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The aim of this study was to evaluate the clinical and microbiological effects of subgingival instrumentation (SI) alone or combined with either local drug delivery (LDD) or photodynamic therapy (PDT) in persistent/recurrent pockets in patients enrolled in supportive periodontal therapy (SPT). A total of 105 patients enrolled in SPT were randomly treated as follows: group A (n = 35): SI +PDT and 7 days later 2nd PDT; group B (n = 35): SI+LDD; group C (n = 35): SI (control). Prior intervention, at 3 and 6 months after therapy, probing pocket depths, clinical attachment level, number of treated sites with bleeding on probing (n BOP), full mouth plaque and bleeding scores (gingival bleeding index, %BOP) were recorded. At the same time points, 8 periodontopathogens were quantitatively determined. All three treatments resulted in statistically significant improvements (p < 0.05) of all clinical parameters without statistically significant intergroup differences (p > 0.05). Several bacterial species were reduced in both test groups, with statistically significantly higher reductions for LDD compared to PDT and the control group. In conclusion, the present data indicate that: (a) In periodontal patients enrolled in SPT, treatment of persistent/recurrent pockets with SI alone or combined with either PDT or LDD may lead to comparable clinical improvements and (b) the adjunctive use of LDD appears to provide better microbiological improvements for some periodontal pathogens than SI alone or combined with PDT.
Simple Summary: Penile cancer is a rare but aggressive malignancy characterized by rapid tumor growth as well as prompt metastasis in groin lymphatics. While localized diseases can be successfully cured by surgery in most cases, no truly effective treatment options have been established for metastatic diseases as of yet. In the current investigation, we assessed the value of selected members of the PI3K/mTOR/AKT pathway to serve as tumor markers or therapeutic targets for this disease. Higher expression of AKT was significantly more prevalent in high-grade tumors and independently predictive of the worse survival parameters, while increased expression of pmTOR was associated with an inferior prognosis as well. Treatment with the pan-AKT inhibitor capivasertib in PeCa cell lines induced significant reduction of cell viability and movement capacity. These findings might aid in the understanding of the molecular tumor background as well as development of novel treatment options for advanced penile cancer.
Abstract: The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan–Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.
Background: Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet.
Methods: To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes.
Findings: We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity.
Interpretation: Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.
Background: Research on chronic subdural hematoma (cSDH) management has primarily focused on potential recurrence after surgical evacuation. Herein, we present a novel postoperative/non-invasive treatment that includes a supervised Valsalva maneuver (SVM), which may serve to reduce SDH recurrence. Accordingly, the aims of the study were to investigate the effects of SVM on SDH recurrence rates and functional outcomes.
Methods: A prospective study was conducted from December 2016 until December 2019 at the Goethe University Hospital Frankfurt. Of the 204 adult patients with surgically treated cSDH who had subdural drains placed, 94 patients were assigned to the SVM group and 82 patients were assigned to the control group. The SVM was performed by having patients blow into a self-made SVM device at least two times/h for 12 h/day. The primary end-point was SDH recurrence rate, while secondary outcomes were morbidity and functional outcomes at 3 months of follow-up.
Results: SDH recurrence was observed in 16 of 94 patients (17%) in the SVM group, which was a significant reduction as compared with the control group, which had 24 of 82 patients (29.3%; p = 0.05) develop recurrent SDHs. Further, the infection rate (e.g., pneumonia) was significantly lower in the SVM group (1.1%) than in the control group (13.4%; p < 0.001; odds ratio [OR] 0.1). At the 3-month follow-up, 85 of 94 patients (90.4%) achieved favorable outcomes in the SVM group compared with 62 of 82 patients (75.6%) in the control group (p = 0.008; OR 3.0). Independent predictors for favorable outcome at follow-up were age (OR 0.9) and infection (OR 0.2).
Conclusion: SVM appears to be safe and effective in the post-operative management of cSDHs, reducing both recurrence rates and infections after surgical evacuation, thereby resulting in favorable outcomes at follow-up.
