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Nonerythroid spectrin αII (SPTAN1) is an important cytoskeletal protein that ensures vital cellular properties including polarity and cell stabilization. In addition, it is involved in cell adhesion, cell-cell contact, and apoptosis. The detection of altered expression of SPTAN1 in tumors indicates that SPTAN1 might be involved in the development and progression of cancer. SPTAN1 has been described in cancer and therapy response and proposed as a potential marker protein for neoplasia, tumor aggressiveness, and therapeutic efficiency. On one hand, the existing data suggest that overexpression of SPTAN1 in tumor cells reflects neoplastic and tumor promoting activity. On the other hand, nuclear SPTAN1 can have tumor suppressing effects by enabling DNA repair through interaction with DNA repair proteins. Moreover, SPTAN1 cleavage products occur during apoptosis and could serve as markers for the efficacy of cancer therapy. Due to SPTAN1’s multifaceted functions and its role in adhesion and migration, SPTAN1 can influence tumor growth and progression in both positive and negative directions depending on its specific regulation. This review summarizes the current knowledge on SPTAN1 in cancer and depicts several mechanisms by which SPTAN1 could impact tumor development and aggressiveness.
Rationale: With advances in contemporary radiotherapy techniques, and as cancer survival improves, severe isolated coronary ostial disease may develop many years following mediastinal radiotherapy, even in the absence of classical cardiovascular risk factors.
Patient concerns: We describe the case of a 73-year-old woman with previous chest radiotherapy for breast cancer who underwent coronary artery bypass graft surgery for severe bilateral coronary ostial lesions.
Diagnoses: Coronary angiography demonstrated severe, isolated bilateral coronary ostial lesions.
Interventions: The patient underwent urgent coronary artery bypass graft surgery to treat her critical coronary artery disease.
Outcomes: Intra-operatively, internal mammary arteries were not amenable to harvesting due to very dense mediastinal adhesions. Therefore, saphenous vein grafts were performed to the left anterior descending, distal left circumflex, obtuse marginal and distal right coronary arteries. The patient made a satisfactory in-hospital recovery, and was subsequently discharged back to her local hospital for rehabilitation.
Lessons: Patients successfully treated with mediastinal radiotherapy require careful long-term follow-up for the assessment of radiation-induced coronary artery disease. Importantly, mediastinal irradiation may preclude internal mammary artery utilization, and thus alter the strategy for surgical myocardial revascularization.
A wealth of data has elucidated the mechanisms by which sensory inputs are encoded in the neocortex, but how these processes are regulated by the behavioral relevance of sensory information is less understood. Here, we focus on neocortical layer 1 (L1), a key location for processing of such top-down information. Using Neuron-Derived Neurotrophic Factor (NDNF) as a selective marker of L1 interneurons (INs) and in vivo 2-photon calcium imaging, electrophysiology, viral tracing, optogenetics, and associative memory, we find that L1 NDNF-INs mediate a prolonged form of inhibition in distal pyramidal neuron dendrites that correlates with the strength of the memory trace. Conversely, inhibition from Martinotti cells remains unchanged after conditioning but in turn tightly controls sensory responses in NDNF-INs. These results define a genetically addressable form of dendritic inhibition that is highly experience dependent and indicate that in addition to disinhibition, salient stimuli are encoded at elevated levels of distal dendritic inhibition.
Introduction: In 2008, the German Council of Science had advised universities to establish a quality management system (QMS) that conforms to international standards. The system was to be implemented within 5 years, i.e., until 2014 at the latest. The aim of the present study was to determine whether a QMS suitable for electronic learning (eLearning) domain of medical education to be used across Germany has meanwhile been identified.
Methods: We approached all medical universities in Germany (n=35), using an anonymous questionnaire (8 domains, 50 items).
Results: Our results (response rate 46.3%) indicated very reluctant application of QMS in eLearning and a major information deficit at the various institutions.
Conclusions: Authors conclude that under the limitations of this study there seems to be a considerable need to improve the current knowledge on QMS for eLearning, and that clear guidelines and standards for their implementation should be further defined.
Background: Aortic stenosis (AS) is the most prevalent primary heart valve disease and the third most prevalent cardiovascular disease in the world, having a severe and slowly progressive evolution. The implementation of Transcatheter Aortic Valve Implantation (TAVI) is necessary because the population is constantly ageing, and most elderly people have various comorbidities, which places them among patients with high surgical risk. The aim was to report immediate and 9 months follow-up results of first TAVI implantations in the Republic of Moldova.
Material and methods: Three patients with severe symptomatic AS and high surgical risk underwent TAVI implantation using Portico valves.
Results: The mean age was 76.7 ± 1.2 years, 2 women and 1 man. The mean Logistic EuroSCORE II was 5.68 ± 0.67%. Procedural success was achieved in all (100%) patients. After the intervention, it was shown that the GP mean decreased by an average of 20.27±1.61 mmHg, the Vmax of the jet through AoV decreased on average by 2.05±0.19 m/s, and they were maintained all over the nine months follow-up period. Quality of life, using the TASQ (Toronto Aortic Stenosis Quality of Life) questionnaire, was improved by 62.3 ± 2.2 points.
