Search Results (8)

Nodal T-follicular helper cell lymphoma, angioimmunoblastic-type (AITL), is characterized by constitutional symptoms, advanced-stage disease, and generalized lymphadenopathy. A genetic hallmark of this lymphoma is the frequent occurrence of the RHOA mutation G17V in neoplastic cells, which is observed in around 60% of patients. Because RHOA is involved in both T-cell receptor downstream signalling and cell migration, we hypothesized that the characteristic presentation of AITL could be the result of enhanced tumor cell migration. Therefore, this study aimed to elucidate the impact of the RHOA variant G17V on the migration of neoplastic T cells. We transfected the T-cell lymphoma cell lines HH and HuT78 to stably express the RHOA-G17V variant. RHOA-G17V-expressing T cells did not exhibit enhanced motility compared to empty-vector-transfected cells in microchannels, a 3D collagen gel, or primary human lymphatic tissue. Cells of the HH cell line expressing RHOA-G17V had an increased number of cells with cleaved collagen compared with the empty-vector-transfected cells. Therefore, we hypothesized that the early spread of AITL tumor cells may be related to remodelling of the extracellular matrix. Accordingly, we observed a significant negative correlation between the relative area of collagen in histological sections from 18 primary AITL and the allele frequency of the RHOA-G17V mutation. In conclusion, our results suggest that the characteristic presentation of AITL with early, widespread dissemination of lymphoma cells is not the result of an enhanced migration capacity due to the RHOA-G17V mutation; instead, this feature may rather be related to extracellular matrix remodelling. Full article

Particle therapy is a well established clinical treatment of tumors. More than one hundred particle therapy centers are in operation world-wide. The advantage of using hadrons like protons or carbon ions as particles for tumor irradiation is the distinct peak in the depth-dependent energy deposition, which can be exploited to accurately deposit doses in the tumor cells. To guarantee this, high accuracy in monitoring and control of the particle beam is of the utmost importance. Before the particle beam enters the patient, it traverses a monitoring system which has to give fast feedback to the beam control system on position and dose rate of the beam while minimally interacting with the beam. The multi-wire chambers mostly used as beam position monitors have their limitations when a fast response time is required (drift time). Future developments such as MRI-guided ion beam therapy pose additional challenges for the beam monitoring system, such as tolerance of magnetic fields and acoustic noise (vibrations). Solid-state detectors promise to overcome these limitations and the higher resolution they offer can create additional benefits. This article presents the evaluation of an HV-CMOS detector for beam monitoring, provides results from feasibility studies in a therapeutic beam, and summarizes the concepts towards the final large-scale assembly and readout system. Full article

(1) Background: Mutation-specific T cell receptor (TCR)-based adoptive T cell therapy represents a truly tumor-specific immunotherapeutic strategy. However, isolating neoepitope-specific TCRs remains a challenge. (2) Methods: We investigated, side by side, different TCR repertoires—patients’ peripheral lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs), PBLs of healthy donors, and a humanized mouse model—to isolate neoepitope-specific TCRs against eight neoepitope candidates from a colon cancer and an ovarian cancer patient. Neoepitope candidates were used to stimulate T cells from different repertoires in vitro to generate neoepitope-specific T cells and isolate the specific TCRs. (3) Results: We isolated six TCRs from healthy donors, directed against four neoepitope candidates and one TCR from the murine T cell repertoire. Endogenous processing of one neoepitope, for which we isolated one TCR from both human and mouse-derived repertoires, could be shown. No neoepitope-specific TCR could be generated from the patients’ own repertoire. (4) Conclusion: Our data indicate that successful isolation of neoepitope-specific TCRs depends on various factors such as the heathy donor’s TCR repertoire or the presence of a tumor microenvironment allowing neoepitope-specific immune responses of the host. We show the advantage and feasibility of using healthy donor repertoires and humanized mouse TCR repertoires to generate mutation-specific TCRs with different specificities, especially in a setting when the availability of patient material is limited. Full article

T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95% confidence interval (CI): 0.044–0.767; p = 0.020;) and EZH2 (HR = 8.245; 95% CI: 1.898–35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients. Full article