In context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with certain comorbidities and high age, as well as male sex are considered to represent the risk group for severe course of disease. Corona-virus disease 2019 (COVID-19) typical CT-patterns include bilateral, peripheral ground glass opacity (GGO), septal thickening, bronchiectasis, consolidation as well as associated pleural effusion. We report a 77-year-old heart transplanted patient with confirmed COVID-19 infection and coronary heart disease, diabetes type II and other risk factors. Notably, only slight clinical symptoms were reported and repeated computed tomography (CT) scans showed an atypical course of CT findings during his hospitalization.
Reactive oxygen species (ROS) are derivatives of molecular oxygen (O2) involved in various physiological and pathological processes. In immune cells, ROS are mediators of pivotal functions such as phagocytosis, antigen presentation and recognition, cytolysis as well as phenotypical differentiation. Furthermore, ROS exert immunosuppressive effects on T and natural killer (NK) cells which is of particular importance in the so-called “tumor microenvironment” (TME) of solid tumors. This term describes the heterogenous group of non-malignant cells including tumor-associated fibroblasts and immune cells, vascular cells, bacteria etc. by which cancer cells are surrounded and with whom they engage in functional crosstalk. Importantly, pharmacological targeting of the TME and, specifically, tumor-associated immune cells utilizing immune checkpoint inhibitors - monoclonal antibodies that mitigate immunosuppression - turned out to be a major breakthrough in the treatment of malignant tumors. In this review, we aim to give an overview of the role that ROS produced in tumor-associated immune cells play during initiation, progression and metastatic outgrowth of solid cancers. Finally, we summarize findings on how ROS in the TME could be targeted therapeutically to increase the efficacy of cancer immunotherapy and discuss factors determining therapeutic success of redox modulation in tumors.
Background: Transfusion of red blood cells (RBC) in patients undergoing major elective cranial surgery is associated with increased morbidity, mortality and prolonged hospital length of stay (LOS). This retrospective single center study aims to identify the impact of RBC transfusions on skull-base and non-skull-base meningioma patients including the identification of risk factors for RBC transfusion.
Methods: From October 2009 - October 2016 we retrospectively analyzed 423 primary meningioma patients undergoing surgery for primary meningioma resection our department.
Results: Of these 423 patients, 68 (16.1%) received RBC transfusion and 355 (83.9%) did not receive RBC units. Preoperative anaemia rate was significantly higher in transfused patients (17.7%) compared to patients without RBC transfusion (6.2%; p = 0.0015). In transfused patients, postoperative complications as well as hospital LOS was significantly higher (p < 00001) compared to non-transfused patients. After multivariate analyses, risk factors for RBC transfusion were preoperative American Society of Anesthesiologists (ASA) physical status score (p = 0.0247), tumor size (p = 0.0006), surgical time (p = 0.0018) and intraoperative blood loss (p < 0.001). Kaplan-Meier curves revealed significant influence on overall survival by preoperative anaemia, RBC transfusion, smoking, cardiovascular disease, preoperative KPS ≤ 60% and age (elderly ≥ 75 years).
Conclusion: We concluded that blood loss due to large tumors or localization near large vessels are the main triggers for RBC transfusion in meningioma patients paired with a potential preselection that masks the effect of preoperative anaemia in multivariate analysis. Further studies evaluating the impact of preoperative anaemia management for reduction of RBC transfusion are needed to improve clinical outcomes of meningioma patients.
Background: Unruptured intracranial aneurysm (UIA) poses a therapeutic dilemma in which the risk-benefit analysis of invasive intervention has to be balanced against the natural history of the disease. To date, there is no medical treatment to prevent aneurysm development and subsequent progression to rupture. We explored the vitamin D system because of its known anti-inflammatory and anti-tissue-remodeling effect as a potential treatment for UIA.
