Universitätspublikationen
Refine
Year of publication
Document Type
- Article (5148) (remove)
Has Fulltext
- yes (5148)
Keywords
- inflammation (80)
- COVID-19 (62)
- SARS-CoV-2 (48)
- cancer (38)
- glioblastoma (38)
- apoptosis (37)
- Inflammation (35)
- breast cancer (34)
- autophagy (29)
- prostate cancer (29)
Institute
- Medizin (5148) (remove)
Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by the accumulation of undifferentiated white blood cells (blasts) in the bone marrow. Valosin-containing protein (VCP) is an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellular compartments prior to their degradation by the proteasome. We found that treatment of AML cell lines with the VCP inhibitor CB-5083 leads to an accumulation of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Using quantitative mass spectrometry-based proteomics we assessed the effects of VCP inhibition on the cellular ubiquitin-modified proteome. We could further show that CB-5083 decreases the survival of the AML cell lines THP-1 and MV4-11 in a concentration-dependent manner, and acts synergistically with the antimetabolite cytarabine and the BH3-mimetic venetoclax. Finally, we showed that prolonged treatment of AML cells with CB-5083 leads to development of resistance mediated by mutations in VCP. Taken together, inhibition of VCP leads to a lethal unfolded protein response in AML cells and might be a relevant therapeutic strategy for treatment of AML, particularly when combined with other drugs. The toxicity and development of resistance possibly limit the utility of VCP inhibitors and have to be further explored in animal models and clinical trials.
Implementation and evaluation of a Tele-OSCE in oral and maxillofacial surgery – a pilot report
(2022)
Background: The ongoing changes in learning and education towards digitalisation have been rapidly accelerated by the COVID-19 pandemic. Especially in dental education where contact to the oral cavity is an integral part of training the chosen digital examination methods and training formats must undergo high requirements to full fill the goal of a real alternative to face-to-face exams. Therefore, this study compared student performance in a newly developed Tele-OSCE with a prior OSCE examinations in presence within an oral- and maxillofacial surgery curriculum.
Methods: Study participants were fourth-year (in a five year curriculum) dental students and board certified maxillofacial surgeons (examiners) that took part in a newly developed Tele-OSCE that comprised three five-minute stations (structured facial examination, management mandibular fracture and squamous cell carcinoma) using the zoom® software. Student performance was measured using validated OSCE-Checklists and compared to a previous OSCE examination from the winter term 2019 with the same OSCE stations that was conducted in presence. Significant differences were tested using the Mann-Whitney U test. Furthermore, the new Tele-OSCE was evaluated by students and examiners using previously developed questionnaires.
Results: Sixty-six dental students (study group: n=34, summer term 2021, control group: n=32 winter term 2019) and nine examiners participated in the study. Compared to previous non-pandemic OSCEs, there were no significant (p=0.53) differences in overall student performance. Evaluation of the Tele-OSCE showed that the demonstration and rating of practical skills was limited due to missing standard patients or phantoms, however, students did not fear to be misjudged. The demonstration and rating of anamnestic and consultation competencies was seen as unproblematic by students and examiners.
Discussion: This pilot-study showed the feasibility of a Tele-OSCE as a formative examination in dental education. However, both students and examiners felt that the demonstration and assessment of practical skills was limited due the new examination format. Nevertheless, Tele-OSCEs might offer an alternative to enable students to complete their dental training.
Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1–19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRDneg, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
We show a shift in the prevalence of respiratory viral pathogens in community-acquired pneumonia patients during the COVID-19 pandemic. Our data support the efficiency of non-pharmaceutical interventions on virus circulation except for rhinoviruses. The consequences of an altered circulation on subsequent winter seasons remain unclear and support the importance of systematic virological surveillance.
Background: Since mammography belongs to the most important preventive techniques in modern medicine, this study maps the related worldwide research output, which encompasses quantitative and qualitative aspects of the scientific activity and socio-economic features.
Methods: The New Quality and Quantity Indices in Science (NewQIS) computing platform identified all mammography-specific articles in the Web of Science within two time periods, from 1900 to 2014 (P1) and from 2015 to 2020 (P2), a combination of density-equalizing mapping projections (DEMP) and socio-economic benchmarking was applied for analysis.
Results: A total of 13,629 articles were retrieved. 8,744 articles were identified in P1 and 4,885 in P2. More than 100 articles were published annually since the 1980s. Regarding productivity and collaborative efforts, the United States was the leading nation in both evaluation periods. In our socioeconomic analysis, it was also ranked at the first place in P1 [72.68 mammography-related publications per GDP/capita (RGDP)]. The US was followed by the UK and Germany in P1 and by UK and India in P2. When population sizes were related to mammography research activities, Scandinavian countries and the Netherlands showed the highest research activity in P1 (e.g., Sweden: 31.89 publications per 1 million inhabitants). Gender analysis illustrated a relative dominance of female researchers in most countries with the exception of Japan.
Conclusions: The global mammography research activity over the last century is paralleled by strong international collaborative efforts and follows largely economic figures and prevalence rates but displays distinct differences in comparison to the research landscape of other biomedical entities.
