Tinnitus and depression Langguth, Berthold; Landgrebe, Michael; Kleinjung, Tobias ...
The world journal of biological psychiatry,
10/2011, Letnik:
12, Številka:
7
Journal Article
Recenzirano
Abstract
Objectives. Depressive symptoms are common in individuals with tinnitus and may substantially aggravate their distress. The mechanisms, however, by which depression and tinnitus mutually ...interact are still not fully understood. Methods. Here we review neurobiological knowledge relevant for the interplay between depression and tinnitus. Results. Neuroimaging studies confirm the existence of neural circuits that are activated both in depression and tinnitus. Studies of neuroendocrine function demonstrate alterations of the HPA-axis in depression and, more recently, in tinnitus. Studies addressing neurotransmission suggest that the dorsal cochlear nucleus that is typically hyperactive in tinnitus, is also involved in the control of attention and emotional responses via projections to the locus coeruleus, the reticular formation and the raphe nuclei. Impaired hippocampal neurogenesis has been documented in animals with tinnitus after noise trauma, as in animal models of depression. Finally, from investigations of human candidate genes, there is some evidence to suggest that variant BDNF may act as a common susceptibility factor in both disorders. Conclusions. These parallels in the pathophysiology of tinnitus and depression argue against comorbidity by chance and against depression as pure reaction on tinnitus. Instead, they stand for a complex interplay between tinnitus and depression. Implications for tinnitus treatment are discussed.
The inability of chimeric antigen receptor (CAR) T cells to sustain their effector function after repeated exposure to tumor cells is a major obstacle to their success in patients with solid tumors. ...To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T cells had a significantly greater ability to expand and produce cytokines in comparison with their unmodified counterparts targeting EPHA2 or HER2.
, CAR.GM18 T cells induced tumor regression at cell doses at which standard CAR T cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T cells to bolster their antitumor activity. SIGNIFICANCE: We designed a chimeric cytokine receptor (GM18) that links CAR T-cell activation to MYD88 signaling. GM18 endows CAR T cells with sustained effector function in the setting of chronic antigen exposure, resulting in potent antitumor activity in preclinical solid tumor models.
.
Ewing sarcoma is an aggressive neoplasm occurring predominantly in adolescent Caucasians. At the genome level, a pathognomonic EWSR1-ETS translocation is present. The resulting fusion protein acts as ...a molecular driver in the tumor development and interferes, amongst others, with endogenous transcription and splicing. The Ewing sarcoma cell shows a poorly differentiated, stem-cell like phenotype. Consequently, the cellular origin of Ewing sarcoma is still a hot discussed topic. To further characterize Ewing sarcoma and to further elucidate the role of EWSR1-ETS fusion protein multiple genome, epigenome and transcriptome level studies were performed. In this review, the data from these studies were combined into a comprehensive overview. Presently, classical morphological predictive markers are used in the clinic and the therapy is dominantly based on systemic chemotherapy in combination with surgical interventions. Using sequencing, novel predictive markers and candidates for immuno- and targeted therapy were identified which were summarized in this review.
The design optimization of reactive distillation columns (RDC) is characterized by complex nonlinear constraints, nonlinear cost functions, and the presence of many local optima. The standard ...approach is to use MINLP solvers that work on a superstructure formulation where structural decisions are represented by discrete variables and lead to an exponential increase in the computational effort. The mathematical programming (MP) methods which solve the continuous sub-problems provide only one local optimum which depends strongly on the initialization. In this contribution a memetic algorithm (MA) is introduced and applied to the global optimization of four different formulations of a computational demanding real-world design problem. An evolution strategy addresses the global optimization of the design decisions, while continuous sub-problems are efficiently solved by a robust MP solver. The MA is compared to MINLP techniques. It is the only algorithm that finds the global solution in reasonable times for all model formulations.