Methods: 25-vitaminD3 levels tested between 2008-2016 and data of SAH patients admitted during the months with a peak versus nadir of VitD3-values were analyzed, retrospectively. We prospectively correlated VitD3 with size and number of aneurysms at the rupture time in patients admitted between 2017-2019. An experimental mice shear stress model and cell culture model were used to investigate the effect of 1,25-dihydroxy-vitaminD3 (1,25-VitD3) and acting mediators in this mechanism.
Results: Based on the retrospective analysis demonstrating an increased frequency of aneurysm rupture rate in patients during the low vitamin D period in winter, we started the prospective study evaluating plasma vitamin D levels at admission. VitD levels were inversely correlated with aneurysm size as well as number of aneurysms. Low number of aneurysms was significantly associated with sufficient plasma Vitamin D level as an independent factor in a multivariate analysis.
From bedside back to bench, active 1,25-VitD3 hormone attenuated the natural history of remodeling in mice basilar artery. Deletion of the vitamin-D-receptor in myeloid cells decreased the protective 1,25-VitD3 effect. Cell-culture of vascular fibroblasts confirmed the anti-tissue remodeling effect of 1,25-VitD3.
Conclusion: 1,25-VitD3 attenuates aneurysm development and subsequent progression to rupture. However, VitD-administration should be tested as optional treatment in management of patients with UIA.
Background: The extent of preoperative peritumoral edema in glioblastoma (GBM) has been negatively correlated with patient outcome. As several ongoing studies are investigating T-cell based immunotherapy in GBM, we conducted this study to assess whether peritumoral edema with potentially increased intracranial pressure, disrupted tissue homeostasis and reduced local blood flow has influence on immune infiltration and affects survival.
Methods: A volumetric analysis of preoperative imaging (gadolinium enhanced T1 weighted MRI sequences for tumor size and T2 weighted sequences for extent of edema (including the infiltrative zone, gliosis etc.) was conducted in 144 patients using the BrainlabÒ software. Immunohistochemical staining was analyzed for lymphocytic- (CD 3+) and myeloid (CD15+) tumor infiltration. A retrospective analysis of patient-, surgical-, and molecular characteristics was performed using medical records.
Results: The edema to tumor ratio was neither associated with progression-free nor overall survival (p=0.90, p=0.74). However, GBM patients displaying IDH-1 wildtype had significantly higher edema to tumor ratio than patients displaying an IDH-1 mutation (p=0.01). Immunohistopathological analysis did not show significant differences in lymphocytic or myeloid tumor infiltration (p=0.78, p=0.74) between these groups.
Conclusion: In our cohort, edema to tumor ratio had no significant correlation with immune infiltration and outcome. However, patients with an IDH-1wildtype GBM had a significantly higher edema to tumor ratio compared to their IDH-1 mutated peer group. Further studies are necessary to elucidate the underlying mechanisms.
The aim of this study was to investigate gender-specific influences of different symmetric and asymmetric occlusion conditions on postural control during standing and walking. The study involved 59 healthy adult volunteers (41 f/19 m) aged between 22 and 53 years (30.2 ± 6.3 years). Postural control measurements were carried out using a pressure plate by measuring plantar pressure distribution during standing and walking test conditions. Seven different occlusion conditions were tested. Prior to a MANOVA model analysis, the relationship between the two test conditions were checked using a factor analysis with a varying number of factors (between 2 and 10). The plantar pressure distributions during walking and standing are independent test conditions. The coefficient of variance across all variables between the conditions and genders was not significant: t(46) = 1.51 (p = 0.13). No statement can be made whether, or not, the influence of gender is greater than the influence of the conditions. Healthy male and female test subjects did not show any difference between seven occlusion conditions on the plantar pressure distribution while standing or walking. No differences between the genders were found for any of the investigated variables. In contrast to custom-made occlusion splints, simple cotton rolls appear not to influence the neuromuscular system in a systematic manner.
Background: Dysphagia is a common and severe symptom of traumatic brain injury (TBI) affecting up to 78% of patients. It is associated with pneumonia, increased morbidity and mortality. Although subdural hematoma (SDH) accounts for over 50% of TBI, the occurrence of dysphagia in this subtype has not been investigated. This study investigates the overall frequency, clinical predictors of dysphagia and functional outcome of patients with SDH associated dysphagia.
