar through a three-dimensional environment, interact with the virtual surroundings, and treat virtual patients. By playful learning with IPS, medical workflows can be repetitively trained and internalized. As there are only a few university-driven IPS with a profound amount of medical knowledge available, we developed a university-based IPS framework. Our simulator is free to use and combines a high degree of immersion with in-depth medical content. By adding disease-specific content modules, the simulator framework can be expanded depending on the curricular demands. However, these new educational tools compete with the traditional teaching

Objective

It was our aim to develop an educational content module that teaches clinical and therapeutic workflows in surgical oncology. Furthermore, we wanted to examine how the use of this module affects student performance.

Methods

The new module was based on the declarative and procedural learning targets of the official German medical examination regulations. The module was added to our custom-made IPS named ALICE (Artificial Learning Interface for Clinical Education). ALICE was evaluated on 62 third-year students.

Results

Students showed a high degree of motivation when using the simulator as most of them had fun using it. ALICE showed positive impact on clinical reasoning as there was a significant improvement in determining the correct therapy after using the simulator. ALICE positively impacted the rise in declarative knowledge as there was improvement in answering multiple-choice questions before and after simulator use.

Conclusions

ALICE has a positive effect on knowledge gain and raises students’ motivation. It is a suitable tool for supporting clinical education in the blended learning context.     

Topiramate‐induced nephrolithiasis

Nephrolithiasis is a less common side effect of the antiepileptic drug topiramate. We report the case of a 3‐year‐old boy who presented to the emergency department with abdominal pain; examinations revealed a large calcification in the left kidney. Regular ultrasound examinations are recommended in children using topiramate.     

Identification of lymphogranuloma venereum‐associated Chlamydia trachomatis serovars by fluorescence in situ hybridisation – a proof‐of‐principle analysis

We describe a proof‐of‐principle evaluation of a fluorescence in situ hybridisation (FISH) procedure to identify Chlamydia trachomatis serovars L1–L3, the causative agents of lymphogranuloma venereum, in cell cultures based on newly designed DNA probes. Rapid and easy‐to‐perform FISH could facilitate the diagnosis of lymphogranuloma venereum without nucleic acid amplification or serotyping, but requires broader evaluation studies, for example, in tropical high‐endemicity regions.     

Adamantinomatous craniopharyngiomas express tumor stem cell markers in cells with activated Wnt signaling: further evidence for the existence of a tumor stem cell niche?

Introduction

Early disease onset, clinical manifestation, histomorphology, and increased tendency to relapse distinguish the adamantinomatous craniopharyngioma (adaCP) from the more favorable papillary variant (papCP). A molecular hallmark of adaCP is the activated Wnt signaling pathway indicated by nuclear β-catenin accumulation in a subset of tumor cells. A mouse model recently illustrated that these cells are the driving force in tumorigenesis of adaCP. This observation and the peculiar growth pattern points to the existence of a specific tumor stem cell (TSC) population in human CP.

Materials and Methods

To prove this hypothesis, the TSC markers CD133 (Prominin1) and CD44 were examined in papCP (n = 8) and adaCP (n = 25) on mRNA level using quantitative real time PCR of total tumor RNA. Furthermore, we investigated protein expression performing immunohistochemical analyses of formalin-fixed paraffin embedded tumor samples.

Results

PapCP revealed a homogenous CD44 expression pattern predominantly at the cell membrane, whereas CD133 labeling was hardly detectable. In adaCP, on the other hand all markers were consistently and predominantly co-expressed in nuclear β-catenin accumulating cell clusters, which was confirmed by double immunofluorescence staining. Overall expression of CD44 was significantly decreased in adaCP versus papCP, whereas CD133 showed significantly higher protein and mRNA levels in adaCP.

Conclusions

Our results indicate tumor stem cell-like characteristics of β-catenin accumulating cell clusters in adaCP, which may represent a tumor stem cell niche and might contribute to tumor recurrence. The potential impact of these special cell groups in regard to future CP management, including postoperative follow-up and additional treatment remains to be explored.     