Ewing sarcoma is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. For patients with metastatic disease in particular, immunotherapy has been ...proposed as possible beneficial additive therapy. CCL21 activation-based immunotherapy was successful in preclinical studies in other tumor types; therefore, we investigated CCL21 expression in Ewing sarcoma as potential target for immunotherapy. The
CCL21
RNA expression was determined in 21 Ewing sarcoma cell lines and 18 primary therapy-naive Ewing sarcoma samples. In the tumor samples, this was correlated with the number and CD4
+
/CD8
+
ratio of infiltrating T cells and clinical parameters. Higher RNA expression levels of
CCL21
significantly correlated with a lower CD4
+
/CD8
+
T cell ratio (
P
= 0.009), good chemotherapeutic response (
P
= 0.01) and improved outcome (
P
< 0.001). In patients with metastases,
CCL21
expression was significantly lower than in patients without (
P
< 0.0005).
CCL21
expression was significantly higher in Ewing sarcoma tissue samples compared to cell lines (
P
< 0.01), implying the involvement of a stromal factor. Protein expression analysis of CCL21 and its receptor CCR7 in 24 therapy-naïve tumors showed that there was no expression in all bar one Ewing sarcoma cells. In conclusion, CCL21 is expressed in clinical Ewing sarcoma samples by nontumor-infiltrating immune cells. The observed positive correlation with survival implies that CCL21 might be a potential prognostic marker for Ewing sarcoma and marks the potential of CCL21 immunotherapy for use in Ewing sarcoma.
Clouded Issues for PHACTR1 Sand, Philipp G
International journal of molecular sciences,
04/2015, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Odprti dostop
I have read with interest the recent paper by Han and coworkers on the putative effects of a PHACTR1 variant in the context of coronary artery disease. The authors conclude to a significant ...risk-enhancing role of rs12526453 on the grounds of 19 earlier case-control studies.
Chemokine receptor CXCR4 is involved in tumor growth, angiogenesis and metastasis. Its function is regulated in many ways and one of them is alternative splicing. We identified two novel coding ...splice variants (CXCR4-3 and CXCR4-4) of CXCR4 in Ewing sarcoma (EWS) cell lines by whole transcriptome sequencing and validated these with reverse transcriptase- PCR and Sanger sequencing. The novel splice variants were expressed at RNA level in Ewing sarcoma samples and in other tumor cell lines and placenta, but not in lung. Due to inclusion of an additional exon the new isoforms have a 70 and 33 amino acid elongation of the N-terminal end of CXCR4. For validation at protein and functional level, the identified isoforms and normal CXCR4 were cloned into an EYFP tagged vector and ectopically expressed in HEK293T cell line and EWS cell line A673. Of the novel isoforms CXCR4-3 showed cell membrane localization and a functional response after addition of CXCR4 ligand CXCL12a. CXCR4-4 showed strong cytoplasmic accumulation and no response to ligand treatment. The role of the newly discovered isoforms in CXCR4 signaling is likely to be limited. Our data stresses the importance of functional validation of newly identified isoforms.
•Two novel CXCR4 splice variants were discovered using whole transcriptome sequencing.•Novel splice variants were expressed in cell lines, tumor samples and placenta.•Validation at protein level demonstrated dominantly unstable proteins.•CXCR4-3 demonstrates an effect in HEK293T cell line at functional level.
Abstract Objective Subjective tinnitus is a frequent symptom characterized by perception of sound in the absence of a corresponding external stimulus. Although many people learn to live with ...tinnitus, some find it severely debilitating. Why tinnitus is debilitating in some patients, but not in others, is still incompletely understood. We aimed to assess the influence of different aspects of psychological distress on perceived tinnitus severity. Methods Three hundred seventeen patients diagnosed with chronic subjective tinnitus at two university clinics completed the Tinnitus Handicap Inventory (THI), the Tinnitus Questionnaire (TQ) and the Symptom Check List-90-Revised. The influence of the different dimensions of psychological distress on perceived tinnitus severity was statistically evaluated. Results Both THI and TQ scores were significantly influenced by gender, site and the dimension “depression”. In addition, TQ scores were significantly influenced by age and “somatization,” whereas “hostility” had an impact on THI scores only. Conclusion Psychological aspects as well as sociodemographic variables had a significant influence on both TQ scores. However, our results indicate, that these scales reflect emotional distress of tinnitus sufferers differently. This should be taken into consideration in the use of these scales as screening tools for assessment of tinnitus handicap.