Methods: All patients presenting in author ́s institution between 2007 and 2020 with SDH were included in the study. Patients with SDH and clinical suspicion for dysphagia received a clinical swallowing assessment by a speech and language pathologist (SLP). Furthermore the severity of dysphagia was rated according to swallowing disorder scale.Functional outcome was evaluated by Glasgow outcome scale (GOS).
Results: Of 545 patients with SDH, 71 patients had dysphagia (13%). The prevalence of dysphagia was significantly lower in the surgical arm compared to the conservative arm (11.8% vs 21.8%; OR 0.23; p=0.02). Independent predictors for dysphagia were GCS <13 at admission (p<0.001; OR 4.17), cardiovascular disease (p=0.002; OR 2.29) and pneumonia (p=0.002; OR 2.88) whereas operation was a protective factor (p<0.001; OR 0.2). All patients with dysphagia improved significantly under SLP treatment from initial diagnosis to hospital discharge (p<0.01). However, patients with most severe grade of dysphagia showed no significant improvement during the clinical course. Patients with dysphagia had significantly worse outcome (GOS 1-3) compared to those without dysphagia (48.8% vs 26.4%; p<0.001).
Conclusion: Dysphagia is a frequent symptom in SDH and the early identification of dysphagia is crucial regarding initiation of treatment and functional outcome. Surgery is effective in preventing dysphagia and should be considered in high-risked patients.
Probably, patients with de novo (synchronous) and recurrent (metachronous) oligometastatic hormone-sensitive prostate cancer have different oncologic outcomes. Thus, we are challenged with different scenarios in clinical practice, where different treatment options may apply. In the last years, several prospective studies have focused on the treatment of patients with de novo oligometastatic hormone-sensitive prostate cancer. Not only the addition of systemic therapeutic treatments, such as chemotherapy with docetaxel, abiraterone, enzalutamide, and apalutamide, next to androgen deprivation therapy, demonstrated to improve outcomes in these patients but also local therapy of the primary has been demonstrated to improve outcomes of low-volume metastatic disease. Next to radiotherapy, also radical prostatectomy has been reported as a feasible and safe treatment option. Additional metastasis-directed therapy in de novo metastatic disease is currently examined by four trials. In the recurrent metastatic setting, less data are available, and it remains uncertain if patients can be treated in the same way as synchronous oligometastatic disease. Metastasis-directed therapy has demonstrated to prolong outcomes, while data on survival are still missing.
Background: While the antidepressant efficacy of guided digital interventions has been proven in randomized controlled trials, findings from routine care are less clear. Low adherence rates are common and limit the potential effectiveness. Adherence has been linked to sociodemographic variables and the amount of guidance, but the role of the guide's profession and their work setting has not yet been studied for routine care.
Methods: Routinely collected log data from a digital intervention for depressed patients (iFightDepression tool) were analyzed in an exploratory manner. The sample is a convenience sample from routine care, where guidance is provided by general practitioners (GP), certified psychotherapists (PT) or medical doctors specialized in mental health. Log data from 2184 patients were analyzed and five usage parameters were extracted to measure adherence (first-to-last login, time on tool, number of sessions, workshops completed and minimal dose). Multiple logistic regression was used to analyze relations between the guide's profession and clinical context as well as other covariates and adherence and symptom change on a brief depression questionnaire (PHQ-9).