According to European Society of Cardiology guidelines (ESC2015) for infective endocarditis (IE) management, modified Duke criteria (mDC) are implemented with a degree of clinical suspicion degree, leading to grades such as “possible” or “rejected” IE despite a persisting high level of clinical suspicion. Herein, we evaluate the ¹⁸F-FDG PET/CT diagnostic and therapeutic impact in IE suspicion, with emphasis on possible/rejected IE with a high clinical suspicion. Excluding cases of definite IE diagnosis, 53 patients who underwent ¹⁸F-FDG PET/CT for IE suspicion were selected and afterwards classified according to both mDC (possible IE/Duke 1, rejected IE/Duke 0) and clinical suspicion degree (high and low IE suspicion). The final status regarding IE diagnosis (gold standard) was based on the multidisciplinary decision of the Endocarditis Team, including the ‘imaging specialist’. PET/CT images of the cardiac area were qualitatively interpreted and the intensity of each focus of extra-physiologic ¹⁸F-FDG uptake was evaluated by a maximum standardized uptake value (SUVmax) measurement. Extra-cardiac ¹⁸F-FDG PET/CT pathological findings were considered to be a possible embolic event, a possible source of IE, or even a concomitant infection. Based on the Endocarditis Team consensus, final diagnosis of IE was retained in 19 (36%) patients and excluded in 34 (64%). With a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and global accuracy of 79%, 100%, 100%, 89%, and 92%, respectively, PET/CT performed significantly better than mDC (p = 0.003), clinical suspicion degree (p = 0.001), and a combination of both (p = 0.001) for IE diagnosis. In 41 patients with possible/rejected IE but high clinical suspicion, sensitivity, specificity, PPV, NPV, and global accuracies were 78%, 100%, 100%, 85%, and 90%, respectively. Moreover, PET/CT contributed to patient management in 24 out of 53 (45%) cases. ¹⁸F-FDG PET/CT represents a valuable diagnostic tool that could be proposed for challenging IE cases with significant differences between mDC and clinical suspicion degree. ¹⁸F-FDG PET/CT allows a binary diagnosis (definite or rejected IE) by removing uncertain diagnostic situations, thus improving patient therapeutic management. Full article

Endogenous electric fields created in bone tissue as a response to mechanical loading are known to influence the activity and differentiation of bone and precursor cells. Thus, electrical stimulation offers an adjunct therapy option for the promotion of bone regeneration. Understanding the influence of electric fields on bone cell function and the identification of suitable electrical stimulation parameters are crucial for the clinical success of stimulation therapy. Therefore, we investigated the impact of alternating electric fields on human osteoblasts that were seeded on titanium electrodes, which delivered the electrical stimulation. Moreover, osteoblasts were seeded on collagen-coated coverslips near the electrodes, representing the bone stock surrounding the implant. Next, 0.2 V, 1.4 V, or 2.8 V were applied to the in vitro system with 20 Hz frequency. After one, three, and seven days, the osteoblast morphology and expression of osteogenic genes were analysed. The actin organisation, as well as the proliferation, were not affected by the electrical stimulation. Changes in the gene expression and protein accumulation after electrical stimulation were voltage-dependent. After three days, the osteogenic gene expression and alkaline phosphatase activity were up to 2.35-fold higher following the electrical stimulation with 0.2 V and 1.4 V on electrodes and coverslips compared to controls. Furthermore, collagen type I mRNA, as well as the amount of the C-terminal propeptide of collagen type I were increased after the stimulation with 0.2 V and 1.4 V, while the higher electrical stimulation with 2.8 V led to decreased levels, especially on the electrodes. Full article

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy. Full article

Due to their bio-based character, oil-based coatings become more and more prevalent in wood surface finishing. These coatings impart appealing optical and haptic properties to the wood surface, but lack sufficient protection against water and mechanical influences. The present study reports a simple green route to improve the performance of linseed oil coating by the addition of nanofibrillated cellulose (NFC). In order to achieve surface chemical compatibility with linseed oil, NFC was chemically modified with acetic anhydride and (2-dodecen-1-yl)succinic anhydride, respectively, using propylene carbonate as a solvent. NFC/linseed oil formulations were prepared and applied to wood substrates. The wear resistance of oil-coated wood surfaces was assessed by a newly developed test combining abrasive loading with subsequent contact angle measurement. As revealed by infrared and nuclear magnetic resonance (NMR) spectroscopy, as well as X-ray diffraction (XRD), NFC has been successfully modified without significantly affecting the structure of cellulose. In abrasion tests, all NFC-modified oil coatings performed better than the original oil. Interestingly, NFC only suspended in propylene carbonate, i.e., without chemical modification, had the strongest improvement effect on the coating’s wear resistance. This was primarily attributed to the loose network structure of this NFC variant which effectively prevents the oil from penetration into the wood surface, thus forming a protective NFC/oil composite layer on the wood surface. Full article