Ewing sarcoma is an aggressive, highly metastatic primary bone and soft tissue tumor most frequently occurring in the bone of young adolescents. Patients, especially those diagnosed with a metastatic ...disease, have a poor overall survival. Chemokine receptor CXCR4 has a key pro-tumorigenic role in the tumor microenvironment of Ewing sarcoma and has been suggested to be involved in the increased metastatic propensity. Earlier studies on CXCR4 protein expression in Ewing sarcoma yielded contradictory results when compared to CXCR4 RNA expression studies. Previously, we demonstrated that CXCR4 expression could be detected in vivo using the fluorescently tagged CXCR4-specific peptide MSAP-Ac-TZ14011. Therefore, we studied the membranous CXCR4 expression in Ewing sarcoma cell lines using MSAP-Ac-TZ14011.
The CXCR4 membrane expression levels were studied in EWS cell lines by flow cytometry using the hybrid peptide MSAP-Ac-TZ14011 and were correlated to CXCR4 RNA expression levels. The measurements were compared to levels detected using the CXCR4 antibody ab2074 under various cell preparation conditions. In addition, the staining patterns were analyzed by confocal fluorescence microscopy over time.
The hybrid peptide MSAP-Ac-TZ14011 levels showed a strong and better correlation of CXCR4 membrane expression with the CXCR4 RNA expression levels than observed with the anti-CXCR4 antibody ab2074. With the hybrid peptide MSAP-Ac-TZ14011 using live cell confocal microscopy CXCR4 membrane staining and internalization was detected and the signal intensity correlated well with CXCR4 mRNA expression levels.
The fluorescently labeled CXCR4 targeting peptide-based method provides a reliable alternative to antibody staining to study the CXCR4 membrane expression in live cells using either flow cytometry or live cell fluorescence microscopy. The fluorescently tagged CXCR4 targeting peptide could enable in vivo detection of CXCR4 expression in Ewing sarcoma which may help to stratify cases for anti-CXCR4 therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and purpose: Dietary anthocyanins hold great promise in the prevention of chronic disease but factors affecting their bioavailability remain poorly defined. Specifically, the role played ...by transport mechanisms at the intestinal and blood–brain barriers (BBB) is currently unknown.
Experimental approach: In the present study, 16 anthocyanins and anthocyanidins were exposed to the human efflux transporters multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), using dye efflux, ATPase and, for BCRP, vesicular transport assays.
Key results: All test compounds interacted with the BCRP transporter in vitro. Of these, seven emerged as potential BCRP substrates (malvidin, petunidin, malvidin‐3‐galactoside, malvidin‐3,5‐diglucoside, cyanidin‐3‐galactoside, peonidin‐3‐glucoside, cyanidin‐3‐glucoside) and 12 as potential inhibitors of BCRP (cyanidin, peonidin, cyanidin‐3,5‐diglucoside, malvidin, pelargonidin, delphinidin, petunidin, delphinidin‐3‐glucoside, cyanidin‐3‐rutinoside, malvidin‐3‐glucoside, pelargonidin‐3,5‐diglucoside, malvidin‐3‐galactoside). Malvidin, malvidin‐3‐galactoside and petunidin exhibited bimodal activities serving as BCRP substrates at low concentrations and, at higher concentrations, as BCRP inhibitors. Effects on MDR1, in contrast, were weak. Only aglycones exerted mild inhibitory activity.
Conclusions and implications: Although the anthocyanidins under study may alter pharmacokinetics of drugs that are BCRP substrates, they are less likely to interfere with activities of MDR1 substrates. The present data suggest that several anthocyanins and anthocyanidins may be actively transported out of intestinal tissues and endothelia, limiting their bioavailability in plasma and brain.
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