Results: The analyses showed a significant relation of guide profession and adherence. Guidance by PT was associated to the highest adherence scores (reference category). The odds ratios (ORs) of scoring above the median in each usage parameter for patients guided by GPs were 0.50–0.63 (all ps < 0.002) and 0.61–0.80 (p = .002–0.197) for MH. Higher age, initial PHQ-9 score and self-reported diagnosis of depression were also significantly associated with higher adherence scores. In a subsample providing enough data on the PHQ-9 (n = 347), no association of guide profession with symptom reduction was found. Instead, a greater reduction was observed for patients with a higher baseline PHQ-9 (β = −0. 39, t(341.75) = −8.814, p < .001) and for those who had achieved minimal dose (β = −2.42, t(340.34) = −4.174, P < .001) and those who had achieved minimal dose and scored high on time on tool (β = 0.22, t(341.75) = 1.965, P = .050).
Conclusion: Being guided by PT was associated with the highest adherence. The lowest adherence was observed in patients who were guided by GP. While no association of guide profession and symptom reduction was found in a subsample, greater adherence was associated with symptom reduction.
The Q80K polymorphism in the NS3-4A protease of the hepatitis C virus is associated with treatment failure of direct-acting antiviral agents. This polymorphism is highly prevalent in genotype 1a infections and stably transmitted between hosts. Here, we investigated the underlying molecular mechanisms of evolutionarily conserved coevolving amino acids in NS3-Q80K and revealed potential implications of epistatic interactions in immune escape and variants persistence. Using purified protein, we characterized the impact of epistatic amino acid substitutions on the physicochemical properties and peptide cleavage kinetics of the NS3-Q80K protease. We found that Q80K destabilized the protease protein fold (p < 0.0001). Although NS3-Q80K showed reduced peptide substrate turnover (p < 0.0002), replicative fitness in an H77S.3 cell culture model of infection was not significantly inferior to the WT virus. Epistatic substitutions at residues 91 and 174 in NS3-Q80K stabilized the protein fold (p < 0.0001) and leveraged the WT protease stability. However, changes in protease stability inversely correlated with enzymatic activity. In infectious cell culture, these secondary substitutions were not associated with a gain of replicative fitness in NS3-Q80K variants. Using molecular dynamics, we observed that the total number of residue contacts in NS3-Q80K mutants correlated with protein folding stability. Changes in the number of contacts reflected the compensatory effect on protein folding instability by epistatic substitutions. In summary, epistatic substitutions in NS3-Q80K contribute to viral fitness by mechanisms not directly related to RNA replication. By compensating for protein-folding instability, epistatic interactions likely protect NS3-Q80K variants from immune cell recognition.
Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.
Design: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation.
Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.
Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.
Purpose: Discordance between pre-operative biopsy and final pathology for Upper Tract Urothelial Carcinoma (UTUC) is high and optimal management remains controversial. The aim of this study is to evaluate the accuracy of pre-operative biopsy, to identify prognostic factors and to evaluate the effect of adjuvant chemotherapy on survival and oncologic outcome in UTUC.
Methods: We analyzed records of patients receiving surgical treatment for UTUC. Pathology of pre-operative biopsy was compared to surgical specimen. We used Kaplan-Meier method to estimate survival probabilities and Cox's proportional hazards models to estimate the association between covariates and event times. Primary endpoint was overall survival (OS). A matched-pair analysis was performed to evaluate the effect of adjuvant chemotherapy.
Results: 151 patients underwent surgical treatment (28% open, 36% laparoscopic, 17% robotic radical nephroureterectomy; 14% segmental ureteral resections and 5% palliative nephrectomy) for UTUC and were included in the analysis. Upstaging from <pT1 in endoscopic biopsy to ≥pT1 in final pathology occurred in 61% of patients and upgrading from low-grade to high-grade occurred in 30% of patients. Five-year OS was 59.5%. In the univariate Cox-regression model pathological stage, grade, lymphovascular invasion and positive surgical margins were associated with OS. Matched pair analysis for stage (<pT3; ≥pT3; pN+) and age revealed a significant survival benefit for adjuvant chemotherapy (HR 0.40, 0.14–0.77, p < 0.018) in this cohort.
Conclusion: UTUC is often underestimated in pre-operative biopsy, and it is associated with significant mortality. Pathological stage and grade, lymphovascular invasion and lymph node metastases are predictors of oncologic outcome and survival.