Conclusions: TAVI, as a new minimally invasive method of treatment for aortic valve stenosis appears to be safe, with a low rate of early and late complications in elderly patients at high surgical risk, with good clinical outcomes at 9 months. Its implementation in the Republic of Moldova is welcome in the conditions of continuously ageing population and the prevalence of associated comorbidities.
Benzene is a ubiquitous, volatile pollutant present at high concentrations in toxins (e.g. tobacco smoke) known to increase cardiovascular disease (CVD) risk. Despite its prevalence, the cardiovascular effects of benzene have rarely been studied. Hence, we examined whether exposure to benzene is associated with increased CVD risk. The effects of benzene exposure in mice were assessed by direct inhalation, while the effects of benzene exposure in humans was assessed in 210 individuals with mild to high CVD risk by measuring urinary levels of the benzene metabolite trans,trans-muconic acid (t,t-MA). Generalized linear models were used to assess the association between benzene exposure and CVD risk. Mice inhaling volatile benzene had significantly reduced levels of circulating angiogenic cells (Flk-1+/Sca-1+) as well as an increased levels of plasma low-density lipoprotein (LDL) compared with control mice breathing filtered air. In the human cohort, urinary levels of t,t-MA were inversely associated several populations of circulating angiogenic cells (CD31+/34+/45+, CD31+/34+/45+/AC133–, CD34+/45+/AC133+). Although t,t-MA was not associated with plasma markers of inflammation or thrombosis, t,t-MA levels were higher in smokers and in individuals with dyslipidemia. In smokers, t,t-MA levels were positively associated with urinary metabolites of nicotine (cotinine) and acrolein (3-hydroxymercapturic acid). Levels of t,t-MA were also associated with CVD risk as assessed using the Framingham Risk Score and this association was independent of smoking. Thus, benzene exposure is associated with increased CVD risk and deficits in circulating angiogenic cells in both smokers and non-smokers.
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Between 28 June and 17 September 2018, 27 cases of human West Nile virus infections were recorded in Austria; four cases of West Nile neuroinvasive disease, 11 cases of West Nile fever, six infections detected by blood donation screening and six imported cases. In addition, 18 cases of human Usutu virus infections (all blood donors) were recorded. This is the highest number of annual infections recorded in Austria since the introduction of both viruses.
Background and Aims: Fecal biomarkers are important non-invasive markers monitoring disease activity in inflammatory bowel disease (IBD). We compared the significance of fecal eosinophil cationic protein (fECP) and fecal calprotectin (fCal).
Methods: fECP and fCal were measured in patients with Crohn's disease (CD, n = 97), ulcerative colitis (UC, n = 53), Clostridioides difficile infection (CDI, n = 9), primary food allergy (PFA, n = 11), pollen-associated food allergy (n = 25) and non-inflammatory controls (n = 78). Results were correlated with clinical and endoscopic IBD activity scores.
Results: fECP was significantly elevated in CD, UC, CDI and PFA compared to controls. fCal was significantly increased in CD, UC and CDI. fECP had lower diagnostic accuracy than fCal (area under the curve (AUC) = 0.88) in differentiating between endoscopically active and inactive patients with IBD (AUC = 0.77, ROC analysis). In contrast to fCal, fECP correlated negatively with age and levels were also elevated in clinically and endoscopically inactive patients with IBD <45 years (endoscopically inactive IBD vs controls; AUC for fECP = 0.86; AUC for fCal = 0.62). However, in those patients with low inflammatory activity (fCal <250 mg/kg), high fECP indicated the need for treatment modification or surgery (fECP <200 µg/kg = 22%; 200–600 µg/kg = 44%; >600 µg/kg = 82%) at month 48 of follow-up.
Conclusions: fECP is a diagnostic and prognostic marker in young patients with IBD in remission.
This article discusses the counterpart of interactive machine learning, i.e., human learning while being in the loop in a human-machine collaboration. For such cases we propose the use of a Contradiction Matrix to assess the overlap and the contradictions of human and machine predictions. We show in a small-scaled user study with experts in the area of pneumology (1) that machine-learning based systems can classify X-rays with respect to diseases with a meaningful accuracy, (2) humans partly use contradictions to reconsider their initial diagnosis, and (3) that this leads to a higher overlap between human and machine diagnoses at the end of the collaboration situation. We argue that disclosure of information on diagnosis uncertainty can be beneficial to make the human expert reconsider her or his initial assessment which may ultimately result in a deliberate agreement. In the light of the observations from our project, it becomes apparent that collaborative learning in such a human-in-the-loop scenario could lead to mutual benefits for both human learning and interactive machine learning. Bearing the differences in reasoning and learning processes of humans and intelligent systems in mind, we argue that interdisciplinary research teams have the best chances at tackling this undertaking and generating valuable insights.