Preclinical In Vitro Assessment of Submicron-Scale Laser Surface Texturing on Ti6Al4V

Loosening of orthodontic and orthopedic implants is a critical and common clinical problem. To minimize the numbers of revision surgeries due to peri-implant inflammation or insufficient osseointegration, developments of new implant manufacturing strategies are indicated. Ultrafast laser surface texturing is a promising contact-free technology to modify the physicochemical properties of surfaces toward an anti-infectious functionalization. This work aims to texture Ti6Al4V surfaces with ultraviolet (UV) and green (GR) radiation for the manufacturing of laser-induced periodic surface structures (LIPSS). The assessment of these surface modifications addresses key aspects of topography, morphology and chemical composition. Human primary mesenchymal stromal cells (hMSCs) were cultured on laser-textured and polished Ti6Al4V to characterize the surfaces in terms of their in vitro biocompatibility, cytotoxicity, and metal release. The outcomes of the in vitro experiment show the successful culture of hMSCs on textured Ti6Al4V surfaces developed within this work. Cells cultured on LIPSS surfaces were not compromised in terms of their viability if compared to polished surfaces. Yet, the hMSC culture on UV-LIPSS show significantly lower lactate dehydrogenase and titanium release into the supernatant compared to polished. Thus, the presented surface modification can be a promising approach for future applications in orthodontics and orthopedics.     

A splice variant of the two-pore domain potassium channel TREK-1 with only one pore domain reduces the surface expression of full-length TREK-1 channels

We have identified a novel splice variant of the human and rat two-pore domain potassium (K_2P) channel TREK-1. The splice variant TREK-1e results from skipping of exon 5, which causes a frame shift in exon 6. The frame shift produces a novel C-terminal amino acid sequence and a premature termination of translation, which leads to a loss of transmembrane domains M3 and M4 and of the second pore domain. RT-PCR experiments revealed a preferential expression of TREK-1e in kidney, adrenal gland, and amygdala. TREK-1e was nonfunctional when expressed in Xenopus oocytes. However, both the surface expression and the current density of full-length TREK-1 were reduced by co-expression of TREK-1e. Live cell imaging in COS-7 cells transfected with GFP-tagged TREK-1e showed that this splice variant was retained in the endoplasmic reticulum (ER). Attachment of the C-terminus of TREK-1e to two different reporter proteins (Kir2.1 and CD8) led to a strong reduction in the surface expression of these fusion proteins. Progressive truncation of the C-terminus of TREK-1e in these reporter constructs revealed a critical region (amino acids 198 to 205) responsible for the intracellular retention. Mutagenesis experiments indicated that amino acids I204 and W205 are key residues mediating the ER retention of TREK-1e. Our results suggest that the TREK-1e splice variant may interfere with the vesicular traffic of full-length TREK-1 channels from the ER to the plasma membrane. Thus, TREK-1e might modulate the copy number of functional TREK-1 channels at the cell surface, providing a novel mechanism for fine tuning of TREK-1 currents.     

Motility index measured by magnetic resonance enterography is associated with sex and mural thickness

BACKGROUND Recently, a technique has been developed to use magnetic resonance enterography(MRE) for the evaluation of small bowel motility. The hypothesis was that assessment of the motility index(MI) should reflect differences in motility between clinical conditions.AIM To aim of the present observational, cross-sectional study was to evaluate the use of the MI in daily clinical practice.METHODS All consecutive patients aged 18-70 years who were referred for MRE at the Department of Radiology during a 2-year period were asked to participate. Healthy volunteers were included as controls. MRE was prepared and conducted in accordance with clinical routines. On the day of examination, all the participants had to complete the visual analog scale for irritable bowel syndrome(IBS) and IBS-symptom severity scale. Maps of MI were calculated from dynamic MR images. ANOVA was used to evaluate differences in MI between groups, classified as healthy, Crohn's disease, ulcerative colitis, IBS, other assorted disorders and dysmotility. Logistic and linear regression were applied to the MI values. All medical records were scrutinized for medical history.RESULTS In all, 224 examinations were included(inclusion prevalence 76.3%), with 22 controls and 202 patients. There was a significant difference in the MI of the jejunum(P = 0.021) and terminal ileum(P = 0.007) between the different groups. The MI was inversely associated with the mural thickness of the terminal ileum in men(P 0.001) and women(P = 0.063) after adjustments, and tended to be lower in men than in women(P = 0.056). Subjectively observed reduction of motility on MRI was accomplished by reduced MI of terminal ileum in men(P 0.001) and women(P = 0.030). In women, diarrhea was inversely associated with the MI of the jejunum(P = 0.029), and constipation was positively associated with the MI of the terminal ileum(P = 0.039).CONCLUSION Although MIs differ across diseases, a lower MI of the terminal ileum is mainly associated with male sex and an increased mural thickness. Symptoms are weakly associated with the MI.