Prognostic assessment of patients with liver cirrhosis allocated for implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a challenging task in clinical practice. The aim of our study was to assess the prognostic value of the CLIF‐C AD (Acute Decompensation) score in patients with TIPS implantation. Transplant‐free survival (TFS) and 3‐month mortality were reviewed in 880 patients who received de novo TIPS implantation for the treatment of cirrhotic portal hypertension. The prognostic value of the CLIF‐C AD score was compared with the Model for End‐Stage Liver Disease (MELD) score, Child‐Pugh score, and albumin‐bilirubin (ALBI) score using Harrell’s C concordance index. The median TFS after TIPS implantation was 40.0 (34.6‐45.4) months. The CLIF‐C AD score (c = 0.635 [0.609‐0.661]) was superior in the prediction of TFS in comparison to MELD score (c = 0.597 [0.570‐0.623], P = 0.006), Child‐Pugh score (c = 0.579 [0.552‐0.606], P < 0.001), and ALBI score (c = 0.573 [0.545‐0.600], P < 0.001). However, the CLIF‐C AD score did not perform significantly better than the MELD‐Na score (c = 0.626 [0.599‐0.653], P = 0.442). There were no profound differences in the scores’ ranking with respect to indication for TIPS implantation, stent type, or underlying liver disease. Subgroup analyses revealed that a CLIF‐C AD score >45 was a predictor of 3‐month mortality in the supposed low‐risk group of patients with a MELD score ≤12 (14.7% vs. 5.1%, P < 0.001). Conclusion: The CLIF‐C AD score is suitable for prognostic assessment of patients with cirrhotic portal hypertension receiving TIPS implantation. In the prediction of TFS, the CLIF‐C AD score is superior to MELD score, Child‐Pugh score, and ALBI score but not the MELD‐Na score.
Cancer is the second leading cause of mortality worldwide. Despite recent advances in cancer treatment including immunotherapy with immune checkpoint inhibitors, new unconventional biomarkers and targets for the detection, prognosis, and treatment of cancer are still in high demand. Tumor cells are characterized by mutations that allow their unlimited growth, program their local microenvironment to support tumor growth, and spread towards distant sites. While a major focus has been on altered tumor genomes and proteomes, crucial signaling molecules such as lipids have been underappreciated. One of these molecules is the membrane phospholipid phosphatidylserine (PS) that is usually found at cytosolic surfaces of cellular membranes but can be rapidly and massively shuttled to the extracellular leaflet of the plasma membrane during apoptosis to serve as a limiting factor for immune responses. These immunosuppressive interactions are exploited by tumor cells to evade the immune system. In this review, we describe mechanisms of immune regulation in tumors, discuss if PS may constitute an inhibitory immune checkpoint, and describe current and future strategies for targeting PS to reactivate the tumor-associated immune system.
Purpose: Polycystic ovary syndrome (PCOS) management has hardly been standardized until recent years. Despite the existence of a detailed, evidence-based guideline published by the European Society of Human Reproduction and Embryology (ESHRE), it remains unclear to what extent healthcare providers adhere to this guideline. Our aim is to evaluate the gynaecological medical care provided in women with PCOS, particularly in terms of mental health, from the patients' perspective.
Methods: For this cross-sectional online cohort study in women with PCOS, we designed a standardized, non-validated questionnaire covering aesthetic aspects, metabolism, menstrual cycle, reproduction, mental health, and prevention of chronic non-communicable diseases.
Results: Among 1879 participants, various mental health aspects were reported: body image (n = 1879), eating patterns/habits (n = 1878), and emotional well-being (n = 1874). Although nearly all women (99.7%) reported complaints on at least one session of mental health, consultation rates were low (body image 9.7%, eating patterns/habits 16.6%, emotional well-being 4.4%). Mean satisfaction with counselling on the different domains varied from moderate to fairly satisfying, with scores of 56.0 points (SD 31.7), 53.5 points (SD 32.0), and 63.7 points (SD 30.2), respectively. More complaints were associated with lower satisfaction. The overall satisfaction with the management provided by the healthcare practitioner (HCP) was low, averaging 36.5 points (SD 29.7). Consequently, most women wished for more counselling (58.9%).
Conclusion: Women affected by PCOS are not properly managed according to ESHRE guideline in regard to mental health issues. Overall consultation rates and corresponding satisfaction with management were poor, highlighting the need for significant improvements in healthcare provision.
Lipid droplets (LDs) are essential for cellular pathophysiology. In two recent reports, Kim et al. and Boutagy et al. show that accumulation of LDs in endothelial cells (ECs) elevates blood pressure and accelerates progression of atherosclerosis. These findings identify a novel mechanism of EC lipid metabolism which drives cardiometabolic diseases.
Background: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC).
Objective: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies.
Design, setting and participants: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany.
Interventions: Cabozantinib was administered as a standard of care.
Outcome measurements and statistical analysis
Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized.
Results and limitations: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study.
Conclusions: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.